Cancer pharmacology has changed dramatically during the recent past, with the improved understanding of cancer biology and an ever-expanding set of new drugs that target vulnerabilities in specific cancers. Effective treatments had been developed earlier for some fatal malignancies, including testicular cancer, lymphomas, and leukemia. Adjuvant chemotherapy and hormonal therapy can extend overall survival and prevent disease recurrence following surgical resection of localized breast, colorectal, and lung cancers. Chemotherapy is also employed as part of the multimodal treatment of locally advanced head and neck, breast, lung, and esophageal cancers; soft-tissue sarcomas; and pediatric solid tumors, thereby allowing for neoadjuvant surgery that is more limited and results in favorable outcomes (Chabner and Roberts, 2005).
In the past 10 years, the ability to harness the power of the immune system in the treatment of cancer has brought about a paradigm shift whereby some of the most feared diseases, such as melanoma and lung cancer and even late-stage metastatic disease, can be eradicated. For some cancers, response rates are surprisingly high: 87% in Hodgkin lymphoma even in heavily pretreated patients (Ansell et al., 2015), and 50% in patients with metastatic melanoma treated with combinations of anti-PD-1 and -CTLA4 immune checkpoint antibodies. Immune checkpoint inhibitors are currently approved for the treatment of over a dozen different cancers that include melanoma and cancers of the bladder, kidneys, liver, lungs as well as Hodgkin lymphoma. In addition to these histologically defined malignancies, any cancers with deficient DNA mismatch repair (e.g., colorectal, ovarian, pancreatic, endometrial cancers) were also approved for treatment.
Despite these major therapeutic successes, few categories of medication have a narrower therapeutic index and greater potential for causing harmful effects than anticancer drugs. A thorough understanding of their mechanisms of action, including clinical pharmacokinetics, drug interactions, and adverse effects, is essential for their safe and effective use. Anticancer drugs are quite varied in structure and mechanism of action. The group includes alkylating agents; antimetabolite analogues of folic acid, pyrimidine, and purine; natural products; hormones and hormone antagonists; and a variety of small-molecule drugs and antibodies directed at specific molecular targets, such as extracellular receptors, intracellular kinases, or the checkpoints of immune surveillance. Figure 69–1 depicts the cellular targets of these classes of drugs, and Chapters 70 to 73 provide information about them.
Mechanisms and sites of action of some of the drugs used in the treatment of cancer.
Anticancer drugs are increasingly used in a variety of nonmalignant diseases and have become treatment standards, for example, for autoimmune diseases (rituximab); rheumatoid arthritis (methotrexate and cyclophosphamide); Crohn’s disease (6-mercaptopurine); organ transplantation (methotrexate and azathioprine); sickle cell anemia (hydroxyurea); psoriasis (methotrexate); and wet macular degeneration (ranibizumab and aflibercept).