This is defined as treatment given in the absence of macroscopic evidence of metastases, to patients at risk of recurrence from micrometastases, after treatment of the primary lesion has been given. ‘Neoadjuvant’ therapy is given before primary therapy, which may shrink the tumour size and treat any micrometastases as soon as possible.

Micrometastatic spread by lymphatic or haematological dissemination often occurs early in the development of the primary tumour, and can be demonstrated by molecular biological methods capable of detecting the small numbers (1 in 106) of circulating cells. Studies correlating prognosis with histological features of the primary cancer, e.g. differentiation or presence of early metastatic invasion of blood vessels or regional lymph nodes, have led to an increasing ability to predict which patients are at high risk of local or distant recurrence from micrometastatic disease.

Trials of treatment with local radiotherapy or endocrine, biological or chemotherapy treatments have shown a significant improvement in survival in common adult cancers such as breast, bowel, prostate, head and neck, cervical cancer, choriocarcinoma and gonadal germ cell cancers. Central to these studies has been the careful selection of patients according to defined risk criteria, and the reduction of treatment toxicity to reach a balanced risk/benefit ratio. Absolute improvements in survival of 5-10% and relative risk reductions in the order of 12-25% (dependent upon the pre-existing risk) have been achieved in common epithelial cancers such as bowel, breast and prostate, with greater absolute improvements of 25% in the more sensitive germ cell tumours.

While these improvements currently translate into many lives saved from common diseases at a public health level, the majority who receive such treatment do not benefit because they were already cured, or because the cancer is resistant to the treatment. Better tests in the future will identify those with the micrometastases who really need treatment. On an individual patient basis the decision on whether adjuvant treatment will be worthwhile must include consideration of other factors such as the patient’s life expectancy, concurrent medical conditions, and lifestyle priorities.

Box 9.2 Definitions of response

Complete response	Complete disappearance of all detectable disease
Partial response	More than 50% reduction in the product of the bidimensional diameters of the tumour
Stable disease	No change, or < 50% reduction and < 25% increase
Progressive disease	Increase in size of tumour by at least 25% at any site

• Superior vena caval obstruction can arise from any upper mediastinal mass but is most commonly associated with lung cancer and lymphoma. The patient presents with difficulty breathing and/or swallowing, with stridor, swollen, oedematous facies and venous congestion. Treatment is with immediate steroids, vascular stents, anticoagulation and mediastinal radiotherapy or chemotherapy. Some tumours, e.g. lymphomas and germ cell tumours, are so sensitive to chemotherapy that this is preferred to radiotherapy, as the masses are likely to be both large and associated with more disseminated disease elsewhere. An early decision is necessary on the patient’s likely prognosis, as ventilatory support may be required until treatment has had time to relieve the obstruction.
• Spinal cord compression needs to be rapidly diagnosed and urgent treatment arranged to salvage as much functional capacity as possible. Early neurological clinical features may be incomplete, more subjective than objective and gradual in onset. MR scanning is the investigation of choice. Treatment should begin with high-dose steroids followed by surgical decompression and radiotherapy to the affected vertebrae to achieve the best disease control and palliation.
• Neutropenic sepsis.
• Acute lysis syndrome. This occurs if treatment produces a massive breakdown of tumour cells, leading to increased serum levels of urate, potassium and phosphate. Urate deposition in the renal tubules can cause renal failure (hyperuricaemic nephropathy) requiring dialysis. The xanthene oxidase inhibitor (allopurinol) is given before treatment is started. Intravenous rasburicase, a recombinant urate oxidase, is occasionally used for prophylaxis and treatment but is very expensive.
• Acute hypercalcaemia presents with vomiting, confusion, constipation and oliguria Treatment is by resuscitation with intravenous fluids until a saline diuresis is established, followed by i.v. pamidronate (Emergency box 18.2).
• Raised intracranial pressure due to intracerebral metastases presents classically with headache, nausea and vomiting. However, for many there is a slower onset with non-specific symptoms such as drowsiness or mental deterioration. Treatment is by high-dose steroids and investigation by MRI as to whether surgery is appropriate or chemotherapy and radiotherapy are required.
• Hyperviscosity affects those with a very high haematocrit (> 50), white cell count (> 100 × 10⁹/L) or platelet cell count (> 1000 × 10⁹/L) from untreated acute leukaemia, or polycythaemia. Treatment is by leucopheresis and plasmapheresis followed by chemotherapy treatment for the underlying malignancy.

For most solid tumours local control is possible but not sufficient for cure because of the presence of systemic (microscopic) disease, while haematological cancers are usually disseminated from the outset. Improvement in the rate of cure of most cancers is thus dependent upon earlier detection and effective systemic treatment. The likelihood of cure of the systemic disease depends upon the type of cancer, its chemo-/hormonal sensitivity, and tumour bulk (microscopic or clinically detectable). A few rare cancers are so chemosensitive that even bulky metastases can be cured, e.g. leukaemia, lymphoma, gonadal germ cell tumours, and choriocarcinoma. For most common solid tumours such as breast and colorectal cancer, there is no current cure of bulky (clinically detectable) metastases, but micrometastatic disease treated by adjuvant chemotherapy (see below) after surgery can be cured in 10-20% of patients.

Aims of treatment

Table 9-5. TNM classification as used for lung cancer

T = extent of primary tumour; N = extent of regional lymph node involvement; M = presence of distant metastases
Tx	Positive cytology only
T1	< 3 cm diameter
T2	> 3 cm/extends to hilar region/invades visceral pleura/partial atelectasis
T3	Involvement of chest wall, diaphragm, pericardium, mediastinum, pleura, total atelectasis
T4	Involvement of heart, great vessels, trachea, oesophagus, malignant effusion
N1	Peribronchial, ipsilateral hilar lymph node involvement
N2	Ipsilateral mediastinal
N3	Contralateral mediastinal, scalene or supraclavicular
M0	No distant metastases
M1	Metastases present

Table 9-6. Eastern Cooperative Oncology Group (ECOG) performance status scale

Status	Description
0	Asymptomatic, fully active and able to carry out all predisease performance without restrictions
1	Symptomatic, fully ambulatory but restricted in physically strenuous activity and able to carry out performance of a light or sedentary nature, e.g. light housework, office work
2	Symptomatic, ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours: in bed less than 50% of day
3	Symptomatic, capable of only limited self-care, confined to bed or chair more than 50% of waking hours, but not bedridden
4	Completely disabled. Cannot carry out any self-care. Totally bedridden

Table 9-7. Serum tumour markers

α-Fetoprotein	Hepatocellular carcinoma, and non-seminomatous germ cell tumours of the gonads
β-Human chorionic gonadotrophin (β-HCG)	Choriocarcinomas, germ cell tumours and lung cancers
Prostate-specific antigen (PSA)	Carcinoma of prostate
Carcinoma embryonic antigen (CEA)	Gastrointestinal cancers
CA-125	Ovarian cancer
CA-19-9	Gastrointestinal cancers particularly pancreatic cancer
CA-15-3	Breast cancer

Cancer treatment requires the cooperation of a multidisciplinary team to coordinate the delivery of the appropriate treatment (surgery, chemotherapy, radiotherapy and biological/endocrine therapy), supportive and symptomatic care, and psychosocial support. While all members will have the patient’s care as their central concern, someone, often the oncologist, has to take responsibility for the coordination of the many professionals involved. Central to this endeavour is the involvement of the patient, through education as to the nature of their disease and the treatment options available. An informed choice can then be made, even if in the end it is simply to abide by the decisions made by the professionals. Good communication embodies a humane approach which preserves hope at an appropriate level through empathy and understanding of the patient’s position.

The diagnosis of cancer may be suspected by both patient and doctor but advice about treatment can usually only be given on the basis of a tissue diagnosis. This may be obtained by surgical biopsy or on the basis of cytology (e.g. lung cancer diagnosed by sputum cytology or cervix cancer diagnosed on the basis of a cervical smear). Malignant lesions can be distinguished morphologically from benign by the pleomorphic nature of the cells, increased numbers of mitoses, nuclear abnormalities in size, chromatin pattern and nucleolar organization, and evidence of invasion into surrounding tissues.

The degree of differentiation (or conversely of anaplasia) of the tumour has prognostic significance: generally speaking, more differentiated tumours have a better prognosis than poorly differentiated ones. Immunocytochemistry, using monoclonal antibodies against tumour antigens, is very helpful in differentiating between lymphoid and epithelial tumours and between some subsets of these, for example T and B cell lymphomas, germ cell tumours, prostatic tumours, neuroendocrine tumours, melanomas, and sarcomas. However, many adenocarcinomas and squamous carcinomas do not bear any distinctive immunohistochemical markers that are diagnostic of their primary site of origin.

There are several tests for genetic markers in tissue sections. For example, fluorescent in situ hybridization (FISH) can be used to look for characteristic chromosomal translocations, deletions or duplications (see genetic basis of cancer). Tissue microarrays can identify genomic imbalances, e.g. in breast cell cancer lines and lymphoma.

Staging

Before a decision about treatment can be made, not only the type of tumour but also its extent and distribution need to be established. Various ’staging investigations’ are therefore performed before a treatment decision is made. To be useful clinically the staging system must subdivide the patients into groups of different prognosis which can guide treatment selection.
The staging systems vary according to the type of tumour and may be site specific (see Hodgkin’s lymphoma), or the TNM (tumour, node, metastases) classification shown in Table 9.5 which can be applied to most common cancers.

Performance status

In addition to anatomical staging, the person’s age and general state of health need to be taken into account when planning treatment. The latter has been called ‘performance status’ and is of great prognostic significance for all tumour types (Table 9.6). Performance status reflects the effects of the cancer on the patient’s functional capacity. An alternative performance rating scale is by Karnowsky.

Tumour markers (Table 9.7)

Tumour markers are intracellular proteins or cell surface glycoproteins released into the circulation and detected by immunoassays. Alpha-fetoprotein, β-human chorionic gonadotrophin and prostate-specific antigen are useful in the diagnosis of cancer but the remainder in Table 9.7 should be used with great care in diagnosis because of low specificity. They can be useful in the serial monitoring of response to treatment, as they can be quite sensitive to changes in the tumour burden.