12 Principles of oncology

Cancer staging
End-of-life care
Introduction
Learning objectives
Oncological emergencies
Prevention
Principles of cancer surgery
Principles of combined treatment
Principles underlying the non-surgical treatment o
Principles underlying the non-surgical treatment of cancer
Screening
Symptom control and palliative care
THE CAUSES OF CANCER The interplay between nature
THE CAUSES OF CANCER The interplay between nature and nurture
THE CAUSES OF CANCER The interplay between nature
THE MANAGEMENT OF CANCER Management is more than t
THE MANAGEMENT OF CANCER Management is more than treatment
The growth of a cancer
The hallmarks of cancer
The range of non-surgical anti-cancer treatments
Therapeutic decision making and the multidisciplin
Therapeutic decision making and the multidisciplinary team
WHAT IS CANCER History

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

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

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

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

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

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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

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

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

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

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

Use effective agents Use agents with different modes of action (synergy) Use agents with non-overlapping toxicities Consider spatial cooperation

Principles of combined treatment

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

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

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

Screening

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

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 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

THE CAUSES OF CANCER The interplay between nature and nurture

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

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

THE MANAGEMENT OF CANCER Management is more than treatment

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

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

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

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.

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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

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

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Ovarian cancer Breast cancer Prostate cancer Breast cancer Prostate cancer Continued

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Ovarian cancer Breast cancer Prostate cancer Breast cancer Prostate cancer Continued

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

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