Neoplastic disease and immunosuppression

Published on 02/03/2015 by admin

Filed under Basic Science

Last modified 02/03/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1430 times

Chapter 31 Neoplastic disease and immunosuppression

Neoplastic disease

Cancer treatments and outcomes

Cancers share some common characteristics:

Cancer treatment employs six established principal modalities:

This account describes the main groups of drugs (see p. 510) but it is important to understand the overall context in which systemic therapy is offered to patients.

Systemic cancer therapy

Cancers originating from different organs of the body differ in their initial behaviour and in their response to treatments (Table 31.1). Primary surgery and/or radiotherapy to a localised cancer offer the best chance of cure for patients. Drug treatments offer cure only for certain types of cancer, often characterised by their high proliferative rate, e.g. lymphoma, testicular cancer, Wilms’ tumour. More often, systemic therapy offers prolongation of life from months to many years and associated improvements in quality of life, even if patients ultimately die from their disease.

Table 31.1 Degree of benefit achieved with systemic therapy for common cancers

Curable: chemosensitive cancers Improved survival: some degree of chemosensitivity Equivocal survival benefit: chemoresistant cancers
Teratoma Colorectal cancer Sarcoma
Seminoma Small cell lung cancer Bladder cancer
High-grade non-Hodgkin’s lymphoma Ovarian cancer Melanoma
Hodgkin’s lymphoma Breast cancer Renal cancer
Insensitive to cytotoxic chemotherapy but now can be controlled temporarily with oral VEGF2 and mTOR inhibitors
Wilms’ tumour Cervical cancer Primary brain cancers
Acute myeloblastic leukaemia Endometrial cancer Nasopharyngeal carcinoma
Acute lymphoblastic leukaemia in childhood Gastro-oesophageal cancer Cholangiocarcinoma and gall bladder cancer Hepatoma
Insensitive to cytotoxic chemotherapy but now can be controlled temporarily with oral VEGF inhibitors
  Myeloma  
  Pancreatic cancer  
  Low-grade non-Hodgkin’s lymphoma  
  Non-small cell lung cancer  
  Adult acute lymphoblastic leukaemia  

Use of drugs as adjuvant therapy attempts to eradicate residual microscopic cancer by treating patients after their primary surgery. This strategy has improved overall survival for patients after surgical resection of primary breast, colorectal and gastric cancer. In some situations, drugs are administered prior to surgery (neoadjuvant therapy), primarily to shrink large, locally advanced disease to subsequently enable surgical resection. Many patients with cancer are not cured by their primary treatment due to the presence of micrometastatic disease; the disease often returns months or years later even though at the time of completing their initial treatment there was no visible evidence of cancer. Clearly, this is a limitation of current standard techniques used to identify residual disease. Currently, radiological techniques cannot clearly visualise lesions smaller than 5 mm in most organs, which equates to over many million cancer cells.

Palliative therapy, offered to patients with advanced, incurable cancer, aims both to increase survival and to improve quality of life by symptom control. Despite significant improvements in cancer outcomes in the last 5–10 years, there remain a number of types of cancer that are poorly responsive to currently available drugs. Patients with chemoresistant cancers who are fit enough and willing may be offered experimental treatments within Phase 1 or 2 clinical trials.

Most treatments currently available are associated with unwanted effects of varying degrees of severity. The risk of causing harm must be weighed against the potential to do good in each individual case. Systemic therapy aims to kill malignant cells or modify their growth but leave the normal cells of the host unharmed or, more usually, temporarily harmed but capable of recovery. When there is realistic expectation of cure or extensive life prolongation, then to risk more severe drug toxicity is justified. For example, the treatment of testicular cancer with potentially life-threatening platinum-based combination chemotherapy regimens offers a greater than 85% chance of cure, even for those with extensive, metastatic disease.

Where expectation is confined to palliation in terms of modest life prolongation of less certain quality, then the benefits and risks of treatment must be judged carefully. Palliative treatments should involve low risk of adverse effects, e.g. 5-fluorouracil-based chemotherapy for advanced colorectal cancer is well tolerated by most patients, while improving survival by around 1–2 years. A modern prerequisite of cancer chemotherapy Phase 3 trials is concomitantly and objectively to assess patient quality of life while on drug therapy. This helps clinicians and nurses to explain the potential benefits and harm of treatment to patients and their families, who may themselves hold strong views about the quality and quantity of life.

Classes of cytotoxic chemotherapy drugs

Cytotoxic chemotherapy drugs exert their effect by inhibiting cell proliferation. All proliferating cells, whether normal and malignant, cycle through a series of phases of: synthesis of DNA (S phase), mitosis (M phase) and rest (G1 phase). Non-cycling cells are quiescent in G0 phase (Fig. 31.1).

Cytotoxic drugs interfere with cell division at various points of the cell cycle, in particular G1/S phase (e.g. synthesis of nucleotides from purines and pyrimidines), S phase (preventing DNA replication) and M phase (e.g. blocking the process of mitosis).

They are thus all potentially mutagenic. Cytotoxic drugs ultimately induce cell death by apoptosis,2 a process by which single cells are removed from living tissue by being fragmented into membrane-bound particles and phagocytosed by other cells. This occurs without disturbing the architecture or function of the tissue, or eliciting an inflammatory response. The instructions for apoptosis are built into the cell’s genetic material, i.e. ‘programmed cell death’.3

In general, cytotoxics are most effective against actively cycling cells and least effective against resting or quiescent cells. The latter are particularly problematic in that, although inactive, they retain the capacity to proliferate and may start cycling again after a completed course of chemotherapy, often leading later to rapid regrowth of the cancer.

Cytotoxic drugs can be classified as either:

Table 31.2 provides a summary of the key groups of anticancer drugs, their common toxicities and main treatment applications.

Table 31.2 Principal classes of cytotoxic drug, their common toxicities and examples of clinical use

Drug class Common toxicities Examples of clinical use
Cytotoxic drugs
Alkylating agents Nausea and vomiting, bone marrow depression (delayed with carmustine and lomustine), cystitis (cyclophosphamide, ifosfamide), pulmonary fibrosis (especially busulfan). Male infertility and premature menopause may occur. Myelodysplasia and secondary neoplasia Widely used in the treatment of both haematological and non-haematological cancers, with varying degrees of success
Platinum drugs Bone marrow depression, nausea and vomiting, allergy reaction (esp. carboplatin), nephrotoxicity, hypomagnesaemia; hypocalcaemia; hypokalaemia; hypophosphataemia; hyperuricaemia (all as a consequence of renal dysfunction, primarily associated with cisplatin); Raynaud’s disease; sterility; teratogenesis; ototoxicity (cisplatin); peripheral neuropathy; cold dysaesthesia and pharyngolaryngeal dysaesthesia (oxaliplatin) Testicular cancers, ovarian cancer; oxaliplatin acts synergistically with 5FU and is licensed in combination with 5FU to treat both advanced and early stages of colorectal cancer
Nucleoside analogues, e.g. cytarabine, gemcitabine, fludarabine Bone marrow depression, mainly affecting platelets; mild nausea and vomiting; diarrhoea; anaphylaxis; sudden respiratory distress with high doses (cytarabine); rash, fluid retention and oedema; profound immunosuppression with fludarabine Cytarabine is used in haematological regimens; gemcitabine is used for pancreatic cancer, bladder cancer and some other solid tumours; fludarabine is active in chronic lymphatic leukaemia and lymphoma
Taxanes Nausea and vomiting, hypersensitivity reactions, bone marrow depression, fluid retention; peripheral neuropathy; alopecia; arthralgias; myalgias; cardiac toxicity; mild GI disturbances; mucositis Breast and gynaecological cancers; recent evidence that docetaxel improves survival in advanced prostate cancer
Anthracyclines Nausea and vomiting, bone marrow depression; cardiotoxicity (may be delayed for years); red-coloured urine; severe local tissue damage and necrosis on extravasation; alopecia; stomatitis; anorexia; conjunctivitis; acral (extremities) pigmentation; dermatitis in previously irradiated areas; hyperuricaemia Common component of many chemotherapy regimens for both haematological and non-haematological malignancies
Antimetabolites, e.g. 5-fluorouracil, methotrexate Nausea and vomiting; diarrhoea; mucositis, bone marrow depression, neurological defects, usually cerebellar; cardiac arrhythmias; angina pectoris, hyperpigmentation, hand–foot syndrome, conjunctivitis Commonly used in haematological and non-haematological malignancies
Topoismerase I inhibitors Nausea and vomiting; cholinergic syndrome; hypersensitivity reactions; bone marrow depression; diarrhoea; colitis; ileus; alopecia; renal impairment; teratogenic Irinotecan is effective in advanced colorectal cancer; topotecan is used in gynaecological malignancies
Mitotic spindle inhibitors (vinca alkaloids) Nausea and vomiting; local reaction and phlebitis with extravasation, neuropathy, bone marrow depression; alopecia; stomatitis; loss of deep tendon reflexes; jaw pain; muscle pain; paralytic ileus Commonly used in haemato-oncology regimens
Hormones
Tamoxifen Hot flushes; transiently increased bone or tumour pain; vaginal bleeding and discharge; rash; thromboembolism; endometrial cancer Oestrogen receptor-positive, advanced and early stage breast cancer
Aromatase inhibitors Nausea; dizziness; rash; bone marrow depression; fever; masculinisation Equivalence with tamoxifen suggested
Medroxyprogesterone acetate Menstrual changes; gynaecomastia; hot flushes; oedema, weight gain; hirsutism; insomnia; fatigue; depression; thrombophlebitis and thromboembolism; nausea; urticaria; headache Third-line therapy for slowly progressive breast cancer in postmenopausal women
Flutamide Nausea; diarrhoea; gynaecomastia; hepatotoxicity Prostate cancer
Goserelin Transient increase in bone pain and urethral obstruction in patients with metastatic prostatic cancer; hot flushes; impotence; testicular atrophy; gynaecomastia Prostate cancer
Leuprolelin (LHRH analogue) Transient increase in bone pain and ureteral obstruction in patients with metastatic prostatic cancer; hot flushes, impotence; testicular atrophy; gynaecomastia; peripheral oedema Prostate cancer
Immunotherapy
BCG (bacille Calmette-Guérin) Bladder irritation; nausea and vomiting; fever; sepsis, granulomatous pyelonephritis; hepatitis; urethral obstruction; epididymitis; renal abscess Localised bladder cancer
Interferon-α Fever; chills; myalgias; fatigue; headache; arthralgias, bone marrow depression; anorexia; confusion; depression; psychiatric disorders; renal toxicity; hepatic toxicity; rash Renal cancer
Interleukin-2 Fever; fluid retention; hypotension; respiratory distress; rash; anaemia, thrombocytopenia; nausea and vomiting; diarrhoea, capillary leak syndrome, nephrotoxicity; myocardial toxicity; hepatotoxicity; erythema nodosum; neuropsychiatric disorders; hypothyroidism; nephrotic syndrome Renal cancer
Trastuzumab (Herceptin) Fever; chills; nausea and vomiting; pain; hypersensitivity and pulmonary reactions, bone marrow depression; cardiomyopathy; ventricular dysfunction; congestive cardiac failure; diarrhoea Advanced and early stage breast cancer, combined with cytotoxic chemotherapy
Rituximab (MabThera) Hypersensitivity reaction, bone marrow depression, angioedema, precipitation of angina or arrhythmia with pre-existing heart disease Non-Hodgkin’s lymphoma

Adverse effects of cytotoxic chemotherapy

Principal adverse effects are manifest as, or follow damage to, the following:

Classes of cytotoxic agents