Management of malignant disease

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CHAPTER 7 Management of malignant disease

Patients with malignant disease form a major part of the workload of a surgical unit. They are assessed and decisions on management are made as part of a multidisciplinary team of surgeons, oncologists, specialist radiologists and pathologists, nurses, dieticians, etc. The total number of patients with malignant disease is rising owing to increased life expectancy. Where possible, the aims should be to prevent malignancy, e.g. cessation of smoking in the prevention of lung cancer, and the avoidance of excessive ultraviolet light in the prevention of skin cancer. Screening programmes should be instituted to make earlier diagnoses of the common forms of cancer and hopefully maximize the cure rate.

Screening

This is the examination of an asymptomatic population at risk of a particular condition, with a view to early diagnosis and consequent increase in cure rate. The basis for screening a normal population is to diagnose cancer at an asymptomatic stage, treatment at which point results in greater survival than cancers diagnosed at a symptomatic stage. For a screening programme to be successful it must adhere to certain principles:

• The cancer being detected must be common enough to represent an important health problem.

• The natural history of the cancer should be established, i.e. its development from a latent phase to symptomatic disease.

• A test should be available to detect the latent stage; the test should be sensitive and specific to the cancer and be acceptable and safe to the patient.

• Early detection of the cancer should lead to a benefit in terms of cost of treatment and survival of the patient.

Examples of screening programmes being carried out at present are:

• Cervical smears for cervical carcinoma

• Mammography for carcinoma of the breast

• Faecal occult bloods for carcinoma of the colon.

Premalignant conditions

It is important that these conditions are recognized and appropriate action taken.

Examples of premalignant conditions include:

• Skin: actinic keratoses, Bowen’s disease, erythroplasia of Queyrat (penis).

• GI tract: leukoplakia (mouth and tongue), Plummer–Vinson syndrome, Barrett’s oesophagus, villous adenoma, familial polyposis coli, ulcerative colitis, Crohn’s disease, Ménétrièr’s syndrome.

• GU tract: leukoplakia of the bladder, bilharzia.

General symptoms and signs of malignant disease

These may relate to the primary tumour, metastases, or generalized systemic manifestations.

They may be broadly classified as follows:

Primary tumour

Palpable swelling

This is usually painless unless invading other structures. Common examples include the palpable masses of the primary tumour in carcinoma of the breast, carcinoma of the thyroid, carcinoma of the caecum.

Obstruction

Examples include dysphagia in carcinoma of the oesophagus, obstructive jaundice in carcinoma of head of pancreas, large bowel obstruction in carcinoma of the colon, vomiting in gastric outlet obstruction from carcinoma of the gastric antrum.

Bleeding

• Overt: haemoptysis, haematemesis, haematuria, rectal bleeding

• Occult: carcinoma of the stomach or carcinoma of the caecum. Anaemia occurs.

Symptoms due to compression or invasion of local structures

SVC obstruction with bronchial carcinoma; back pain with retroperitoneal invasion with pancreatic cancer; invasion of nerves, e.g. facial paralysis with carcinoma of the parotid gland, recurrent laryngeal nerve palsy with anaplastic carcinoma of the thyroid.

Generalized manifestations

Examples include cachexia, PUO (lymphoma, hypernephroma), hypertrophic pulmonary osteoarthropathy (carcinoma of the bronchus), thrombophlebitis migrans (carcinoma of the pancreas), neuropathies and myopathies (carcinoma of the bronchus), endocrine manifestations, e.g. ADH or ACTH production in bronchial carcinoma.

Asymptomatic incidental findings

Axillary lymphadenopathy on routine examination, e.g. with small impalpable carcinoma of the breast. Silent pulmonary primary or metastases on routine CXR.

Diagnostic procedures

Biopsy

This is mandatory, and may be carried out in a variety of ways:

• Fine-needle aspiration using a 22G needle: smear produced on slide; read by experienced cytologist

• Core biopsy, e.g. Tru-Cut: core of tissue removed for histological examination

• Incisional biopsy: removes a small accessible piece of the lesion for histological examination

• Excisional biopsy: the complete removal of a discrete lesion without a wide margin and without it being considered curative of the malignancy

• Evaluation under anaesthetic: to assess presence or extent of disease, e.g. staging laparotomy (largely superseded by CT scanning), panendoscopy, mediastinoscopy, bronchoscopy with biopsy of suspicious or high-risk areas.

Imaging (e.g. ultrasound, CT or MRI)

This is used for confirming a suspected diagnosis and assessing spread. A negative study does not exclude microscopic disease.

Positron emission tomography (PET)

This is complementary to other imaging modalities but differs from them as the scanner detects the metabolic activity of cancer cells via their increased uptake of a radioactive tracer (fluorodeoxyglucose) and subsequent emission of positrons. It can be used to detect the site of an unknown primary malignancy in the patient who presents with metastatic disease that cannot be identified by conventional clinical, radiological or histological means (e.g. SCC of the head and neck); for identification of metastases, e.g. lung cancer or non-Hodgkin’s lymphoma; or for monitoring of response to therapy, and evaluation of recurrence. Further evidence is required to evaluate the roles for this relatively new modality.

Staging and grading of cancer

The extent of the malignancy of a tumour may be established clinically to provide an indication of the prognosis and to act as a guide for the type of treatment. It is also necessary for comparing the efficacies of different treatments in clinical trials. Three methods may be used – clinical, pathological and histological. Pathological staging is very subjective and there is a degree of observer variation. A tumour’s apparent growth rate may be graded according to its histological appearance and its resemblance to mature cells of its lineage (degree of differentiation) can be commented on to indicate aggression.

Clinical staging

An example of this is the Manchester Classification of carcinoma of the breast (→ Ch. 10). This is based purely on clinical findings but is somewhat imprecise.

Clinical and pathological staging

The TNM Classification is recommended by the International Union Against Cancer. This method uses both clinical and laboratory results to grade the tumour. The clinician assesses three factors:

• Extent of the tumour (T)

• Node status (N)

• Presence of metastases (M).

A method that is based on pathological staging only is Dukes’ Classification for colorectal carcinoma (→ Ch. 14).

Grading of tumours

The histological appearance of specimens are graded according to various criteria such as the proportions of cells undergoing mitosis, the degree of differentiation, the degree of nuclear pleomorphism, etc. This represents the ‘aggressive’ nature of the cancer. Examples include Broder’s grading of squamous cell carcinoma or the Bloom-Richardson grading of breast carcinoma.

The multidisciplinary team (MDT) meeting

Patients’ case histories are presented at a regular MDT meeting comprising of specialists, e.g. surgeons, oncologists, radiologists, pathologists, nurses, etc. who manage those particular conditions, e.g. breast, head and neck, skin, sarcoma. The clinical findings are correlated with the radiological and pathological investigations, including staging and grading where known, and if the findings are concordant with a diagnosis, a course of action is decided. This may be, for example, surgery with curative or palliative intent, primary radiotherapy or chemotherapy, neo-adjuvant therapy or further investigation prior to treatment.

Tumour markers

These are substances present in the body in a concentration related to the presence of a tumour. They are rarely sufficiently specific to be of diagnostic value. The tumour marker may be a substance secreted into the blood or other body fluid or expressed at the cell’s surface by malignant cells in larger quantities than that of their normal counterparts. Detection is by measuring the concentration of the marker in the body fluids, usually by immunoassay, although some markers may be detected in histological sections by immunohistochemistry. The main value of tumour markers is in following the course of a malignant disease and monitoring the response to treatment and hence determining the prognosis. They may also be used for tumour localization and antibody-directed therapy. The following are examples of tumour markers in common use.

α-fetoprotein (AFP)

Normally synthesized in the fetal yolk sac and liver. It is increased in hepatocellular cancer and germ cell tumours, i.e. testicular teratoma. It can be useful in monitoring the presence of metastases and response to treatment. Non-neoplastic causes of a raised AFP include cirrhosis, hepatitis and pregnancy.

Carcinoembryonic antigen (CEA)

Normally produced by the fetal gut, liver and pancreas. It is raised in tumours of the colon, pancreas and stomach. In colonic malignancy, CEA is raised in 3% of Dukes A, 25% of Dukes B, 45% of Dukes C and 65% of metastatic cancer. It can be useful in assessing response to treatment and diagnosing recurrence before clinical detection. Non-neoplastic causes of raised CEA include ulcerative colitis, Crohn’s and cirrhosis.

Human chorionic gonadotrophin (hCG)

This was one of the first tumour markers to be recognized. It is raised in choriocarcinoma and hydatidiform moles. β-hCG is a valuable tumour marker for testicular cancers.

Prostate-specific antigen (PSA)

PSA is a serine protease. Its normal function is to liquefy gel around spermatozoa. It is a very useful marker in prostatic cancer – it is organ-specific and is elevated in a higher proportion of patients than prostatic acid phosphatase (PAP). In patients with a PSA of 4–10 ng/mL, 20–30% will have prostate cancer. With a PSA <20 ng/mL, bony metastases are rare. Non-neoplastic causes of a raised PSA include benign prostatic hypertrophy and prostatitis.

CA 19-9

A tumour antigen elevated in gastrointestinal malignancy. It is not diagnostic but has been used commonly in association with pancreatic malignancy. It has a sensitivity and specificity of 80–90% for pancreatic cancer and is used to monitor the success of chemotherapy. It can also be elevated in pancreatitis, gallstones, cholecystitis and cirrhosis.

CA125

Most commonly used tumour marker in ovarian malignancy. It is associated with non-mucinous tumours. An elevated level is not diagnostic of ovarian malignancy – fewer than 50% of patients with stage I have a raised CA125. In addition, raised levels are also seen in pregnancy, endometriosis and cirrhosis. CA125 is also elevated in advanced non-ovarian malignancies.

CA15-3

This is a mucin marker used in the assessment of breast cancer. Patients with stage I disease may only show raised CA15-3 in approximately 10–20% of cases. In advanced cancer, the number of patients with increased levels is 50–100%. Benign breast disease may lead to elevated levels. However, CA15-3 has been used in assessing recurrence and has been shown to be prognostic – initially elevated levels are associated with a poorer prognosis. CA15-3 levels may also be raised in benign breast or ovarian disease or endometriosis.

Treatment of cancer

Major treatments are surgical excision, radiotherapy, chemotherapy and hormonal manipulation.

Surgery

Curative

The ideal operation for cancer is the one that completely eradicates the tumour. This may require wide excision of the tumour together with removal of the lymph nodes in continuity with the tumour. Sometimes, when the tumour is explored, it is found that it cannot be removed. On other occasions, the tumour is operable, i.e. the primary tumour can be removed but tumour remains behind, in which case it is incurable. Pre-malignant conditions may be treated by surgery, but other modes of management such as curettage and cautery, cryotherapy or photodynamic therapy (the ablation of pharmacologically photosensitized cells using a laser), e.g. in Bowen’s disease or Barrett’s oesophagus are also available.

Palliative

When operating on a tumour, it may be discovered that it is impossible to remove the primary lesion. However, a palliative operation may be carried out, e.g. bypassing an obstructing tumour in the GI tract to prevent the symptoms of intestinal obstruction.

Occasionally, operations are undertaken purely for palliative reasons when it is known that it will be impossible to remove the primary tumour, e.g. for bleeding, pain, obstruction. Occasionally, surgery is used to ‘debulk’ a tumour. This is often the case in extensive ovarian malignancy where removal of the greater mass of tumour will improve the efficacy of subsequent chemotherapy. Metastasis may also be excised, such as solitary lung metastases, subcutaneous metastases, etc. for local control. Other modes of therapy include radiofrequency ablation for liver metastases.

Radiotherapy

Delivery of radiotherapy

Radiotherapy can be delivered to the site of a tumour in three ways:

• External beam radiation

• Implantation radiotherapy

• Systemic irradiation.

Radiation damages cells by inducing DNA damage. Cancer cells are affected more than normal cells because their DNA repair mechanisms are impaired. As a general rule, the higher the mitotic rate of a tumour, the greater the response to radiotherapy.

The absorbed dose of radiotherapy is quantified as the SI unit, the Gray (Gy) where 1 Gy = 1 J.kg⁻¹. The total dose (typically around 50 Gy in solid tumours) is often divided into multiple exposures, or fractions to enable normal cells to recover, and to ensure more cancer cells are exposed during radiosensitive points in the cell cycle.

External beam radiation

This method is the most commonly used form of radiotherapy for skin and deeper tumours. The doses from beams from several angles can summate deep to the skin, thus avoiding the severe skin lesions that previously were a side effect of radiotherapy. Three-dimensional conformational mapping using a planning CT scan, and intensity modulated radiotherapy (IMRT) enables accurate dosing of radiotherapy fractions through computer-controlled X-ray accelerators for deep asymmetric tumours while minimizing collateral damage.

Implantation radiotherapy (e.g. intracavitary or intralesional)

The source of irradiation may be placed within a cavity, e.g. in the vagina for irradiation of the cervix or directly into the lesion, e.g. iridium-192 (¹⁹²Ir) wires in carcinoma of the tongue.

Systemic irradiation

¹³¹I can be administered orally for follicular and papillary carcinoma of the thyroid gland. Experimentally, radioisotopes can be directed at cancer cells by attaching them to tumour-specific antibodies.

Use of radiotherapy

Radiotherapy can be used in four ways:

• Primary treatment (radical radiotherapy)

• Neoadjuvant prior to surgery and adjuvant after surgery

• Systemic treatment.

Primary treatment

Radiotherapy is used as the primary treatment with a view to a cure. Certain tumours, e.g. laryngeal, have a cure rate equal to surgery. Examples of tumours treated by radiotherapy include:

• Basal cell and squamous cell carcinoma of the skin

• Some head and neck tumours and laryngeal tumours

• Hodgkin’s disease

• Lymph node metastases of a testicular seminoma following orchidectomy.

Adjuvant and neoadjuvant treatment

Neoadjuvant treatment is used preoperatively to down-stage tumours, i.e. decrease size and potentially convert an inoperable tumour into an operable one. Adjuvant radiotherapy aims to control microscopic tumour deposits that have spread beyond the resection margins or are spilt during surgery. An example is radiotherapy to the scar, axillary nodes, supraclavicular and internal mammary nodes in breast cancer.

Palliative radiotherapy

• Bony metastases – pain relief is often dramatic

• Cerebral metastases

• Ulcerating or fungating breast cancer – controls oozing and bleeding and allows skin healing

• Lung cancer – to prevent cough and haemoptysis.

The complications of radiotherapy are shown in Table 7.1.

TABLE 7.1 Complications of radiotherapy

General	Tiredness, malaise
Skin	Rashes, moist desquamation
Blood vessels	Endarteritis obliterans. Impairs blood supply. Progresses for many years after treatment. Many of the effects on other systems may have endarteritis obliterans as a precipitating cause
Healing	This is delayed, e.g. failure of skin grafts, anastomotic breakdown, intestinal fistulae
Renal tract	Frequency, cystitis
GI tract	Nausea, vomiting, anorexia. Irradiation proctitis (after irradiation of the cervix), causes rectal bleeding and tenesmus. Small bowel irradiation may give rise to intestinal fistulae and strictures
Head and neck	Xerostomia (dry mouth). Epiphora (red-watery eye) due to damage to tear duct

Systemic

Two types of systemic radiotherapy are used:

Total body irradiation

Leads to bone marrow failure and thus necessitates a bone marrow transplant; it is used in the treatment of leukaemias.

Radioactive isotopes

This form of radiotherapy uses radioisotopes that are concentrated in the tumour and lead to local irradiation of the tumour. Examples include ¹³¹I in thyroid cancer and strontium-89 in prostatic metastatic disease.

Chemotherapy

Chemotherapeutic agents destroy tumour cells in a variety of different ways. Most tumours are treated by a combination of cytotoxic drugs, the combinations being chosen so that their toxic effects on any particular organ are minimized. The most appropriate combinations have usually been established by clinical trials based on initial empiricism. Drugs are usually given in short courses with a period of rest between courses to allow recovery of the normal tissues. The response of tumours to chemotherapy is very variable. Some are highly sensitive while others are insensitive.

Highly sensitive tumours in which there are prospects of a cure include Hodgkin’s disease, testicular teratoma, childhood leukaemias, osteogenic sarcoma (lung secondaries).

Moderately sensitive tumours where palliation is the aim include ovarian tumours, breast cancer, and bronchial carcinoma.

Apart from oral and intravenous administration, cytotoxic agents may be directly administered into a tumour, e.g. 5-fluorouracil for liver metastases and close intra-arterial injection in malignant melanoma; instillation into the bladder for superficial bladder tumours.

Side-effects

Chemotherapy is not only toxic to malignant cells but also to normal body cells, especially those with a high turnover rate, e.g. bone marrow and GI epithelium. Many side-effects are extremely unpleasant and should be carefully explained to, and discussed with, the patient prior to starting the course (→ Table 7.2).

TABLE 7.2 Side-effects of chemotherapy

Non-specific	Nausea, vomiting, metallic taste, general malaise
GI tract	Oral ulceration, diarrhoea
Reproductive system	Loss of libido, sterility, mutagenesis
Bone marrow	Bone marrow suppression with anaemia, thrombocytopenia, (bleeding), leukopenia (infection)
Immune system	Immunosuppression. Opportunistic infections, e.g. candidiasis, and Pneumocystis carinii
Skin	Rashes, ulceration, hair loss (regrows after course is stopped)
Urinary tract	Cystitis (cyclophosphamide), gout due to massive tumour destruction, leads to hyperuricaemia, which may lead to renal failure – prevented with allopurinol
Oncogenesis	20-fold increase in incidence of other malignancies

Hormonal manipulation

This is applicable to carcinoma of the breast and carcinoma of the prostate. Removal of the source of hormones or blocking their effect may inhibit tumour growth.

Breast

The options available for hormonal treatment in breast cancer include:

• Inhibition of ovarian function

• Blocking the binding of oestrogen to cancer cells

• Blocking peripheral oestrogen production.

Inhibition of ovarian function

There are three methods available to decrease oestrogen production by the ovaries:

• Surgery – oophorectomy

• Pelvic irradiation – radiotherapy

• LHRH agonists, i.e. goserelin.

Inhibition of ovarian function is important in the management of breast cancer in premenopausal women. Meta-analysis of various trials of ovarian ablation in women <50 years old demonstrated a 26% reduction in annual recurrence and 25% reduction in the annual death rate.

Blocking the binding of oestrogen to cancer cells

The anti-oestrogen tamoxifen is effective in pre- and postmenopausal women with oestrogen receptor positive breast cancer. Tamoxifen is a non-steroidal drug that competes with oestrogen to bind the oestrogen receptor. Meta-analysis of trials demonstrated a 25% reduction in annual recurrence and a 17% reduction in annual death rate. Tamoxifen is also a first-line drug in metastatic disease. Long-term use may be associated with an increased risk of endometrial cancer. Fulvestrant is a new anti-oestrogen that causes downregulation of the oestrogen receptor. It can be used in tamoxifen-resistant metastatic disease.

Blocking peripheral oestrogen production

Following the menopause, the main source of oestrogen production is by the peripheral conversion of adrenal androgens in liver, muscle, breast and fat – this is mediated by the aromatase enzymes. The aromatase inhibitors, e.g. anastrozole, are useful in first-line treatment and in patients who have tamoxifen-resistant metastatic disease.

Prostate

The main aetiological factor in prostate cancer is dependence on testosterone. A number of modalities are available to reduce androgen exposure.

Surgical orchidectomy

The gold standard; has become less popular with the advent of medical alternatives.

LHRH analogues, e.g. goserelin

This results in chemical castration by the downregulation of receptors in the pituitary gland. It must be remembered that initial use will stimulate androgen production before inhibition (androgen flare). This may result in an exacerbation of symptoms and thus should always be given with an anti-androgen.

Oestrogen, e.g. diethylstilboestrol

Rarely used due to considerable side-effects. Results in castrate levels of androgens in 1–2 weeks.

Anti-androgens

These may be steroidal or non-steroidal. Steroidal anti-androgens, e.g. cyproterone acetate, inhibit LH release from the pituitary and decrease the binding of dihydrotestosterone to androgen receptors. Non-steroidal anti-androgens, e.g. flutamide, block dihydrotestosterone binding but not LH production.

Inhibition of adrenal enzyme synthesis

Used as second- or third-line treatment. Ketoconazole at 6× the normal dose causes chemical castration in 24 h.

Biological therapies

Man made agents targeting specific cellular processes, rather than the DNA itself, have been developed and are used in certain cancers.

Examples include tyrosine kinase inhibitors (e.g. Imatinib for gastrointestinal stromal tumours) and monoclonal antibodies (MAb).

Examples of MAb agents currently in use include:

• Trastuzumab (Herceptin) in HER2 receptor positive breast cancer

• Rituximab targeting the CD20 antigen over-expressed in non-Hodgkin’s lymphoma

• Bevacizumab (Avastin) targeting vascular endothelial growth factor (VEGF) to inhibit angiogenesis in bowel cancer.

Terminal care

Most patients with disseminated malignancy deteriorate until they reach a terminal phase. This phase is often accompanied by many unpleasant symptoms that are difficult to control. Support should not only be medical but should be emotional, psychological and spiritual. Initially, it may be possible to manage the patient at home with the support of family, friends, Macmillan nurse and family doctor. Death should be met with privacy and dignity. Eventually, hospitalization may be required for terminal care. Patients may be best managed in a hospice where all expertise is available to support the patients and their relatives.

Treatment of symptoms

Pain

Regular opiates are needed to prevent ‘breakthrough’ pain. Suitable analgesics include MST tablets, fentanyl patches, morphine elixir, subcutaneous morphine, PCA via pump and spinal opioids; local blocks may help. In addition, steroids and chlorpromazine may be helpful. The correct dose of analgesic is that which relieves the pain. Opiate dependency and respiratory depression are irrelevant in the dying patient.

Nausea and vomiting

Anti-emetics should be given, e.g. metoclopramide, domperidone, prochlorperazine. Ondansetron is a very effective anti-emetic. If there is a mechanical reason for the nausea and vomiting, it may be difficult to control. If possible, a tube gastrostomy carried out under local anaesthetic may help. It allows the patient to swallow a suitable liquidized diet, which will then drain through the gastrostomy tube without subsequent vomiting.

Constipation

Regular laxatives and enemas may be required.

Dysphagia

A stent may be already in situ. Tasty liquidized food is helpful.

Mouth care

Careful attention to oral hygiene may prevent problems. ‘Swish and swallow’ nystatin may prevent candidiasis. If ulcers develop they may be treated with local anaesthetic gel and metronidazole gel.

Cough

This may be treated with morphine or codeine.

Insomnia

Treat with chlorpromazine or benzodiazepines.

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