Chapter 65: General Principles in the Pharmacotherapy of Cancer

INTRODUCTION

Cancer pharmacology has changed dramatically during the recent past with the improved understanding of cancer biology and an ever-expanding set of newly developed drugs that target vulnerabilities in individual cancers. Effective early treatments have been developed for some fatal malignancies, including testicular cancer, lymphomas, and leukemia. Also, 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 surgery that is more limited with favorable outcomes (Chabner and Roberts, 2005). In the past 5 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 PD-1 and CTLA4 immune checkpoint antibodies. Immune checkpoint inhibitors are currently approved for the treatment of bladder cancer, Hodgkin lymphoma, kidney cancer, lung cancer, and melanoma; more approvals are anticipated in the near future based on several hundred ongoing clinical trials.

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 65–1 depicts the cellular targets of these drugs, and Chapters 66–68 provide information on the different classes of drugs.

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 disease (6-mercaptopurine); organ transplantation (methotrexate and azathioprine); sickle cell anemia (hydroxyurea); psoriasis (methotrexate); and wet macular degeneration (ranibizumab and aflibercept).

ABBREVIATIONS