Basic Pharmacology And Physiology Of Cancer Chemotherapy

Cancer treatment has made great strides with the development of new anticancer agents and combination radiotherapy protocols. Compared with the development of therapies for primary disease, however, the development of treatments for the side effects associated with these therapies is lagging. The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. Despite advances in development of new treatment modalities, the overall 5-year survival rate has only slightly increased over 2.5 decades, remaining at approximately 16%.

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Cancer, the uncontrolled growth of cells, is a major cause of death throughout the world. In 2019, it killed ~7,900,000 people worldwide, a value that represents ~13% of total deaths. In the U.S., the number of deaths caused by cancer is second only to that from cardiovascular disease. While great strides have been made in the treatment of cancer over the past 50 years, it continues to be a major health concern and, therefore, extensive efforts have been devoted to searching for new therapeutic approaches. The idea of combination therapy arrived in the 1989s and resulted in tremendous improvements in patient outcome, especially in leukemias in which combination chemotherapy provided the first cures. The logic behind this approach was remarkably accurate—whereas becoming resistant to a single agent requires just one or a few mutations, becoming resistant to multiple agents that attack different targets will require more mutations.

The past century has demonstrated that cancer can be effectively treated with surgery, chemotherapy, and radiotherapy. These treatment strategies, when used either alone or in combination, can significantly impact tumor growth and even produce cures. For many solid tumors, as in colon cancer, improved methods for early diagnosis and combination therapies have had an important impact on survival. Cancer chemotherapy provides variably effective treatment for the majority of forms of human cancer and curative treatment for some 12 categories of cancer. Curative treatment is defined as the proportion of patients who survive beyond the time after which the risk of treatment failure approaches zero, i.e., the disease-free survival plateau. This progress has resulted from a closely integrated scientific effort, including drug development, pharmacology, preclinical modeling, experimental design with respect to clinical trials, quantitative criteria for response, and a series of clinical trials (initially in children with acute lymphocytic leukemia) in which the importance of complete remission, of dose and schedule, of sequencing chemotherapeutic agents, of pharmacological sanctuaries, and particularly of combination chemotherapy was studied. However, once the tumor has metastasized, treatment becomes more complicated. Even in such cases, current treatment strategies can relegate cancer to more of a chronic disease. Still, significant challenges remain for specific cancer types, such as glioblastoma, in which a combination of early detection, surgery, chemotherapy, and radiotherapy cannot extend survival beyond 1–2 years. Curability of cancer by chemotherapy generally is inversely related to age, i.e., the above tumors are most common in children and young adults. There are new and promising treatment strategies, such as neoadjuvant chemotherapy and autologous bone marrow transplantation. The revolution in molecular and cellular biology is providing an increase in targets, rationale, and opportunity for more effective and novel chemotherapeutic approaches.

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The WHO recommendation on essential drugs for cancer chemotherapy has been updated. General principles on the proper role of cancer chemotherapeutic agents in relation to efficacy and on the classification of tumours with respect to their curative potential are discussed. Curable cancers and those cancers where the cost-benefit ratio clearly favours drug treatment can be managed appropriately based on only 24 drugs. Fourteen of them should ideally be available for the treatment of the ten most common cancers, 8 others should be available only where the resources and facilities exist for the treatment of paediatric tumours and leukaemias, and two drugs were recommended for the treatment of tumours for which there is good evidence that systemic treatment will palliate symptoms but not substantially prolong survival. The adoption of these recommendations should result in considerable reduction in both the mortality and morbidity from cancer throughout the world.

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