Principles of Cancer Management

Benign Neoplasms

Benign neoplasms usually grow slowly, are typically well demarcated and often encapsulated, with a histological appearance closely reminiscent of the tissue of origin. Benign tumours present to the surgeon in many ways, summarised in Box 13.1 . Most neoplasms can be readily categorised as benign or malignant according to histological determinants, making it possible to predict whether invasion or metastasis is likely. Sometimes this is difficult, for example, distinguishing between leiomyoma and leiomyosarcoma, or when there is insufficient tissue sampling; note that parts of benign lesions may transform into malignant lesions. Neoplasms may also be difficult to distinguish clinically from other tumour-like disorders, such as hyperplasia (e.g., parathyroid adenoma from hyperplasia) or hamartomatous growth (a growth composed of a mixture of tissues usually found in that area of the body—these are benign but may still require removal).

Malignant Neoplasms

Malignant neoplasms are typically nonencapsulated with a poorly defined, irregular outline because of local tissue invasion. They usually grow progressively and often rapidly. Histologically, the cells range from well differentiated to anaplastic (i.e., little or no resemblance to parent tissue), with the aggression generally increasing with greater dedifferentiation, although well differentiated malignancies can be highly aggressive. The cells and nuclei of malignant neoplasms often vary widely in shape and size. The extent of this pleomorphism also tends to correlate with the degree of malignancy and the future clinical behaviour of the tumour, as can the extent of lymphovascular and perineural invasion. These histological features are taken into account by the pathologist when classifying and grading the tumour. The supporting tissue stroma of some malignancies may undergo fibrous hyperplasia, which accounts for some of the characteristic clinical features; these include hardness to palpation (induration), intestinal obstruction caused by annular carcinomas of the large bowel, and retraction and dimpling of skin overlying breast cancers. On the other hand, in highly aggressive tumours, the supporting tissue stroma may be inadequate for metabolic support, leading to necrosis and patchy haemorrhage within the tumour. This can present with sudden onset of pain and/or a mass. Malignant tumours present in a variety of ways summarised in Box 13.2 .

Carcinogenesis

Most cancers are probably caused by a complex (and chance-driven) interplay between environmental factors and patient-intrinsic factors. About two-thirds of cancers may be attributed (to some extent) to external environmental factors, such as ultraviolet light, ionising radiation, virus infections and carcinogens in air, food and water. Often the mutation pattern (e.g., guanine-cytosine>thymine-adenine transversion from carcinogens in tobacco smoke) can point to the relevant carcinogen. Given the widespread ‘field’ effect of preceding risk factors, patients with one carcinogen-induced cancer are at risk of developing another in that tissue, and must be kept under close surveillance after curative treatment for the first cancer—large swathes of the tissue may have inherited predisposing mutations. While this helps decide follow-up schedules after radical treatment, it can be difficult to distinguish between new primaries and recurrences. Certain tissues, particularly those of the bladder, breast, skin, head and neck, lung and large bowel, are at particular risk of new primaries.

Growth and Spread of Malignant Tumours

Most malignancies probably arise from a single cell that has become capable of growing progressively. About 30 cell division cycles are probably needed to produce a clinically detectable lesion of 1 cm diameter containing 1000 million cells. Many properties must be acquired for the tumour to progress (see Table 13.2 ). Particular cellular properties enable a tumour to invade surrounding tissues, invade lymphatic or blood capillaries, disseminate and ‘take root’ in regional lymph nodes or spread to coelomic cavities or distant organs. These properties often arise through mutation and a change in cellular programming known as epithelial-to-mesenchymal transition (EMT), where the tumour cells lose the original tumour properties and become more migratory and stem cell-like. The precise changes that promote vascular versus lymphatic invasion, and which dictate preferred sites of distant metastases remain largely unknown, although the latter can be simply anatomical (e.g., liver metastasis from colorectal or pancreatic cancer).

These pathophysiological factors have important clinical consequences. Firstly, the earlier the primary tumour is detected and removed (i.e., the fewer cell division cycles and the fewer the number of tumour subclones), the greater the chance of complete cure. Unfortunately, changes that permit metastasis can appear very early, that is, by about 20 cell division cycles, when the primary lesion is too small to be detected (about 1 mm). The hallmarks of cancer can be acquired in any order, and additional metastasis-inducing genetic mutations may not even be required to produce the EMT phenotype as it can be promoted by other signals, such as aberrant growth factor receptor signalling.

In practice, when lymph node metastases are present and fully resectable, the probability of surgical cure depends when the cancer develops its capacity for further spread. This can be as early as when lymph node metastases appear, so haematogenous metastases may already be multifocal and make surgical removal of detected metastases ineffective. Evidence-based guidelines dictate which groups of lymph nodes (and how many) need to be removed for optimal surgical/pathological staging. The liver, lungs, bone and brain are common organs for haematogenous spread, with each tumour type having particular propensities to metastasise most often to certain organs.

Principles of Cancer Management

Two broad considerations determine the approach to treatment for any cancer patient. The first is whether an attempt can and should be made to achieve a cure or whether palliation is more appropriate—note that palliation does not necessarily mean that prognosis will be short, since life can be substantially prolonged with other treatments. For example, well over 20% of metastatic oestrogen receptor-positive breast cancer patients survive beyond 5 years, and this continues to rise. The choice between curative-intent and palliative-intent management depends on the nature of the tumour, the extent of local spread and whether distant metastases are believed to be present. The next considerations are the natural history of the type of cancer (including molecular features) and the patient’s age (although only if relevant and evidence based) and comorbidities determining the ability to withstand surgery.

Systems of staging have been devised for each tumour type, many based on the TNM system developed by the Union for International Cancer Control, which scores characteristics of the primary T umour itself, the extent of regional lymph N ode involvement and the presence or absence of distant or other M etastases. Staging is used in planning treatment, as a guide to prognosis and as a standardised descriptive tool for comparing efficacies of treatments in similar populations in clinical trials, and in comparisons between different centres.

Cancer can recur at any time after the primary treatment, and treatment success is often described in terms of survival after a given number of years rather than ‘cure’. Five- or 10- year survival are common yardsticks and can imply cure. Some tumours however, such as breast cancer, may recur in a disseminated form as long as 40 years after apparently successful treatment, probably owing to activation of long dormant micrometastases. Conversely, others, such as localised colorectal cancers, rarely recur after 10 years. Clinicians should be cautious about using the term ‘cure’, bearing in mind the tumour type and its likely behaviour, and the likelihood of complete elimination of tumour by therapy. The probability of cure can be discussed, but where recurrence remains possible, the term should be avoided in its absolute sense. Tumour- and risk-specific follow-up schedules are determined by prospects for treatment should recurrences be found. Most include clinical review, imaging and sometimes blood tests for tumour markers, and ideally should be able to detect recurrence early (whilst still salvageable), but balanced against the burdens and risks of active surveillance.

Tumour Markers

Proteins shed by tumour cells can be helpful in diagnosis, surveillance, and monitoring the effects of treatment. Some commonly used blood-borne tumour markers are carcinoembryonic antigen (CEA; colorectal cancer), carbohydrate antigen (CA)19-9 (pancreatic cancer), alpha-fetoprotein (AFP) and β-human chorionic gonadotropin (HCG; germ cell tumours), CA125 (ovarian cancer), prostate-specific antigen (PSA; prostate cancer), and CA15-3 (breast cancer).

Team Working in Cancer Management

There is a growing international trend towards involving a range of specialists working in cooperative teams to manage patients with complex problems. Structured MDTs are recommended for managing most cancer cases, but particularly where the diagnosis needs consideration and where treatment may involve radiotherapy, chemotherapy or targeted therapy pre- or postoperatively, meticulous planning of an operation, prostheses or reconstructive surgery, stoma care and specialist nursing or physiotherapy, as well as nutritional, social and psychological support.

The benefits of working in this way arise from the battery of experience brought by experts in different disciplines, particularly where diagnostic and therapeutic options are not clear. Cases can be discussed at any stage in the diagnostic or treatment process and an optimum treatment plan generated; the group has joint responsibility for implementing the plan. For rarer, and more difficult to manage, cancers (such as sarcoma), patients should be referred to specialist centres that deal with larger numbers to ensure optimal care.

Treatment Options

The general principles of cancer management are highlighted in Box 13.3 . The treatment options for malignant disease include surgical excision, radiotherapy, chemotherapy , hormonal manipulation and other molecularly targeted therapies (including immunotherapy) , with two or more often used in combination. A treatment strategy usually depends on the tumour type and stage, histopathological and molecular profile (at the genetic/protein level), the patient’s overall fitness and whether the aim is cure or palliation. A radical or aggressive approach may be recommended where the aim is cure, provided evidence supports this approach. Where cure is not possible, or where disease has relapsed after radical treatment, the aim is to use palliative treatments, that is, to extend or improve quality of life and/or alleviate cancer-related symptoms.

A diagnosis of cancer should never be concealed from a competent patient. Aside from the obvious ethical ramifications, suspicion and fear of the unknown often causes more distress than a frank explanation of the diagnosis and its ramifications. Likewise, prognostic information (with its associated uncertainty) should be offered, although patients should be allowed to decline this information. Time should be allowed for the patient to formulate further questions and a follow-up consultation arranged in a few days. It usually helps the patient to have a friend or relative present. Patients are also helped by well-constructed printed information, by patient groups and cancer charities, and by specially trained cancer nurses who can spend the necessary time and act as an intermediary if necessary.

All anticancer treatments can involve unpleasant and sometimes life-threatening side-effects , and these risks must be weighed against their intended benefits after a full and frank discussion with the patient to ensure valid informed consent. Patients need to be appropriately informed and involved in treatment decisions, though the amount of information given varies, with some patients wanting as much information as possible, and others as little as they absolutely need—nevertheless, when treatment has the potential to do harm, patients need enough information to decide if it is actually in their best interests.

Palliative Care

Palliative care focuses on quality of life when cure is not possible and involves weighing up the benefits of any treatment against its burdens and toxicities while focusing on what is important to the patient and their family. Active palliative-intent anticancer treatments (which aim to control cancer growth) should be distinguished from symptomatic palliative care (which uses supportive treatments or procedures including radiotherapy to alleviate cancer-related symptoms). In practice, these two approaches usually occur in parallel, and there is a growing trend for palliative care physicians and nurses to be involved early (alongside oncologists) in the care of patients with incurable disease, rather than when anticancer treatments have been exhausted or are not appropriate.

Specialist palliative care teams can offer invaluable outpatient support in difficult matters of symptom control, or psychological, social or spiritual problems. Some patients may need short admissions to specialist units (often called hospices ) for symptom control and eventually for terminal care.

General Principles of Cancer Surgery (see Box 13.3 )

The ideal result from cancer surgery is complete eradication of all malignant disease without radically interfering with organ function. Around a third of cancer patients can be cured in this way, although this varies greatly by cancer type. Decisions about whether to embark on major elective surgery depends on assessment of the nature of the disease (usually through analysis of diagnostic biopsies or cytological specimens) and its radiological stage. Modern techniques of cross-sectional imaging with CT/magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography imaging, laparoscopy, endoscopic staging (e.g., endobronchial ultrasound in lung cancer) and intraoperative ultrasound, greatly assist in accurate diagnosis, and can save patients from fruitless radical surgery. Guidelines have been produced to ensure cancer-type specific staging. Current evidence-based guidelines should be consulted to determine the best treatment approaches.

Sometimes, cancer cells can seed a biopsy tract (e.g., in soft tissue sarcoma), and these tracts need to be removed at the time of operation. For this reason, in suspected sarcoma, biopsies and surgery are performed at regional and national centres with expertise in the marking of biopsy tracts and subsequent surgery.

Metastases apparently confined to local lymph nodes are usually excised along with the primary tumour. In many cancer types, regional lymph nodes are removed and examined histologically even in the absence of evident metastases, to complete pathological staging . As well as a possible therapeutic benefit for removing viable cancer cells, this helps decide on optimal adjuvant treatment or surveillance.

Occasionally blood-borne metastasis appears to be a solitary event ( oligometastatic disease ) and a cure can still be achieved—for example, by partial hepatectomy for colorectal cancer or pulmonary lobectomy for renal cell carcinoma. Even in the presence of incurable metastatic disease, palliative surgery may be required for specific distressing symptoms from locally advanced or metastatic disease (e.g., dysphagia, pain or severe haemorrhage, spinal cord compression or bowel obstruction). Similar results can sometimes be obtained by less invasive techniques, such as radiotherapy, chemotherapy, embolisation, or other approaches to destroy cancer tissue, including radiofrequency probes or lasers. Endoscopic and interventional radiological procedures are often useful in palliation, and can prolong quality and length of life, for example, in relieving shortness of breath by stenting in superior vena caval obstruction, in relieving dysphagia by stenting a blocked oesophagus, or insertion of a biliary stent to relieve a blocked common bile duct.

Sometimes surgery is used to debulk a tumour, usually combined with chemotherapy to improve its efficacy (as in ovarian carcinoma), or to remove potentially viable tissue after curative-intent chemotherapy (e.g., retroperitoneal nodal masses in testicular germ cell tumours). Increasingly, chemotherapy and/or radiotherapy is used in the neoadjuvant setting to ‘downsize’ a malignant tumour to facilitate excisional surgery, for example, rectal cancer. This is sometimes inaccurately called ‘down-staging ’ since the effect on metastatic disease is unclear. Sometimes, however, removal of the primary tumour by a cytoreductive procedure can result in shrinkage of metastatic disease, most notably in renal cell carcinoma.

Tissue removed at operation should always be sent for histopathological analysis. This may be to histologically confirm malignancy (e.g., after orchidectomy in presumed testicular cancer). Even after a definitive diagnostic biopsy, surgical specimens are needed for pathological staging (in curative intent treatment). They contain more tumour cells than biopsies and provide more substrate for histopathological and molecular tests to give additional diagnostic and prognostic material and better inform decisions about future treatment. This can sometimes lead to a second diagnosis, for example, lymphoma after removal of enlarged nodes thought to be secondary to gastrointestinal cancer.

Cancer patients are at high risk of venous thromboembolic events, and low-molecular-weight heparin prophylaxis should be considered in hospitalised patients but carefully balanced against the risk of bleeding (or exacerbating ongoing bleeding).