Malignant disease

Malignant disease is common and is the second most common cause of death after cardiovascular disease. Most tumours arise from genetic muta-tions within a single population of precursor stem cells and over subsequent cell divisions there is an accumulation of further abnormalities. The genes most commonly affected are those that control cell cycle check points, DNA repair and DNA damage recognition, apoptosis, differentiation and growth signalling. Gene mutations may be:

■ Germline - e.g. mutations in BRCA1 and BRCA2 account for most cases of familial breast cancer. The protein product of these mutated genes is unable to bind to the DNA repair enzyme Rad51 to make it functional in repairing DNA breaks.

■ Somatic - in response to environmental carcinogens, e.g. smoking.

DIAGNOSIS OF MALIGNANCY

The diagnosis of malignancy is made by:

■ Screening in an asymptomatic person with the aim of detecting cancer at an earlier stage than symptomatic presentation and hopefully a better outcome. This is by population screening or individual screening of at-risk individuals. In the UK, population screening programmes are established for breast, cervical and colon cancer. Individual screening programmes are established for persons with a higher than average risk, usually because of family history, e.g. colonoscopy in persons with a family history of colon cancer at a young age.

■ Surveillance in a patient with a disease that places them at higher risk of developing malignancy, e.g. liver ultrasound and measurement of serum a-fetoprotein in a patient with cirrhosis with the aim of detecting hepato-cellular carcinoma at an earlier stage than symptomatic presentation.

■ Investigation in a symptomatic patient. Symptoms are the result of:

■ The primary tumour

■ Metastases

Table 6.1 Serum tumour markers

a-fetoprotein

Hepatocellular carcinoma and non-seminomatous germ cell tumour of the gonads

β-human chorionic gonadotrophin (β-hCG)

Choriocarcinomas, germ cell tumours (testicular) and lung cancer

Prostate-speciAc antigen (PSA)

Prostate cancer

Carcinoembryonic antigen (CEA)

Colorectal cancer. May also be raised in other gastrointestinal malignancies

Ca-125

Ovarian cancer. May also be raised in breast, cervical, endometrial and gastrointestinal malignancies

CA19-9

Upper gastrointestinal malignancies

CA15-3

Breast cancer

Osteopontin

Many cancers including mesothelioma

■ Paraneoplastic symptoms. These are a consequence of the cancer but are not due to the local presence of the cancer and may be medi-ated by hormones or cytokines secreted by the cancer (e.g. ectopic adrenocorticotropic hormone [ACTH] secretion in small cell lung cancer) or an immune response directed against the cancer e.g. dermatomyositis

■ Non-specific effects such as weight loss, tiredness and lethargy. Investigations

■ To confirm the presence of malignancy in a patient with suspicious symptoms of signs. This is by radiological imaging (with the specific test depending on the site) and biopsy of a suspicious lesion (e.g. at endo-scopy) with histological examination and tissue tumour markers. Serum tumour markers (Table 6.1) are intracellular proteins or cell surface glycoproteins released into the circulation and may be present in higher than usual concentration in patients with cancer. In many cases they are requested inappropriately as most tumour markers are neither sensi-tive nor specific for a particular malignancy and can also be raised in benign conditions. They are mainly used in monitoring response to treatment.

■ To stage the cancer once diagnosed. Staging the cancer will divide the patients into groups of different prognosis which can guide treatment selection. The staging systems vary according to tumour type and may be site specific (see Hodgkin's lymphoma) or the TNM (tumour, node, metastasis) classification which can be adapted for application to most common cancers.

■ To assess a patients suitability for treatment, e.g. full cardiac and respira-tory work-up before liver transplantation for hepatocellular carcinoma.

Cancer treatment

The management of patients with cancer must be coordinated by a multi-disciplinary team (MDT) which includes, depending on tumour type, a surgeon, oncologist, radiologist, histopathologist, physician, specialist nurse and sometimes other healthcare workers, e.g. dietician. Discussion with the patient about the treatment plan at each step will allow them to make a fully informed choice about their management.

In some solid tumours, treatment (chemotherapy, radiotherapy or hormone) is given after the primary treatment, e.g. surgical resection, where dissemi-nation is undetectable but patients are at risk of micromelaslases. This is called adjuvant therapy. Neoadjuvant therapy is given before the primary treatment to shrink the tumour to improve the efficacy of the local excision and to treat micrometastases as soon as possible. If effective, these treat-ments should lead to an increased chance of cure or overall disease-free survival.

Chemotherapy

There are many chemotherapy drugs in common use. These drugs directly damage DNA and/or RNA and kill cells by promoting apoptosis and some-times cell necrosis. They therefore affect not only tumour cells, but also the rapidly dividing normal cells of the bone marrow, gastrointestinal tract and germinal epithelium.

Side-effects include bone marrow suppression (leading to anaemia, thrombocytopenia and neutropenia [p. 205]), mucositis (causing mouth ulceration), loss of hair (alopecia) and sterility (which can be irreversible). To minimize these side-effects, chemotherapy is given at intervals to allow some recovery of normal cell function between cycles. Nausea and vomiting may be severe with some drugs, such as cisplatin, and are related to the direct actions of cytotoxic agents on the brainstem chemoreceptor trigger zone. Antiemetics such as metoclopramide (p. 136) and domperidone (p. 136) are used initially, but the serotonin 5-HT3 antagonists (ondansetron and graniset-ron) combined with dexamethasone are used for severe vomiting. Chemo-therapy drugs may themselves cause cancer, particularly acute leukaemia presenting years after treatment. There are additional side-effects that are specific to one class of drug, e.g. cardiotoxicity with the anthracyclines such as doxorubicin and neurotoxicity and nephrotoxicity with cisplatin.

Radiotherapy

Radiation induces strand breaks in DNA and apoptosis. The complications of radiotherapy depend on the radiosensitivity of normal tissue in the path of the radiation field. There may be damage to the skin (erythema and desquamation), gut (nausea, mucosal ulceration and diarrhoea), testes (steril-ity) and bone marrow (anaemia, leucopenia). General side-effects are leth-argy and loss of energy.

Endocrine therapy

This is used in the treatment of breast and prostate cancer to block the effects of oestrogens and androgens which may act as growth factors. Tamoxifen is a mixed agonist and antagonist of oestrogen on the oestrogen receptor and is used as an adjuvant therapy in breast cancer and in advanced metastatic breast disease. Aromatase inhibitors, e.g. anastrozole, letrozole and exemes-tane, block the conversion of androgens (synthesized by the adrenal glands) to estrone in the subcutaneous fat of post-menopausal women. They have greater efficacy than tamoxifen in the treatment of metastatic breast cancer and equal efficacy in the adjuvant setting. Gonadotropin-releasing hormone (GnRH) agonists, e.g. goserelin, which lower levels of circulating androgens and androgen receptor blockers, e.g. flutamide, are both used in the treat-ment of prostate cancer.

Biological therapy

This group includes a range of protein molecules, from small peptide chem-okines and larger cytokines to complex antibody molecules, made available by genetic engineering.

■ Interferons such as interferon alfa have many actions in treatment of malignant disease, with both antiproliferative activity and stimulation of humoral and cell-mediated immune responses to the tumour.

■ Interleukins have widespread activity in coordinating cellular activity in many organs. Interleukin 2 is used in renal cell carcinoma and melanoma.

■ Tyrosine kinase inhibitors (imatinib, sunitinib, sorafenib) have diverse effects on cell growth, differentiation and metabolism.

■ Anti-growth factor agents e.g. bevacizumab (antivascular endothelial growth factor receptor) and cetuximab (antiepidermal growth factor receptor) are added to chemotherapy to improve response.

■ Anti-CD20 (rituximab) inhibits CD20 on B cells, which normally plays a role in the development and differentiation of B cells into plasma cells. Anti-CD52 (alemtuzumab) inhibits CD52 expressed on T and B lym-phocytes and monocytes.

■ Haemopoietic growth factors such as erythropoietin and granulocyte colony-stimulating factor (G-CSF) are used to treat anaemia or to reduce the duration of neutropenia following chemotherapy.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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