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Cancer chemotherapy and radiation therapy 

Cancer chemotherapy and radiation therapy

Chapter:
Cancer chemotherapy and radiation therapy
Author(s):

Bruce A. Chabner

and Jay Loeffler

DOI:
10.1093/med/9780199204854.003.0606_update_004

Update:

Thorough updates include discussion of

(1) drugs that target protein degradation pathways, including proteasome inhibitors and ubiquitin ligase inhibitors in treatment of myeloma;

(2) a growing array of targeted drugs to treat haematological malignancies;

(3) use of hypofractionated radiation therapy schemes (higher dose per day, less fractions).

Updated on 30 Jul 2015. The previous version of this content can be found here.
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date: 28 March 2017

The last two decades have brought significant improvements in cancer therapy: patients with previously fatal diseases, including acute leukaemia, non-Hodgkin’s lymphoma, Hodgkin’s disease, and germ cell tumours, now have a high expectation of cure. For patients with the more common solid tumours, including lung, colon, and breast cancer, new chemotherapeutic and hormonal agents, molecularly targeted drugs, and monoclonal antibodies have improved treatment of both early and late stage disease and have extended survival. Nevertheless, cancer remains the second leading cause of death in the Western world, and nearly one third of patients diagnosed with cancer will die of their disease.

Surgery, chemotherapy, and radiation therapy are the major modalities of cancer therapy, and are employed together in various sequences and combinations in most cancer patients. In recent years, small molecules targeted for specific cancer mutations, vaccines, monoclonal antibodies, monoclonals coupled to toxic molecules, and monoclonals that induce antitumour immunity have expanded the repertoire of agents useful for cancer treatment.

Chemotherapy

Mechanism of action—most chemotherapy drugs block steps in the synthesis of DNA or its precursor nucleotides (purines and pyrimidines), or attack the integrity of DNA. These drugs are maximally effective if tumour cells are exposed during the S phase of the cell cycle, although some drugs (e.g. vinca alkaloids and taxanes) directly block cells during mitosis, and others (e.g. alkylating agents) act throughout the cell cycle.

Clinical use—chemotherapy can be applied as (1) combination chemotherapy with multiple drugs to cure leukaemias, lymphomas, and testicular cancer, or to diminish tumour-related symptoms, improve the quality of life, and extend survival in less sensitive epithelial cancers, such as those arising from lung, colon, and breast; (2) adjuvant therapy, administered before or after the completion of definitive local surgery and/or radiation therapy to decrease the risk of recurrence of disease locally and at distant sites. Adjuvant therapy improves survival in patients with breast and colon cancers.

Complications—most of the commonly used chemotherapy agents cause acute myelosuppression and epithelial damage; nausea and vomiting are frequent, but can often be helped by corticosteroids and serotonin uptake inhibitors (e.g. ondansetron). Other toxicities specific to particular agents or classes of agent include (1) alopecia—doxorubicin and alkylating agents, (2) peripheral neuropathy—vinca alkaloids, bortezomib, and platinum analogues, (3) heart failure—doxorubicin and trastuzumab, (4) pneumonitis—bleomycin, fludarabine, gemcitabine, methotrexate, (5) infertility—alkylating agents. Secondary leukaemias may develop as a late complication of therapy with alkylating agents, platinum analogues, and topoisomerase II inhibitors.

Targeted anti-cancer molecules constitute a new approach to cancer treatment. In the past decade, both small molecules and monoclonal antibodies have proven useful for treating tumors that express mutated intracellular proteins or cell surface receptors essential for tumour growth. These molecules, such as those that target the braf signalling molecule in melanoma, the epidermal growth factor receptor (EGFR) in lung cancers, and the brc-abl kinase of chronic myeloid leukemia, produce remissions with very limited toxicity to normal tissues. Antibodies to the her2 receptor in breast and gastric cancer, EGFR in colon and head and neck cancers, and anti-CD 20 and anti-CD30 in lymphomas, have become significant new treatments. Anti-CD 30 antibody coupled to a toxic mitotic inhibitor, orastatin A (brentuximab vedotin), is highly effective in relapsed/refractory Hodgkin disease.

Immunotherapies are becoming increasingly useful for cancer treatment. A dendritic cell vaccine, Sipuleucel-T, extends survival in men with angrogen insensitivity prostate cancer, and ipilimumab, an anti-CTLA4 antibody, enhances host auto-immunity directed against melanoma, lung cancer, and renal cell cancers. Anti-PD-1 (nivolumab and pembrolizumab) antibodies have similar action in enhancing immunity against melanoma.

Pomalidomide, lenalidomide, and thalidomide are all effective agents against multiple myeloma. Their mechanism of action is related to the inhibition of degradation of key proteins, including IkappaB kinase. They exert a broad array of actions on the immune system, inhibiting cytokine production, and display anti-angiogenic activity.

Radiation therapy

Mechanism of action—radiation therapy generates free radicals that damage DNA, producing breaks that must be repaired if the cell is to survive. Many tumours are less able than normal tissues to repair these breaks, providing a therapeutic window for uncomplicated tumor control. Irradiation also inflicts potent damaging effects on tumour vasculature.

Clinical use—radiation doses are usually delivered as an external beam from a source outside the body in a number of daily fractions, the total fractionated dose being determined by tumour sensitivity and irradiated local normal tissue tolerance. Other methods of delivery include (1) brachytherapy—when the radiation source is implanted within the substance of the tumour, e.g. cervical cancer; (2) intraoperative radiation therapy—delivering a single, large fraction of radiation directly to the tumour bed; (3) radioisotopes—e.g. iodine-131 taken up by local and metastatic thyroid tissue; monoclonal antibodies coupled with radioisotopes to localize at tumour sites. For palliative irradiation of metastatic tumours, single large doses (radiosurgery) or abbreviated courses of irradiation (hypofractionated radiotherapy) may be administered to relieve symptoms. Radiosurgery is also used as curative therapy for small, benign brain tumours such as meningiomas, acoustic neuromas and pituitary adenomas.

Complications—toxicity to normal tissues within the field of radiation therapy or at its margins can be significant. Effects can be (1) acute—during the treatment course—particularly including damage to skin (erythema, desquamation, oedema), mucosal linings (diarrhoea, nausea, vomiting) and bone marrow (cytopenias); (2) subacute—after treatment but within a few months of therapy—e.g. radiation pneumonitis; cerebral oedema and (3) late—permanent—including local tissue damage (e.g. transverse myelitis, bowel strictures, renal failure) and secondary tumours that can develop within radiation fields years after therapy.

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