# 12 Principles of oncology

# Cancer staging

Cancer staging

It is not su ﬃ cient simply to know what and where a cancer is; its extent must also be known. If  it is localised, then locoregional treatments such as surgery and radiation therapy may be curative. If  the disease is widespread then, although such local interventions may contribute to cure, they will be insu ﬃ cient and systemic treatment, for example with drugs or hormones, will also be required. - Staging is the process whereby the extent of disease is mapped out. Staging used to be a fairly crude process based on clinical examination, chest x-ray and occasionally ultrasound; it is now a sophisticated process, reliant on advanced imaging techniques such as CT , magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These techno - logical advances bring with them the implication that patients staged as having localised disease today are not comparable to patients described in 1985 as having localised disease. Many of  these latter patients would, had they been imaged using the technology of  today , have had occult metastatic disease detected. The Union for International Cancer Control (UICC) is - responsible for the TNM (tumour, nodes, metastases) staging system for cancer. This system is compatible with, and relates to, the American Joint Committee on Cancer (AJCC) system 

a, The tumour has grown into the surface of the visceral peritoneum
b, The tumour has grown into or has attached to other organs or structures

pathological staging system for colorectal cancer is shown in Table 12.3 . The purpose of  staging is twofold: to estimate prognosis and to help select appropriate treatment options. Anatomi cal staging provides important information as to the surgical resectability of  disease and the risk of  its recurrence. Howev the risk assessment for most cancers is suboptimal and pro vides a wide conﬁdence interval. Better staging techniques are entering care, such as the determination of  circulating tumour DNA (ctDNA) in the blood of  postoperativ e patients. Patients who demonstrate ctDNA postoperatively have a substantially higher risk of  relapse than patients who do not. This informa tion may be useful in the future to select patients who should be o ﬀ ered further treatment to eliminate residual tumour cells and, of  equal importance, to identify patients with a low chance of  relapse who can avoid further treatment. Cancer staging

It is not su ﬃ cient simply to know what and where a cancer is; its extent must also be known. If  it is localised, then locoregional treatments such as surgery and radiation therapy may be curative. If  the disease is widespread then, although such local interventions may contribute to cure, they will be insu ﬃ cient and systemic treatment, for example with drugs or hormones, will also be required. - Staging is the process whereby the extent of disease is mapped out. Staging used to be a fairly crude process based on clinical examination, chest x-ray and occasionally ultrasound; it is now a sophisticated process, reliant on advanced imaging techniques such as CT , magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These techno - logical advances bring with them the implication that patients staged as having localised disease today are not comparable to patients described in 1985 as having localised disease. Many of  these latter patients would, had they been imaged using the technology of  today , have had occult metastatic disease detected. The Union for International Cancer Control (UICC) is - responsible for the TNM (tumour, nodes, metastases) staging system for cancer. This system is compatible with, and relates to, the American Joint Committee on Cancer (AJCC) system 

a, The tumour has grown into the surface of the visceral peritoneum
b, The tumour has grown into or has attached to other organs or structures

pathological staging system for colorectal cancer is shown in Table 12.3 . The purpose of  staging is twofold: to estimate prognosis and to help select appropriate treatment options. Anatomi cal staging provides important information as to the surgical resectability of  disease and the risk of  its recurrence. Howev the risk assessment for most cancers is suboptimal and pro vides a wide conﬁdence interval. Better staging techniques are entering care, such as the determination of  circulating tumour DNA (ctDNA) in the blood of  postoperativ e patients. Patients who demonstrate ctDNA postoperatively have a substantially higher risk of  relapse than patients who do not. This informa tion may be useful in the future to select patients who should be o ﬀ ered further treatment to eliminate residual tumour cells and, of  equal importance, to identify patients with a low chance of  relapse who can avoid further treatment. Cancer staging

It is not su ﬃ cient simply to know what and where a cancer is; its extent must also be known. If  it is localised, then locoregional treatments such as surgery and radiation therapy may be curative. If  the disease is widespread then, although such local interventions may contribute to cure, they will be insu ﬃ cient and systemic treatment, for example with drugs or hormones, will also be required. - Staging is the process whereby the extent of disease is mapped out. Staging used to be a fairly crude process based on clinical examination, chest x-ray and occasionally ultrasound; it is now a sophisticated process, reliant on advanced imaging techniques such as CT , magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These techno - logical advances bring with them the implication that patients staged as having localised disease today are not comparable to patients described in 1985 as having localised disease. Many of  these latter patients would, had they been imaged using the technology of  today , have had occult metastatic disease detected. The Union for International Cancer Control (UICC) is - responsible for the TNM (tumour, nodes, metastases) staging system for cancer. This system is compatible with, and relates to, the American Joint Committee on Cancer (AJCC) system 

a, The tumour has grown into the surface of the visceral peritoneum
b, The tumour has grown into or has attached to other organs or structures

pathological staging system for colorectal cancer is shown in Table 12.3 . The purpose of  staging is twofold: to estimate prognosis and to help select appropriate treatment options. Anatomi cal staging provides important information as to the surgical resectability of  disease and the risk of  its recurrence. Howev the risk assessment for most cancers is suboptimal and pro vides a wide conﬁdence interval. Better staging techniques are entering care, such as the determination of  circulating tumour DNA (ctDNA) in the blood of  postoperativ e patients. Patients who demonstrate ctDNA postoperatively have a substantially higher risk of  relapse than patients who do not. This informa tion may be useful in the future to select patients who should be o ﬀ ered further treatment to eliminate residual tumour cells and, of  equal importance, to identify patients with a low chance of  relapse who can avoid further treatment.

# End-of-life care

End-of-life care

End-of-life care is distinct from palliative care. Patients treated - palliatively may survive for many years; end-of-life care concerns the last few months of a patient’s life. Many issues, such as symptom control, are common to both palliative care to the sense of approaching death. These include a heightened sense of  spiritual need, profound fear and the speciﬁc needs of  those who are facing bereavement. The concept of  a ‘good death’ has been embedded in many cultures over many centuries. Healthcare professionals deal with many deaths and sometimes forget that the patient who hopes for a good death has only one chance to get it right. This is why end-of-life care is worth considering in its own right and not as a mere appendage to palliative care. Summary box 12.5 Issues at the end of life /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Allison JP . Immune checkpoint blockade in cancer therapy: the 2015 Lasker–DeBakey Clinical Medical Research Award. JAMA 2015; 314 (11): 1113–14. Atun R, Ja ﬀ ray DA, Barton MB et al. Expanding global access to ra - diotherapy . Lancet Oncol 2015; 16 (10): 1153–86. Bailar JC 3rd, Gornik HL. Cancer undefeated. N Engl J Med 1997; 336 (19): 1569–74. Doll R. The Pierre Denoix Memorial Lecture: nature and nurture in the control of  cancer. Eur J Cancer 1999; 35 (1): 16–23. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100 (1): 57–70. Hanahan D, Weinberg RA. Hallmarks of  cancer: the next generation. Cell 2011; 144 (5): 646–74. Martincorena I, Raine KM, Gerstung M et al. Universal patterns of selection in cancer and somatic tissues. Cell 2017; 171 (5): 1029–41. Meara JG, Leather AJM, Hagander L et al . Global surgery 2030: ev - idence and solutions for achieving health, welfare, and economic development. Lancet 2015; 386 (9993): 569–624. Murtaza M, Dawson SJ, Tsui D et al. Non-invasive analysis of  acquired resistance to cancer therapy by sequencing of  plasma DNA. Nature 2013; 497 (7447): 108–12. Solda F , Lodge M, Ashley S et al . Stereotactic radiotherapy (SABR) for the treatment of  primary non-small cell lung cancer; systematic re - view and comparison with a surgical cohort. Radiother Oncol 2013; 109 (1): 1–7. Tomasetti C, V ogelstein B. Cancer etiology . Variation in cancer risk among tissues can be explained by the number of stem cell divi - sions. Science 2015; 347 (6217): 78–81. Tree AC, Khoo VS, Eeles RA et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013; 14 (1): e28–e37. Weinberg RA. The biology of  cancer, 2nd edn. New Y ork, London: Gar - land Science, 2013. Wu S, Powers S, Zhu W , Hannun YA. Substantial contribution of  ex - trinsic risk factors to cancer development. Nature 2016; 529 (7584): 43–7. 

Appropriateness of active intervention
Euthanasia
Physician-assisted suicide
Living wills
Bereavement
Spirituality
Support to allow death at home
The problem of the medicalisation of death

End-of-life care

End-of-life care is distinct from palliative care. Patients treated - palliatively may survive for many years; end-of-life care concerns the last few months of a patient’s life. Many issues, such as symptom control, are common to both palliative care to the sense of approaching death. These include a heightened sense of  spiritual need, profound fear and the speciﬁc needs of  those who are facing bereavement. The concept of  a ‘good death’ has been embedded in many cultures over many centuries. Healthcare professionals deal with many deaths and sometimes forget that the patient who hopes for a good death has only one chance to get it right. This is why end-of-life care is worth considering in its own right and not as a mere appendage to palliative care. Summary box 12.5 Issues at the end of life /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Allison JP . Immune checkpoint blockade in cancer therapy: the 2015 Lasker–DeBakey Clinical Medical Research Award. JAMA 2015; 314 (11): 1113–14. Atun R, Ja ﬀ ray DA, Barton MB et al. Expanding global access to ra - diotherapy . Lancet Oncol 2015; 16 (10): 1153–86. Bailar JC 3rd, Gornik HL. Cancer undefeated. N Engl J Med 1997; 336 (19): 1569–74. Doll R. The Pierre Denoix Memorial Lecture: nature and nurture in the control of  cancer. Eur J Cancer 1999; 35 (1): 16–23. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100 (1): 57–70. Hanahan D, Weinberg RA. Hallmarks of  cancer: the next generation. Cell 2011; 144 (5): 646–74. Martincorena I, Raine KM, Gerstung M et al. Universal patterns of selection in cancer and somatic tissues. Cell 2017; 171 (5): 1029–41. Meara JG, Leather AJM, Hagander L et al . Global surgery 2030: ev - idence and solutions for achieving health, welfare, and economic development. Lancet 2015; 386 (9993): 569–624. Murtaza M, Dawson SJ, Tsui D et al. Non-invasive analysis of  acquired resistance to cancer therapy by sequencing of  plasma DNA. Nature 2013; 497 (7447): 108–12. Solda F , Lodge M, Ashley S et al . Stereotactic radiotherapy (SABR) for the treatment of  primary non-small cell lung cancer; systematic re - view and comparison with a surgical cohort. Radiother Oncol 2013; 109 (1): 1–7. Tomasetti C, V ogelstein B. Cancer etiology . Variation in cancer risk among tissues can be explained by the number of stem cell divi - sions. Science 2015; 347 (6217): 78–81. Tree AC, Khoo VS, Eeles RA et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013; 14 (1): e28–e37. Weinberg RA. The biology of  cancer, 2nd edn. New Y ork, London: Gar - land Science, 2013. Wu S, Powers S, Zhu W , Hannun YA. Substantial contribution of  ex - trinsic risk factors to cancer development. Nature 2016; 529 (7584): 43–7. 

Appropriateness of active intervention
Euthanasia
Physician-assisted suicide
Living wills
Bereavement
Spirituality
Support to allow death at home
The problem of the medicalisation of death

End-of-life care

End-of-life care is distinct from palliative care. Patients treated - palliatively may survive for many years; end-of-life care concerns the last few months of a patient’s life. Many issues, such as symptom control, are common to both palliative care to the sense of approaching death. These include a heightened sense of  spiritual need, profound fear and the speciﬁc needs of  those who are facing bereavement. The concept of  a ‘good death’ has been embedded in many cultures over many centuries. Healthcare professionals deal with many deaths and sometimes forget that the patient who hopes for a good death has only one chance to get it right. This is why end-of-life care is worth considering in its own right and not as a mere appendage to palliative care. Summary box 12.5 Issues at the end of life /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Allison JP . Immune checkpoint blockade in cancer therapy: the 2015 Lasker–DeBakey Clinical Medical Research Award. JAMA 2015; 314 (11): 1113–14. Atun R, Ja ﬀ ray DA, Barton MB et al. Expanding global access to ra - diotherapy . Lancet Oncol 2015; 16 (10): 1153–86. Bailar JC 3rd, Gornik HL. Cancer undefeated. N Engl J Med 1997; 336 (19): 1569–74. Doll R. The Pierre Denoix Memorial Lecture: nature and nurture in the control of  cancer. Eur J Cancer 1999; 35 (1): 16–23. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100 (1): 57–70. Hanahan D, Weinberg RA. Hallmarks of  cancer: the next generation. Cell 2011; 144 (5): 646–74. Martincorena I, Raine KM, Gerstung M et al. Universal patterns of selection in cancer and somatic tissues. Cell 2017; 171 (5): 1029–41. Meara JG, Leather AJM, Hagander L et al . Global surgery 2030: ev - idence and solutions for achieving health, welfare, and economic development. Lancet 2015; 386 (9993): 569–624. Murtaza M, Dawson SJ, Tsui D et al. Non-invasive analysis of  acquired resistance to cancer therapy by sequencing of  plasma DNA. Nature 2013; 497 (7447): 108–12. Solda F , Lodge M, Ashley S et al . Stereotactic radiotherapy (SABR) for the treatment of  primary non-small cell lung cancer; systematic re - view and comparison with a surgical cohort. Radiother Oncol 2013; 109 (1): 1–7. Tomasetti C, V ogelstein B. Cancer etiology . Variation in cancer risk among tissues can be explained by the number of stem cell divi - sions. Science 2015; 347 (6217): 78–81. Tree AC, Khoo VS, Eeles RA et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013; 14 (1): e28–e37. Weinberg RA. The biology of  cancer, 2nd edn. New Y ork, London: Gar - land Science, 2013. Wu S, Powers S, Zhu W , Hannun YA. Substantial contribution of  ex - trinsic risk factors to cancer development. Nature 2016; 529 (7584): 43–7. 

Appropriateness of active intervention
Euthanasia
Physician-assisted suicide
Living wills
Bereavement
Spirituality
Support to allow death at home
The problem of the medicalisation of death

# Introduction

## Introduction

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# Learning objectives

Learning objectives

To understand: The biological nature of cancer • That curative treatment is only one component in the • overall management of cancer The principles of cancer prevention, early detection and • screening The principles underlying non-surgical treatments for • cancer Learning objectives

To understand: The biological nature of cancer • That curative treatment is only one component in the • overall management of cancer The principles of cancer prevention, early detection and • screening The principles underlying non-surgical treatments for • cancer Learning objectives

To understand: The biological nature of cancer • That curative treatment is only one component in the • overall management of cancer The principles of cancer prevention, early detection and • screening The principles underlying non-surgical treatments for • cancer

# Oncological emergencies

Oncological emergencies

There are a limited number of  true emergencies in oncology . Those that require immediate recognition and management are: /uni25CF Cord compression : rapid diagnosis and management to relieve pressure on the spinal cord is essential to obtain ). the best results for patients. Ideally , treatment should be instituted when cord compression is threatened rather than when it has already occurred. Management is likely to include steroids and either neurosurgery or radiotherapy . /uni25CF Neutropenic sepsis : rapid diagnosis and antibiotic therapy are essential. There is a strong inverse relationship between the time taken to start antibiotics and the chance of  patient survival. /uni25CF Immune side e ﬀ ects including hypophysitis, adrenal - failure and insulin-dependent diabetes. In contrast, there are many urgent oncological situations that are very unpleasant for the patient or that can rapidly deteriorate if  not recognised quickly . These include thrombo - sis, e ﬀ usion, superior vena cav a obstruction and pain, among many others. As early diagnosis becomes more common and treatment outcomes improve, so an increasing number of  people are cured of  cancer. However, the impact of  a cancer diagnosis and its treatment is profound. Organisations such as UK-based Macmillan Cancer Support can provide information and support to patients facing the health, work and ﬁnancial sequelae of  cancer. Oncological emergencies

There are a limited number of  true emergencies in oncology . Those that require immediate recognition and management are: /uni25CF Cord compression : rapid diagnosis and management to relieve pressure on the spinal cord is essential to obtain ). the best results for patients. Ideally , treatment should be instituted when cord compression is threatened rather than when it has already occurred. Management is likely to include steroids and either neurosurgery or radiotherapy . /uni25CF Neutropenic sepsis : rapid diagnosis and antibiotic therapy are essential. There is a strong inverse relationship between the time taken to start antibiotics and the chance of  patient survival. /uni25CF Immune side e ﬀ ects including hypophysitis, adrenal - failure and insulin-dependent diabetes. In contrast, there are many urgent oncological situations that are very unpleasant for the patient or that can rapidly deteriorate if  not recognised quickly . These include thrombo - sis, e ﬀ usion, superior vena cav a obstruction and pain, among many others. As early diagnosis becomes more common and treatment outcomes improve, so an increasing number of  people are cured of  cancer. However, the impact of  a cancer diagnosis and its treatment is profound. Organisations such as UK-based Macmillan Cancer Support can provide information and support to patients facing the health, work and ﬁnancial sequelae of  cancer. Oncological emergencies

There are a limited number of  true emergencies in oncology . Those that require immediate recognition and management are: /uni25CF Cord compression : rapid diagnosis and management to relieve pressure on the spinal cord is essential to obtain ). the best results for patients. Ideally , treatment should be instituted when cord compression is threatened rather than when it has already occurred. Management is likely to include steroids and either neurosurgery or radiotherapy . /uni25CF Neutropenic sepsis : rapid diagnosis and antibiotic therapy are essential. There is a strong inverse relationship between the time taken to start antibiotics and the chance of  patient survival. /uni25CF Immune side e ﬀ ects including hypophysitis, adrenal - failure and insulin-dependent diabetes. In contrast, there are many urgent oncological situations that are very unpleasant for the patient or that can rapidly deteriorate if  not recognised quickly . These include thrombo - sis, e ﬀ usion, superior vena cav a obstruction and pain, among many others. As early diagnosis becomes more common and treatment outcomes improve, so an increasing number of  people are cured of  cancer. However, the impact of  a cancer diagnosis and its treatment is profound. Organisations such as UK-based Macmillan Cancer Support can provide information and support to patients facing the health, work and ﬁnancial sequelae of  cancer.

# Prevention

Prevention

There is much written on the evidence on the preventable causes of  cancer. It is concluded that many cancers could be prevented if  people ate sensibly , exercised more and avoided carcinogens such as cigarette smoke. Early identiﬁcation of premalignant conditions may also prevent certain malignan cies developing, e.g. Barrett’s oesophagus as a premalignant condition in oesophageal cancer. This advice supplements the preventative measures outlined in Table 12.2 . Moritz Kaposi (originally Kohn), 1837–1902, Professor of  Dermatology , Vienna, Austria, described pigmented sarcoma of  the skin in 1872. Norman Rupert Barrett , 1903–1979, surgeon, St Thomas’ Hospital, London, UK. 

Associated tumours
Strategy for prevention/early
diagnosis
Avoid unprotected sex
Kaposi’s sarcoma
Lymphomas
Germ cell tumours
Anal cancer
Hepatocellular carcinoma
Avoid contaminated injections/
infusions
Vaccination
Bladder cancer
Treatment of infection
Stomach cancer
Eradication therapy
Mesothelioma
Protect workers from inhaled dusts
and
/f_i
bres
Paranasal sinus cancers
Protection of exposed workers;
Angiosarcoma (vinyl chloride)
avoid chemical discharge and
Bladder cancer (aniline dyes,
spillages
vulcanisation of rubber)
Lung, nasal cavity (nickel)
Skin (arsenic)
Lung (beryllium, cadmium,
chromium)
All sites (dioxins)
Avoid over-treatment; only combine
Leukaemia
drugs with ionising radiation when
Lymphoma
absolutely necessary
Lung cancer
Kaposi’
s sarcoma
As low a dose as possible, for as
short a period as possible
Endometrial cancer
Biopsy if patient on tamoxifen
develops uterine bleeding
Hepatocellular carcinoma
Appropriate food storage, scr
een for
fungal contamination of foodstuffs
Maintain ideal body weight, regular
Breast
exercise
Endometrium
Kidney
Colon
Oesophagus

Prevention

There is much written on the evidence on the preventable causes of  cancer. It is concluded that many cancers could be prevented if  people ate sensibly , exercised more and avoided carcinogens such as cigarette smoke. Early identiﬁcation of premalignant conditions may also prevent certain malignan cies developing, e.g. Barrett’s oesophagus as a premalignant condition in oesophageal cancer. This advice supplements the preventative measures outlined in Table 12.2 . Moritz Kaposi (originally Kohn), 1837–1902, Professor of  Dermatology , Vienna, Austria, described pigmented sarcoma of  the skin in 1872. Norman Rupert Barrett , 1903–1979, surgeon, St Thomas’ Hospital, London, UK. 

Associated tumours
Strategy for prevention/early
diagnosis
Avoid unprotected sex
Kaposi’s sarcoma
Lymphomas
Germ cell tumours
Anal cancer
Hepatocellular carcinoma
Avoid contaminated injections/
infusions
Vaccination
Bladder cancer
Treatment of infection
Stomach cancer
Eradication therapy
Mesothelioma
Protect workers from inhaled dusts
and
/f_i
bres
Paranasal sinus cancers
Protection of exposed workers;
Angiosarcoma (vinyl chloride)
avoid chemical discharge and
Bladder cancer (aniline dyes,
spillages
vulcanisation of rubber)
Lung, nasal cavity (nickel)
Skin (arsenic)
Lung (beryllium, cadmium,
chromium)
All sites (dioxins)
Avoid over-treatment; only combine
Leukaemia
drugs with ionising radiation when
Lymphoma
absolutely necessary
Lung cancer
Kaposi’
s sarcoma
As low a dose as possible, for as
short a period as possible
Endometrial cancer
Biopsy if patient on tamoxifen
develops uterine bleeding
Hepatocellular carcinoma
Appropriate food storage, scr
een for
fungal contamination of foodstuffs
Maintain ideal body weight, regular
Breast
exercise
Endometrium
Kidney
Colon
Oesophagus

Prevention

There is much written on the evidence on the preventable causes of  cancer. It is concluded that many cancers could be prevented if  people ate sensibly , exercised more and avoided carcinogens such as cigarette smoke. Early identiﬁcation of premalignant conditions may also prevent certain malignan cies developing, e.g. Barrett’s oesophagus as a premalignant condition in oesophageal cancer. This advice supplements the preventative measures outlined in Table 12.2 . Moritz Kaposi (originally Kohn), 1837–1902, Professor of  Dermatology , Vienna, Austria, described pigmented sarcoma of  the skin in 1872. Norman Rupert Barrett , 1903–1979, surgeon, St Thomas’ Hospital, London, UK. 

Associated tumours
Strategy for prevention/early
diagnosis
Avoid unprotected sex
Kaposi’s sarcoma
Lymphomas
Germ cell tumours
Anal cancer
Hepatocellular carcinoma
Avoid contaminated injections/
infusions
Vaccination
Bladder cancer
Treatment of infection
Stomach cancer
Eradication therapy
Mesothelioma
Protect workers from inhaled dusts
and
/f_i
bres
Paranasal sinus cancers
Protection of exposed workers;
Angiosarcoma (vinyl chloride)
avoid chemical discharge and
Bladder cancer (aniline dyes,
spillages
vulcanisation of rubber)
Lung, nasal cavity (nickel)
Skin (arsenic)
Lung (beryllium, cadmium,
chromium)
All sites (dioxins)
Avoid over-treatment; only combine
Leukaemia
drugs with ionising radiation when
Lymphoma
absolutely necessary
Lung cancer
Kaposi’
s sarcoma
As low a dose as possible, for as
short a period as possible
Endometrial cancer
Biopsy if patient on tamoxifen
develops uterine bleeding
Hepatocellular carcinoma
Appropriate food storage, scr
een for
fungal contamination of foodstuffs
Maintain ideal body weight, regular
Breast
exercise
Endometrium
Kidney
Colon
Oesophagus

# Principles of cancer surgery

Principles of cancer surgery

For most solid tumours, surgery remains the deﬁnitive treat - ment and the only realistic hope of  cure. However, surgery has many roles in cancer treatment from diagnosis, prevention, removal of primary disease, removal of metastatic disease, reconstruction through to palliation of  symptoms. Role in diagnosis and staging In most, but not all, patients the diagnosis of  cancer has been conﬁrmed by biopsy before deﬁnitive surgery is carried out; - however, occasionally a surgical procedure is required to make the diagnosis, e.g. in renal cell cancer where not all patients with a renal mass will undergo a biopsy , prior to deﬁnitive surgery to remove and diagnose the tumour as either malignant or benign. Laparoscopic surgery is used as part of  the staging of  intra-abdominal malignancy , particularly oesophageal and gastric cancer. By this means it is often possible to diagnose - widespread peritoneal disease and small liver metastases that may have been missed on cross-sectional imaging. Laparoscopic 

Disadvantages
Less con
/f_i
dent and less articulate members of the team may not
be able to express their views, even though their views may be
extremely important
May become a rubber-stamping exercise in which the class
solutions implied by guidelines are applied to disparate individuals
Decisions are made in the absence of patients and their carers
Clinicians are able to avoid having to take responsibility for their
decisions and their actions – ‘corporate responsibility’
Time-consuming and resource intensive: takes multiple busy
clinicians away from clinical practice for hours at a time

Potential members of the cancer multidisciplinary team /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF ultrasound is a particularly useful adjunct for the diagnosis of intrahepatic metastases. Other examples of  when surgery is central to the diagnosis of  cancer include orchidectomy , in a patient suspected of  testicular cancer; lymph node biopsy in a patient with lymphoma; and sentinel node biopsy in melanoma and breast cancer. Removal of primary disease Radical surgery for cancer involves removal of  the primary tumour and as much of  the surrounding tissue and lymph node drainage as possible in order not only to ensure local control but also to prevent spread of  tumour through the lymphat ics. Although the principle of  local control is still extremely important, it is now recognised that ultra-radical surgery probably has little e ﬀ ect on the development of  metastatic disease, as evidenced by the randomised trials of  radical versus simple mastectomy for breast cancer. It is important, however, to appreciate that high-quality , meticulous surgery taking care not to disrupt the primary tumour at the time of  excision is of the utmost importance in obtaining a cure in localised disease and in preventing local recurrence. Removal of metastatic disease Under certain circumstances surgery for metastatic disease may be appropriate. This is particularly true for liver metasta ses arising from colorectal cancer where successful resection of all detectable disease can lead to long-term survival in about one-third of  patients. With multiple liver metastases, it may still be possible to take a surgical approach by using in situ ablation with cryotherapy or radiofrequency energy . Another situation in which surgery may be curative in metastatic disease is that of pulmonary resection for isolated lung metastases, particularly from renal cell carcinoma. In many cases surgery is not appropriate for cure but may be valuable for palliation. A good example of  this is the patient with a symptomatic primary tumour who also has distant metastases, e.g. a patient with a large, symptomatic renal cell cancer but di ﬀ use metastatic disease. In this case, removal of the primary will increase the patient’s quality of life but will have little e ﬀ ect on the ultimate outcome. 

Site-specialist surgeon
Surgical oncologist
Plastic and reconstructive surgeon
Clinical oncologist/radiotherapist
Medical oncologist
Diagnostic radiologist
Interventional radiologist
Palliative care physician
Pathologist
Speech therapist
Physiotherapist
Prosthetist
Clinical nurse specialist (rehabilitation, supportive care)
Clinical trial team representative
Palliative care nurse
Social worker/counsellor
Medical secretary/administrator
Multidisciplinary team coordinator

Principles of cancer surgery

For most solid tumours, surgery remains the deﬁnitive treat - ment and the only realistic hope of  cure. However, surgery has many roles in cancer treatment from diagnosis, prevention, removal of primary disease, removal of metastatic disease, reconstruction through to palliation of  symptoms. Role in diagnosis and staging In most, but not all, patients the diagnosis of  cancer has been conﬁrmed by biopsy before deﬁnitive surgery is carried out; - however, occasionally a surgical procedure is required to make the diagnosis, e.g. in renal cell cancer where not all patients with a renal mass will undergo a biopsy , prior to deﬁnitive surgery to remove and diagnose the tumour as either malignant or benign. Laparoscopic surgery is used as part of  the staging of  intra-abdominal malignancy , particularly oesophageal and gastric cancer. By this means it is often possible to diagnose - widespread peritoneal disease and small liver metastases that may have been missed on cross-sectional imaging. Laparoscopic 

Disadvantages
Less con
/f_i
dent and less articulate members of the team may not
be able to express their views, even though their views may be
extremely important
May become a rubber-stamping exercise in which the class
solutions implied by guidelines are applied to disparate individuals
Decisions are made in the absence of patients and their carers
Clinicians are able to avoid having to take responsibility for their
decisions and their actions – ‘corporate responsibility’
Time-consuming and resource intensive: takes multiple busy
clinicians away from clinical practice for hours at a time

Potential members of the cancer multidisciplinary team /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF ultrasound is a particularly useful adjunct for the diagnosis of intrahepatic metastases. Other examples of  when surgery is central to the diagnosis of  cancer include orchidectomy , in a patient suspected of  testicular cancer; lymph node biopsy in a patient with lymphoma; and sentinel node biopsy in melanoma and breast cancer. Removal of primary disease Radical surgery for cancer involves removal of  the primary tumour and as much of  the surrounding tissue and lymph node drainage as possible in order not only to ensure local control but also to prevent spread of  tumour through the lymphat ics. Although the principle of  local control is still extremely important, it is now recognised that ultra-radical surgery probably has little e ﬀ ect on the development of  metastatic disease, as evidenced by the randomised trials of  radical versus simple mastectomy for breast cancer. It is important, however, to appreciate that high-quality , meticulous surgery taking care not to disrupt the primary tumour at the time of  excision is of the utmost importance in obtaining a cure in localised disease and in preventing local recurrence. Removal of metastatic disease Under certain circumstances surgery for metastatic disease may be appropriate. This is particularly true for liver metasta ses arising from colorectal cancer where successful resection of all detectable disease can lead to long-term survival in about one-third of  patients. With multiple liver metastases, it may still be possible to take a surgical approach by using in situ ablation with cryotherapy or radiofrequency energy . Another situation in which surgery may be curative in metastatic disease is that of pulmonary resection for isolated lung metastases, particularly from renal cell carcinoma. In many cases surgery is not appropriate for cure but may be valuable for palliation. A good example of  this is the patient with a symptomatic primary tumour who also has distant metastases, e.g. a patient with a large, symptomatic renal cell cancer but di ﬀ use metastatic disease. In this case, removal of the primary will increase the patient’s quality of life but will have little e ﬀ ect on the ultimate outcome. 

Site-specialist surgeon
Surgical oncologist
Plastic and reconstructive surgeon
Clinical oncologist/radiotherapist
Medical oncologist
Diagnostic radiologist
Interventional radiologist
Palliative care physician
Pathologist
Speech therapist
Physiotherapist
Prosthetist
Clinical nurse specialist (rehabilitation, supportive care)
Clinical trial team representative
Palliative care nurse
Social worker/counsellor
Medical secretary/administrator
Multidisciplinary team coordinator

Principles of cancer surgery

For most solid tumours, surgery remains the deﬁnitive treat - ment and the only realistic hope of  cure. However, surgery has many roles in cancer treatment from diagnosis, prevention, removal of primary disease, removal of metastatic disease, reconstruction through to palliation of  symptoms. Role in diagnosis and staging In most, but not all, patients the diagnosis of  cancer has been conﬁrmed by biopsy before deﬁnitive surgery is carried out; - however, occasionally a surgical procedure is required to make the diagnosis, e.g. in renal cell cancer where not all patients with a renal mass will undergo a biopsy , prior to deﬁnitive surgery to remove and diagnose the tumour as either malignant or benign. Laparoscopic surgery is used as part of  the staging of  intra-abdominal malignancy , particularly oesophageal and gastric cancer. By this means it is often possible to diagnose - widespread peritoneal disease and small liver metastases that may have been missed on cross-sectional imaging. Laparoscopic 

Disadvantages
Less con
/f_i
dent and less articulate members of the team may not
be able to express their views, even though their views may be
extremely important
May become a rubber-stamping exercise in which the class
solutions implied by guidelines are applied to disparate individuals
Decisions are made in the absence of patients and their carers
Clinicians are able to avoid having to take responsibility for their
decisions and their actions – ‘corporate responsibility’
Time-consuming and resource intensive: takes multiple busy
clinicians away from clinical practice for hours at a time

Potential members of the cancer multidisciplinary team /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF ultrasound is a particularly useful adjunct for the diagnosis of intrahepatic metastases. Other examples of  when surgery is central to the diagnosis of  cancer include orchidectomy , in a patient suspected of  testicular cancer; lymph node biopsy in a patient with lymphoma; and sentinel node biopsy in melanoma and breast cancer. Removal of primary disease Radical surgery for cancer involves removal of  the primary tumour and as much of  the surrounding tissue and lymph node drainage as possible in order not only to ensure local control but also to prevent spread of  tumour through the lymphat ics. Although the principle of  local control is still extremely important, it is now recognised that ultra-radical surgery probably has little e ﬀ ect on the development of  metastatic disease, as evidenced by the randomised trials of  radical versus simple mastectomy for breast cancer. It is important, however, to appreciate that high-quality , meticulous surgery taking care not to disrupt the primary tumour at the time of  excision is of the utmost importance in obtaining a cure in localised disease and in preventing local recurrence. Removal of metastatic disease Under certain circumstances surgery for metastatic disease may be appropriate. This is particularly true for liver metasta ses arising from colorectal cancer where successful resection of all detectable disease can lead to long-term survival in about one-third of  patients. With multiple liver metastases, it may still be possible to take a surgical approach by using in situ ablation with cryotherapy or radiofrequency energy . Another situation in which surgery may be curative in metastatic disease is that of pulmonary resection for isolated lung metastases, particularly from renal cell carcinoma. In many cases surgery is not appropriate for cure but may be valuable for palliation. A good example of  this is the patient with a symptomatic primary tumour who also has distant metastases, e.g. a patient with a large, symptomatic renal cell cancer but di ﬀ use metastatic disease. In this case, removal of the primary will increase the patient’s quality of life but will have little e ﬀ ect on the ultimate outcome. 

Site-specialist surgeon
Surgical oncologist
Plastic and reconstructive surgeon
Clinical oncologist/radiotherapist
Medical oncologist
Diagnostic radiologist
Interventional radiologist
Palliative care physician
Pathologist
Speech therapist
Physiotherapist
Prosthetist
Clinical nurse specialist (rehabilitation, supportive care)
Clinical trial team representative
Palliative care nurse
Social worker/counsellor
Medical secretary/administrator
Multidisciplinary team coordinator

# Principles of combined treatment

Principles of combined treatment

Non-surgical treatments are often used in combination. For example, radiotherapy and chemotherapy are often given together as an alternative to surgery , e.g. in the treatment of rectal, cervical, head and neck or brain cancers ( Table 12.5 The rationale behind combination, as opposed to single- modality therapy , is straightforward and is somewhat analogous to that used for combined antibiotic therapy: it is a strategy designed to combat resistance. By the time of  diagnosis many tumours will contain cancer cells that, through spontaneous mutation, have acquired resistance to individual modalities of  treatment. Unlike antibiotic resistance, there is no need for previous exposure to the treatment. Spontaneous mutation rates are high enough to allow chance to permit the occur rence, and subsequent expansion, of  clones of  cells resistant to a treatment to which they have never been exposed. If only single-modality treatments were used, then the further expansion of  these de novo resistant subclones would limit cure. The problem can be mitigated by , from the outset of  treatment, combining treatment modalities. drugs for combination therapy is based: (i) use drugs active against the diseases in question; (ii) use drugs with distinct modes of action; (iii) use drugs with non-overlapping toxicities . By using drugs with di ﬀ erent biological e ﬀ ects, for example by combining an antimetabolite with an agent that actively dam - ages DNA, it may be possible to obtain a truly synergistic e ﬀ ect, i.e. where the e ﬀ ects of  the two modalities together are supe - rior to the additive e ﬀ ects of  both separately . It is inadvisable to combine drugs with similar adverse e ﬀ ects: combining two highly myelosuppressive drugs may produce an unacce ptably - high risk of  neutropenic sepsis. Where possible, combinations - should be based upon a consideration of  the toxicity proﬁles of  the drugs concerned. In considering the combination of  radiotherapy and che - motherapy , radiation could be considered as just another drug. There is, in addition to synergy and toxicity , another factor to consider in the combination of  drugs and radiation – the concept of  spatial cooperation. Chemotherapy is a systemic treatment, radiotherap y is not. Radiotherapy is, however, able - to reach sites, such as the central nervous system and testis, that - drugs may not reach e ﬀ ectively . This is why , for example in patients treated primarily with chemotherapy for leukaemias, lymphomas and small cell lung cancer, prophylactic cranial irradiation may be part of  the treatment protocol. Summary box 12.4 Principles of combined treatment /uni25CF /uni25CF - /uni25CF /uni25CF - 

Use effective agents
Use agents with different modes of action (synergy)
Use agents with non-overlapping toxicities
Consider spatial cooperation

Principles of combined treatment

Non-surgical treatments are often used in combination. For example, radiotherapy and chemotherapy are often given together as an alternative to surgery , e.g. in the treatment of rectal, cervical, head and neck or brain cancers ( Table 12.5 The rationale behind combination, as opposed to single- modality therapy , is straightforward and is somewhat analogous to that used for combined antibiotic therapy: it is a strategy designed to combat resistance. By the time of  diagnosis many tumours will contain cancer cells that, through spontaneous mutation, have acquired resistance to individual modalities of  treatment. Unlike antibiotic resistance, there is no need for previous exposure to the treatment. Spontaneous mutation rates are high enough to allow chance to permit the occur rence, and subsequent expansion, of  clones of  cells resistant to a treatment to which they have never been exposed. If only single-modality treatments were used, then the further expansion of  these de novo resistant subclones would limit cure. The problem can be mitigated by , from the outset of  treatment, combining treatment modalities. drugs for combination therapy is based: (i) use drugs active against the diseases in question; (ii) use drugs with distinct modes of action; (iii) use drugs with non-overlapping toxicities . By using drugs with di ﬀ erent biological e ﬀ ects, for example by combining an antimetabolite with an agent that actively dam - ages DNA, it may be possible to obtain a truly synergistic e ﬀ ect, i.e. where the e ﬀ ects of  the two modalities together are supe - rior to the additive e ﬀ ects of  both separately . It is inadvisable to combine drugs with similar adverse e ﬀ ects: combining two highly myelosuppressive drugs may produce an unacce ptably - high risk of  neutropenic sepsis. Where possible, combinations - should be based upon a consideration of  the toxicity proﬁles of  the drugs concerned. In considering the combination of  radiotherapy and che - motherapy , radiation could be considered as just another drug. There is, in addition to synergy and toxicity , another factor to consider in the combination of  drugs and radiation – the concept of  spatial cooperation. Chemotherapy is a systemic treatment, radiotherap y is not. Radiotherapy is, however, able - to reach sites, such as the central nervous system and testis, that - drugs may not reach e ﬀ ectively . This is why , for example in patients treated primarily with chemotherapy for leukaemias, lymphomas and small cell lung cancer, prophylactic cranial irradiation may be part of  the treatment protocol. Summary box 12.4 Principles of combined treatment /uni25CF /uni25CF - /uni25CF /uni25CF - 

Use effective agents
Use agents with different modes of action (synergy)
Use agents with non-overlapping toxicities
Consider spatial cooperation

Principles of combined treatment

Non-surgical treatments are often used in combination. For example, radiotherapy and chemotherapy are often given together as an alternative to surgery , e.g. in the treatment of rectal, cervical, head and neck or brain cancers ( Table 12.5 The rationale behind combination, as opposed to single- modality therapy , is straightforward and is somewhat analogous to that used for combined antibiotic therapy: it is a strategy designed to combat resistance. By the time of  diagnosis many tumours will contain cancer cells that, through spontaneous mutation, have acquired resistance to individual modalities of  treatment. Unlike antibiotic resistance, there is no need for previous exposure to the treatment. Spontaneous mutation rates are high enough to allow chance to permit the occur rence, and subsequent expansion, of  clones of  cells resistant to a treatment to which they have never been exposed. If only single-modality treatments were used, then the further expansion of  these de novo resistant subclones would limit cure. The problem can be mitigated by , from the outset of  treatment, combining treatment modalities. drugs for combination therapy is based: (i) use drugs active against the diseases in question; (ii) use drugs with distinct modes of action; (iii) use drugs with non-overlapping toxicities . By using drugs with di ﬀ erent biological e ﬀ ects, for example by combining an antimetabolite with an agent that actively dam - ages DNA, it may be possible to obtain a truly synergistic e ﬀ ect, i.e. where the e ﬀ ects of  the two modalities together are supe - rior to the additive e ﬀ ects of  both separately . It is inadvisable to combine drugs with similar adverse e ﬀ ects: combining two highly myelosuppressive drugs may produce an unacce ptably - high risk of  neutropenic sepsis. Where possible, combinations - should be based upon a consideration of  the toxicity proﬁles of  the drugs concerned. In considering the combination of  radiotherapy and che - motherapy , radiation could be considered as just another drug. There is, in addition to synergy and toxicity , another factor to consider in the combination of  drugs and radiation – the concept of  spatial cooperation. Chemotherapy is a systemic treatment, radiotherap y is not. Radiotherapy is, however, able - to reach sites, such as the central nervous system and testis, that - drugs may not reach e ﬀ ectively . This is why , for example in patients treated primarily with chemotherapy for leukaemias, lymphomas and small cell lung cancer, prophylactic cranial irradiation may be part of  the treatment protocol. Summary box 12.4 Principles of combined treatment /uni25CF /uni25CF - /uni25CF /uni25CF - 

Use effective agents
Use agents with different modes of action (synergy)
Use agents with non-overlapping toxicities
Consider spatial cooperation

# Principles underlying the non-surgical treatment o

Principles underlying the non-surgical treatment of cancer

Medical and clinical (radiation) oncology are rapidly changing ﬁelds. Both understanding of  cancer and the technology avail - able are expanding at a rapid pace. Nevertheless, there are basic principles that remain constant. These are to ascertain as precisely as possible the diagnosis, stage of  disease and molec - ular characteristics of  the tumour and, from this information, assess via the multidisciplinary team the management options f or the patient. In general terms, where a local treatment, i.e. surgery or ablation, is as e ﬀ ective as a systemic trea tment, the local treatment will be preferred. The range of  options will be speciﬁc to each tumour type and is constantly evolving. This is most true of  the systemic therapy options available to patients. The purposes of  oncology treatment can be conveniently divided into: /uni25CF curative primary : the e ﬀ ect of  non-surgical treatment alone is highly e ﬀ ective, e.g. head and neck cancers ( Table 12.5 ); /uni25CF neoadjuvant : where non-surgical treatment prior to sur - gery can substantially reduce the morbidity of  treatment and increase its chances of  success, e.g. radiotherapy to downstage rectal carcinoma prior to surgery; /uni25CF adjuvant : where non-surgical treatment after surgery - can increase the chance of  cure, e.g. radiotherapy and chemotherapy after breast cancer; /uni25CF life-prolonging/palliative : these terms are better separated, especially in the case of  life-prolonging treat - ments in a non-curative setting that may add years to life, e.g. use of  olaparib in BRCA -mutated ovarian cancer. Systemic therapies In recent decades, drug development has evolved from screen - ing large libraries of  chemicals for their ability to interfere with cellular processes. Increased understanding of  the molecular pathophysiology of  cancers has identiﬁed key molecules essen - tial to tumour function. Many of  these molecules can be inhib - - ited and are ter med ‘druggable targets’. Three-dimensional characterisation of  these targets and synthesis of  molecules to inhibit them has produced a large number of  highly e ﬀ ective targeted therapies. The pace of  change is su ﬃ ciently rapid that it is now only possib le for an individual clinician to keep abreast of  developments in a limited number of  cancers. The following principles are key in decision making over systemic therapy administration to individual patients: /uni25CF Assess the ﬁtness and willingness of  the patient to tolerate each of  these options. Most cancers occur in middle-aged or older patients. The older a patient is, the more likely they are to have comor bidities or be frail. It is important to note that middle-aged patients may be unﬁt or have serious comorbidities and that older patients may actually be very ﬁt. Organ dys function and frailty may substantially increase the risks of treatment and r educe its chance of  success. This must be assessed on an individual basis. /uni25CF Support the patient to understand the options and choose the most appropriate management approach. Discussions about prognosis and treatment options are complex, di ﬃ cult and any decisions made are often irre vocable. They also take place when the patient and their family are at their most anxious and vulnerable. It is of ten necessary to provide information in digestible amounts and to do so repeatedly . Ther e are few oncological situa tions where an immediate decision needs to be taken by the patient. The di ﬃ culties of drawing a balance between risk and beneﬁt ar e illustrated by considering adjuvant therapy f a solid malignancy . In the absence of  a good test to as certain individual risk of  relapse, it is necessary to treat Max Wilms , 1867–1918, Professor of  Surgery , Heidelberg, Germany . often around 10% ( Figure 12.5 ). Although 10% is a small proportion, it represents a small chance of  a major bene - ﬁt, namely cure. If  there were a test that could accurately determine patients with no residual disease after resection, then a lower proportion of  patients would need to have ad - juvant therapy , each of whom would have a higher chance of beneﬁt ( Figures 12.5 and 12.6 ) . /uni25CF Frequently reassess the balance of  risk and beneﬁt during treatment. For patients receiving repeated cycles of  treatment, there are three key questions to consider before proceeding with the next cycle of  treatment: 1 Is the treatment working ? Where there is mea - surable disease, this is usually assessed by radiologi - cal restaging at intervals of  6–12 weeks. The test for whether the treatment is working will depend on the goals of  treatment: if  the goal is stabilisation of  disease then it may be su ﬃ cient that the tumour is not gro w - ing; if  the goal is elimination of  disease then progres - sive shrinkage of  the radiological abnormalities will be necessary . 2 Is the patient tolerating treatment? This can only be discovered by asking the patient what side e ﬀ ects they are experiencing. Clinicians should be used to detecting and managing the side e ﬀ ects of  the drugs they are prescribing. In addition to open questions, the clinician should enquire speciﬁcally about common or dangerous side e ﬀ ects. If  the patient is not tolerating treatment, then it may be necessary to delay the next cycle or to reduce the dose, even though this may be at the expense of  reducing the e ﬀ ectiveness of treatment. 3 Is it safe to give the next cycle of  treatment? To answer this question, the clinician will have to assess what side e ﬀ ects the patient is experiencing and also ensure that laboratory measures are within acceptable - limits. The necessary laboratory tests will commonly include full blood count, urea and electrolytes and liver function tests as well as other tests determined by which - treatments are being used. 

without the need for surgical excision.
Malignancy
Potentially curative treatment
Leukaemia
Chemotherapy (+/–
radiotherapy)
Lymphoma
Chemotherapy (+/–
radiotherapy)
Small cell lung cancer
Chemotherapy (+/–
radiotherapy)
Chemotherapy (+/–
Tumours of childhood
radiotherapy)
(rhabdomyosarcoma, Wilms’
tumour)
Early laryngeal cancer
Radiotherapy
Advanced head and neck
Chemoradiation (synchronous
cancer
chemotherapy and
radiotherapy)
Oesophageal cancer
Chemoradiation (synchronous
chemotherapy and
radiotherapy)
Squamous cell cancer of the
Chemoradiation (synchronous
anus
chemotherapy and
radiotherapy)
Advanced cancer of the cervix
Radiotherapy (+/–
chemotherapy)
Medulloblastoma
Radiotherapy (+/–
chemotherapy)
Skin tumours (BCC, SCC)
Radiotherapy
BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

Principles underlying the non-surgical treatment of cancer

Medical and clinical (radiation) oncology are rapidly changing ﬁelds. Both understanding of  cancer and the technology avail - able are expanding at a rapid pace. Nevertheless, there are basic principles that remain constant. These are to ascertain as precisely as possible the diagnosis, stage of  disease and molec - ular characteristics of  the tumour and, from this information, assess via the multidisciplinary team the management options f or the patient. In general terms, where a local treatment, i.e. surgery or ablation, is as e ﬀ ective as a systemic trea tment, the local treatment will be preferred. The range of  options will be speciﬁc to each tumour type and is constantly evolving. This is most true of  the systemic therapy options available to patients. The purposes of  oncology treatment can be conveniently divided into: /uni25CF curative primary : the e ﬀ ect of  non-surgical treatment alone is highly e ﬀ ective, e.g. head and neck cancers ( Table 12.5 ); /uni25CF neoadjuvant : where non-surgical treatment prior to sur - gery can substantially reduce the morbidity of  treatment and increase its chances of  success, e.g. radiotherapy to downstage rectal carcinoma prior to surgery; /uni25CF adjuvant : where non-surgical treatment after surgery - can increase the chance of  cure, e.g. radiotherapy and chemotherapy after breast cancer; /uni25CF life-prolonging/palliative : these terms are better separated, especially in the case of  life-prolonging treat - ments in a non-curative setting that may add years to life, e.g. use of  olaparib in BRCA -mutated ovarian cancer. Systemic therapies In recent decades, drug development has evolved from screen - ing large libraries of  chemicals for their ability to interfere with cellular processes. Increased understanding of  the molecular pathophysiology of  cancers has identiﬁed key molecules essen - tial to tumour function. Many of  these molecules can be inhib - - ited and are ter med ‘druggable targets’. Three-dimensional characterisation of  these targets and synthesis of  molecules to inhibit them has produced a large number of  highly e ﬀ ective targeted therapies. The pace of  change is su ﬃ ciently rapid that it is now only possib le for an individual clinician to keep abreast of  developments in a limited number of  cancers. The following principles are key in decision making over systemic therapy administration to individual patients: /uni25CF Assess the ﬁtness and willingness of  the patient to tolerate each of  these options. Most cancers occur in middle-aged or older patients. The older a patient is, the more likely they are to have comor bidities or be frail. It is important to note that middle-aged patients may be unﬁt or have serious comorbidities and that older patients may actually be very ﬁt. Organ dys function and frailty may substantially increase the risks of treatment and r educe its chance of  success. This must be assessed on an individual basis. /uni25CF Support the patient to understand the options and choose the most appropriate management approach. Discussions about prognosis and treatment options are complex, di ﬃ cult and any decisions made are often irre vocable. They also take place when the patient and their family are at their most anxious and vulnerable. It is of ten necessary to provide information in digestible amounts and to do so repeatedly . Ther e are few oncological situa tions where an immediate decision needs to be taken by the patient. The di ﬃ culties of drawing a balance between risk and beneﬁt ar e illustrated by considering adjuvant therapy f a solid malignancy . In the absence of  a good test to as certain individual risk of  relapse, it is necessary to treat Max Wilms , 1867–1918, Professor of  Surgery , Heidelberg, Germany . often around 10% ( Figure 12.5 ). Although 10% is a small proportion, it represents a small chance of  a major bene - ﬁt, namely cure. If  there were a test that could accurately determine patients with no residual disease after resection, then a lower proportion of  patients would need to have ad - juvant therapy , each of whom would have a higher chance of beneﬁt ( Figures 12.5 and 12.6 ) . /uni25CF Frequently reassess the balance of  risk and beneﬁt during treatment. For patients receiving repeated cycles of  treatment, there are three key questions to consider before proceeding with the next cycle of  treatment: 1 Is the treatment working ? Where there is mea - surable disease, this is usually assessed by radiologi - cal restaging at intervals of  6–12 weeks. The test for whether the treatment is working will depend on the goals of  treatment: if  the goal is stabilisation of  disease then it may be su ﬃ cient that the tumour is not gro w - ing; if  the goal is elimination of  disease then progres - sive shrinkage of  the radiological abnormalities will be necessary . 2 Is the patient tolerating treatment? This can only be discovered by asking the patient what side e ﬀ ects they are experiencing. Clinicians should be used to detecting and managing the side e ﬀ ects of  the drugs they are prescribing. In addition to open questions, the clinician should enquire speciﬁcally about common or dangerous side e ﬀ ects. If  the patient is not tolerating treatment, then it may be necessary to delay the next cycle or to reduce the dose, even though this may be at the expense of  reducing the e ﬀ ectiveness of treatment. 3 Is it safe to give the next cycle of  treatment? To answer this question, the clinician will have to assess what side e ﬀ ects the patient is experiencing and also ensure that laboratory measures are within acceptable - limits. The necessary laboratory tests will commonly include full blood count, urea and electrolytes and liver function tests as well as other tests determined by which - treatments are being used. 

without the need for surgical excision.
Malignancy
Potentially curative treatment
Leukaemia
Chemotherapy (+/–
radiotherapy)
Lymphoma
Chemotherapy (+/–
radiotherapy)
Small cell lung cancer
Chemotherapy (+/–
radiotherapy)
Chemotherapy (+/–
Tumours of childhood
radiotherapy)
(rhabdomyosarcoma, Wilms’
tumour)
Early laryngeal cancer
Radiotherapy
Advanced head and neck
Chemoradiation (synchronous
cancer
chemotherapy and
radiotherapy)
Oesophageal cancer
Chemoradiation (synchronous
chemotherapy and
radiotherapy)
Squamous cell cancer of the
Chemoradiation (synchronous
anus
chemotherapy and
radiotherapy)
Advanced cancer of the cervix
Radiotherapy (+/–
chemotherapy)
Medulloblastoma
Radiotherapy (+/–
chemotherapy)
Skin tumours (BCC, SCC)
Radiotherapy
BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

# Principles underlying the non-surgical treatment of cancer

Principles underlying the non-surgical treatment of cancer

Medical and clinical (radiation) oncology are rapidly changing ﬁelds. Both understanding of  cancer and the technology avail - able are expanding at a rapid pace. Nevertheless, there are basic principles that remain constant. These are to ascertain as precisely as possible the diagnosis, stage of  disease and molec - ular characteristics of  the tumour and, from this information, assess via the multidisciplinary team the management options f or the patient. In general terms, where a local treatment, i.e. surgery or ablation, is as e ﬀ ective as a systemic trea tment, the local treatment will be preferred. The range of  options will be speciﬁc to each tumour type and is constantly evolving. This is most true of  the systemic therapy options available to patients. The purposes of  oncology treatment can be conveniently divided into: /uni25CF curative primary : the e ﬀ ect of  non-surgical treatment alone is highly e ﬀ ective, e.g. head and neck cancers ( Table 12.5 ); /uni25CF neoadjuvant : where non-surgical treatment prior to sur - gery can substantially reduce the morbidity of  treatment and increase its chances of  success, e.g. radiotherapy to downstage rectal carcinoma prior to surgery; /uni25CF adjuvant : where non-surgical treatment after surgery - can increase the chance of  cure, e.g. radiotherapy and chemotherapy after breast cancer; /uni25CF life-prolonging/palliative : these terms are better separated, especially in the case of  life-prolonging treat - ments in a non-curative setting that may add years to life, e.g. use of  olaparib in BRCA -mutated ovarian cancer. Systemic therapies In recent decades, drug development has evolved from screen - ing large libraries of  chemicals for their ability to interfere with cellular processes. Increased understanding of  the molecular pathophysiology of  cancers has identiﬁed key molecules essen - tial to tumour function. Many of  these molecules can be inhib - - ited and are ter med ‘druggable targets’. Three-dimensional characterisation of  these targets and synthesis of  molecules to inhibit them has produced a large number of  highly e ﬀ ective targeted therapies. The pace of  change is su ﬃ ciently rapid that it is now only possib le for an individual clinician to keep abreast of  developments in a limited number of  cancers. The following principles are key in decision making over systemic therapy administration to individual patients: /uni25CF Assess the ﬁtness and willingness of  the patient to tolerate each of  these options. Most cancers occur in middle-aged or older patients. The older a patient is, the more likely they are to have comor bidities or be frail. It is important to note that middle-aged patients may be unﬁt or have serious comorbidities and that older patients may actually be very ﬁt. Organ dys function and frailty may substantially increase the risks of treatment and r educe its chance of  success. This must be assessed on an individual basis. /uni25CF Support the patient to understand the options and choose the most appropriate management approach. Discussions about prognosis and treatment options are complex, di ﬃ cult and any decisions made are often irre vocable. They also take place when the patient and their family are at their most anxious and vulnerable. It is of ten necessary to provide information in digestible amounts and to do so repeatedly . Ther e are few oncological situa tions where an immediate decision needs to be taken by the patient. The di ﬃ culties of drawing a balance between risk and beneﬁt ar e illustrated by considering adjuvant therapy f a solid malignancy . In the absence of  a good test to as certain individual risk of  relapse, it is necessary to treat Max Wilms , 1867–1918, Professor of  Surgery , Heidelberg, Germany . often around 10% ( Figure 12.5 ). Although 10% is a small proportion, it represents a small chance of  a major bene - ﬁt, namely cure. If  there were a test that could accurately determine patients with no residual disease after resection, then a lower proportion of  patients would need to have ad - juvant therapy , each of whom would have a higher chance of beneﬁt ( Figures 12.5 and 12.6 ) . /uni25CF Frequently reassess the balance of  risk and beneﬁt during treatment. For patients receiving repeated cycles of  treatment, there are three key questions to consider before proceeding with the next cycle of  treatment: 1 Is the treatment working ? Where there is mea - surable disease, this is usually assessed by radiologi - cal restaging at intervals of  6–12 weeks. The test for whether the treatment is working will depend on the goals of  treatment: if  the goal is stabilisation of  disease then it may be su ﬃ cient that the tumour is not gro w - ing; if  the goal is elimination of  disease then progres - sive shrinkage of  the radiological abnormalities will be necessary . 2 Is the patient tolerating treatment? This can only be discovered by asking the patient what side e ﬀ ects they are experiencing. Clinicians should be used to detecting and managing the side e ﬀ ects of  the drugs they are prescribing. In addition to open questions, the clinician should enquire speciﬁcally about common or dangerous side e ﬀ ects. If  the patient is not tolerating treatment, then it may be necessary to delay the next cycle or to reduce the dose, even though this may be at the expense of  reducing the e ﬀ ectiveness of treatment. 3 Is it safe to give the next cycle of  treatment? To answer this question, the clinician will have to assess what side e ﬀ ects the patient is experiencing and also ensure that laboratory measures are within acceptable - limits. The necessary laboratory tests will commonly include full blood count, urea and electrolytes and liver function tests as well as other tests determined by which - treatments are being used. 

without the need for surgical excision.
Malignancy
Potentially curative treatment
Leukaemia
Chemotherapy (+/–
radiotherapy)
Lymphoma
Chemotherapy (+/–
radiotherapy)
Small cell lung cancer
Chemotherapy (+/–
radiotherapy)
Chemotherapy (+/–
Tumours of childhood
radiotherapy)
(rhabdomyosarcoma, Wilms’
tumour)
Early laryngeal cancer
Radiotherapy
Advanced head and neck
Chemoradiation (synchronous
cancer
chemotherapy and
radiotherapy)
Oesophageal cancer
Chemoradiation (synchronous
chemotherapy and
radiotherapy)
Squamous cell cancer of the
Chemoradiation (synchronous
anus
chemotherapy and
radiotherapy)
Advanced cancer of the cervix
Radiotherapy (+/–
chemotherapy)
Medulloblastoma
Radiotherapy (+/–
chemotherapy)
Skin tumours (BCC, SCC)
Radiotherapy
BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

# Screening

Screening

Screening involves the detection of  disease in an asymptomatic population in order to improve outcomes by early diagnosis of cancer at a curable stage. It follows that a successful screening programme must achieve early diagnosis and that the disease in question has a better outcome when treated at an early stage. The criteria that must be fulﬁlled for the disease, screening test and the screening programme itself  are given in Summary box 12.2 . Merely to prove that screening picks up disease at an early stage, and that the outcome is better for patients with screen-detected disease than for those who present with symp - toms, is an insu ﬃ cient criterion for the success of  a screening programme. This is because of  potential inherent biases of - screening (lead time bias, selection bias and length bias), which make screen-detected disease appear to be associated with better outcomes than symptomatic disease. Summary box 12.2 Criteria for screening (based on Wilson–Junger criteria for a screening programme) /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Lead time bias describes the phenomenon whereby early detec tion of a disease will always prolong survival from the time of diagnosis when compared with disease picked up at a later stage in its development whether or not detection in the screening pr ocess has altered the progression of  the cancer ( Figure 12.4 Selection bias describes the ﬁnding that individuals who accept an invitation for screening are, in general, healthier than those James Maxwell Glover Wilson , 1913-2006, Principal Medical O ﬃ cer at the Ministry of  Health in London, England. Gunnar Jungner , 1914–1982, Chief  Clinical Chemistry , Sahlgrenska Hospital, Gothenburg, Sweden. who do not. It follows that individuals with screen-detected disease will tend to live longer, independently of  the condition for which screening is being performed. Length bias occurs because small, slow-growing tumours are likely to be picked up by screening whereas larger, fast-growing tumours are likely to arise and produce symptoms in between screening rounds. Screen-detected tumours will therefore tend to be less aggres - sive than symptomatic tumours. Because of these biases it is essential to carry out population-based randomised controlled trials and to compare the mortality rate in a whole population o ﬀ ered screening (including those who refuse to be screened and those who develop cancer after a nega tive test) with the mortality rate in a population that has not been o ﬀ ered screen - ing. This research design has been applied to both breast cancer and colorectal cancer: in both cases there was a reduction in disease-speciﬁc mortality . However, in general, clinical trials of screening with the gold-standard endpoint of  overall survival have not been undertaken because of the very large number of participants required with long study follow-up periods. - Cancer screening remains a controversial topic with advo - cates on both sides of  the argument. Targeted, risk-based screening approaches, such as computed tomography (CT) scan-based screening of  smokers and ex-smokers for lung can - ). cer, are being ev aluated as methods of  developing more con - clusive screening programmes. 

Prevention, Screening, Diagnosis, Staging,
Treatment, Follow-up, Rehabilitation, Palliation
Individual
(primary
care)
Within this space we can
Family
categorise all aspects of
(primary
cancer management: from
care)
an individual person’s
Community
decision to give up smoking
(local
to the World Health
hospital)
Organization’s decision to
recommend morphine rather
Region
than radiotherapy to treat
(tertiary
cancer-related pain in
centre)
resource-poor countries
Country
(national
healthcare
system)
Continent
World
(WHO)
Figure 12.3
The management of cancer spans the natural history of
the disease and all humankind, from the individual to the population
of the world.
The disease:
Recognisable early stage
Treatment at early stage more effective than at later stage
Suf
/f_i
ciently common to warrant screening
The test:
Sensitive and speci
/f_i
c
Acceptable to the screened population
Safe
Inexpensive
The programme:
Adequate diagnostic facilities for those with a positive test
High-quality treatment for screen-detected disease to minimise
morbidity and mortality
Screening repeated at intervals if disease of insidious onset
Bene
/f_i
t must outweigh physical and psychological harm
Fatal
B
Clinically detectable
C
Detected by screening
A
Tumour size
Tumour a
Tumour b
x
y
0 1 2 3 4 5 6 7 8 9 10
Time (y)
Figure 12.4
An illustration of lead time and length bias.
Tumour a
is a steadily growing tumour; its progress is unin
/f_l
uenced by any
treatment. Point A indicates the time at which the tumour would be
diagnosed in a screening programme, and point B indicates the time
at which the tumour
would be diagnosed clinically, i.e. in the absence
of any screening programme. If the date of diagnosis is used as the
start time for measuring survival, then, in the absence of any effect
from treatment, the screening programme will, artefactually, add to the
survival time. The amount of ‘increased’ survival is equal to
y – x
years,
in this example just over 2 years. This artefactual in
/f_l
ation of survival
time is referred to as lead time bias.
Tumour b
is a rapidly growing
tumour; again its progress is unin
/f_l
uenced by treatment. It grows so
rapidly that, in the interval between two screening tests, it can cross
both the threshold for detectability by screening and that of clinical
detectability (at point C). It will continue to progress rapidly after diag
-
nosis and the measured survival time will be short. This phenomenon,
whereby those tumours that are ‘missed’ by the screening programme
are associated with decreased survival, is called length time bias.

Accurate diagnosis is the key to successful management of cancer. Precise diagnosis is crucial to the choice of  correct therapy; the wrong operation, no matter how well performed, is useless. An unequivocal diagnosis is also the key to an accurate prognosis. Only rarely can a diagnosis of  cancer be conﬁdently made in the absence of  tissue for pathological or cytological examination. Cancer is a disease of cells and, for accurate diagnosis, the abnormal cells need to be obtained and visualised by a histopathologist. Di ﬀ erent tumours are classiﬁed in di ﬀ erent ways: most squamous epithelial tumours are classed as well (G1), moderate (G2) or poorly (G3) di ﬀ er entiated. Adenocarcinomas are also often classiﬁed as G1, G2 or G3 but prostate cancer is an exception, with widespread use of  the Gleason system. The Gleason system grades prostate cancer according to the degree of  di ﬀ erentia tion of  the two most prevalent architectural patterns. The ﬁnal score is the sum of  the two grades and can vary from 6 (3 /uni00A0 + /uni00A0 3) to 10 (5 /uni00A0 + /uni00A0 5) with the higher scores indicating poorer prognosis. The ongoing development of  molecular classiﬁers in many cancer types is beginning to profoundly alter our approach to treatment of  these malignancies based on genetic mutations and other molecular fea tures identiﬁed in individual patients, i.e. in melanoma where patients with BRAF gene mutations can be successfully treated with the BRAF inhibitors. Molecu lar characterisation of  malignancies and identiﬁcation of  their vulnerabilities have already become standard of  care in many Donald F Gleason , 1920–2008, pathologist, The University of  Minnesota, Minneapolis, MN, USA. likely to expand. 

TABLE 12.3
Staging of colorectal cancer.
TNM
TX, Primary tumour cannot be assessed
T0, No evidence of primary tumour
Tis, Carcinoma
in situ
or intramucosal carcinoma
T1, Tumour invades submucosa
T2, Tumour invades muscularis propria
T3, The tumour has grown through the muscularis propria and into the subserosa, which is a thin layer of connective tissue beneath the
outer layer of some parts of the large intestine, or it has grown into tissues surrounding the colon or rectum
T4, Tumour directly invades beyond bowel
NX, Regional lymph nodes cannot be assessed
N0, No metastases in regional nodes
N1a, Metastases in 1 regional lymph node
N1b, Metastases in 2 or 3 r
egional lymph nodes
N1c, There are nodules made up of tumour cells found in the structures near the colon that do not appear to be lymph nodes
N2a, Metastases in 4–6 regional lymph nodes
N2a, Metastases in
≥
7 regional lymph nodes
MX, Not possible to assess the presence of distant metastases
M0,
No distant metastases
M1a, The cancer has spread to 1 other part of the body beyond the colon or rectum
M1b, The cancer has spread to more than 1 part of the body other than the colon or rectum
M1c, The cancer has spread to the peritoneal surface

Screening

Screening involves the detection of  disease in an asymptomatic population in order to improve outcomes by early diagnosis of cancer at a curable stage. It follows that a successful screening programme must achieve early diagnosis and that the disease in question has a better outcome when treated at an early stage. The criteria that must be fulﬁlled for the disease, screening test and the screening programme itself  are given in Summary box 12.2 . Merely to prove that screening picks up disease at an early stage, and that the outcome is better for patients with screen-detected disease than for those who present with symp - toms, is an insu ﬃ cient criterion for the success of  a screening programme. This is because of  potential inherent biases of - screening (lead time bias, selection bias and length bias), which make screen-detected disease appear to be associated with better outcomes than symptomatic disease. Summary box 12.2 Criteria for screening (based on Wilson–Junger criteria for a screening programme) /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Lead time bias describes the phenomenon whereby early detec tion of a disease will always prolong survival from the time of diagnosis when compared with disease picked up at a later stage in its development whether or not detection in the screening pr ocess has altered the progression of  the cancer ( Figure 12.4 Selection bias describes the ﬁnding that individuals who accept an invitation for screening are, in general, healthier than those James Maxwell Glover Wilson , 1913-2006, Principal Medical O ﬃ cer at the Ministry of  Health in London, England. Gunnar Jungner , 1914–1982, Chief  Clinical Chemistry , Sahlgrenska Hospital, Gothenburg, Sweden. who do not. It follows that individuals with screen-detected disease will tend to live longer, independently of  the condition for which screening is being performed. Length bias occurs because small, slow-growing tumours are likely to be picked up by screening whereas larger, fast-growing tumours are likely to arise and produce symptoms in between screening rounds. Screen-detected tumours will therefore tend to be less aggres - sive than symptomatic tumours. Because of these biases it is essential to carry out population-based randomised controlled trials and to compare the mortality rate in a whole population o ﬀ ered screening (including those who refuse to be screened and those who develop cancer after a nega tive test) with the mortality rate in a population that has not been o ﬀ ered screen - ing. This research design has been applied to both breast cancer and colorectal cancer: in both cases there was a reduction in disease-speciﬁc mortality . However, in general, clinical trials of screening with the gold-standard endpoint of  overall survival have not been undertaken because of the very large number of participants required with long study follow-up periods. - Cancer screening remains a controversial topic with advo - cates on both sides of  the argument. Targeted, risk-based screening approaches, such as computed tomography (CT) scan-based screening of  smokers and ex-smokers for lung can - ). cer, are being ev aluated as methods of  developing more con - clusive screening programmes. 

Prevention, Screening, Diagnosis, Staging,
Treatment, Follow-up, Rehabilitation, Palliation
Individual
(primary
care)
Within this space we can
Family
categorise all aspects of
(primary
cancer management: from
care)
an individual person’s
Community
decision to give up smoking
(local
to the World Health
hospital)
Organization’s decision to
recommend morphine rather
Region
than radiotherapy to treat
(tertiary
cancer-related pain in
centre)
resource-poor countries
Country
(national
healthcare
system)
Continent
World
(WHO)
Figure 12.3
The management of cancer spans the natural history of
the disease and all humankind, from the individual to the population
of the world.
The disease:
Recognisable early stage
Treatment at early stage more effective than at later stage
Suf
/f_i
ciently common to warrant screening
The test:
Sensitive and speci
/f_i
c
Acceptable to the screened population
Safe
Inexpensive
The programme:
Adequate diagnostic facilities for those with a positive test
High-quality treatment for screen-detected disease to minimise
morbidity and mortality
Screening repeated at intervals if disease of insidious onset
Bene
/f_i
t must outweigh physical and psychological harm
Fatal
B
Clinically detectable
C
Detected by screening
A
Tumour size
Tumour a
Tumour b
x
y
0 1 2 3 4 5 6 7 8 9 10
Time (y)
Figure 12.4
An illustration of lead time and length bias.
Tumour a
is a steadily growing tumour; its progress is unin
/f_l
uenced by any
treatment. Point A indicates the time at which the tumour would be
diagnosed in a screening programme, and point B indicates the time
at which the tumour
would be diagnosed clinically, i.e. in the absence
of any screening programme. If the date of diagnosis is used as the
start time for measuring survival, then, in the absence of any effect
from treatment, the screening programme will, artefactually, add to the
survival time. The amount of ‘increased’ survival is equal to
y – x
years,
in this example just over 2 years. This artefactual in
/f_l
ation of survival
time is referred to as lead time bias.
Tumour b
is a rapidly growing
tumour; again its progress is unin
/f_l
uenced by treatment. It grows so
rapidly that, in the interval between two screening tests, it can cross
both the threshold for detectability by screening and that of clinical
detectability (at point C). It will continue to progress rapidly after diag
-
nosis and the measured survival time will be short. This phenomenon,
whereby those tumours that are ‘missed’ by the screening programme
are associated with decreased survival, is called length time bias.

Accurate diagnosis is the key to successful management of cancer. Precise diagnosis is crucial to the choice of  correct therapy; the wrong operation, no matter how well performed, is useless. An unequivocal diagnosis is also the key to an accurate prognosis. Only rarely can a diagnosis of  cancer be conﬁdently made in the absence of  tissue for pathological or cytological examination. Cancer is a disease of cells and, for accurate diagnosis, the abnormal cells need to be obtained and visualised by a histopathologist. Di ﬀ erent tumours are classiﬁed in di ﬀ erent ways: most squamous epithelial tumours are classed as well (G1), moderate (G2) or poorly (G3) di ﬀ er entiated. Adenocarcinomas are also often classiﬁed as G1, G2 or G3 but prostate cancer is an exception, with widespread use of  the Gleason system. The Gleason system grades prostate cancer according to the degree of  di ﬀ erentia tion of  the two most prevalent architectural patterns. The ﬁnal score is the sum of  the two grades and can vary from 6 (3 /uni00A0 + /uni00A0 3) to 10 (5 /uni00A0 + /uni00A0 5) with the higher scores indicating poorer prognosis. The ongoing development of  molecular classiﬁers in many cancer types is beginning to profoundly alter our approach to treatment of  these malignancies based on genetic mutations and other molecular fea tures identiﬁed in individual patients, i.e. in melanoma where patients with BRAF gene mutations can be successfully treated with the BRAF inhibitors. Molecu lar characterisation of  malignancies and identiﬁcation of  their vulnerabilities have already become standard of  care in many Donald F Gleason , 1920–2008, pathologist, The University of  Minnesota, Minneapolis, MN, USA. likely to expand. 

TABLE 12.3
Staging of colorectal cancer.
TNM
TX, Primary tumour cannot be assessed
T0, No evidence of primary tumour
Tis, Carcinoma
in situ
or intramucosal carcinoma
T1, Tumour invades submucosa
T2, Tumour invades muscularis propria
T3, The tumour has grown through the muscularis propria and into the subserosa, which is a thin layer of connective tissue beneath the
outer layer of some parts of the large intestine, or it has grown into tissues surrounding the colon or rectum
T4, Tumour directly invades beyond bowel
NX, Regional lymph nodes cannot be assessed
N0, No metastases in regional nodes
N1a, Metastases in 1 regional lymph node
N1b, Metastases in 2 or 3 r
egional lymph nodes
N1c, There are nodules made up of tumour cells found in the structures near the colon that do not appear to be lymph nodes
N2a, Metastases in 4–6 regional lymph nodes
N2a, Metastases in
≥
7 regional lymph nodes
MX, Not possible to assess the presence of distant metastases
M0,
No distant metastases
M1a, The cancer has spread to 1 other part of the body beyond the colon or rectum
M1b, The cancer has spread to more than 1 part of the body other than the colon or rectum
M1c, The cancer has spread to the peritoneal surface

Screening

Screening involves the detection of  disease in an asymptomatic population in order to improve outcomes by early diagnosis of cancer at a curable stage. It follows that a successful screening programme must achieve early diagnosis and that the disease in question has a better outcome when treated at an early stage. The criteria that must be fulﬁlled for the disease, screening test and the screening programme itself  are given in Summary box 12.2 . Merely to prove that screening picks up disease at an early stage, and that the outcome is better for patients with screen-detected disease than for those who present with symp - toms, is an insu ﬃ cient criterion for the success of  a screening programme. This is because of  potential inherent biases of - screening (lead time bias, selection bias and length bias), which make screen-detected disease appear to be associated with better outcomes than symptomatic disease. Summary box 12.2 Criteria for screening (based on Wilson–Junger criteria for a screening programme) /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Lead time bias describes the phenomenon whereby early detec tion of a disease will always prolong survival from the time of diagnosis when compared with disease picked up at a later stage in its development whether or not detection in the screening pr ocess has altered the progression of  the cancer ( Figure 12.4 Selection bias describes the ﬁnding that individuals who accept an invitation for screening are, in general, healthier than those James Maxwell Glover Wilson , 1913-2006, Principal Medical O ﬃ cer at the Ministry of  Health in London, England. Gunnar Jungner , 1914–1982, Chief  Clinical Chemistry , Sahlgrenska Hospital, Gothenburg, Sweden. who do not. It follows that individuals with screen-detected disease will tend to live longer, independently of  the condition for which screening is being performed. Length bias occurs because small, slow-growing tumours are likely to be picked up by screening whereas larger, fast-growing tumours are likely to arise and produce symptoms in between screening rounds. Screen-detected tumours will therefore tend to be less aggres - sive than symptomatic tumours. Because of these biases it is essential to carry out population-based randomised controlled trials and to compare the mortality rate in a whole population o ﬀ ered screening (including those who refuse to be screened and those who develop cancer after a nega tive test) with the mortality rate in a population that has not been o ﬀ ered screen - ing. This research design has been applied to both breast cancer and colorectal cancer: in both cases there was a reduction in disease-speciﬁc mortality . However, in general, clinical trials of screening with the gold-standard endpoint of  overall survival have not been undertaken because of the very large number of participants required with long study follow-up periods. - Cancer screening remains a controversial topic with advo - cates on both sides of  the argument. Targeted, risk-based screening approaches, such as computed tomography (CT) scan-based screening of  smokers and ex-smokers for lung can - ). cer, are being ev aluated as methods of  developing more con - clusive screening programmes. 

Prevention, Screening, Diagnosis, Staging,
Treatment, Follow-up, Rehabilitation, Palliation
Individual
(primary
care)
Within this space we can
Family
categorise all aspects of
(primary
cancer management: from
care)
an individual person’s
Community
decision to give up smoking
(local
to the World Health
hospital)
Organization’s decision to
recommend morphine rather
Region
than radiotherapy to treat
(tertiary
cancer-related pain in
centre)
resource-poor countries
Country
(national
healthcare
system)
Continent
World
(WHO)
Figure 12.3
The management of cancer spans the natural history of
the disease and all humankind, from the individual to the population
of the world.
The disease:
Recognisable early stage
Treatment at early stage more effective than at later stage
Suf
/f_i
ciently common to warrant screening
The test:
Sensitive and speci
/f_i
c
Acceptable to the screened population
Safe
Inexpensive
The programme:
Adequate diagnostic facilities for those with a positive test
High-quality treatment for screen-detected disease to minimise
morbidity and mortality
Screening repeated at intervals if disease of insidious onset
Bene
/f_i
t must outweigh physical and psychological harm
Fatal
B
Clinically detectable
C
Detected by screening
A
Tumour size
Tumour a
Tumour b
x
y
0 1 2 3 4 5 6 7 8 9 10
Time (y)
Figure 12.4
An illustration of lead time and length bias.
Tumour a
is a steadily growing tumour; its progress is unin
/f_l
uenced by any
treatment. Point A indicates the time at which the tumour would be
diagnosed in a screening programme, and point B indicates the time
at which the tumour
would be diagnosed clinically, i.e. in the absence
of any screening programme. If the date of diagnosis is used as the
start time for measuring survival, then, in the absence of any effect
from treatment, the screening programme will, artefactually, add to the
survival time. The amount of ‘increased’ survival is equal to
y – x
years,
in this example just over 2 years. This artefactual in
/f_l
ation of survival
time is referred to as lead time bias.
Tumour b
is a rapidly growing
tumour; again its progress is unin
/f_l
uenced by treatment. It grows so
rapidly that, in the interval between two screening tests, it can cross
both the threshold for detectability by screening and that of clinical
detectability (at point C). It will continue to progress rapidly after diag
-
nosis and the measured survival time will be short. This phenomenon,
whereby those tumours that are ‘missed’ by the screening programme
are associated with decreased survival, is called length time bias.

Accurate diagnosis is the key to successful management of cancer. Precise diagnosis is crucial to the choice of  correct therapy; the wrong operation, no matter how well performed, is useless. An unequivocal diagnosis is also the key to an accurate prognosis. Only rarely can a diagnosis of  cancer be conﬁdently made in the absence of  tissue for pathological or cytological examination. Cancer is a disease of cells and, for accurate diagnosis, the abnormal cells need to be obtained and visualised by a histopathologist. Di ﬀ erent tumours are classiﬁed in di ﬀ erent ways: most squamous epithelial tumours are classed as well (G1), moderate (G2) or poorly (G3) di ﬀ er entiated. Adenocarcinomas are also often classiﬁed as G1, G2 or G3 but prostate cancer is an exception, with widespread use of  the Gleason system. The Gleason system grades prostate cancer according to the degree of  di ﬀ erentia tion of  the two most prevalent architectural patterns. The ﬁnal score is the sum of  the two grades and can vary from 6 (3 /uni00A0 + /uni00A0 3) to 10 (5 /uni00A0 + /uni00A0 5) with the higher scores indicating poorer prognosis. The ongoing development of  molecular classiﬁers in many cancer types is beginning to profoundly alter our approach to treatment of  these malignancies based on genetic mutations and other molecular fea tures identiﬁed in individual patients, i.e. in melanoma where patients with BRAF gene mutations can be successfully treated with the BRAF inhibitors. Molecu lar characterisation of  malignancies and identiﬁcation of  their vulnerabilities have already become standard of  care in many Donald F Gleason , 1920–2008, pathologist, The University of  Minnesota, Minneapolis, MN, USA. likely to expand. 

TABLE 12.3
Staging of colorectal cancer.
TNM
TX, Primary tumour cannot be assessed
T0, No evidence of primary tumour
Tis, Carcinoma
in situ
or intramucosal carcinoma
T1, Tumour invades submucosa
T2, Tumour invades muscularis propria
T3, The tumour has grown through the muscularis propria and into the subserosa, which is a thin layer of connective tissue beneath the
outer layer of some parts of the large intestine, or it has grown into tissues surrounding the colon or rectum
T4, Tumour directly invades beyond bowel
NX, Regional lymph nodes cannot be assessed
N0, No metastases in regional nodes
N1a, Metastases in 1 regional lymph node
N1b, Metastases in 2 or 3 r
egional lymph nodes
N1c, There are nodules made up of tumour cells found in the structures near the colon that do not appear to be lymph nodes
N2a, Metastases in 4–6 regional lymph nodes
N2a, Metastases in
≥
7 regional lymph nodes
MX, Not possible to assess the presence of distant metastases
M0,
No distant metastases
M1a, The cancer has spread to 1 other part of the body beyond the colon or rectum
M1b, The cancer has spread to more than 1 part of the body other than the colon or rectum
M1c, The cancer has spread to the peritoneal surface

# Symptom control and palliative care

Symptom control and palliative care

The distinction between palliative and curative treatment is not always clear-cut and will become increasingly blurred as professional and public attitudes towards the management of  cancer change. Twenty years ago cancer was perceived as a disease that was either cured or it was not; patients either lived or died. There was little appreciation that, for many patients, cancer might be a chronic disease. Nowadays, it is appreciated that many patients will have multiple di ﬀ erent treatment options during their cancer journey . Five-year survival is not necessarily tantamount to cure. With the development of  targeted therapies that regulate, rather than eradicate, cancer this state of a ﬀ airs is likely to continue. The aim of  treatment will be growth control rather than the extir pation of  every last cancer cell. Patients will live with their cancers, perhaps for years. They will die with cancer, but not necessarily of  cancer. Patients fear the symptoms, distress and disruption associ a ted with cancer almost as much as they fear the disease itself. Palliative treatment has as its goal the relief  of  symptoms. Sometimes this will involve treating the underlying problem, as with palliative radiotherapy for bone metastases; sometimes it will not. Sometimes it may be inappropriate to treat the can cer itself, but that does not imply that there is nothing more to be done – it simply means that there may be better ways to assuage the distress and discomfort caused by the tumour. Palliativ e medicine in the twenty-ﬁrst century is about far more than optimal control of pain: its scope is wide and its impact immense ( Table 12.7 ). The most important factor in the suc cessful palliative management of  a patient with cancer is early referral. Transition between curative and palliative modes of management should be seamless. Common problems that may be e ﬀ ectively palliated include: /uni25CF Cerebral metastases : stereotactic radiosurgery for small lesions is highly e ﬀ ective, although limited to patients who are likely to survive long enough to beneﬁt. /uni25CF E ﬀ usions : pleural and ascitic drains may control these chronic problems. In the case of  pleural e ﬀ usion pleurode sis may prevent reaccumulation. /uni25CF Thrombosis : increased coagulability and pressure on blood vessels make this a common problem in oncology . /uni25CF Hypercalcaemia : bisphosphonates may control the pa tient’s calcium level and regular infusions will be necessary when the underlying tumour process is not controlled by other means. - - - /uni25CF Fatigue : this is often a di ﬃ cult symptom, which is partly due to the tumour and partly due to its treatment. Encour - aging aerobic exercise, even at a low level, can improve fatigue and also stimulate appetite. - /uni25CF Weight loss : patients often lose their appetite and consequently lose weight. Eating little and often with food supplements as necessary may be e ﬀ ective in mitigating weight loss. /uni25CF Fever : recurrent fevers are a feature of  certain tumours such as lymphoma and renal cell cancer. Tumour fever must be distinguished from infection and this can often only be done by exclusion. /uni25CF Paraneoplastic syndromes : these are varied and often di ﬃ cult to recognise. Management of  the underlying malignancy may not necessarily resolve the syndrome. - 

included within palliative and supportive care.
Holistic needs
Pain, anorexia, fatigue, dyspnoea, etc.
assessment
Treatment-related toxicity
Symptom relief
Drugs
Surgery
Radiotherapy
Complementary
Acupuncture
therapies:
Homeopathy
Aromatherapy, etc.
Psychosocial
Psychological support
interventions
Relaxation techniques
Cognitive behavioural therapy
Counselling
Group therapy
Music therapy
Emotional support
Physical and practical
Physiotherapy
support
Occupational therapy
Speech therapy
Information and
Macmillan
knowledge
Maggie’s centres
Nutritional support
Dietary advice
Nutritional supplements
Social support
Patients
Relatives and carers
Financial support
Ensure uptake of entitlements
Grants from charities, e.g. Macmillan
Spiritual support

Symptom control and palliative care

The distinction between palliative and curative treatment is not always clear-cut and will become increasingly blurred as professional and public attitudes towards the management of  cancer change. Twenty years ago cancer was perceived as a disease that was either cured or it was not; patients either lived or died. There was little appreciation that, for many patients, cancer might be a chronic disease. Nowadays, it is appreciated that many patients will have multiple di ﬀ erent treatment options during their cancer journey . Five-year survival is not necessarily tantamount to cure. With the development of  targeted therapies that regulate, rather than eradicate, cancer this state of a ﬀ airs is likely to continue. The aim of  treatment will be growth control rather than the extir pation of  every last cancer cell. Patients will live with their cancers, perhaps for years. They will die with cancer, but not necessarily of  cancer. Patients fear the symptoms, distress and disruption associ a ted with cancer almost as much as they fear the disease itself. Palliative treatment has as its goal the relief  of  symptoms. Sometimes this will involve treating the underlying problem, as with palliative radiotherapy for bone metastases; sometimes it will not. Sometimes it may be inappropriate to treat the can cer itself, but that does not imply that there is nothing more to be done – it simply means that there may be better ways to assuage the distress and discomfort caused by the tumour. Palliativ e medicine in the twenty-ﬁrst century is about far more than optimal control of pain: its scope is wide and its impact immense ( Table 12.7 ). The most important factor in the suc cessful palliative management of  a patient with cancer is early referral. Transition between curative and palliative modes of management should be seamless. Common problems that may be e ﬀ ectively palliated include: /uni25CF Cerebral metastases : stereotactic radiosurgery for small lesions is highly e ﬀ ective, although limited to patients who are likely to survive long enough to beneﬁt. /uni25CF E ﬀ usions : pleural and ascitic drains may control these chronic problems. In the case of  pleural e ﬀ usion pleurode sis may prevent reaccumulation. /uni25CF Thrombosis : increased coagulability and pressure on blood vessels make this a common problem in oncology . /uni25CF Hypercalcaemia : bisphosphonates may control the pa tient’s calcium level and regular infusions will be necessary when the underlying tumour process is not controlled by other means. - - - /uni25CF Fatigue : this is often a di ﬃ cult symptom, which is partly due to the tumour and partly due to its treatment. Encour - aging aerobic exercise, even at a low level, can improve fatigue and also stimulate appetite. - /uni25CF Weight loss : patients often lose their appetite and consequently lose weight. Eating little and often with food supplements as necessary may be e ﬀ ective in mitigating weight loss. /uni25CF Fever : recurrent fevers are a feature of  certain tumours such as lymphoma and renal cell cancer. Tumour fever must be distinguished from infection and this can often only be done by exclusion. /uni25CF Paraneoplastic syndromes : these are varied and often di ﬃ cult to recognise. Management of  the underlying malignancy may not necessarily resolve the syndrome. - 

included within palliative and supportive care.
Holistic needs
Pain, anorexia, fatigue, dyspnoea, etc.
assessment
Treatment-related toxicity
Symptom relief
Drugs
Surgery
Radiotherapy
Complementary
Acupuncture
therapies:
Homeopathy
Aromatherapy, etc.
Psychosocial
Psychological support
interventions
Relaxation techniques
Cognitive behavioural therapy
Counselling
Group therapy
Music therapy
Emotional support
Physical and practical
Physiotherapy
support
Occupational therapy
Speech therapy
Information and
Macmillan
knowledge
Maggie’s centres
Nutritional support
Dietary advice
Nutritional supplements
Social support
Patients
Relatives and carers
Financial support
Ensure uptake of entitlements
Grants from charities, e.g. Macmillan
Spiritual support

Symptom control and palliative care

The distinction between palliative and curative treatment is not always clear-cut and will become increasingly blurred as professional and public attitudes towards the management of  cancer change. Twenty years ago cancer was perceived as a disease that was either cured or it was not; patients either lived or died. There was little appreciation that, for many patients, cancer might be a chronic disease. Nowadays, it is appreciated that many patients will have multiple di ﬀ erent treatment options during their cancer journey . Five-year survival is not necessarily tantamount to cure. With the development of  targeted therapies that regulate, rather than eradicate, cancer this state of a ﬀ airs is likely to continue. The aim of  treatment will be growth control rather than the extir pation of  every last cancer cell. Patients will live with their cancers, perhaps for years. They will die with cancer, but not necessarily of  cancer. Patients fear the symptoms, distress and disruption associ a ted with cancer almost as much as they fear the disease itself. Palliative treatment has as its goal the relief  of  symptoms. Sometimes this will involve treating the underlying problem, as with palliative radiotherapy for bone metastases; sometimes it will not. Sometimes it may be inappropriate to treat the can cer itself, but that does not imply that there is nothing more to be done – it simply means that there may be better ways to assuage the distress and discomfort caused by the tumour. Palliativ e medicine in the twenty-ﬁrst century is about far more than optimal control of pain: its scope is wide and its impact immense ( Table 12.7 ). The most important factor in the suc cessful palliative management of  a patient with cancer is early referral. Transition between curative and palliative modes of management should be seamless. Common problems that may be e ﬀ ectively palliated include: /uni25CF Cerebral metastases : stereotactic radiosurgery for small lesions is highly e ﬀ ective, although limited to patients who are likely to survive long enough to beneﬁt. /uni25CF E ﬀ usions : pleural and ascitic drains may control these chronic problems. In the case of  pleural e ﬀ usion pleurode sis may prevent reaccumulation. /uni25CF Thrombosis : increased coagulability and pressure on blood vessels make this a common problem in oncology . /uni25CF Hypercalcaemia : bisphosphonates may control the pa tient’s calcium level and regular infusions will be necessary when the underlying tumour process is not controlled by other means. - - - /uni25CF Fatigue : this is often a di ﬃ cult symptom, which is partly due to the tumour and partly due to its treatment. Encour - aging aerobic exercise, even at a low level, can improve fatigue and also stimulate appetite. - /uni25CF Weight loss : patients often lose their appetite and consequently lose weight. Eating little and often with food supplements as necessary may be e ﬀ ective in mitigating weight loss. /uni25CF Fever : recurrent fevers are a feature of  certain tumours such as lymphoma and renal cell cancer. Tumour fever must be distinguished from infection and this can often only be done by exclusion. /uni25CF Paraneoplastic syndromes : these are varied and often di ﬃ cult to recognise. Management of  the underlying malignancy may not necessarily resolve the syndrome. - 

included within palliative and supportive care.
Holistic needs
Pain, anorexia, fatigue, dyspnoea, etc.
assessment
Treatment-related toxicity
Symptom relief
Drugs
Surgery
Radiotherapy
Complementary
Acupuncture
therapies:
Homeopathy
Aromatherapy, etc.
Psychosocial
Psychological support
interventions
Relaxation techniques
Cognitive behavioural therapy
Counselling
Group therapy
Music therapy
Emotional support
Physical and practical
Physiotherapy
support
Occupational therapy
Speech therapy
Information and
Macmillan
knowledge
Maggie’s centres
Nutritional support
Dietary advice
Nutritional supplements
Social support
Patients
Relatives and carers
Financial support
Ensure uptake of entitlements
Grants from charities, e.g. Macmillan
Spiritual support

# THE CAUSES OF CANCER The interplay between nature

THE CAUSES OF CANCER The interplay between nature and nurture

Both inheritance and environment are important determi nants of  cancer development. Neither inﬂuence is completely dominant. The balance between genes and the environment is context speciﬁc and not consistent. Two contrasting examples are br east and lung cancer. Although not all smokers develop lung cancer and lung cancer can occur in people who have Otto Warburg , 1883–1970, chemist, Director of  the Kaiser Wilhelm Institute for Cell Physiology , Berlin-Dahlem, Germany . Awarded the Nobel Prize in Physiol ogy or Medicine in 1931 for ‘his discovery of  the nature and mode of  action of  the respiratory enzyme’. Benjamin Gompertz , 1779–1865, an insurance actuary who described mathematically the relationship between life expectancy and age. The Gompertzian function provides an excellent ﬁt to data points plotting tumour siz e against time. - never smoked, non-small cell lung cancer is much more common in smokers and is such a powerful risk factor that it accounts for approximately 80% of  the disease. Conversely , germline BRCA gene mutations are highly penetrant and 13 , it women with a BRCA1 mutation can have a 60–90% lifetime risk of  being diagnosed with breast cancer and 40–60% will develop ovarian cancer. Knowledge about the causes of  cancer can be used to design appropriate strategies for prevention or earlier diagnosis. As we ﬁnd out more about the genes associated with cancer, genetic testing and counselling play increasingly important roles in the prevention of  cancer. These considerations are incorporated into Table 12.1 , on the inherited cancer syndromes, and into Table 12.2 , on the environmental contribution to cancer. 

12
10
10
10
Limit of clinical detection
8
10
Cells
6
10
4
10
2
10
1
0 100 200
300 400 500
600
Time
Figure 12.2
The Gompertzian curve describing the growth of a typical
tumour. In its early stages, growth is exponential but, as the tumour
grows, the growth rate slows. This decrease in growth rate probably
arises because of dif
/f_i
culties with nutrition and oxygenation. The
tumour cells are in competition: not only with the tissues of the host,
but also with each other.

# THE CAUSES OF CANCER The interplay between nature and nurture

THE CAUSES OF CANCER The interplay between nature and nurture

Both inheritance and environment are important determi nants of  cancer development. Neither inﬂuence is completely dominant. The balance between genes and the environment is context speciﬁc and not consistent. Two contrasting examples are br east and lung cancer. Although not all smokers develop lung cancer and lung cancer can occur in people who have Otto Warburg , 1883–1970, chemist, Director of  the Kaiser Wilhelm Institute for Cell Physiology , Berlin-Dahlem, Germany . Awarded the Nobel Prize in Physiol ogy or Medicine in 1931 for ‘his discovery of  the nature and mode of  action of  the respiratory enzyme’. Benjamin Gompertz , 1779–1865, an insurance actuary who described mathematically the relationship between life expectancy and age. The Gompertzian function provides an excellent ﬁt to data points plotting tumour siz e against time. - never smoked, non-small cell lung cancer is much more common in smokers and is such a powerful risk factor that it accounts for approximately 80% of  the disease. Conversely , germline BRCA gene mutations are highly penetrant and 13 , it women with a BRCA1 mutation can have a 60–90% lifetime risk of  being diagnosed with breast cancer and 40–60% will develop ovarian cancer. Knowledge about the causes of  cancer can be used to design appropriate strategies for prevention or earlier diagnosis. As we ﬁnd out more about the genes associated with cancer, genetic testing and counselling play increasingly important roles in the prevention of  cancer. These considerations are incorporated into Table 12.1 , on the inherited cancer syndromes, and into Table 12.2 , on the environmental contribution to cancer. 

12
10
10
10
Limit of clinical detection
8
10
Cells
6
10
4
10
2
10
1
0 100 200
300 400 500
600
Time
Figure 12.2
The Gompertzian curve describing the growth of a typical
tumour. In its early stages, growth is exponential but, as the tumour
grows, the growth rate slows. This decrease in growth rate probably
arises because of dif
/f_i
culties with nutrition and oxygenation. The
tumour cells are in competition: not only with the tissues of the host,
but also with each other.

# THE CAUSES OF CANCER The interplay between nature

THE CAUSES OF CANCER The interplay between nature and nurture

Both inheritance and environment are important determi nants of  cancer development. Neither inﬂuence is completely dominant. The balance between genes and the environment is context speciﬁc and not consistent. Two contrasting examples are br east and lung cancer. Although not all smokers develop lung cancer and lung cancer can occur in people who have Otto Warburg , 1883–1970, chemist, Director of  the Kaiser Wilhelm Institute for Cell Physiology , Berlin-Dahlem, Germany . Awarded the Nobel Prize in Physiol ogy or Medicine in 1931 for ‘his discovery of  the nature and mode of  action of  the respiratory enzyme’. Benjamin Gompertz , 1779–1865, an insurance actuary who described mathematically the relationship between life expectancy and age. The Gompertzian function provides an excellent ﬁt to data points plotting tumour siz e against time. - never smoked, non-small cell lung cancer is much more common in smokers and is such a powerful risk factor that it accounts for approximately 80% of  the disease. Conversely , germline BRCA gene mutations are highly penetrant and 13 , it women with a BRCA1 mutation can have a 60–90% lifetime risk of  being diagnosed with breast cancer and 40–60% will develop ovarian cancer. Knowledge about the causes of  cancer can be used to design appropriate strategies for prevention or earlier diagnosis. As we ﬁnd out more about the genes associated with cancer, genetic testing and counselling play increasingly important roles in the prevention of  cancer. These considerations are incorporated into Table 12.1 , on the inherited cancer syndromes, and into Table 12.2 , on the environmental contribution to cancer. 

12
10
10
10
Limit of clinical detection
8
10
Cells
6
10
4
10
2
10
1
0 100 200
300 400 500
600
Time
Figure 12.2
The Gompertzian curve describing the growth of a typical
tumour. In its early stages, growth is exponential but, as the tumour
grows, the growth rate slows. This decrease in growth rate probably
arises because of dif
/f_i
culties with nutrition and oxygenation. The
tumour cells are in competition: not only with the tissues of the host,
but also with each other.

# THE MANAGEMENT OF CANCER Management is more than t

THE MANAGEMENT OF CANCER Management is more than treatment

The traditional approach to cancer concentrates on diagnosis and active treatment. This is a very limited view that, in terms - of  public health, may not have served society well. It implies a fatalistic attitude to the occurrence of  cancer and an assump - tion that, once active treatment is complete, there is little more to be done. Prevention was forgotten and rehabilitation was ignored. - Abraham Vater , 1684–1751, Professor of Anatomy and Botany , and la Jacques Turcot , 1914–1977, surgeon, Hôtel-Dieu de Quebec hospital, Quebec, Canada. Henry Thompson Lynch , 1928–2019, Chair of  Preventative Medicine, Creighton Univer John Law Augustine Peutz , 1886–1968, Chief  Specialist for Internal Medicine, St John’s Hospital, The Hague, The Netherlands. Harold Joseph Jeghers , 1904–1990, Professor of  Internal Medicine, The New Jersey College of  Medicine and Dentistry , Jersey City , NJ, USA. Frederick Pei Li , 1940–2015, Professor of  Medicine, Harvard University Medical School, Boston, MA, USA. Joseph F Fraumeni , b.1933, Director of  Cancer Epidemiology and Genetics, The National Cancer Institute, Bethesda, MD, USA. ter of  P atholog y and Therapeutics, Wittenberg, Germany . sity , Omaha, NE, USA. 

Syndrome
Gene(s)
Inheritance
implicated
Familial adenomatous
APC
gene
D
polyposis (FAP)
D
DNA mismatch
Hereditary non-polyposis
repair genes
colorectal cancer
(
MLH1; MSH2;
(HNPCC1), Lynch
MSH6
)
syndrome 1
D
HNPCC2
DNA mismatch
repair genes
(MLH1; MSH2;
MSH6)
Peutz–Jeghers syndrome
STK11
D
a
Cowden
syndrome
PTEN
D
Retinoblastoma
RB
D
Multiple endocrine
Menin
D
neoplasia (MEN) type 1
MEN type 2A
RET
D
MEN type 2B
RET
D
Li–Fraumeni
P53
D
Familial breast cancer
BRCA1; BRCA2
D
Familial cutaneous
CDNK2A; CDK4
D
malignant melanoma
Associated tumours and abnormalities
Strategies for prevention/
early diagnosis
Pr
ophylactic
Colorectal cancer under the age of 25
panproctocolectomy
Papillary carcinoma of the thyroid
Cancer of the ampulla of Vater
Hepatoblastomas
Primary brain tumours (Turcot syndrome)
Osteomas of the jaw
CHRPE (congenital hypertrophy of the retinal
pigment epithelium)
Color
ectal cancer (typically in forties and
Surveillance colonoscopies/
/f_i
fties)
polypectomies
Non-ster
oidal anti
-
in
/f_l
ammatory drugs
HNPCC associated with other cancers of the
gastrointestinal or reproductive system
Bowel cancer; br
east cancer; freckles round
Surveillance colonoscopy;
the mouth
mammography
Active surveillance
Multiple hamartomas of skin, breast and
mucous membranes
Breast cancer
Neuroendocrine tumours
Endometrial cancer
Thyroid cancer
Surveillance of uninvolved
Retinoblastoma
eye
Pinealoma
Osteosarcoma
Awareness of associations
Parathyroid tumours
and paying attention to
Islet cell tumours
relevant symptoms
Pituitary tumours
Regular screening of blood
Medullary carcinoma of the thyroid
pressure, serum calcitonin
Phaeochromocytoma
and urinary catecholamines
Parathyroid tumours
Prophylactic thyroidectomy
Regular screening of blood
Medullary car
cinoma of the thyroid
pressure, serum calcitonin
Phaeochr
omocytoma
and urinary catecholamines
Mucosal neuromas
Prophylactic thyroidectomy
Ganglioneuromas of the gut
V
ery dif
/f_i
cult, since pattern of
Sarcomas
tumours is so heterogeneous
Leukaemia
and varies between patients
Osteosar
comas
Brain tumours
Adrenocortical carcinomas
Scr
eening mammography;
Breast cancer
pelvic ultrasound
Ovarian cancer
PSA (in males)
Papillary serous carcinoma of the peritoneum
Pr
ophylactic mastectomy;
Prostate cancer
prophylactic oophorectomy
Cutaneous malignant melanoma
Avoid exposure to sunlight,
careful surveillance
Continued

Robert Gorlin , 1923–2006, Professor of Dentistry , The University of Eugen von Hippel , 1867–1939, Professor of  Ophthalmology , Göttingen, Germany . Arvid Lindau , 1892–1958, Professor of  Pathology , Lund, Sweden. David Bloom , 1892–1985, dermatologist at the Skin and Cancer Clinic, New Y ork University , New Y ork, NY , USA, described the syndrome in 1954. Minnesota, Minneapolis, MN , USA. 

Syndrome
Gene(s)
Inheritance
implicated
Basal cell naevus
PTCH
D
syndrome (Gorlin)
von Hippel–Lindau
VHL
D
disease
Neuro
/f_i
bromatosis type 1
NF1
D
Neuro
/f_i
bromatosis type 2
NF2
D
R
Xeroderma pigmentosum
De
/f_i
cient
nucleotide
excision repair
(
XPA,B,C
)
Ataxia–telangiectasia
AT
R
Bloom syndrome
BLM helicase
R
D, dominant; PSA, prostate-speci
/f_i
c antigen; R, recessive.
a
One of the few clinical syndromes named for the patient rather than the clinician. Rachel Cowden was, in 1963, the
/f_i
rst patient described
with the syndrome. She died from breast cancer at the age of 20.
TABLE 12.2
Environmental causes of cancer (and suggested measures for reducing their impact).
Environmental/behavioural factor
Tobacco
Alcohol
Ultraviolet exposure
Ionising radiation
Viral infections
Human papillomavirus
Associated tumours and abnormalities
Strategies for prevention/
early diagnosis
Careful surveillance,
Basal cell carcinomas
awareness of diagnosis (look
Medulloblastoma
for bi
/f_i
d ribs on x-ray)
Bi
/f_i
d ribs
Urinary catecholamines
Clear cell renal cell carcinoma
Phaeochromocytoma
Haemangiomas of the cerebellum and retina
A dif
/f_i
cult problem; maintain
Astrocytomas
a high index of suspicion
Primitive neuroectodermal tumours
concerning any rapid
Optic gliomas
changes in growth or
Multiple neuro
/f_i
bromas
character of any nodule
Acoustic neuromas
Spinal tumours
Meningiomas
Multiple neuro
/f_i
bromas
Skin sensitive to sunlight. Early onset of
Avoidance of sun exposure
cutaneous squamous or basal cell carcinomas
Active surveillance and early
treatment
Retinoids for
chemoprevention
Active surveillance
Progressive cerebellar ataxia
Leukaemia
Lymphoma
Breast cancer
Melanoma
Upper gastrointestinal tumours
Active surveillance
Sensitivity to ultraviolet light
Leukaemia
Lymphoma
Associated tumours
Strategy for prevention/early
diagnosis
Ban tobacco
Lung cancer
Ban smoking in public places
Head and neck cancer
Punitive taxes on tobacco
Bladder cancer
Avoid excess alcohol
Head and neck cancer
Surveillance of high-risk individuals
Oesophageal cancer
Hepatocellular carcinoma
Melanoma
Avoid excessive sun exposure,
Non-melanoma skin cancer
use high-factor sunscreen, avoid
sunbeds
Limit medical exposures to absolute
Leukaemia
minimum; safety precautions at
Breast cancer
nuclear facilities; monitor radiation
Lymphoma
workers
Thyroid cancer
Avoid unprotected sex
Cervical cancer
Vaccination
Penile cancer
Head and neck cancer
Continued

A more comprehensive view considers the management of  cancer as taking place along two axes: one is an axis of scale, from the individual to the world population; the other is an axis based on the development of  the disease, from prevention through to rehabilitation or palliative care ( Figure 12.3 ). 

Environmental/behavioural factor
Viral infections – Human immunode
/f_i
ciency virus
continued
Hepatitis B
Other infections Schistosomiasis
Helicobacter pylori
Inhaled particles
Asbestos
Wood dust
Chemicals
Environmental pollutants/chemicals used
in industry
Medical
Alkylating agents used in
cytotoxic chemotherapy
Immunosuppressive
treatment
Tamoxifen
Fungal and plant A
/f_l
atoxins
toxins
Obesity/lack of physical exercise

THE MANAGEMENT OF CANCER Management is more than treatment

The traditional approach to cancer concentrates on diagnosis and active treatment. This is a very limited view that, in terms - of  public health, may not have served society well. It implies a fatalistic attitude to the occurrence of  cancer and an assump - tion that, once active treatment is complete, there is little more to be done. Prevention was forgotten and rehabilitation was ignored. - Abraham Vater , 1684–1751, Professor of Anatomy and Botany , and la Jacques Turcot , 1914–1977, surgeon, Hôtel-Dieu de Quebec hospital, Quebec, Canada. Henry Thompson Lynch , 1928–2019, Chair of  Preventative Medicine, Creighton Univer John Law Augustine Peutz , 1886–1968, Chief  Specialist for Internal Medicine, St John’s Hospital, The Hague, The Netherlands. Harold Joseph Jeghers , 1904–1990, Professor of  Internal Medicine, The New Jersey College of  Medicine and Dentistry , Jersey City , NJ, USA. Frederick Pei Li , 1940–2015, Professor of  Medicine, Harvard University Medical School, Boston, MA, USA. Joseph F Fraumeni , b.1933, Director of  Cancer Epidemiology and Genetics, The National Cancer Institute, Bethesda, MD, USA. ter of  P atholog y and Therapeutics, Wittenberg, Germany . sity , Omaha, NE, USA. 

Syndrome
Gene(s)
Inheritance
implicated
Familial adenomatous
APC
gene
D
polyposis (FAP)
D
DNA mismatch
Hereditary non-polyposis
repair genes
colorectal cancer
(
MLH1; MSH2;
(HNPCC1), Lynch
MSH6
)
syndrome 1
D
HNPCC2
DNA mismatch
repair genes
(MLH1; MSH2;
MSH6)
Peutz–Jeghers syndrome
STK11
D
a
Cowden
syndrome
PTEN
D
Retinoblastoma
RB
D
Multiple endocrine
Menin
D
neoplasia (MEN) type 1
MEN type 2A
RET
D
MEN type 2B
RET
D
Li–Fraumeni
P53
D
Familial breast cancer
BRCA1; BRCA2
D
Familial cutaneous
CDNK2A; CDK4
D
malignant melanoma
Associated tumours and abnormalities
Strategies for prevention/
early diagnosis
Pr
ophylactic
Colorectal cancer under the age of 25
panproctocolectomy
Papillary carcinoma of the thyroid
Cancer of the ampulla of Vater
Hepatoblastomas
Primary brain tumours (Turcot syndrome)
Osteomas of the jaw
CHRPE (congenital hypertrophy of the retinal
pigment epithelium)
Color
ectal cancer (typically in forties and
Surveillance colonoscopies/
/f_i
fties)
polypectomies
Non-ster
oidal anti
-
in
/f_l
ammatory drugs
HNPCC associated with other cancers of the
gastrointestinal or reproductive system
Bowel cancer; br
east cancer; freckles round
Surveillance colonoscopy;
the mouth
mammography
Active surveillance
Multiple hamartomas of skin, breast and
mucous membranes
Breast cancer
Neuroendocrine tumours
Endometrial cancer
Thyroid cancer
Surveillance of uninvolved
Retinoblastoma
eye
Pinealoma
Osteosarcoma
Awareness of associations
Parathyroid tumours
and paying attention to
Islet cell tumours
relevant symptoms
Pituitary tumours
Regular screening of blood
Medullary carcinoma of the thyroid
pressure, serum calcitonin
Phaeochromocytoma
and urinary catecholamines
Parathyroid tumours
Prophylactic thyroidectomy
Regular screening of blood
Medullary car
cinoma of the thyroid
pressure, serum calcitonin
Phaeochr
omocytoma
and urinary catecholamines
Mucosal neuromas
Prophylactic thyroidectomy
Ganglioneuromas of the gut
V
ery dif
/f_i
cult, since pattern of
Sarcomas
tumours is so heterogeneous
Leukaemia
and varies between patients
Osteosar
comas
Brain tumours
Adrenocortical carcinomas
Scr
eening mammography;
Breast cancer
pelvic ultrasound
Ovarian cancer
PSA (in males)
Papillary serous carcinoma of the peritoneum
Pr
ophylactic mastectomy;
Prostate cancer
prophylactic oophorectomy
Cutaneous malignant melanoma
Avoid exposure to sunlight,
careful surveillance
Continued

Robert Gorlin , 1923–2006, Professor of Dentistry , The University of Eugen von Hippel , 1867–1939, Professor of  Ophthalmology , Göttingen, Germany . Arvid Lindau , 1892–1958, Professor of  Pathology , Lund, Sweden. David Bloom , 1892–1985, dermatologist at the Skin and Cancer Clinic, New Y ork University , New Y ork, NY , USA, described the syndrome in 1954. Minnesota, Minneapolis, MN , USA. 

Syndrome
Gene(s)
Inheritance
implicated
Basal cell naevus
PTCH
D
syndrome (Gorlin)
von Hippel–Lindau
VHL
D
disease
Neuro
/f_i
bromatosis type 1
NF1
D
Neuro
/f_i
bromatosis type 2
NF2
D
R
Xeroderma pigmentosum
De
/f_i
cient
nucleotide
excision repair
(
XPA,B,C
)
Ataxia–telangiectasia
AT
R
Bloom syndrome
BLM helicase
R
D, dominant; PSA, prostate-speci
/f_i
c antigen; R, recessive.
a
One of the few clinical syndromes named for the patient rather than the clinician. Rachel Cowden was, in 1963, the
/f_i
rst patient described
with the syndrome. She died from breast cancer at the age of 20.
TABLE 12.2
Environmental causes of cancer (and suggested measures for reducing their impact).
Environmental/behavioural factor
Tobacco
Alcohol
Ultraviolet exposure
Ionising radiation
Viral infections
Human papillomavirus
Associated tumours and abnormalities
Strategies for prevention/
early diagnosis
Careful surveillance,
Basal cell carcinomas
awareness of diagnosis (look
Medulloblastoma
for bi
/f_i
d ribs on x-ray)
Bi
/f_i
d ribs
Urinary catecholamines
Clear cell renal cell carcinoma
Phaeochromocytoma
Haemangiomas of the cerebellum and retina
A dif
/f_i
cult problem; maintain
Astrocytomas
a high index of suspicion
Primitive neuroectodermal tumours
concerning any rapid
Optic gliomas
changes in growth or
Multiple neuro
/f_i
bromas
character of any nodule
Acoustic neuromas
Spinal tumours
Meningiomas
Multiple neuro
/f_i
bromas
Skin sensitive to sunlight. Early onset of
Avoidance of sun exposure
cutaneous squamous or basal cell carcinomas
Active surveillance and early
treatment
Retinoids for
chemoprevention
Active surveillance
Progressive cerebellar ataxia
Leukaemia
Lymphoma
Breast cancer
Melanoma
Upper gastrointestinal tumours
Active surveillance
Sensitivity to ultraviolet light
Leukaemia
Lymphoma
Associated tumours
Strategy for prevention/early
diagnosis
Ban tobacco
Lung cancer
Ban smoking in public places
Head and neck cancer
Punitive taxes on tobacco
Bladder cancer
Avoid excess alcohol
Head and neck cancer
Surveillance of high-risk individuals
Oesophageal cancer
Hepatocellular carcinoma
Melanoma
Avoid excessive sun exposure,
Non-melanoma skin cancer
use high-factor sunscreen, avoid
sunbeds
Limit medical exposures to absolute
Leukaemia
minimum; safety precautions at
Breast cancer
nuclear facilities; monitor radiation
Lymphoma
workers
Thyroid cancer
Avoid unprotected sex
Cervical cancer
Vaccination
Penile cancer
Head and neck cancer
Continued

A more comprehensive view considers the management of  cancer as taking place along two axes: one is an axis of scale, from the individual to the world population; the other is an axis based on the development of  the disease, from prevention through to rehabilitation or palliative care ( Figure 12.3 ). 

Environmental/behavioural factor
Viral infections – Human immunode
/f_i
ciency virus
continued
Hepatitis B
Other infections Schistosomiasis
Helicobacter pylori
Inhaled particles
Asbestos
Wood dust
Chemicals
Environmental pollutants/chemicals used
in industry
Medical
Alkylating agents used in
cytotoxic chemotherapy
Immunosuppressive
treatment
Tamoxifen
Fungal and plant A
/f_l
atoxins
toxins
Obesity/lack of physical exercise

# THE MANAGEMENT OF CANCER Management is more than treatment

THE MANAGEMENT OF CANCER Management is more than treatment

The traditional approach to cancer concentrates on diagnosis and active treatment. This is a very limited view that, in terms - of  public health, may not have served society well. It implies a fatalistic attitude to the occurrence of  cancer and an assump - tion that, once active treatment is complete, there is little more to be done. Prevention was forgotten and rehabilitation was ignored. - Abraham Vater , 1684–1751, Professor of Anatomy and Botany , and la Jacques Turcot , 1914–1977, surgeon, Hôtel-Dieu de Quebec hospital, Quebec, Canada. Henry Thompson Lynch , 1928–2019, Chair of  Preventative Medicine, Creighton Univer John Law Augustine Peutz , 1886–1968, Chief  Specialist for Internal Medicine, St John’s Hospital, The Hague, The Netherlands. Harold Joseph Jeghers , 1904–1990, Professor of  Internal Medicine, The New Jersey College of  Medicine and Dentistry , Jersey City , NJ, USA. Frederick Pei Li , 1940–2015, Professor of  Medicine, Harvard University Medical School, Boston, MA, USA. Joseph F Fraumeni , b.1933, Director of  Cancer Epidemiology and Genetics, The National Cancer Institute, Bethesda, MD, USA. ter of  P atholog y and Therapeutics, Wittenberg, Germany . sity , Omaha, NE, USA. 

Syndrome
Gene(s)
Inheritance
implicated
Familial adenomatous
APC
gene
D
polyposis (FAP)
D
DNA mismatch
Hereditary non-polyposis
repair genes
colorectal cancer
(
MLH1; MSH2;
(HNPCC1), Lynch
MSH6
)
syndrome 1
D
HNPCC2
DNA mismatch
repair genes
(MLH1; MSH2;
MSH6)
Peutz–Jeghers syndrome
STK11
D
a
Cowden
syndrome
PTEN
D
Retinoblastoma
RB
D
Multiple endocrine
Menin
D
neoplasia (MEN) type 1
MEN type 2A
RET
D
MEN type 2B
RET
D
Li–Fraumeni
P53
D
Familial breast cancer
BRCA1; BRCA2
D
Familial cutaneous
CDNK2A; CDK4
D
malignant melanoma
Associated tumours and abnormalities
Strategies for prevention/
early diagnosis
Pr
ophylactic
Colorectal cancer under the age of 25
panproctocolectomy
Papillary carcinoma of the thyroid
Cancer of the ampulla of Vater
Hepatoblastomas
Primary brain tumours (Turcot syndrome)
Osteomas of the jaw
CHRPE (congenital hypertrophy of the retinal
pigment epithelium)
Color
ectal cancer (typically in forties and
Surveillance colonoscopies/
/f_i
fties)
polypectomies
Non-ster
oidal anti
-
in
/f_l
ammatory drugs
HNPCC associated with other cancers of the
gastrointestinal or reproductive system
Bowel cancer; br
east cancer; freckles round
Surveillance colonoscopy;
the mouth
mammography
Active surveillance
Multiple hamartomas of skin, breast and
mucous membranes
Breast cancer
Neuroendocrine tumours
Endometrial cancer
Thyroid cancer
Surveillance of uninvolved
Retinoblastoma
eye
Pinealoma
Osteosarcoma
Awareness of associations
Parathyroid tumours
and paying attention to
Islet cell tumours
relevant symptoms
Pituitary tumours
Regular screening of blood
Medullary carcinoma of the thyroid
pressure, serum calcitonin
Phaeochromocytoma
and urinary catecholamines
Parathyroid tumours
Prophylactic thyroidectomy
Regular screening of blood
Medullary car
cinoma of the thyroid
pressure, serum calcitonin
Phaeochr
omocytoma
and urinary catecholamines
Mucosal neuromas
Prophylactic thyroidectomy
Ganglioneuromas of the gut
V
ery dif
/f_i
cult, since pattern of
Sarcomas
tumours is so heterogeneous
Leukaemia
and varies between patients
Osteosar
comas
Brain tumours
Adrenocortical carcinomas
Scr
eening mammography;
Breast cancer
pelvic ultrasound
Ovarian cancer
PSA (in males)
Papillary serous carcinoma of the peritoneum
Pr
ophylactic mastectomy;
Prostate cancer
prophylactic oophorectomy
Cutaneous malignant melanoma
Avoid exposure to sunlight,
careful surveillance
Continued

Robert Gorlin , 1923–2006, Professor of Dentistry , The University of Eugen von Hippel , 1867–1939, Professor of  Ophthalmology , Göttingen, Germany . Arvid Lindau , 1892–1958, Professor of  Pathology , Lund, Sweden. David Bloom , 1892–1985, dermatologist at the Skin and Cancer Clinic, New Y ork University , New Y ork, NY , USA, described the syndrome in 1954. Minnesota, Minneapolis, MN , USA. 

Syndrome
Gene(s)
Inheritance
implicated
Basal cell naevus
PTCH
D
syndrome (Gorlin)
von Hippel–Lindau
VHL
D
disease
Neuro
/f_i
bromatosis type 1
NF1
D
Neuro
/f_i
bromatosis type 2
NF2
D
R
Xeroderma pigmentosum
De
/f_i
cient
nucleotide
excision repair
(
XPA,B,C
)
Ataxia–telangiectasia
AT
R
Bloom syndrome
BLM helicase
R
D, dominant; PSA, prostate-speci
/f_i
c antigen; R, recessive.
a
One of the few clinical syndromes named for the patient rather than the clinician. Rachel Cowden was, in 1963, the
/f_i
rst patient described
with the syndrome. She died from breast cancer at the age of 20.
TABLE 12.2
Environmental causes of cancer (and suggested measures for reducing their impact).
Environmental/behavioural factor
Tobacco
Alcohol
Ultraviolet exposure
Ionising radiation
Viral infections
Human papillomavirus
Associated tumours and abnormalities
Strategies for prevention/
early diagnosis
Careful surveillance,
Basal cell carcinomas
awareness of diagnosis (look
Medulloblastoma
for bi
/f_i
d ribs on x-ray)
Bi
/f_i
d ribs
Urinary catecholamines
Clear cell renal cell carcinoma
Phaeochromocytoma
Haemangiomas of the cerebellum and retina
A dif
/f_i
cult problem; maintain
Astrocytomas
a high index of suspicion
Primitive neuroectodermal tumours
concerning any rapid
Optic gliomas
changes in growth or
Multiple neuro
/f_i
bromas
character of any nodule
Acoustic neuromas
Spinal tumours
Meningiomas
Multiple neuro
/f_i
bromas
Skin sensitive to sunlight. Early onset of
Avoidance of sun exposure
cutaneous squamous or basal cell carcinomas
Active surveillance and early
treatment
Retinoids for
chemoprevention
Active surveillance
Progressive cerebellar ataxia
Leukaemia
Lymphoma
Breast cancer
Melanoma
Upper gastrointestinal tumours
Active surveillance
Sensitivity to ultraviolet light
Leukaemia
Lymphoma
Associated tumours
Strategy for prevention/early
diagnosis
Ban tobacco
Lung cancer
Ban smoking in public places
Head and neck cancer
Punitive taxes on tobacco
Bladder cancer
Avoid excess alcohol
Head and neck cancer
Surveillance of high-risk individuals
Oesophageal cancer
Hepatocellular carcinoma
Melanoma
Avoid excessive sun exposure,
Non-melanoma skin cancer
use high-factor sunscreen, avoid
sunbeds
Limit medical exposures to absolute
Leukaemia
minimum; safety precautions at
Breast cancer
nuclear facilities; monitor radiation
Lymphoma
workers
Thyroid cancer
Avoid unprotected sex
Cervical cancer
Vaccination
Penile cancer
Head and neck cancer
Continued

A more comprehensive view considers the management of  cancer as taking place along two axes: one is an axis of scale, from the individual to the world population; the other is an axis based on the development of  the disease, from prevention through to rehabilitation or palliative care ( Figure 12.3 ). 

Environmental/behavioural factor
Viral infections – Human immunode
/f_i
ciency virus
continued
Hepatitis B
Other infections Schistosomiasis
Helicobacter pylori
Inhaled particles
Asbestos
Wood dust
Chemicals
Environmental pollutants/chemicals used
in industry
Medical
Alkylating agents used in
cytotoxic chemotherapy
Immunosuppressive
treatment
Tamoxifen
Fungal and plant A
/f_l
atoxins
toxins
Obesity/lack of physical exercise

# The growth of a cancer

The growth of a cancer

If  it is accepted that a cancer starts from a single transformed cell then it is possible, using straightforward arithmetic, to describe the progression from a single cell to a mass of  cells large enough to kill the host. The division of  a cell produces two daughter cells. The relationship 2 n will describe the number of  cells produced after n generations of  division. There 13 14 are between 10 and 10 cells in a typical human being. A 9 tumour 10 /uni00A0 mm in diameter will contain about 10 cells. Since 30 9 /uni00A0/uni00A0 2 = 10 this implies that it would take 30 generations to reach 45 /uni00A0 the threshold of  clinical detectability and, as 2 = /uni00A0 3 /uni00A0×/uni00A0 10 will take fewer than 15 subsequent generations to produce a tumour that, through sheer bulk alone, would be fatal. This is an oversimpliﬁcation because cell loss is a feature of  many cancers: for squamous cancers as many as 99% of  the cells produced may be lost, mainly by exfoliation. It will, in the presence of  cell loss, take many cellular divisions to produce a clinically evident tumour. The growth of  a typical human tumour can be described by an exponential relationship, the doubling time of  which increases exponentially – so-called Gompertzian growth ( Figure 12.2 ). The growth of a cancer

If  it is accepted that a cancer starts from a single transformed cell then it is possible, using straightforward arithmetic, to describe the progression from a single cell to a mass of  cells large enough to kill the host. The division of  a cell produces two daughter cells. The relationship 2 n will describe the number of  cells produced after n generations of  division. There 13 14 are between 10 and 10 cells in a typical human being. A 9 tumour 10 /uni00A0 mm in diameter will contain about 10 cells. Since 30 9 /uni00A0/uni00A0 2 = 10 this implies that it would take 30 generations to reach 45 /uni00A0 the threshold of  clinical detectability and, as 2 = /uni00A0 3 /uni00A0×/uni00A0 10 will take fewer than 15 subsequent generations to produce a tumour that, through sheer bulk alone, would be fatal. This is an oversimpliﬁcation because cell loss is a feature of  many cancers: for squamous cancers as many as 99% of  the cells produced may be lost, mainly by exfoliation. It will, in the presence of  cell loss, take many cellular divisions to produce a clinically evident tumour. The growth of  a typical human tumour can be described by an exponential relationship, the doubling time of  which increases exponentially – so-called Gompertzian growth ( Figure 12.2 ). The growth of a cancer

If  it is accepted that a cancer starts from a single transformed cell then it is possible, using straightforward arithmetic, to describe the progression from a single cell to a mass of  cells large enough to kill the host. The division of  a cell produces two daughter cells. The relationship 2 n will describe the number of  cells produced after n generations of  division. There 13 14 are between 10 and 10 cells in a typical human being. A 9 tumour 10 /uni00A0 mm in diameter will contain about 10 cells. Since 30 9 /uni00A0/uni00A0 2 = 10 this implies that it would take 30 generations to reach 45 /uni00A0 the threshold of  clinical detectability and, as 2 = /uni00A0 3 /uni00A0×/uni00A0 10 will take fewer than 15 subsequent generations to produce a tumour that, through sheer bulk alone, would be fatal. This is an oversimpliﬁcation because cell loss is a feature of  many cancers: for squamous cancers as many as 99% of  the cells produced may be lost, mainly by exfoliation. It will, in the presence of  cell loss, take many cellular divisions to produce a clinically evident tumour. The growth of  a typical human tumour can be described by an exponential relationship, the doubling time of  which increases exponentially – so-called Gompertzian growth ( Figure 12.2 ).

# The hallmarks of cancer

The hallmarks of cancer

Cancer cells are able to proliferate in an uncontrolled fashion; - their ability to divide and spread is unbounded. Cancer cell growth destroys ﬁrst the tissue from which they arise and - eventually the person in which they are present. In order to survive, divide, invade and spread, cancer cells have to acquire a number of  characteristics. No one charac - teristic is su ﬃ cient and not all characteristics ar e absolutely necessary . These features, based on articles by Hanahan and Weinberg, are given in Summary box 12.1 . Establish an autonomous lineage Cells develop independence from the normal signals that control supply and demand. The healing of  a wound is a physiological process; the cellular response is exquisitely coordinated so that - proliferation occurs when it is needed and ceases when it is no - longer required. The whole process is controlled by a series of - Maurice Hugh Frederick Wilkins , 1916–2004, of Summary box 12.1 Features of malignant transformation /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF signals telling cells when, and when not, to divide. Cancer cells escape from this normal system of  checks and balances: they grow and proliferate in the absence of  external stimuli and regardless of  signals telling them to desist. Oncogenes are genes with the potential to cause cancer if  mutated and expressed at high levels; they are key factors in carcinogenesis. Most oncogenes are normally inv olved in physiological processes, i.e. cell growth, but if  mutated they can predispose a cell to cancer and in concert with other onco genes can enable cancer cell survival and development of  an established tumour. The implication is that we all carry the seeds of  our own destruction: genetic sequences that, through mutation, can turn into active oncogenes and thereby cause malignant transformation. Indeed, through study of  the timing of  key genetic events in adult cancer development, a handful of  cells develop the founder mutations of  cancer development several decades prior to diagnosis. If  the individual is unfor tunate enough to accumulate further mutations in key driver genes, that cell becomes malignant and, if  it proliferates, a can cer may develop. Only very rarely is a single mutation su ﬃ cient to cause cancer; multiple mutations are usually required. Colo rectal cancer pro vides the classical example of  how multiple mutations are necessary for the complete transformation from normal cell to malignant cell. V ogelstein and his colleagues identiﬁed the genes implicated and also postula ted that it is necessary to have mutations in all the relevant genes; they also noted that these mutations must be acquired in a speciﬁc sequence for malignant transformation to occur. Obtain replicative immortality According to the Hayﬂick hypothesis, normal cells are permit ted to undergo only a ﬁnite number of  divisions. For humans this number is between 40 and 60. The limitation is imposed by the progressive shortening of the end of  the chr omosome (the telomere) that occurs each time a cell divides; eventually the lineage will die out. Cancer cells utilise the enzyme telomerase to rebuild the telomere at each cell division, such that there is Bert Vogelstein , b.1949, molecular biologist, Johns Hopkins Hospital, Baltimore, MD, USA. Leonard Hayﬂick , b.1928, while working at the Wistar Institute in Philadelphia in 1962, he noted that normal mammalian cells growing in culture had a limited, rather than an indeﬁnite, capacity for self-replication. cancer cell hence develops immortality . Evade apoptosis Apoptosis, taken from the Greek for ‘leaf  fall’, is a form of programmed cell death that occurs as the direct result of  inter - nal cellular events instructing the cell to die. Unlike necrosis, which is a form of  traumatic cell death resulting from acute cellular injury , apoptosis is an orderly and internally driven process. The cell dismantles itself neatly for disposal ( Figure 12.1 ) . There is minimal inﬂammatory response. Apoptosis is a physiological process. Cells that are redundant normally die by apoptosis and this is an important self-regulatory mechanism in growth and development, i.e . cells in the web space of  the embryo die by apoptosis, or lymphocytes that could react to self. Genes, such as p53, that can activate apoptosis function as tumour suppressor genes. Mutation in such genes causes a loss of  this inhibitory function, which will contribute to malignant transformation as apoptosis is evaded; this means that the wrong cells can be in the wrong places at the wrong times. - - - - Acquire angiogenic competence A mass of  cancer cells cannot, in the absence of  a blood supply , grow beyond a diameter of  about 1 /uni00A0 mm. This places a severe restriction on the capabilities of  the tumour (note - that the word tumour means swelling and does not mean the lesion is malignant, although ‘tumour’ is often taken by patients to be synonymous with cancer). It cannot grow much larger or spread widely within the body . If, however, the mass of  cancer cells is able to attract or to construct a blood supply then it is able to quit its dormant state and behave in a far 

Establish an autonomous lineage
Resist signals that inhibit growth
Sustain proliferative signalling
Obtain replicative immortality
Evade apoptosis
Acquire angiogenic competence
Acquire ability to invade, disseminate and implant
Evocation of in
/f_l
ammation
Evade detection/elimination
Loss of specialist cell function
Develop ability to change energy metabolism
AB
AB
MC
AB
MN
Figure 12.1
Electron micrograph of apoptotic bodies (AB) engulfed by
a macrophage. Note the macrophage nucleus (MN) and macrophage
cytoplasm (MC).

vessels is termed angiogenesis and is a key feature of  malignant transformation. Acquire ability to invade Cancer cells have no respect for the structure of  normal tissues. They acquire the ability to breach the basement membrane and gain direct access to blood and lymph vessels. Cancer cells use three main mechanisms to facilitate invasion: (i) cause a rise in the interstitial pressure within a tissue; (ii) secrete enzymes that dissolve extracellular matrix; and (iii) become mobile. Unrestrained proliferation and a lack of  contact inhibition enable cancer cells to exert pressure directly on the surrounding tissue and push beyond the normal limits. They secrete collagenases and proteases that chemically dissolve any extracellular boundaries that would otherwise limit their spread through tissues and, by modulating the expression of cell surface molecules called integrins, are able to detach them selves from the extracellular matrix. The abnormal integrins associated with malignancy can also transmit signals from the environment to the cytoplasm and nucleus of  the cancer cells (‘outside-in signalling’) and these signals can induce increased motility . These processes are similar to those involved in normal development, i.e. in the migration of  the neural crest or the formation of  the heart. Epithelial cells behave as if  they were mesenchymal cells and the process is termed epithelial– mesenchymal transition (EMT). EMT is a crucial step in malignant transformation and many of  the genes and proteins implicated in the formation of  cancer control processes are involved in EMT , e.g. Src, Ras, integrins, Wnt / β -catenin, Notch. Acquire ability to disseminate and implant Once cancer cells gain access to vascular and lymphovascular spaces, they can be readily distributed systemically throughout the body . This is not, of  itself, su ﬃ cient to cause tumours to develop at distant sites. The cells also need to acquire the ability to implant. As Paget pointed out over a century ago, there is a crucial relationship here between the seed (the tumour cell) and the soil (the distant tissue). Most of  the cancer cells discharged into the circulation probably do not form viable metastases. Circulating cancer cells can be identiﬁed in patients who never develop clinical evidence of metastatic disease; presumably these cells die if  they cannot implant or they are destroyed by the patient’s immune system. Cancer can spread as individual cells or cell clumps that migrate and implant. Whether spread occurs in groups or as individual cells there is still the problem of crossing the vascular endothelium (and basement membrane) to gain access to the Stephen Paget , 1855–1926, surgeon, The West London Hospital, London, UK. Paget’s ‘seed and soil’ hypothesis is contained in his paper ‘The distribution of secondary growths in cancer of  the breast’, published in the Lancet in 1889. Paul Ehrlich , 1854–1915, Professor of  Hygiene, the University of  Berlin, and later Director of the Institute for Infectious Diseases, Berlin, Germany . In 1908, he shared the Nobel Prize in Physiology or Medicine with Elie Metchniko ﬀ Zoology at Odessa in Russia, and later worked at the Pasteur Institute in Paris, France. Sir Frank McFarlane Burnet , 1899–1985, Australian virologist, Walter and Eliza Hall Institute, Melbourne, Australia. Burnett shared the 1960 Nobel Prize in Physiology or Medicine with Sir Peter Brian Medawar , 1915–1987, Jodrell Professor of  Zoology , University College, London, UK, ‘for their discovery of acquired immunological tolerance’. Lewis Thomas , 1913–1993, American pathologist and immunologist, who became President of  the Sloan Kettering Memorial Institute, New Y ork, NY , USA. tissues by exploiting, and subverting, the normal inﬂammatory response. By expressing inﬂammatory cytokines, cancer cells can deceiv e the endothelium of  the host tissue into becoming activated and allowing cancer cells access to the extravascular space. Activated endothelium expresses receptors that bind to integrins and selectins on the surface of cells, allowing the can - cer cells to move across the endothelial barrier. Tumour-related inﬂammation A malignancy can provoke an inﬂammatory response and the cytokines and other factors produced as a result of  that response may act to promote and sustain malignant transformation. Growth factors, mutagenic reactive oxygen species, angiogenic factors and anti-apoptotic factors may all be produced as part of  an inﬂammatory process and all may contribute to the progression of  a cancer. - Evade detection/elimination Although derived from normal cells (‘self ’) cancer cells are, in terms of  their genetic make-up, behaviour and character - istics, foreign (‘not self ’). As such, they ought to provoke an immune response and be eliminated. It is entirely possible that malignant transformation is a more frequent event than the emergence of  clinical cancer. T he possible role of  the immune system in eliminating nascent cancers was proposed by Paul Ehrlich in 1909 and revisited by both Sir Frank McFarlane Burnet and Lewis Thomas in the late 1950s. Cancer cells, or at least those that give rise to clinical disease, appear to gain the ability to escape detection by the immune system. This may be through suppressing expression of  tumour-associated antigens or it may be through actively co-opting one part of the immune system to help the tumour escape detection by other parts of  the immune surveillance system. This hallmark has been exploited in recent years in the development of  T-cell checkpoint inhibitors, which ‘take the brakes’ o ﬀ the immune system to re-enable T-cell killing of  cancer cells, e.g. in renal cell carcinoma, lung cancer and melanoma. Loss of specialist cell function Cancer cells are geared to excessive proliferation. They do not need to develop or retain those specialised functions that prior to malignant transformation were their physiological function. These cells can therefore a ﬀ ord to repress or permanently lose those genes that control such functions. The longer term disadvantage to this process is that cancer cells are vulnerable to external stressors, which may , in part, explain why some cancer treatments work. , 1845–1916, ‘in recognition of  his work on immunity’. Metchniko ﬀ was Professor of Blood ﬂow in malignant tumours is often sporadic and unre liable. As a result, cancer cells may have to spend prolonged periods in low-oxygen states (i.e. relative hypoxia). Compared with the corresponding normal cells, some cancer cells may be better able to surviv e in hypoxic conditions. This ability may enable tumours to grow and develop despite an impoverished blood supply . Cancer cells can alter their metabolism even when oxygen is abundant; they break down glucose but do not, as normal cells would do, send the resulting pyruvate to the mitochondria for conversion, in an oxygen-dependent process, to carbon dioxide. This is the phenomenon of  aerobic glycolysis, or the Warburg e ﬀ ect, and leads to the production of lactate. In an act of  symbiosis, lactate-producing cancer cells may provide lactate for adjacent cancer cells, which are then able to use it, via the citric acid cycle, for energy production. This cooperation is similar to that which occurs in skeletal muscle during exercise. The hallmarks of cancer

Cancer cells are able to proliferate in an uncontrolled fashion; - their ability to divide and spread is unbounded. Cancer cell growth destroys ﬁrst the tissue from which they arise and - eventually the person in which they are present. In order to survive, divide, invade and spread, cancer cells have to acquire a number of  characteristics. No one charac - teristic is su ﬃ cient and not all characteristics ar e absolutely necessary . These features, based on articles by Hanahan and Weinberg, are given in Summary box 12.1 . Establish an autonomous lineage Cells develop independence from the normal signals that control supply and demand. The healing of  a wound is a physiological process; the cellular response is exquisitely coordinated so that - proliferation occurs when it is needed and ceases when it is no - longer required. The whole process is controlled by a series of - Maurice Hugh Frederick Wilkins , 1916–2004, of Summary box 12.1 Features of malignant transformation /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF signals telling cells when, and when not, to divide. Cancer cells escape from this normal system of  checks and balances: they grow and proliferate in the absence of  external stimuli and regardless of  signals telling them to desist. Oncogenes are genes with the potential to cause cancer if  mutated and expressed at high levels; they are key factors in carcinogenesis. Most oncogenes are normally inv olved in physiological processes, i.e. cell growth, but if  mutated they can predispose a cell to cancer and in concert with other onco genes can enable cancer cell survival and development of  an established tumour. The implication is that we all carry the seeds of  our own destruction: genetic sequences that, through mutation, can turn into active oncogenes and thereby cause malignant transformation. Indeed, through study of  the timing of  key genetic events in adult cancer development, a handful of  cells develop the founder mutations of  cancer development several decades prior to diagnosis. If  the individual is unfor tunate enough to accumulate further mutations in key driver genes, that cell becomes malignant and, if  it proliferates, a can cer may develop. Only very rarely is a single mutation su ﬃ cient to cause cancer; multiple mutations are usually required. Colo rectal cancer pro vides the classical example of  how multiple mutations are necessary for the complete transformation from normal cell to malignant cell. V ogelstein and his colleagues identiﬁed the genes implicated and also postula ted that it is necessary to have mutations in all the relevant genes; they also noted that these mutations must be acquired in a speciﬁc sequence for malignant transformation to occur. Obtain replicative immortality According to the Hayﬂick hypothesis, normal cells are permit ted to undergo only a ﬁnite number of  divisions. For humans this number is between 40 and 60. The limitation is imposed by the progressive shortening of the end of  the chr omosome (the telomere) that occurs each time a cell divides; eventually the lineage will die out. Cancer cells utilise the enzyme telomerase to rebuild the telomere at each cell division, such that there is Bert Vogelstein , b.1949, molecular biologist, Johns Hopkins Hospital, Baltimore, MD, USA. Leonard Hayﬂick , b.1928, while working at the Wistar Institute in Philadelphia in 1962, he noted that normal mammalian cells growing in culture had a limited, rather than an indeﬁnite, capacity for self-replication. cancer cell hence develops immortality . Evade apoptosis Apoptosis, taken from the Greek for ‘leaf  fall’, is a form of programmed cell death that occurs as the direct result of  inter - nal cellular events instructing the cell to die. Unlike necrosis, which is a form of  traumatic cell death resulting from acute cellular injury , apoptosis is an orderly and internally driven process. The cell dismantles itself neatly for disposal ( Figure 12.1 ) . There is minimal inﬂammatory response. Apoptosis is a physiological process. Cells that are redundant normally die by apoptosis and this is an important self-regulatory mechanism in growth and development, i.e . cells in the web space of  the embryo die by apoptosis, or lymphocytes that could react to self. Genes, such as p53, that can activate apoptosis function as tumour suppressor genes. Mutation in such genes causes a loss of  this inhibitory function, which will contribute to malignant transformation as apoptosis is evaded; this means that the wrong cells can be in the wrong places at the wrong times. - - - - Acquire angiogenic competence A mass of  cancer cells cannot, in the absence of  a blood supply , grow beyond a diameter of  about 1 /uni00A0 mm. This places a severe restriction on the capabilities of  the tumour (note - that the word tumour means swelling and does not mean the lesion is malignant, although ‘tumour’ is often taken by patients to be synonymous with cancer). It cannot grow much larger or spread widely within the body . If, however, the mass of  cancer cells is able to attract or to construct a blood supply then it is able to quit its dormant state and behave in a far 

Establish an autonomous lineage
Resist signals that inhibit growth
Sustain proliferative signalling
Obtain replicative immortality
Evade apoptosis
Acquire angiogenic competence
Acquire ability to invade, disseminate and implant
Evocation of in
/f_l
ammation
Evade detection/elimination
Loss of specialist cell function
Develop ability to change energy metabolism
AB
AB
MC
AB
MN
Figure 12.1
Electron micrograph of apoptotic bodies (AB) engulfed by
a macrophage. Note the macrophage nucleus (MN) and macrophage
cytoplasm (MC).

vessels is termed angiogenesis and is a key feature of  malignant transformation. Acquire ability to invade Cancer cells have no respect for the structure of  normal tissues. They acquire the ability to breach the basement membrane and gain direct access to blood and lymph vessels. Cancer cells use three main mechanisms to facilitate invasion: (i) cause a rise in the interstitial pressure within a tissue; (ii) secrete enzymes that dissolve extracellular matrix; and (iii) become mobile. Unrestrained proliferation and a lack of  contact inhibition enable cancer cells to exert pressure directly on the surrounding tissue and push beyond the normal limits. They secrete collagenases and proteases that chemically dissolve any extracellular boundaries that would otherwise limit their spread through tissues and, by modulating the expression of cell surface molecules called integrins, are able to detach them selves from the extracellular matrix. The abnormal integrins associated with malignancy can also transmit signals from the environment to the cytoplasm and nucleus of  the cancer cells (‘outside-in signalling’) and these signals can induce increased motility . These processes are similar to those involved in normal development, i.e. in the migration of  the neural crest or the formation of  the heart. Epithelial cells behave as if  they were mesenchymal cells and the process is termed epithelial– mesenchymal transition (EMT). EMT is a crucial step in malignant transformation and many of  the genes and proteins implicated in the formation of  cancer control processes are involved in EMT , e.g. Src, Ras, integrins, Wnt / β -catenin, Notch. Acquire ability to disseminate and implant Once cancer cells gain access to vascular and lymphovascular spaces, they can be readily distributed systemically throughout the body . This is not, of  itself, su ﬃ cient to cause tumours to develop at distant sites. The cells also need to acquire the ability to implant. As Paget pointed out over a century ago, there is a crucial relationship here between the seed (the tumour cell) and the soil (the distant tissue). Most of  the cancer cells discharged into the circulation probably do not form viable metastases. Circulating cancer cells can be identiﬁed in patients who never develop clinical evidence of metastatic disease; presumably these cells die if  they cannot implant or they are destroyed by the patient’s immune system. Cancer can spread as individual cells or cell clumps that migrate and implant. Whether spread occurs in groups or as individual cells there is still the problem of crossing the vascular endothelium (and basement membrane) to gain access to the Stephen Paget , 1855–1926, surgeon, The West London Hospital, London, UK. Paget’s ‘seed and soil’ hypothesis is contained in his paper ‘The distribution of secondary growths in cancer of  the breast’, published in the Lancet in 1889. Paul Ehrlich , 1854–1915, Professor of  Hygiene, the University of  Berlin, and later Director of the Institute for Infectious Diseases, Berlin, Germany . In 1908, he shared the Nobel Prize in Physiology or Medicine with Elie Metchniko ﬀ Zoology at Odessa in Russia, and later worked at the Pasteur Institute in Paris, France. Sir Frank McFarlane Burnet , 1899–1985, Australian virologist, Walter and Eliza Hall Institute, Melbourne, Australia. Burnett shared the 1960 Nobel Prize in Physiology or Medicine with Sir Peter Brian Medawar , 1915–1987, Jodrell Professor of  Zoology , University College, London, UK, ‘for their discovery of acquired immunological tolerance’. Lewis Thomas , 1913–1993, American pathologist and immunologist, who became President of  the Sloan Kettering Memorial Institute, New Y ork, NY , USA. tissues by exploiting, and subverting, the normal inﬂammatory response. By expressing inﬂammatory cytokines, cancer cells can deceiv e the endothelium of  the host tissue into becoming activated and allowing cancer cells access to the extravascular space. Activated endothelium expresses receptors that bind to integrins and selectins on the surface of cells, allowing the can - cer cells to move across the endothelial barrier. Tumour-related inﬂammation A malignancy can provoke an inﬂammatory response and the cytokines and other factors produced as a result of  that response may act to promote and sustain malignant transformation. Growth factors, mutagenic reactive oxygen species, angiogenic factors and anti-apoptotic factors may all be produced as part of  an inﬂammatory process and all may contribute to the progression of  a cancer. - Evade detection/elimination Although derived from normal cells (‘self ’) cancer cells are, in terms of  their genetic make-up, behaviour and character - istics, foreign (‘not self ’). As such, they ought to provoke an immune response and be eliminated. It is entirely possible that malignant transformation is a more frequent event than the emergence of  clinical cancer. T he possible role of  the immune system in eliminating nascent cancers was proposed by Paul Ehrlich in 1909 and revisited by both Sir Frank McFarlane Burnet and Lewis Thomas in the late 1950s. Cancer cells, or at least those that give rise to clinical disease, appear to gain the ability to escape detection by the immune system. This may be through suppressing expression of  tumour-associated antigens or it may be through actively co-opting one part of the immune system to help the tumour escape detection by other parts of  the immune surveillance system. This hallmark has been exploited in recent years in the development of  T-cell checkpoint inhibitors, which ‘take the brakes’ o ﬀ the immune system to re-enable T-cell killing of  cancer cells, e.g. in renal cell carcinoma, lung cancer and melanoma. Loss of specialist cell function Cancer cells are geared to excessive proliferation. They do not need to develop or retain those specialised functions that prior to malignant transformation were their physiological function. These cells can therefore a ﬀ ord to repress or permanently lose those genes that control such functions. The longer term disadvantage to this process is that cancer cells are vulnerable to external stressors, which may , in part, explain why some cancer treatments work. , 1845–1916, ‘in recognition of  his work on immunity’. Metchniko ﬀ was Professor of Blood ﬂow in malignant tumours is often sporadic and unre liable. As a result, cancer cells may have to spend prolonged periods in low-oxygen states (i.e. relative hypoxia). Compared with the corresponding normal cells, some cancer cells may be better able to surviv e in hypoxic conditions. This ability may enable tumours to grow and develop despite an impoverished blood supply . Cancer cells can alter their metabolism even when oxygen is abundant; they break down glucose but do not, as normal cells would do, send the resulting pyruvate to the mitochondria for conversion, in an oxygen-dependent process, to carbon dioxide. This is the phenomenon of  aerobic glycolysis, or the Warburg e ﬀ ect, and leads to the production of lactate. In an act of  symbiosis, lactate-producing cancer cells may provide lactate for adjacent cancer cells, which are then able to use it, via the citric acid cycle, for energy production. This cooperation is similar to that which occurs in skeletal muscle during exercise. The hallmarks of cancer

Cancer cells are able to proliferate in an uncontrolled fashion; - their ability to divide and spread is unbounded. Cancer cell growth destroys ﬁrst the tissue from which they arise and - eventually the person in which they are present. In order to survive, divide, invade and spread, cancer cells have to acquire a number of  characteristics. No one charac - teristic is su ﬃ cient and not all characteristics ar e absolutely necessary . These features, based on articles by Hanahan and Weinberg, are given in Summary box 12.1 . Establish an autonomous lineage Cells develop independence from the normal signals that control supply and demand. The healing of  a wound is a physiological process; the cellular response is exquisitely coordinated so that - proliferation occurs when it is needed and ceases when it is no - longer required. The whole process is controlled by a series of - Maurice Hugh Frederick Wilkins , 1916–2004, of Summary box 12.1 Features of malignant transformation /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF signals telling cells when, and when not, to divide. Cancer cells escape from this normal system of  checks and balances: they grow and proliferate in the absence of  external stimuli and regardless of  signals telling them to desist. Oncogenes are genes with the potential to cause cancer if  mutated and expressed at high levels; they are key factors in carcinogenesis. Most oncogenes are normally inv olved in physiological processes, i.e. cell growth, but if  mutated they can predispose a cell to cancer and in concert with other onco genes can enable cancer cell survival and development of  an established tumour. The implication is that we all carry the seeds of  our own destruction: genetic sequences that, through mutation, can turn into active oncogenes and thereby cause malignant transformation. Indeed, through study of  the timing of  key genetic events in adult cancer development, a handful of  cells develop the founder mutations of  cancer development several decades prior to diagnosis. If  the individual is unfor tunate enough to accumulate further mutations in key driver genes, that cell becomes malignant and, if  it proliferates, a can cer may develop. Only very rarely is a single mutation su ﬃ cient to cause cancer; multiple mutations are usually required. Colo rectal cancer pro vides the classical example of  how multiple mutations are necessary for the complete transformation from normal cell to malignant cell. V ogelstein and his colleagues identiﬁed the genes implicated and also postula ted that it is necessary to have mutations in all the relevant genes; they also noted that these mutations must be acquired in a speciﬁc sequence for malignant transformation to occur. Obtain replicative immortality According to the Hayﬂick hypothesis, normal cells are permit ted to undergo only a ﬁnite number of  divisions. For humans this number is between 40 and 60. The limitation is imposed by the progressive shortening of the end of  the chr omosome (the telomere) that occurs each time a cell divides; eventually the lineage will die out. Cancer cells utilise the enzyme telomerase to rebuild the telomere at each cell division, such that there is Bert Vogelstein , b.1949, molecular biologist, Johns Hopkins Hospital, Baltimore, MD, USA. Leonard Hayﬂick , b.1928, while working at the Wistar Institute in Philadelphia in 1962, he noted that normal mammalian cells growing in culture had a limited, rather than an indeﬁnite, capacity for self-replication. cancer cell hence develops immortality . Evade apoptosis Apoptosis, taken from the Greek for ‘leaf  fall’, is a form of programmed cell death that occurs as the direct result of  inter - nal cellular events instructing the cell to die. Unlike necrosis, which is a form of  traumatic cell death resulting from acute cellular injury , apoptosis is an orderly and internally driven process. The cell dismantles itself neatly for disposal ( Figure 12.1 ) . There is minimal inﬂammatory response. Apoptosis is a physiological process. Cells that are redundant normally die by apoptosis and this is an important self-regulatory mechanism in growth and development, i.e . cells in the web space of  the embryo die by apoptosis, or lymphocytes that could react to self. Genes, such as p53, that can activate apoptosis function as tumour suppressor genes. Mutation in such genes causes a loss of  this inhibitory function, which will contribute to malignant transformation as apoptosis is evaded; this means that the wrong cells can be in the wrong places at the wrong times. - - - - Acquire angiogenic competence A mass of  cancer cells cannot, in the absence of  a blood supply , grow beyond a diameter of  about 1 /uni00A0 mm. This places a severe restriction on the capabilities of  the tumour (note - that the word tumour means swelling and does not mean the lesion is malignant, although ‘tumour’ is often taken by patients to be synonymous with cancer). It cannot grow much larger or spread widely within the body . If, however, the mass of  cancer cells is able to attract or to construct a blood supply then it is able to quit its dormant state and behave in a far 

Establish an autonomous lineage
Resist signals that inhibit growth
Sustain proliferative signalling
Obtain replicative immortality
Evade apoptosis
Acquire angiogenic competence
Acquire ability to invade, disseminate and implant
Evocation of in
/f_l
ammation
Evade detection/elimination
Loss of specialist cell function
Develop ability to change energy metabolism
AB
AB
MC
AB
MN
Figure 12.1
Electron micrograph of apoptotic bodies (AB) engulfed by
a macrophage. Note the macrophage nucleus (MN) and macrophage
cytoplasm (MC).

vessels is termed angiogenesis and is a key feature of  malignant transformation. Acquire ability to invade Cancer cells have no respect for the structure of  normal tissues. They acquire the ability to breach the basement membrane and gain direct access to blood and lymph vessels. Cancer cells use three main mechanisms to facilitate invasion: (i) cause a rise in the interstitial pressure within a tissue; (ii) secrete enzymes that dissolve extracellular matrix; and (iii) become mobile. Unrestrained proliferation and a lack of  contact inhibition enable cancer cells to exert pressure directly on the surrounding tissue and push beyond the normal limits. They secrete collagenases and proteases that chemically dissolve any extracellular boundaries that would otherwise limit their spread through tissues and, by modulating the expression of cell surface molecules called integrins, are able to detach them selves from the extracellular matrix. The abnormal integrins associated with malignancy can also transmit signals from the environment to the cytoplasm and nucleus of  the cancer cells (‘outside-in signalling’) and these signals can induce increased motility . These processes are similar to those involved in normal development, i.e. in the migration of  the neural crest or the formation of  the heart. Epithelial cells behave as if  they were mesenchymal cells and the process is termed epithelial– mesenchymal transition (EMT). EMT is a crucial step in malignant transformation and many of  the genes and proteins implicated in the formation of  cancer control processes are involved in EMT , e.g. Src, Ras, integrins, Wnt / β -catenin, Notch. Acquire ability to disseminate and implant Once cancer cells gain access to vascular and lymphovascular spaces, they can be readily distributed systemically throughout the body . This is not, of  itself, su ﬃ cient to cause tumours to develop at distant sites. The cells also need to acquire the ability to implant. As Paget pointed out over a century ago, there is a crucial relationship here between the seed (the tumour cell) and the soil (the distant tissue). Most of  the cancer cells discharged into the circulation probably do not form viable metastases. Circulating cancer cells can be identiﬁed in patients who never develop clinical evidence of metastatic disease; presumably these cells die if  they cannot implant or they are destroyed by the patient’s immune system. Cancer can spread as individual cells or cell clumps that migrate and implant. Whether spread occurs in groups or as individual cells there is still the problem of crossing the vascular endothelium (and basement membrane) to gain access to the Stephen Paget , 1855–1926, surgeon, The West London Hospital, London, UK. Paget’s ‘seed and soil’ hypothesis is contained in his paper ‘The distribution of secondary growths in cancer of  the breast’, published in the Lancet in 1889. Paul Ehrlich , 1854–1915, Professor of  Hygiene, the University of  Berlin, and later Director of the Institute for Infectious Diseases, Berlin, Germany . In 1908, he shared the Nobel Prize in Physiology or Medicine with Elie Metchniko ﬀ Zoology at Odessa in Russia, and later worked at the Pasteur Institute in Paris, France. Sir Frank McFarlane Burnet , 1899–1985, Australian virologist, Walter and Eliza Hall Institute, Melbourne, Australia. Burnett shared the 1960 Nobel Prize in Physiology or Medicine with Sir Peter Brian Medawar , 1915–1987, Jodrell Professor of  Zoology , University College, London, UK, ‘for their discovery of acquired immunological tolerance’. Lewis Thomas , 1913–1993, American pathologist and immunologist, who became President of  the Sloan Kettering Memorial Institute, New Y ork, NY , USA. tissues by exploiting, and subverting, the normal inﬂammatory response. By expressing inﬂammatory cytokines, cancer cells can deceiv e the endothelium of  the host tissue into becoming activated and allowing cancer cells access to the extravascular space. Activated endothelium expresses receptors that bind to integrins and selectins on the surface of cells, allowing the can - cer cells to move across the endothelial barrier. Tumour-related inﬂammation A malignancy can provoke an inﬂammatory response and the cytokines and other factors produced as a result of  that response may act to promote and sustain malignant transformation. Growth factors, mutagenic reactive oxygen species, angiogenic factors and anti-apoptotic factors may all be produced as part of  an inﬂammatory process and all may contribute to the progression of  a cancer. - Evade detection/elimination Although derived from normal cells (‘self ’) cancer cells are, in terms of  their genetic make-up, behaviour and character - istics, foreign (‘not self ’). As such, they ought to provoke an immune response and be eliminated. It is entirely possible that malignant transformation is a more frequent event than the emergence of  clinical cancer. T he possible role of  the immune system in eliminating nascent cancers was proposed by Paul Ehrlich in 1909 and revisited by both Sir Frank McFarlane Burnet and Lewis Thomas in the late 1950s. Cancer cells, or at least those that give rise to clinical disease, appear to gain the ability to escape detection by the immune system. This may be through suppressing expression of  tumour-associated antigens or it may be through actively co-opting one part of the immune system to help the tumour escape detection by other parts of  the immune surveillance system. This hallmark has been exploited in recent years in the development of  T-cell checkpoint inhibitors, which ‘take the brakes’ o ﬀ the immune system to re-enable T-cell killing of  cancer cells, e.g. in renal cell carcinoma, lung cancer and melanoma. Loss of specialist cell function Cancer cells are geared to excessive proliferation. They do not need to develop or retain those specialised functions that prior to malignant transformation were their physiological function. These cells can therefore a ﬀ ord to repress or permanently lose those genes that control such functions. The longer term disadvantage to this process is that cancer cells are vulnerable to external stressors, which may , in part, explain why some cancer treatments work. , 1845–1916, ‘in recognition of  his work on immunity’. Metchniko ﬀ was Professor of Blood ﬂow in malignant tumours is often sporadic and unre liable. As a result, cancer cells may have to spend prolonged periods in low-oxygen states (i.e. relative hypoxia). Compared with the corresponding normal cells, some cancer cells may be better able to surviv e in hypoxic conditions. This ability may enable tumours to grow and develop despite an impoverished blood supply . Cancer cells can alter their metabolism even when oxygen is abundant; they break down glucose but do not, as normal cells would do, send the resulting pyruvate to the mitochondria for conversion, in an oxygen-dependent process, to carbon dioxide. This is the phenomenon of  aerobic glycolysis, or the Warburg e ﬀ ect, and leads to the production of lactate. In an act of  symbiosis, lactate-producing cancer cells may provide lactate for adjacent cancer cells, which are then able to use it, via the citric acid cycle, for energy production. This cooperation is similar to that which occurs in skeletal muscle during exercise.

# The range of non-surgical anti-cancer treatments

The range of non-surgical anti-cancer treatments

Radiotherapy Half  of  all patients will receive radiotherapy during their - cancer journey . The mechanism of  action of  radiotherapy is that ionising radiation causes single- and double-stranded - DNA breaks. Cells most sensitive to radiotherapy are in mitosis or late G2 in the cell cycle. Damage may be caused - by the direct e ﬀ ect of  the ionising radiation on the DNA. However, the predominant therapeutic e ﬀ ect is indirect, and is achieved by ionising radiation causing the creation of  oxygen free radicals, which then damage the DNA. The fact that the or indirect damage is predominant explains why hypoxic cells - are relatively resistant to radiotherapy . In practice, adequate oxygenation of  tissues is assisted by simple measures such as correcting anaemia prior to radiotherapy . Cancer types di ﬀ er greatly in their sensitivity to radiother apy . Similarly , higher doses of  radiotherapy are needed to con trol bulky disease (~70 /uni00A0 Gy) than to eliminate residual tumour cells (~50 /uni00A0 Gy) or to palliate symptoms (~30 /uni00A0 Gy). Radiotherapy is mainly used as a localised treatment ( Figure 12.7 ). The target area is deﬁned by imaging, which will include anatomical imaging, such as CT and MRI, to identify the tumour mass, neighbouring structur es and landmarks for radiotherapy planning. Sometimes functional imaging, such as PET , is used to further deﬁne structures that should be included in the radiation ﬁeld such as lymph nodes containing small volumes of  tumour, whose metabolic signatur e is detected by PET . The planning and technical set-up of radiotherapy is a highly specialised subject. Planning can be extremely di ﬃ cult and time-consuming, e.g. in the treatment of head and neck cancer, where the treatment intent is curative but there are multiple vital and highly sensitive structures close to the target area. In general terms, the radiotherapy team will aim to pro vide a uniform therapeutic radiation dose to the target area, while sparing adjacent structures from signiﬁcant damage. The most common form of  treatment is external beam radiother apy in which x-rays are aimed at the tar get volume from an external source. Where necessary , modern radiotherapy can employ sophisticated computer programs and algorithms to sculpt the shape of  the treatment volume. It is no w possible to irradiate irregularly shaped target volumes using techniques such as intensity-modulated radiation therapy (IMRT) and - image-guided radiation therapy (IGRT). The ability to give - high fractional doses in this way has led to the development of  stereotactic ablative radiotherapy (SAbR), in which a small number of  fractions can be used to treat primary tumours, or isolated metastases, to curative dose levels. Other ways of  targeting the tumour volume include brachytherapy , in which the radiation source is brought ver y close to the tumour by insertion of  radioactive seeds, and radionuclide therapy , in which a radioactive source is concen - trated at the tumour site. One of  the main problems in determining the optimal schedule of  radiation is that there is a dissociation between the acute e ﬀ ects on normal tissues and the late damage. The acute reaction is not a reliable guide to the adverse consequences of treatment in the longer term. Since the late e ﬀ ects following irradiation can take over 20 years to develop, this poses an obvious di ﬃ culty: if  a radiation schedule is changed it will be known within 2 or 3 years whether or not the new schedule - has improved tumour control; it may , however, be two decades before it is known, with any degree of  certainty , whether or not the new technique is safe. - Anti-cancer drugs The classes of  anti-cancer drugs, their modes of  action and clinical indications are summarised in Table 12.6 . 

upon for cure
70 with no
30 with
residual cancer
residual cancer
15 sensitive to
15 resistant to
adjuvant therapy
adjuvant therapy
5 relapse (inadequate
15 relapse despite
therapy, toxicity, etc.)
adjuvant therapy
despite adjuvant
therapy
10 patients whose
residual disease was
eradicated by
adjuvant therapy
Net bene
/f_i
ts
Futile therapy
20% 90% treated
inappropriately
Unnecessary therapy
70%
Bene
/f_i
cial therapy
10%
10% treated
appropriately
No therapy
0%
Figure 12.5
The concept of adjuvant chemotherapy.
upon for cure
Imperfect but clinically adequate test for residual disease
60 with no
40 with
residual cancer,
‘residual cancer’,
none are
all are treated
treated
15 sensitive to
10 with no 15 resistant to
adjuvant therapy
residual disease adjuvant therapy
5 relapse (inadequate
15 relapse despite
therapy, toxicity, etc.)
adjuvant therapy
despite adjuvant
therapy
10 patients whose
residual disease was
eradicated by
Net bene
/f_i
ts
adjuvant therapy
Futile therapy 20% 30% treated
inappropriately
Unnecessary therapy
10%
Bene
/f_i
cial therapy
10%
70% treated
appropriately
No therapy
60%
Figure 12.6
The concept of adjuvant chemotherapy and testing for minimal
residual disease.

• • • • • • • • • • • • • • • • • • • • • • • • • 

Knowledge of
Anatomy
Patter
ns and probability of spread of disease
Cross-sectional imaging
CT, MRI
Functional imaging
Positron emission tomography (PET)
Functional MRI
Radiotherapy dose prescription
Optimise the therapeutic ratio
Choose that combination of total
dose, number of treatments
(fractions) and overall treatment
time so that the damage to normal
tissues is minimised and the effects
on tumour are maximised
Figure 12.7
The processes involved in clinical radiotherapy. CT, computed tomography; MRI, magnetic resonance imaging.
TABLE 12.6
Examples of anti-cancer drugs currently in use.
Class
Examples
Putative mode of action
Drugs that interfere
Vincristine
Interfere with formation of microtubules: ‘spindle
with mitosis
Vinblastine
poisons’
Stabilise microtubules
Taxanes:
paclitaxel
docetaxel
cabazitaxel
5-Fluorouracil
Inhibition of thymidylate synthase, false substrate
Drugs that interfere
Capecitabine
for both DNA and RNA synthesis
with DNA synthesis
(antimetabolites)
Methotrexate
Inhibition of dihydrofolate reductase
6-Mercaptopurine
Inhibit
de novo
6-Thioguanine
Technical set-up
Optimal use of radiation beams
Simulate the ‘beam’s-eye view’ of the target
Diagnostic quality screening and
/f_i
lms
Images digitally reconstructed from CT
planning images
Three-dimensional planning
Careful shaping of beams (‘conformal therapy’)
Alter energy pro
/f_i
le across the beam to sculpt the
dose distribution to complex shapes (‘intensity
modulated radiation therapy’ – IMRT)
Optimal delivery of treatment
Ensure day-to-day reproducibility of set up
Online veri
/f_i
cation (portal imaging)
Reference tattoos
Immobilisation of patient (moulds, shells)
Ensure that only the target is treated
Eliminate effect of physiological movement
(breathing, peristalsis): ‘image-guided
radiation therapy’ – IGRT
Quality control and cross-checking procedures
throughout the whole process from target de
/f_i
nition
to follow-up
Tumour types that may be sensitive
to drug
Lymphomas
Leukaemias
Brain tumours
Sarcomas
Breast cancer
Non-small cell lung cancer
Ovarian cancer
Prostate cancer
Head and neck cancer
Breast cancer
GI cancer
Breast cancer
Bladder cancer
Lymphomas
Cervical cancer
purine synthesis
Leukaemias
Continued



Class
Examples
Putative mode of action
Cytosine arabinoside False substrate in DNA synthesis
Drugs that interfere
with DNA synthesis
(antimetabolites)
Gemcitabine Inhibits ribonucleotide reductase
–
continued
Mitomycin C DNA cross-linking, preferentially active at sites of Anal cancer
Drugs that directly
low oxygen tension (a bioreductive drug)
damage DNA or
interfere with its
function
Cisplatin
Form adducts between DNA strands and interferes Germ cell tumours
Carboplatin
with replication
Oxaliplatin
Forms adducts between DNA strands and interferes Colorectal cancer
with replication
Doxorubicin Intercalates between DNA strands and interferes Breast cancer
with replication
Cyclophosphamide A prodrug converted via hepatic cytochrome p450
to phosphoramide mustard. Causes DNA cross-
links
Ifosfamide
Related to cyclophosphamide, causes DNA cross- Small cell lung cancer
links
Bleomycin
DNA strand breakage via formation of metal Germ cell tumours
complex
Irinotecan
Inhibits topoisomerase 1, prevents DNA from Colorectal cancer
unwinding and repairing during replication
Etoposide
Inhibits topoisomerase 2, prevents DNA from Small cell lung cancer
unwinding and repairing during replication
Dacarbazine A nitrosourea that requires activation by hepatic
cytochrome p450. Methylates guanine residues in
DNA
Temozolomide A nitrosourea but, unlike dacarbazine, does not
require activation by hepatic cytochrome p450.
Methylates guanine residues in DNA
Actinomycin D Intercalation between DNA strands, DNA strand Rhabdomyosarcoma
breaks
Inhibit DNA repair by PARP , especially in
DNA damage
Olaparib
mutated cancers
response inhibitors
Niraparib
Rucaparib
Hormones
Tamoxifen
Blocks oestrogen receptors
Aromatase inhibitors that block postmenopausal Breast cancer
Anastrozole
(non-ovarian) oestrogen production
Letrozole
Exemestane
Analogues of gonadotropin-releasing hormone,
Leuprolide
continued use produces downregulation of the
Goserelin
anterior pituitary with consequent fall in testosterone
Buserelin
levels
Cabergoline Blocks prolactin release, a long-acting dopamine Prolactin-secreting pituitary tumours
agonist
Tumour types that may be sensitive
to drug
Leukaemias
Lymphomas
Non-small lung cancer
Pancreatic cancer
Bladder cancer
Gastric cancer
Head and neck cancer
Rectal cancer
Ovarian cancer
Non-small cell lung cancer
Head and neck cancer
Oesophageal cancer
Lymphomas
Sarcomas
Kaposi’s sarcoma
Breast cancer
Lymphomas
Sarcomas
Sarcomas
Lymphomas
Germ cell tumours
Lymphomas
Brain tumours
Sarcoma
Glioblastoma multiforme
Wilms’ tumour
BRCA
- Ovarian cancer
Breast cancer
Prostate cancer
Breast cancer
Prostate cancer
Continued

κ 

Class
Examples
Putative mode of action
Hormones
Bromocriptine
Dopamine agonist, blocks stimulation of anterior
–
continued
pituitary
Block the effect of androgens
Cyproterone acetate
Flutamide
Nilutamide
Bicalutamide
Abiraterone
Block testosterone production
Cyproterone acetate
Inhibit EGFR tyrosine kinase
Inhibitors of receptor
Osimertinib
tyrosine kinases
Erlotinib
Afatinib
Ge
/f_i
tinib
Imatinib
Blocks ability of mutant BCR-ABL fusion protein to
bind ATP
Imatinib
Inhibition of mutant c-KIT
Erlotinib
Inhibits EGFR tyrosine kinase
Promiscuous tyrosine kinase inhibitors (PDGFR,
Sunitinib
VEGFR, KIT, FLT)
Regorafenib
Lenvatinib
Lapatinib
Inhibits tyrosine kinases associated with EGFR and
HER2
Axitinib
Inhibits tyrosine kinase associated with VEGFR
Cyclin-dependent
Palbociclib
Inhibits growth signal
kinase inhibitors
Protease inhibitors
Bortezomib
Interferes with proteasomal degradation of
r
egulatory proteins, in particular stops NF-
preventing apoptosis
Differentiating
All-
trans
-retinoic acid
Induces terminal differentiation
agents
Farnesyl transferase
Lonafarnib
Inhibition of far
inhibitors
inactivation of
Tipifarnib
Inhibition of farnesyl transferase and consequent
inactivation of
Trastuzumab
Antibody directed against HER2 receptor
Antibodies directed
to cell surface
Cetuximab
Antibody directed against EGFR
antigens
Bevacizumab
Antibody directed against VEGFR
Rituximab
Antibody against CD20 antigen
Alemtuzumab
Antibody against CD52 antigen
Antibody drug
Trastuzumab
Targets chemotherapy to
conjugates
deruxtecan
Sacituzumab
Targets chemotherapy to
govitecan
Enfortumab vedotin
Targets chemotherapy to
Inducers of
Arsenic trioxide
Induces apoptosis by caspase inhibition
apoptosis
Inhibition of nitric oxide
Venetoclax
BH3 mimetic
Tumour types that may be sensitive
to drug
Pituitary tumours
Prostate cancer
Prostate cancer
Non-small cell lung cancer
Chronic myeloid leukaemia
GISTs
Non-small cell lung cancer
Pancreatic cancer
Renal cancer
GIST refractory to Imatinib
Colorectal cancer
Thyroid cancer
Breast cancer
Renal cancer
Breast cancer
Multiple myeloma
B from
Acute promyelocytic leukaemia
nesyl transferase and consequent
Leukaemia
ras
-dependent signal transduction
Acute leukaemia
ras
-dependent signal transduction
Myelodysplastic syndrome
Breast cancer
Colorectal cancer
Head and neck cancer
Colorectal cancer
Lymphomas
Lymphomas
Her2
expressing tumour
Breast cancer
Trop2
expressing tumour
Breast cancer
Nectin4
expressing tumour
Urothelial cancer
Acute promyelocytic leukaemia
CML
AML
Lymphoma
Continued

Cytotoxic chemotherapy Selective toxicity is the fundamental principle underlying cytotoxic chemotherapy . Tumour types vary greatly in their sensitivity to cytotoxic chemotherapy and their vulnerability to drugs with speciﬁc mechanisms of  action. Treatments are often given for a limited number of  treatment days during a cycle of  treatment lasting typically 3–4 weeks. This allows the tumour to receive an e ﬀ ective dose while providing su ﬃ cient time for the patient to recover in time for the next cycle. Many treatment regimens give a limited number of  cycles, typically three to six in total. Other regimens are maintenance treat ments, in which an unlimited number of  cycles are given. Hormonal treatments Several tumour types, notably breast cancer and prostate cancer, are stimulated by endogenous hormones. Removal of this stimulus from sensitive tumours will result in their shrink age. An understanding of  the relevant endocrine pathways has identiﬁed several points for therapeutic intervention, including interference with hormone receptors and with hormone production. Targeted treatments The explosion of  knowledge about the molecular biology of cancer has identiﬁed multiple therapeutic targets. This has ushered in an era of  highly speciﬁc treatments that aim to inhibit a target essential for tumour survival while leaving other tissues una ﬀ ected. At present, most targeted therapies are not absolutely speciﬁc for their primary target and therefore do - have unwanted or ‘o ﬀ -target’ side e ﬀ ects. In addition, successful inhibition of  the target may have inevitable undesirable conse - quences in addition to the desired e ﬀ ect, so-called ‘on-target’ side e ﬀ ects. Many targeted treatments are given in continuous cycles and the dosing and toxicity management strategies are therefor e of  particular importance. These treatments will only work if  a patient’s tumour - depends on a therapeutic target. The kinase inhibitor vemu - rafenib will only be e ﬀ ective in patients with melanoma whose 

Class
Examples
Putative mode of action
Immunological
Ipilimumab
Blocks CTLA-4 and thus releases the brakes on the
mediators
activation of T cells
Block the PD-1 signalling on T lymphocytes and
Pembrolizumab
thereby prevents the inhibition of T-cell activation
Nivolumab
Atezolizumab
Durvalumab
Interferon alpha-2b
Activates macrophages, increases the cytotoxicity
of T lymphocytes, inhibits cell division (and viral
replication)
Thalidomide
Anti-in
/f_l
ammatory, stimulates T cells, antiangiogenic
HDAC inhibitors
Panobinostat
Acetylation of histones is associated with increased
Vorinostat
transcription of genes; inhibiting deacetylation can
decrease expression of mutated or dysregulated
genes
Entinostat
Acetylation of histones is associated with increased
transcription of genes; inhibiting deacetylation can
decrease expression of mutated or dysregulated
genes
PI3K inhibitors
Idelalisib
Inhibits signalling via the PI3K/AKT/mTOR
pathway and thereby switch off stimulus to cellular
proliferation
mTOR inhibitors
Temsirolimus
Inhibit mTOR, a key component in the PI3K/AKT/
Everolimus
mTOR pathway
MEK inhibitors
Trametinib
Inhibit the MAPK pathway
Selumetinib
RAF inhibitors
Dabrafenib
Inhibit the MAPK pathway
Vemurafenib
AML, acute myeloid leukaemia; ATP
, adenosine triphosphate; CML, chronic myeloid leukaemia; CTLA-4, cytotoxic T-lymphocyte-associated
protein 4; EGFR, epidermal growth factor receptor; FLT3, FMS-like tyrosine kinase; GI, gastrointestinal; GIST, gastrointestinal stromal tumour;
HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated pr
target of rapamycin; NF , nuclear factor; PARP , poly-ADP ribose polymerase; PD-1, pr
growth factor receptor; PI3K, phosphoinositide 3-kinase; RAF , rapidly accelerated
/f_i
brosarcoma; TKI, tyrosine kinase inhibitor; VEGFR,
vascular endothelial growth factor receptor.
Tumour types that may be sensitive
to drug
Melanoma
Lung cancer
Renal cancer
Melanoma
Lung cancer
Renal cancer
Bladder cancer
Hairy-cell leukaemia
Myeloma
Cutaneous T-cell lymphoma
Melanoma
B-cell lymphomas
Renal cancer
Neuroendocrine tumours
Melanoma
Neuro
/f_i
broma
Melanoma
otein kinase; mTOR, mammalian
ogrammed cell death protein 1; PDGFR, platelet-derived

e ﬀ ective in patients with colorectal cancer who have wild-type (non-mutated) ras ; imatinib is particularly e ﬀ ective in patients with gastrointestinal stromal tumours who have mutations in exon 11 of  the Kit gene – patients with mutations in exon 9 may still respond to imatinib but will require higher doses and patients without mutations in Kit are far less likely to respond to imatinib. Treatment choice therefore requires a molecular analysis of  the patient’s tumour. It is this determination of  treatment at the individual level that has led to the concept of  ‘personalised medicine’. Although major adv ances have been made, import ant targets such as ras remain elusive at present, although sev eral ras -targeted molecules are in development. Immunotherapy Treatments to activate the immune system against cancer have a long history , stimulated by the observation that up to half  of  the volume of  certain tumours was known to be made up of  immune cells, which appeared to be inactive or dead. There is now an appreciation that multiple malignan cies activate mechanisms whose normal purpose is to down regulate the immune system after elimination of  an infectious organism. These mechanisms are called T-cell checkpoints. Inhibition of  these checkpoints can reactiva te the immune cells and has had remarkable success in previously virtually untreatable diseases such as metastatic melanoma. This novel form of  treatment is generally much better tolerated than cytotoxic chemotherapy but may result in side e ﬀ ects owing to the uncontrolled activation of the immune system. Side e ﬀ ects such as pneumonitis, colitis, adrenal failure and hypophysitis (pituitary inﬂammation) may be life-changing or life-threatening and are more common when using a combi nation of  checkpoint inhibitors. Immunotherapy is a very active ﬁeld of  research and it is likely that vaccines and engineered immune cells will increas ingly enter treatment protocols in the coming years. The range of non-surgical anti-cancer treatments

Radiotherapy Half  of  all patients will receive radiotherapy during their - cancer journey . The mechanism of  action of  radiotherapy is that ionising radiation causes single- and double-stranded - DNA breaks. Cells most sensitive to radiotherapy are in mitosis or late G2 in the cell cycle. Damage may be caused - by the direct e ﬀ ect of  the ionising radiation on the DNA. However, the predominant therapeutic e ﬀ ect is indirect, and is achieved by ionising radiation causing the creation of  oxygen free radicals, which then damage the DNA. The fact that the or indirect damage is predominant explains why hypoxic cells - are relatively resistant to radiotherapy . In practice, adequate oxygenation of  tissues is assisted by simple measures such as correcting anaemia prior to radiotherapy . Cancer types di ﬀ er greatly in their sensitivity to radiother apy . Similarly , higher doses of  radiotherapy are needed to con trol bulky disease (~70 /uni00A0 Gy) than to eliminate residual tumour cells (~50 /uni00A0 Gy) or to palliate symptoms (~30 /uni00A0 Gy). Radiotherapy is mainly used as a localised treatment ( Figure 12.7 ). The target area is deﬁned by imaging, which will include anatomical imaging, such as CT and MRI, to identify the tumour mass, neighbouring structur es and landmarks for radiotherapy planning. Sometimes functional imaging, such as PET , is used to further deﬁne structures that should be included in the radiation ﬁeld such as lymph nodes containing small volumes of  tumour, whose metabolic signatur e is detected by PET . The planning and technical set-up of radiotherapy is a highly specialised subject. Planning can be extremely di ﬃ cult and time-consuming, e.g. in the treatment of head and neck cancer, where the treatment intent is curative but there are multiple vital and highly sensitive structures close to the target area. In general terms, the radiotherapy team will aim to pro vide a uniform therapeutic radiation dose to the target area, while sparing adjacent structures from signiﬁcant damage. The most common form of  treatment is external beam radiother apy in which x-rays are aimed at the tar get volume from an external source. Where necessary , modern radiotherapy can employ sophisticated computer programs and algorithms to sculpt the shape of  the treatment volume. It is no w possible to irradiate irregularly shaped target volumes using techniques such as intensity-modulated radiation therapy (IMRT) and - image-guided radiation therapy (IGRT). The ability to give - high fractional doses in this way has led to the development of  stereotactic ablative radiotherapy (SAbR), in which a small number of  fractions can be used to treat primary tumours, or isolated metastases, to curative dose levels. Other ways of  targeting the tumour volume include brachytherapy , in which the radiation source is brought ver y close to the tumour by insertion of  radioactive seeds, and radionuclide therapy , in which a radioactive source is concen - trated at the tumour site. One of  the main problems in determining the optimal schedule of  radiation is that there is a dissociation between the acute e ﬀ ects on normal tissues and the late damage. The acute reaction is not a reliable guide to the adverse consequences of treatment in the longer term. Since the late e ﬀ ects following irradiation can take over 20 years to develop, this poses an obvious di ﬃ culty: if  a radiation schedule is changed it will be known within 2 or 3 years whether or not the new schedule - has improved tumour control; it may , however, be two decades before it is known, with any degree of  certainty , whether or not the new technique is safe. - Anti-cancer drugs The classes of  anti-cancer drugs, their modes of  action and clinical indications are summarised in Table 12.6 . 

upon for cure
70 with no
30 with
residual cancer
residual cancer
15 sensitive to
15 resistant to
adjuvant therapy
adjuvant therapy
5 relapse (inadequate
15 relapse despite
therapy, toxicity, etc.)
adjuvant therapy
despite adjuvant
therapy
10 patients whose
residual disease was
eradicated by
adjuvant therapy
Net bene
/f_i
ts
Futile therapy
20% 90% treated
inappropriately
Unnecessary therapy
70%
Bene
/f_i
cial therapy
10%
10% treated
appropriately
No therapy
0%
Figure 12.5
The concept of adjuvant chemotherapy.
upon for cure
Imperfect but clinically adequate test for residual disease
60 with no
40 with
residual cancer,
‘residual cancer’,
none are
all are treated
treated
15 sensitive to
10 with no 15 resistant to
adjuvant therapy
residual disease adjuvant therapy
5 relapse (inadequate
15 relapse despite
therapy, toxicity, etc.)
adjuvant therapy
despite adjuvant
therapy
10 patients whose
residual disease was
eradicated by
Net bene
/f_i
ts
adjuvant therapy
Futile therapy 20% 30% treated
inappropriately
Unnecessary therapy
10%
Bene
/f_i
cial therapy
10%
70% treated
appropriately
No therapy
60%
Figure 12.6
The concept of adjuvant chemotherapy and testing for minimal
residual disease.

• • • • • • • • • • • • • • • • • • • • • • • • • 

Knowledge of
Anatomy
Patter
ns and probability of spread of disease
Cross-sectional imaging
CT, MRI
Functional imaging
Positron emission tomography (PET)
Functional MRI
Radiotherapy dose prescription
Optimise the therapeutic ratio
Choose that combination of total
dose, number of treatments
(fractions) and overall treatment
time so that the damage to normal
tissues is minimised and the effects
on tumour are maximised
Figure 12.7
The processes involved in clinical radiotherapy. CT, computed tomography; MRI, magnetic resonance imaging.
TABLE 12.6
Examples of anti-cancer drugs currently in use.
Class
Examples
Putative mode of action
Drugs that interfere
Vincristine
Interfere with formation of microtubules: ‘spindle
with mitosis
Vinblastine
poisons’
Stabilise microtubules
Taxanes:
paclitaxel
docetaxel
cabazitaxel
5-Fluorouracil
Inhibition of thymidylate synthase, false substrate
Drugs that interfere
Capecitabine
for both DNA and RNA synthesis
with DNA synthesis
(antimetabolites)
Methotrexate
Inhibition of dihydrofolate reductase
6-Mercaptopurine
Inhibit
de novo
6-Thioguanine
Technical set-up
Optimal use of radiation beams
Simulate the ‘beam’s-eye view’ of the target
Diagnostic quality screening and
/f_i
lms
Images digitally reconstructed from CT
planning images
Three-dimensional planning
Careful shaping of beams (‘conformal therapy’)
Alter energy pro
/f_i
le across the beam to sculpt the
dose distribution to complex shapes (‘intensity
modulated radiation therapy’ – IMRT)
Optimal delivery of treatment
Ensure day-to-day reproducibility of set up
Online veri
/f_i
cation (portal imaging)
Reference tattoos
Immobilisation of patient (moulds, shells)
Ensure that only the target is treated
Eliminate effect of physiological movement
(breathing, peristalsis): ‘image-guided
radiation therapy’ – IGRT
Quality control and cross-checking procedures
throughout the whole process from target de
/f_i
nition
to follow-up
Tumour types that may be sensitive
to drug
Lymphomas
Leukaemias
Brain tumours
Sarcomas
Breast cancer
Non-small cell lung cancer
Ovarian cancer
Prostate cancer
Head and neck cancer
Breast cancer
GI cancer
Breast cancer
Bladder cancer
Lymphomas
Cervical cancer
purine synthesis
Leukaemias
Continued



Class
Examples
Putative mode of action
Cytosine arabinoside False substrate in DNA synthesis
Drugs that interfere
with DNA synthesis
(antimetabolites)
Gemcitabine Inhibits ribonucleotide reductase
–
continued
Mitomycin C DNA cross-linking, preferentially active at sites of Anal cancer
Drugs that directly
low oxygen tension (a bioreductive drug)
damage DNA or
interfere with its
function
Cisplatin
Form adducts between DNA strands and interferes Germ cell tumours
Carboplatin
with replication
Oxaliplatin
Forms adducts between DNA strands and interferes Colorectal cancer
with replication
Doxorubicin Intercalates between DNA strands and interferes Breast cancer
with replication
Cyclophosphamide A prodrug converted via hepatic cytochrome p450
to phosphoramide mustard. Causes DNA cross-
links
Ifosfamide
Related to cyclophosphamide, causes DNA cross- Small cell lung cancer
links
Bleomycin
DNA strand breakage via formation of metal Germ cell tumours
complex
Irinotecan
Inhibits topoisomerase 1, prevents DNA from Colorectal cancer
unwinding and repairing during replication
Etoposide
Inhibits topoisomerase 2, prevents DNA from Small cell lung cancer
unwinding and repairing during replication
Dacarbazine A nitrosourea that requires activation by hepatic
cytochrome p450. Methylates guanine residues in
DNA
Temozolomide A nitrosourea but, unlike dacarbazine, does not
require activation by hepatic cytochrome p450.
Methylates guanine residues in DNA
Actinomycin D Intercalation between DNA strands, DNA strand Rhabdomyosarcoma
breaks
Inhibit DNA repair by PARP , especially in
DNA damage
Olaparib
mutated cancers
response inhibitors
Niraparib
Rucaparib
Hormones
Tamoxifen
Blocks oestrogen receptors
Aromatase inhibitors that block postmenopausal Breast cancer
Anastrozole
(non-ovarian) oestrogen production
Letrozole
Exemestane
Analogues of gonadotropin-releasing hormone,
Leuprolide
continued use produces downregulation of the
Goserelin
anterior pituitary with consequent fall in testosterone
Buserelin
levels
Cabergoline Blocks prolactin release, a long-acting dopamine Prolactin-secreting pituitary tumours
agonist
Tumour types that may be sensitive
to drug
Leukaemias
Lymphomas
Non-small lung cancer
Pancreatic cancer
Bladder cancer
Gastric cancer
Head and neck cancer
Rectal cancer
Ovarian cancer
Non-small cell lung cancer
Head and neck cancer
Oesophageal cancer
Lymphomas
Sarcomas
Kaposi’s sarcoma
Breast cancer
Lymphomas
Sarcomas
Sarcomas
Lymphomas
Germ cell tumours
Lymphomas
Brain tumours
Sarcoma
Glioblastoma multiforme
Wilms’ tumour
BRCA
- Ovarian cancer
Breast cancer
Prostate cancer
Breast cancer
Prostate cancer
Continued

κ 

Class
Examples
Putative mode of action
Hormones
Bromocriptine
Dopamine agonist, blocks stimulation of anterior
–
continued
pituitary
Block the effect of androgens
Cyproterone acetate
Flutamide
Nilutamide
Bicalutamide
Abiraterone
Block testosterone production
Cyproterone acetate
Inhibit EGFR tyrosine kinase
Inhibitors of receptor
Osimertinib
tyrosine kinases
Erlotinib
Afatinib
Ge
/f_i
tinib
Imatinib
Blocks ability of mutant BCR-ABL fusion protein to
bind ATP
Imatinib
Inhibition of mutant c-KIT
Erlotinib
Inhibits EGFR tyrosine kinase
Promiscuous tyrosine kinase inhibitors (PDGFR,
Sunitinib
VEGFR, KIT, FLT)
Regorafenib
Lenvatinib
Lapatinib
Inhibits tyrosine kinases associated with EGFR and
HER2
Axitinib
Inhibits tyrosine kinase associated with VEGFR
Cyclin-dependent
Palbociclib
Inhibits growth signal
kinase inhibitors
Protease inhibitors
Bortezomib
Interferes with proteasomal degradation of
r
egulatory proteins, in particular stops NF-
preventing apoptosis
Differentiating
All-
trans
-retinoic acid
Induces terminal differentiation
agents
Farnesyl transferase
Lonafarnib
Inhibition of far
inhibitors
inactivation of
Tipifarnib
Inhibition of farnesyl transferase and consequent
inactivation of
Trastuzumab
Antibody directed against HER2 receptor
Antibodies directed
to cell surface
Cetuximab
Antibody directed against EGFR
antigens
Bevacizumab
Antibody directed against VEGFR
Rituximab
Antibody against CD20 antigen
Alemtuzumab
Antibody against CD52 antigen
Antibody drug
Trastuzumab
Targets chemotherapy to
conjugates
deruxtecan
Sacituzumab
Targets chemotherapy to
govitecan
Enfortumab vedotin
Targets chemotherapy to
Inducers of
Arsenic trioxide
Induces apoptosis by caspase inhibition
apoptosis
Inhibition of nitric oxide
Venetoclax
BH3 mimetic
Tumour types that may be sensitive
to drug
Pituitary tumours
Prostate cancer
Prostate cancer
Non-small cell lung cancer
Chronic myeloid leukaemia
GISTs
Non-small cell lung cancer
Pancreatic cancer
Renal cancer
GIST refractory to Imatinib
Colorectal cancer
Thyroid cancer
Breast cancer
Renal cancer
Breast cancer
Multiple myeloma
B from
Acute promyelocytic leukaemia
nesyl transferase and consequent
Leukaemia
ras
-dependent signal transduction
Acute leukaemia
ras
-dependent signal transduction
Myelodysplastic syndrome
Breast cancer
Colorectal cancer
Head and neck cancer
Colorectal cancer
Lymphomas
Lymphomas
Her2
expressing tumour
Breast cancer
Trop2
expressing tumour
Breast cancer
Nectin4
expressing tumour
Urothelial cancer
Acute promyelocytic leukaemia
CML
AML
Lymphoma
Continued

Cytotoxic chemotherapy Selective toxicity is the fundamental principle underlying cytotoxic chemotherapy . Tumour types vary greatly in their sensitivity to cytotoxic chemotherapy and their vulnerability to drugs with speciﬁc mechanisms of  action. Treatments are often given for a limited number of  treatment days during a cycle of  treatment lasting typically 3–4 weeks. This allows the tumour to receive an e ﬀ ective dose while providing su ﬃ cient time for the patient to recover in time for the next cycle. Many treatment regimens give a limited number of  cycles, typically three to six in total. Other regimens are maintenance treat ments, in which an unlimited number of  cycles are given. Hormonal treatments Several tumour types, notably breast cancer and prostate cancer, are stimulated by endogenous hormones. Removal of this stimulus from sensitive tumours will result in their shrink age. An understanding of  the relevant endocrine pathways has identiﬁed several points for therapeutic intervention, including interference with hormone receptors and with hormone production. Targeted treatments The explosion of  knowledge about the molecular biology of cancer has identiﬁed multiple therapeutic targets. This has ushered in an era of  highly speciﬁc treatments that aim to inhibit a target essential for tumour survival while leaving other tissues una ﬀ ected. At present, most targeted therapies are not absolutely speciﬁc for their primary target and therefore do - have unwanted or ‘o ﬀ -target’ side e ﬀ ects. In addition, successful inhibition of  the target may have inevitable undesirable conse - quences in addition to the desired e ﬀ ect, so-called ‘on-target’ side e ﬀ ects. Many targeted treatments are given in continuous cycles and the dosing and toxicity management strategies are therefor e of  particular importance. These treatments will only work if  a patient’s tumour - depends on a therapeutic target. The kinase inhibitor vemu - rafenib will only be e ﬀ ective in patients with melanoma whose 

Class
Examples
Putative mode of action
Immunological
Ipilimumab
Blocks CTLA-4 and thus releases the brakes on the
mediators
activation of T cells
Block the PD-1 signalling on T lymphocytes and
Pembrolizumab
thereby prevents the inhibition of T-cell activation
Nivolumab
Atezolizumab
Durvalumab
Interferon alpha-2b
Activates macrophages, increases the cytotoxicity
of T lymphocytes, inhibits cell division (and viral
replication)
Thalidomide
Anti-in
/f_l
ammatory, stimulates T cells, antiangiogenic
HDAC inhibitors
Panobinostat
Acetylation of histones is associated with increased
Vorinostat
transcription of genes; inhibiting deacetylation can
decrease expression of mutated or dysregulated
genes
Entinostat
Acetylation of histones is associated with increased
transcription of genes; inhibiting deacetylation can
decrease expression of mutated or dysregulated
genes
PI3K inhibitors
Idelalisib
Inhibits signalling via the PI3K/AKT/mTOR
pathway and thereby switch off stimulus to cellular
proliferation
mTOR inhibitors
Temsirolimus
Inhibit mTOR, a key component in the PI3K/AKT/
Everolimus
mTOR pathway
MEK inhibitors
Trametinib
Inhibit the MAPK pathway
Selumetinib
RAF inhibitors
Dabrafenib
Inhibit the MAPK pathway
Vemurafenib
AML, acute myeloid leukaemia; ATP
, adenosine triphosphate; CML, chronic myeloid leukaemia; CTLA-4, cytotoxic T-lymphocyte-associated
protein 4; EGFR, epidermal growth factor receptor; FLT3, FMS-like tyrosine kinase; GI, gastrointestinal; GIST, gastrointestinal stromal tumour;
HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated pr
target of rapamycin; NF , nuclear factor; PARP , poly-ADP ribose polymerase; PD-1, pr
growth factor receptor; PI3K, phosphoinositide 3-kinase; RAF , rapidly accelerated
/f_i
brosarcoma; TKI, tyrosine kinase inhibitor; VEGFR,
vascular endothelial growth factor receptor.
Tumour types that may be sensitive
to drug
Melanoma
Lung cancer
Renal cancer
Melanoma
Lung cancer
Renal cancer
Bladder cancer
Hairy-cell leukaemia
Myeloma
Cutaneous T-cell lymphoma
Melanoma
B-cell lymphomas
Renal cancer
Neuroendocrine tumours
Melanoma
Neuro
/f_i
broma
Melanoma
otein kinase; mTOR, mammalian
ogrammed cell death protein 1; PDGFR, platelet-derived

e ﬀ ective in patients with colorectal cancer who have wild-type (non-mutated) ras ; imatinib is particularly e ﬀ ective in patients with gastrointestinal stromal tumours who have mutations in exon 11 of  the Kit gene – patients with mutations in exon 9 may still respond to imatinib but will require higher doses and patients without mutations in Kit are far less likely to respond to imatinib. Treatment choice therefore requires a molecular analysis of  the patient’s tumour. It is this determination of  treatment at the individual level that has led to the concept of  ‘personalised medicine’. Although major adv ances have been made, import ant targets such as ras remain elusive at present, although sev eral ras -targeted molecules are in development. Immunotherapy Treatments to activate the immune system against cancer have a long history , stimulated by the observation that up to half  of  the volume of  certain tumours was known to be made up of  immune cells, which appeared to be inactive or dead. There is now an appreciation that multiple malignan cies activate mechanisms whose normal purpose is to down regulate the immune system after elimination of  an infectious organism. These mechanisms are called T-cell checkpoints. Inhibition of  these checkpoints can reactiva te the immune cells and has had remarkable success in previously virtually untreatable diseases such as metastatic melanoma. This novel form of  treatment is generally much better tolerated than cytotoxic chemotherapy but may result in side e ﬀ ects owing to the uncontrolled activation of the immune system. Side e ﬀ ects such as pneumonitis, colitis, adrenal failure and hypophysitis (pituitary inﬂammation) may be life-changing or life-threatening and are more common when using a combi nation of  checkpoint inhibitors. Immunotherapy is a very active ﬁeld of  research and it is likely that vaccines and engineered immune cells will increas ingly enter treatment protocols in the coming years. The range of non-surgical anti-cancer treatments

Radiotherapy Half  of  all patients will receive radiotherapy during their - cancer journey . The mechanism of  action of  radiotherapy is that ionising radiation causes single- and double-stranded - DNA breaks. Cells most sensitive to radiotherapy are in mitosis or late G2 in the cell cycle. Damage may be caused - by the direct e ﬀ ect of  the ionising radiation on the DNA. However, the predominant therapeutic e ﬀ ect is indirect, and is achieved by ionising radiation causing the creation of  oxygen free radicals, which then damage the DNA. The fact that the or indirect damage is predominant explains why hypoxic cells - are relatively resistant to radiotherapy . In practice, adequate oxygenation of  tissues is assisted by simple measures such as correcting anaemia prior to radiotherapy . Cancer types di ﬀ er greatly in their sensitivity to radiother apy . Similarly , higher doses of  radiotherapy are needed to con trol bulky disease (~70 /uni00A0 Gy) than to eliminate residual tumour cells (~50 /uni00A0 Gy) or to palliate symptoms (~30 /uni00A0 Gy). Radiotherapy is mainly used as a localised treatment ( Figure 12.7 ). The target area is deﬁned by imaging, which will include anatomical imaging, such as CT and MRI, to identify the tumour mass, neighbouring structur es and landmarks for radiotherapy planning. Sometimes functional imaging, such as PET , is used to further deﬁne structures that should be included in the radiation ﬁeld such as lymph nodes containing small volumes of  tumour, whose metabolic signatur e is detected by PET . The planning and technical set-up of radiotherapy is a highly specialised subject. Planning can be extremely di ﬃ cult and time-consuming, e.g. in the treatment of head and neck cancer, where the treatment intent is curative but there are multiple vital and highly sensitive structures close to the target area. In general terms, the radiotherapy team will aim to pro vide a uniform therapeutic radiation dose to the target area, while sparing adjacent structures from signiﬁcant damage. The most common form of  treatment is external beam radiother apy in which x-rays are aimed at the tar get volume from an external source. Where necessary , modern radiotherapy can employ sophisticated computer programs and algorithms to sculpt the shape of  the treatment volume. It is no w possible to irradiate irregularly shaped target volumes using techniques such as intensity-modulated radiation therapy (IMRT) and - image-guided radiation therapy (IGRT). The ability to give - high fractional doses in this way has led to the development of  stereotactic ablative radiotherapy (SAbR), in which a small number of  fractions can be used to treat primary tumours, or isolated metastases, to curative dose levels. Other ways of  targeting the tumour volume include brachytherapy , in which the radiation source is brought ver y close to the tumour by insertion of  radioactive seeds, and radionuclide therapy , in which a radioactive source is concen - trated at the tumour site. One of  the main problems in determining the optimal schedule of  radiation is that there is a dissociation between the acute e ﬀ ects on normal tissues and the late damage. The acute reaction is not a reliable guide to the adverse consequences of treatment in the longer term. Since the late e ﬀ ects following irradiation can take over 20 years to develop, this poses an obvious di ﬃ culty: if  a radiation schedule is changed it will be known within 2 or 3 years whether or not the new schedule - has improved tumour control; it may , however, be two decades before it is known, with any degree of  certainty , whether or not the new technique is safe. - Anti-cancer drugs The classes of  anti-cancer drugs, their modes of  action and clinical indications are summarised in Table 12.6 . 

upon for cure
70 with no
30 with
residual cancer
residual cancer
15 sensitive to
15 resistant to
adjuvant therapy
adjuvant therapy
5 relapse (inadequate
15 relapse despite
therapy, toxicity, etc.)
adjuvant therapy
despite adjuvant
therapy
10 patients whose
residual disease was
eradicated by
adjuvant therapy
Net bene
/f_i
ts
Futile therapy
20% 90% treated
inappropriately
Unnecessary therapy
70%
Bene
/f_i
cial therapy
10%
10% treated
appropriately
No therapy
0%
Figure 12.5
The concept of adjuvant chemotherapy.
upon for cure
Imperfect but clinically adequate test for residual disease
60 with no
40 with
residual cancer,
‘residual cancer’,
none are
all are treated
treated
15 sensitive to
10 with no 15 resistant to
adjuvant therapy
residual disease adjuvant therapy
5 relapse (inadequate
15 relapse despite
therapy, toxicity, etc.)
adjuvant therapy
despite adjuvant
therapy
10 patients whose
residual disease was
eradicated by
Net bene
/f_i
ts
adjuvant therapy
Futile therapy 20% 30% treated
inappropriately
Unnecessary therapy
10%
Bene
/f_i
cial therapy
10%
70% treated
appropriately
No therapy
60%
Figure 12.6
The concept of adjuvant chemotherapy and testing for minimal
residual disease.

• • • • • • • • • • • • • • • • • • • • • • • • • 

Knowledge of
Anatomy
Patter
ns and probability of spread of disease
Cross-sectional imaging
CT, MRI
Functional imaging
Positron emission tomography (PET)
Functional MRI
Radiotherapy dose prescription
Optimise the therapeutic ratio
Choose that combination of total
dose, number of treatments
(fractions) and overall treatment
time so that the damage to normal
tissues is minimised and the effects
on tumour are maximised
Figure 12.7
The processes involved in clinical radiotherapy. CT, computed tomography; MRI, magnetic resonance imaging.
TABLE 12.6
Examples of anti-cancer drugs currently in use.
Class
Examples
Putative mode of action
Drugs that interfere
Vincristine
Interfere with formation of microtubules: ‘spindle
with mitosis
Vinblastine
poisons’
Stabilise microtubules
Taxanes:
paclitaxel
docetaxel
cabazitaxel
5-Fluorouracil
Inhibition of thymidylate synthase, false substrate
Drugs that interfere
Capecitabine
for both DNA and RNA synthesis
with DNA synthesis
(antimetabolites)
Methotrexate
Inhibition of dihydrofolate reductase
6-Mercaptopurine
Inhibit
de novo
6-Thioguanine
Technical set-up
Optimal use of radiation beams
Simulate the ‘beam’s-eye view’ of the target
Diagnostic quality screening and
/f_i
lms
Images digitally reconstructed from CT
planning images
Three-dimensional planning
Careful shaping of beams (‘conformal therapy’)
Alter energy pro
/f_i
le across the beam to sculpt the
dose distribution to complex shapes (‘intensity
modulated radiation therapy’ – IMRT)
Optimal delivery of treatment
Ensure day-to-day reproducibility of set up
Online veri
/f_i
cation (portal imaging)
Reference tattoos
Immobilisation of patient (moulds, shells)
Ensure that only the target is treated
Eliminate effect of physiological movement
(breathing, peristalsis): ‘image-guided
radiation therapy’ – IGRT
Quality control and cross-checking procedures
throughout the whole process from target de
/f_i
nition
to follow-up
Tumour types that may be sensitive
to drug
Lymphomas
Leukaemias
Brain tumours
Sarcomas
Breast cancer
Non-small cell lung cancer
Ovarian cancer
Prostate cancer
Head and neck cancer
Breast cancer
GI cancer
Breast cancer
Bladder cancer
Lymphomas
Cervical cancer
purine synthesis
Leukaemias
Continued



Class
Examples
Putative mode of action
Cytosine arabinoside False substrate in DNA synthesis
Drugs that interfere
with DNA synthesis
(antimetabolites)
Gemcitabine Inhibits ribonucleotide reductase
–
continued
Mitomycin C DNA cross-linking, preferentially active at sites of Anal cancer
Drugs that directly
low oxygen tension (a bioreductive drug)
damage DNA or
interfere with its
function
Cisplatin
Form adducts between DNA strands and interferes Germ cell tumours
Carboplatin
with replication
Oxaliplatin
Forms adducts between DNA strands and interferes Colorectal cancer
with replication
Doxorubicin Intercalates between DNA strands and interferes Breast cancer
with replication
Cyclophosphamide A prodrug converted via hepatic cytochrome p450
to phosphoramide mustard. Causes DNA cross-
links
Ifosfamide
Related to cyclophosphamide, causes DNA cross- Small cell lung cancer
links
Bleomycin
DNA strand breakage via formation of metal Germ cell tumours
complex
Irinotecan
Inhibits topoisomerase 1, prevents DNA from Colorectal cancer
unwinding and repairing during replication
Etoposide
Inhibits topoisomerase 2, prevents DNA from Small cell lung cancer
unwinding and repairing during replication
Dacarbazine A nitrosourea that requires activation by hepatic
cytochrome p450. Methylates guanine residues in
DNA
Temozolomide A nitrosourea but, unlike dacarbazine, does not
require activation by hepatic cytochrome p450.
Methylates guanine residues in DNA
Actinomycin D Intercalation between DNA strands, DNA strand Rhabdomyosarcoma
breaks
Inhibit DNA repair by PARP , especially in
DNA damage
Olaparib
mutated cancers
response inhibitors
Niraparib
Rucaparib
Hormones
Tamoxifen
Blocks oestrogen receptors
Aromatase inhibitors that block postmenopausal Breast cancer
Anastrozole
(non-ovarian) oestrogen production
Letrozole
Exemestane
Analogues of gonadotropin-releasing hormone,
Leuprolide
continued use produces downregulation of the
Goserelin
anterior pituitary with consequent fall in testosterone
Buserelin
levels
Cabergoline Blocks prolactin release, a long-acting dopamine Prolactin-secreting pituitary tumours
agonist
Tumour types that may be sensitive
to drug
Leukaemias
Lymphomas
Non-small lung cancer
Pancreatic cancer
Bladder cancer
Gastric cancer
Head and neck cancer
Rectal cancer
Ovarian cancer
Non-small cell lung cancer
Head and neck cancer
Oesophageal cancer
Lymphomas
Sarcomas
Kaposi’s sarcoma
Breast cancer
Lymphomas
Sarcomas
Sarcomas
Lymphomas
Germ cell tumours
Lymphomas
Brain tumours
Sarcoma
Glioblastoma multiforme
Wilms’ tumour
BRCA
- Ovarian cancer
Breast cancer
Prostate cancer
Breast cancer
Prostate cancer
Continued

κ 

Class
Examples
Putative mode of action
Hormones
Bromocriptine
Dopamine agonist, blocks stimulation of anterior
–
continued
pituitary
Block the effect of androgens
Cyproterone acetate
Flutamide
Nilutamide
Bicalutamide
Abiraterone
Block testosterone production
Cyproterone acetate
Inhibit EGFR tyrosine kinase
Inhibitors of receptor
Osimertinib
tyrosine kinases
Erlotinib
Afatinib
Ge
/f_i
tinib
Imatinib
Blocks ability of mutant BCR-ABL fusion protein to
bind ATP
Imatinib
Inhibition of mutant c-KIT
Erlotinib
Inhibits EGFR tyrosine kinase
Promiscuous tyrosine kinase inhibitors (PDGFR,
Sunitinib
VEGFR, KIT, FLT)
Regorafenib
Lenvatinib
Lapatinib
Inhibits tyrosine kinases associated with EGFR and
HER2
Axitinib
Inhibits tyrosine kinase associated with VEGFR
Cyclin-dependent
Palbociclib
Inhibits growth signal
kinase inhibitors
Protease inhibitors
Bortezomib
Interferes with proteasomal degradation of
r
egulatory proteins, in particular stops NF-
preventing apoptosis
Differentiating
All-
trans
-retinoic acid
Induces terminal differentiation
agents
Farnesyl transferase
Lonafarnib
Inhibition of far
inhibitors
inactivation of
Tipifarnib
Inhibition of farnesyl transferase and consequent
inactivation of
Trastuzumab
Antibody directed against HER2 receptor
Antibodies directed
to cell surface
Cetuximab
Antibody directed against EGFR
antigens
Bevacizumab
Antibody directed against VEGFR
Rituximab
Antibody against CD20 antigen
Alemtuzumab
Antibody against CD52 antigen
Antibody drug
Trastuzumab
Targets chemotherapy to
conjugates
deruxtecan
Sacituzumab
Targets chemotherapy to
govitecan
Enfortumab vedotin
Targets chemotherapy to
Inducers of
Arsenic trioxide
Induces apoptosis by caspase inhibition
apoptosis
Inhibition of nitric oxide
Venetoclax
BH3 mimetic
Tumour types that may be sensitive
to drug
Pituitary tumours
Prostate cancer
Prostate cancer
Non-small cell lung cancer
Chronic myeloid leukaemia
GISTs
Non-small cell lung cancer
Pancreatic cancer
Renal cancer
GIST refractory to Imatinib
Colorectal cancer
Thyroid cancer
Breast cancer
Renal cancer
Breast cancer
Multiple myeloma
B from
Acute promyelocytic leukaemia
nesyl transferase and consequent
Leukaemia
ras
-dependent signal transduction
Acute leukaemia
ras
-dependent signal transduction
Myelodysplastic syndrome
Breast cancer
Colorectal cancer
Head and neck cancer
Colorectal cancer
Lymphomas
Lymphomas
Her2
expressing tumour
Breast cancer
Trop2
expressing tumour
Breast cancer
Nectin4
expressing tumour
Urothelial cancer
Acute promyelocytic leukaemia
CML
AML
Lymphoma
Continued

Cytotoxic chemotherapy Selective toxicity is the fundamental principle underlying cytotoxic chemotherapy . Tumour types vary greatly in their sensitivity to cytotoxic chemotherapy and their vulnerability to drugs with speciﬁc mechanisms of  action. Treatments are often given for a limited number of  treatment days during a cycle of  treatment lasting typically 3–4 weeks. This allows the tumour to receive an e ﬀ ective dose while providing su ﬃ cient time for the patient to recover in time for the next cycle. Many treatment regimens give a limited number of  cycles, typically three to six in total. Other regimens are maintenance treat ments, in which an unlimited number of  cycles are given. Hormonal treatments Several tumour types, notably breast cancer and prostate cancer, are stimulated by endogenous hormones. Removal of this stimulus from sensitive tumours will result in their shrink age. An understanding of  the relevant endocrine pathways has identiﬁed several points for therapeutic intervention, including interference with hormone receptors and with hormone production. Targeted treatments The explosion of  knowledge about the molecular biology of cancer has identiﬁed multiple therapeutic targets. This has ushered in an era of  highly speciﬁc treatments that aim to inhibit a target essential for tumour survival while leaving other tissues una ﬀ ected. At present, most targeted therapies are not absolutely speciﬁc for their primary target and therefore do - have unwanted or ‘o ﬀ -target’ side e ﬀ ects. In addition, successful inhibition of  the target may have inevitable undesirable conse - quences in addition to the desired e ﬀ ect, so-called ‘on-target’ side e ﬀ ects. Many targeted treatments are given in continuous cycles and the dosing and toxicity management strategies are therefor e of  particular importance. These treatments will only work if  a patient’s tumour - depends on a therapeutic target. The kinase inhibitor vemu - rafenib will only be e ﬀ ective in patients with melanoma whose 

Class
Examples
Putative mode of action
Immunological
Ipilimumab
Blocks CTLA-4 and thus releases the brakes on the
mediators
activation of T cells
Block the PD-1 signalling on T lymphocytes and
Pembrolizumab
thereby prevents the inhibition of T-cell activation
Nivolumab
Atezolizumab
Durvalumab
Interferon alpha-2b
Activates macrophages, increases the cytotoxicity
of T lymphocytes, inhibits cell division (and viral
replication)
Thalidomide
Anti-in
/f_l
ammatory, stimulates T cells, antiangiogenic
HDAC inhibitors
Panobinostat
Acetylation of histones is associated with increased
Vorinostat
transcription of genes; inhibiting deacetylation can
decrease expression of mutated or dysregulated
genes
Entinostat
Acetylation of histones is associated with increased
transcription of genes; inhibiting deacetylation can
decrease expression of mutated or dysregulated
genes
PI3K inhibitors
Idelalisib
Inhibits signalling via the PI3K/AKT/mTOR
pathway and thereby switch off stimulus to cellular
proliferation
mTOR inhibitors
Temsirolimus
Inhibit mTOR, a key component in the PI3K/AKT/
Everolimus
mTOR pathway
MEK inhibitors
Trametinib
Inhibit the MAPK pathway
Selumetinib
RAF inhibitors
Dabrafenib
Inhibit the MAPK pathway
Vemurafenib
AML, acute myeloid leukaemia; ATP
, adenosine triphosphate; CML, chronic myeloid leukaemia; CTLA-4, cytotoxic T-lymphocyte-associated
protein 4; EGFR, epidermal growth factor receptor; FLT3, FMS-like tyrosine kinase; GI, gastrointestinal; GIST, gastrointestinal stromal tumour;
HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated pr
target of rapamycin; NF , nuclear factor; PARP , poly-ADP ribose polymerase; PD-1, pr
growth factor receptor; PI3K, phosphoinositide 3-kinase; RAF , rapidly accelerated
/f_i
brosarcoma; TKI, tyrosine kinase inhibitor; VEGFR,
vascular endothelial growth factor receptor.
Tumour types that may be sensitive
to drug
Melanoma
Lung cancer
Renal cancer
Melanoma
Lung cancer
Renal cancer
Bladder cancer
Hairy-cell leukaemia
Myeloma
Cutaneous T-cell lymphoma
Melanoma
B-cell lymphomas
Renal cancer
Neuroendocrine tumours
Melanoma
Neuro
/f_i
broma
Melanoma
otein kinase; mTOR, mammalian
ogrammed cell death protein 1; PDGFR, platelet-derived

e ﬀ ective in patients with colorectal cancer who have wild-type (non-mutated) ras ; imatinib is particularly e ﬀ ective in patients with gastrointestinal stromal tumours who have mutations in exon 11 of  the Kit gene – patients with mutations in exon 9 may still respond to imatinib but will require higher doses and patients without mutations in Kit are far less likely to respond to imatinib. Treatment choice therefore requires a molecular analysis of  the patient’s tumour. It is this determination of  treatment at the individual level that has led to the concept of  ‘personalised medicine’. Although major adv ances have been made, import ant targets such as ras remain elusive at present, although sev eral ras -targeted molecules are in development. Immunotherapy Treatments to activate the immune system against cancer have a long history , stimulated by the observation that up to half  of  the volume of  certain tumours was known to be made up of  immune cells, which appeared to be inactive or dead. There is now an appreciation that multiple malignan cies activate mechanisms whose normal purpose is to down regulate the immune system after elimination of  an infectious organism. These mechanisms are called T-cell checkpoints. Inhibition of  these checkpoints can reactiva te the immune cells and has had remarkable success in previously virtually untreatable diseases such as metastatic melanoma. This novel form of  treatment is generally much better tolerated than cytotoxic chemotherapy but may result in side e ﬀ ects owing to the uncontrolled activation of the immune system. Side e ﬀ ects such as pneumonitis, colitis, adrenal failure and hypophysitis (pituitary inﬂammation) may be life-changing or life-threatening and are more common when using a combi nation of  checkpoint inhibitors. Immunotherapy is a very active ﬁeld of  research and it is likely that vaccines and engineered immune cells will increas ingly enter treatment protocols in the coming years.

# Therapeutic decision making and the multidisciplin

Therapeutic decision making and the multidisciplinary team

As the management of  cancer becomes more complex, it becomes impossible for an individual clinician to have the competence that is necessary to manage all patients presenting with a particular type of  tumour. The formation of  multidisci plinary teams represents an attempt to make certain that each and every patient with a particular type of  cancer is managed appropriately . Teams should not only be multidisciplinary – they should also be multiprofessional. The advantages and disadvantages of multidisciplinary teams are summarised in Table 12.4 . The multidisciplinary team needs to answer three basic questions for every patient: /uni25CF What is the patient’s diagnosis, stage and molecular char acteristics of  disease? /uni25CF What is the goal of  treatment for the patient? In simple terms, this can be divided into cure, prolongation of  life and palliation of  symptoms. /uni25CF What treatment options are there to achieve these aims with the fewest possible side e ﬀ ects? Options may include surgery , radiotherapy , anti-cancer systemic (drug) treat ment, symptom control measures, a combination of  these options and, in some cases, observation. makes recommendations, rather than deﬁnite treatment deci - sions. Several other factor s must be considered, which can only be done by a clinician making a direct assessment of the patient’s health and wishes. The clinician must ascertain the - patient’s ﬁtness and hence their ability to tolerate treatment. This will be heavily inﬂuenced b y comorbidities. Patients vary er, greatly in their willingness to tolerate treatment for a given - beneﬁt and particularly how they value quality of  life com - pared with length of  life or chance of  cure. There are often several possible treatment plans and the clinical team must take the time to explain the options care - fully to the patient and the patient’s supporters. In many can - - cer centres, there will be both standard-of-care and resear ch options available for patients. Explanations should include what is involved in the treatment, what beneﬁts may r esult and the chance of  the patient receiving those beneﬁts. The clinical team must also explain the possible downsides of  treatment and the likelihood of  experiencing them. Patients are often faced with a large amount of  complex and di ﬃ cult informa - tion at a time when they are extremely vulnerable. The clinical team must support patients to reach a decision and this may take time and repeated explanation. - 

TABLE 12.4
The advantages and disadvantages of the multidisciplinary team.
Advantages
Open debate concerning management of complex patients with
many specialists
Decision making is open, transparent and explicit
Team members educate each other
A useful educational experience for trainees and students
Performance can be monitored by managers

Therapeutic decision making and the multidisciplinary team

As the management of  cancer becomes more complex, it becomes impossible for an individual clinician to have the competence that is necessary to manage all patients presenting with a particular type of  tumour. The formation of  multidisci plinary teams represents an attempt to make certain that each and every patient with a particular type of  cancer is managed appropriately . Teams should not only be multidisciplinary – they should also be multiprofessional. The advantages and disadvantages of multidisciplinary teams are summarised in Table 12.4 . The multidisciplinary team needs to answer three basic questions for every patient: /uni25CF What is the patient’s diagnosis, stage and molecular char acteristics of  disease? /uni25CF What is the goal of  treatment for the patient? In simple terms, this can be divided into cure, prolongation of  life and palliation of  symptoms. /uni25CF What treatment options are there to achieve these aims with the fewest possible side e ﬀ ects? Options may include surgery , radiotherapy , anti-cancer systemic (drug) treat ment, symptom control measures, a combination of  these options and, in some cases, observation. makes recommendations, rather than deﬁnite treatment deci - sions. Several other factor s must be considered, which can only be done by a clinician making a direct assessment of the patient’s health and wishes. The clinician must ascertain the - patient’s ﬁtness and hence their ability to tolerate treatment. This will be heavily inﬂuenced b y comorbidities. Patients vary er, greatly in their willingness to tolerate treatment for a given - beneﬁt and particularly how they value quality of  life com - pared with length of  life or chance of  cure. There are often several possible treatment plans and the clinical team must take the time to explain the options care - fully to the patient and the patient’s supporters. In many can - - cer centres, there will be both standard-of-care and resear ch options available for patients. Explanations should include what is involved in the treatment, what beneﬁts may r esult and the chance of  the patient receiving those beneﬁts. The clinical team must also explain the possible downsides of  treatment and the likelihood of  experiencing them. Patients are often faced with a large amount of  complex and di ﬃ cult informa - tion at a time when they are extremely vulnerable. The clinical team must support patients to reach a decision and this may take time and repeated explanation. - 

TABLE 12.4
The advantages and disadvantages of the multidisciplinary team.
Advantages
Open debate concerning management of complex patients with
many specialists
Decision making is open, transparent and explicit
Team members educate each other
A useful educational experience for trainees and students
Performance can be monitored by managers

# Therapeutic decision making and the multidisciplinary team

Therapeutic decision making and the multidisciplinary team

As the management of  cancer becomes more complex, it becomes impossible for an individual clinician to have the competence that is necessary to manage all patients presenting with a particular type of  tumour. The formation of  multidisci plinary teams represents an attempt to make certain that each and every patient with a particular type of  cancer is managed appropriately . Teams should not only be multidisciplinary – they should also be multiprofessional. The advantages and disadvantages of multidisciplinary teams are summarised in Table 12.4 . The multidisciplinary team needs to answer three basic questions for every patient: /uni25CF What is the patient’s diagnosis, stage and molecular char acteristics of  disease? /uni25CF What is the goal of  treatment for the patient? In simple terms, this can be divided into cure, prolongation of  life and palliation of  symptoms. /uni25CF What treatment options are there to achieve these aims with the fewest possible side e ﬀ ects? Options may include surgery , radiotherapy , anti-cancer systemic (drug) treat ment, symptom control measures, a combination of  these options and, in some cases, observation. makes recommendations, rather than deﬁnite treatment deci - sions. Several other factor s must be considered, which can only be done by a clinician making a direct assessment of the patient’s health and wishes. The clinician must ascertain the - patient’s ﬁtness and hence their ability to tolerate treatment. This will be heavily inﬂuenced b y comorbidities. Patients vary er, greatly in their willingness to tolerate treatment for a given - beneﬁt and particularly how they value quality of  life com - pared with length of  life or chance of  cure. There are often several possible treatment plans and the clinical team must take the time to explain the options care - fully to the patient and the patient’s supporters. In many can - - cer centres, there will be both standard-of-care and resear ch options available for patients. Explanations should include what is involved in the treatment, what beneﬁts may r esult and the chance of  the patient receiving those beneﬁts. The clinical team must also explain the possible downsides of  treatment and the likelihood of  experiencing them. Patients are often faced with a large amount of  complex and di ﬃ cult informa - tion at a time when they are extremely vulnerable. The clinical team must support patients to reach a decision and this may take time and repeated explanation. - 

TABLE 12.4
The advantages and disadvantages of the multidisciplinary team.
Advantages
Open debate concerning management of complex patients with
many specialists
Decision making is open, transparent and explicit
Team members educate each other
A useful educational experience for trainees and students
Performance can be monitored by managers

# WHAT IS CANCER  History

WHAT IS CANCER? History

The word ‘cancer’ is credited to Hippocrates (460 /uni00A0 /b.sc/c.sc/e.sc –370 /uni00A0/b.sc/c.sc/e.sc ), who is widely agreed to be the father of  medicine, and comes from the Greek word for a crab, referring to the ﬁnger-like projections of  a cancer from a central mass, which have simi larities to a crab’s claws and legs. The study of  cancer has long been a part of  clinical med icine: theories have moved from divine intervention and are now ﬁrmly based on the molecular origins of  cancer. Rudolf Virchow was the ﬁrst to demonstrate that cancer is a disease of  cells and that the disease progresses as a r esult of  abnormal proliferation, encapsulated by his dictum omnes cellula e cellula (every cell from a cell). In 1914, Theodor Boveri pointed out the importance of  chromosomal abnormalities in cancer cells and, in the 1940s, Oswald Avery demonstrated that DNA was the genetic material within the chromosomes. In 1953, Watson and Crick described the structure of  DNA, which was the key discovery leading to the understanding of  the molecular biol ogy of cancer. This understanding has allowed the investiga tion and understanding of  the molecular mechanisms whereby Hippocrates , 460 /uni00A0 /b.sc/c.sc/e.sc –375 /uni00A0/b.sc/c.sc/e.sc , was a Greek Physician and, by common consent, ‘the father of  medicine’. Rudolf  Ludwig Carl Virchow , 1821–1902, Professor of  Pathology , Berlin, Germany . Theodor Heinrich Boveri , 1862–1913, Professor of  Zoology and Comparative Anatomy , Würzburg, Germany . Oswald Theodore Avery , 1877–1955, bacteriologist, Rockefeller Institute, New Y ork, NY , USA. James Dewey Watson , b.1928, American biologist who worked in Cambridge, UK, and later became Director of  the Cold Spring Harbor Laboratory , New Yo rk ,  N Y,  U S A . Francis Harry Compton Crick , 1916–2004, British molecular biologist who worked at the Cavendish Laboratory , Cambridge, UK, and later at the Salk In stitute, San Diego, CA, USA. Watson and Crick shared the 1962 Nobel Prize in Physiology or Medicine with Kings College, London, UK. Douglas Hanahan , b.1951, American biologist and director of  the Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland. Robert Allan Weinberg , b.1942, The Whitehead Institute of  Biomedical Research and Department of  Biology , The Massachusetts Institute of  Technology , Cambridge, MA, USA. cancer cells are formed and their abnormal behaviours are mediated; in turn, this has allowed modern molecular-based therapies to be developed. 

To appreciate:
The principles of cancer aetiology and the major causative
•
factors
The multidisciplinary management of cancer
•
The distinction between palliative care and end-of-life care
•
The principles of palliative care
•

WHAT IS CANCER? History

The word ‘cancer’ is credited to Hippocrates (460 /uni00A0 /b.sc/c.sc/e.sc –370 /uni00A0/b.sc/c.sc/e.sc ), who is widely agreed to be the father of  medicine, and comes from the Greek word for a crab, referring to the ﬁnger-like projections of  a cancer from a central mass, which have simi larities to a crab’s claws and legs. The study of  cancer has long been a part of  clinical med icine: theories have moved from divine intervention and are now ﬁrmly based on the molecular origins of  cancer. Rudolf Virchow was the ﬁrst to demonstrate that cancer is a disease of  cells and that the disease progresses as a r esult of  abnormal proliferation, encapsulated by his dictum omnes cellula e cellula (every cell from a cell). In 1914, Theodor Boveri pointed out the importance of  chromosomal abnormalities in cancer cells and, in the 1940s, Oswald Avery demonstrated that DNA was the genetic material within the chromosomes. In 1953, Watson and Crick described the structure of  DNA, which was the key discovery leading to the understanding of  the molecular biol ogy of cancer. This understanding has allowed the investiga tion and understanding of  the molecular mechanisms whereby Hippocrates , 460 /uni00A0 /b.sc/c.sc/e.sc –375 /uni00A0/b.sc/c.sc/e.sc , was a Greek Physician and, by common consent, ‘the father of  medicine’. Rudolf  Ludwig Carl Virchow , 1821–1902, Professor of  Pathology , Berlin, Germany . Theodor Heinrich Boveri , 1862–1913, Professor of  Zoology and Comparative Anatomy , Würzburg, Germany . Oswald Theodore Avery , 1877–1955, bacteriologist, Rockefeller Institute, New Y ork, NY , USA. James Dewey Watson , b.1928, American biologist who worked in Cambridge, UK, and later became Director of  the Cold Spring Harbor Laboratory , New Yo rk ,  N Y,  U S A . Francis Harry Compton Crick , 1916–2004, British molecular biologist who worked at the Cavendish Laboratory , Cambridge, UK, and later at the Salk In stitute, San Diego, CA, USA. Watson and Crick shared the 1962 Nobel Prize in Physiology or Medicine with Kings College, London, UK. Douglas Hanahan , b.1951, American biologist and director of  the Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland. Robert Allan Weinberg , b.1942, The Whitehead Institute of  Biomedical Research and Department of  Biology , The Massachusetts Institute of  Technology , Cambridge, MA, USA. cancer cells are formed and their abnormal behaviours are mediated; in turn, this has allowed modern molecular-based therapies to be developed. 

To appreciate:
The principles of cancer aetiology and the major causative
•
factors
The multidisciplinary management of cancer
•
The distinction between palliative care and end-of-life care
•
The principles of palliative care
•

WHAT IS CANCER? History

The word ‘cancer’ is credited to Hippocrates (460 /uni00A0 /b.sc/c.sc/e.sc –370 /uni00A0/b.sc/c.sc/e.sc ), who is widely agreed to be the father of  medicine, and comes from the Greek word for a crab, referring to the ﬁnger-like projections of  a cancer from a central mass, which have simi larities to a crab’s claws and legs. The study of  cancer has long been a part of  clinical med icine: theories have moved from divine intervention and are now ﬁrmly based on the molecular origins of  cancer. Rudolf Virchow was the ﬁrst to demonstrate that cancer is a disease of  cells and that the disease progresses as a r esult of  abnormal proliferation, encapsulated by his dictum omnes cellula e cellula (every cell from a cell). In 1914, Theodor Boveri pointed out the importance of  chromosomal abnormalities in cancer cells and, in the 1940s, Oswald Avery demonstrated that DNA was the genetic material within the chromosomes. In 1953, Watson and Crick described the structure of  DNA, which was the key discovery leading to the understanding of  the molecular biol ogy of cancer. This understanding has allowed the investiga tion and understanding of  the molecular mechanisms whereby Hippocrates , 460 /uni00A0 /b.sc/c.sc/e.sc –375 /uni00A0/b.sc/c.sc/e.sc , was a Greek Physician and, by common consent, ‘the father of  medicine’. Rudolf  Ludwig Carl Virchow , 1821–1902, Professor of  Pathology , Berlin, Germany . Theodor Heinrich Boveri , 1862–1913, Professor of  Zoology and Comparative Anatomy , Würzburg, Germany . Oswald Theodore Avery , 1877–1955, bacteriologist, Rockefeller Institute, New Y ork, NY , USA. James Dewey Watson , b.1928, American biologist who worked in Cambridge, UK, and later became Director of  the Cold Spring Harbor Laboratory , New Yo rk ,  N Y,  U S A . Francis Harry Compton Crick , 1916–2004, British molecular biologist who worked at the Cavendish Laboratory , Cambridge, UK, and later at the Salk In stitute, San Diego, CA, USA. Watson and Crick shared the 1962 Nobel Prize in Physiology or Medicine with Kings College, London, UK. Douglas Hanahan , b.1951, American biologist and director of  the Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland. Robert Allan Weinberg , b.1942, The Whitehead Institute of  Biomedical Research and Department of  Biology , The Massachusetts Institute of  Technology , Cambridge, MA, USA. cancer cells are formed and their abnormal behaviours are mediated; in turn, this has allowed modern molecular-based therapies to be developed. 

To appreciate:
The principles of cancer aetiology and the major causative
•
factors
The multidisciplinary management of cancer
•
The distinction between palliative care and end-of-life care
•
The principles of palliative care
•