Introduction to Cancer Chemotherapy

Cancer chemotherapy refers to a "wide range of therapeutic options used in the treatment of malignant diseases, including categories such as cytotoxic drugs, biologics, immunotherapies, targeted drug therapies, hormonal treatments, and high dose chemotherapy regimens supported with hematopoietic stem cell transplant".  This course provides an overview of chemotherapeutic agents, modes of action, methods of administration and common side effects.

Modern medical treatment of cancer evolved from the discovery that mustard gas exposure during World War I resulted in leukopenia and mutations that increased the risk of leukemia and lymphoma. During WWII, Yale scientists Louis Goodman and Alfred Gilman discovered that the nitrogen mustard gas, being studied for weaponization, also had the ability to shrink certain cancer tumors.

In 1948, the UK chemist, Professor Alexander Haddow, demonstrated that two chlorine atoms on the nitrogen mustard molecule were needed to kill cancer cells. He also found how to make the chemical less toxic to normal cells, while increasing its cancer-killing activity.

"He continued his research, showing how these chemicals actually worked – it was by somehow linking together other molecules inside the cancer cell, ultimately leading the cell on a suicidal path. Other researchers then went on to show that these linked molecules were in fact strands of DNA. This triggered the cell’s self-destruct mechanism causing the cell to shut down and break apart, destroying it."  

The same year, Sidney Farber "demonstrated that a number of folic acid antagonists, including 4-aminopteroyl-glutamic acid (aminopterin) produced temporary remissions in children with acute undifferentiated leukaemia. These observations lead to the development and use of other chemotherapeutic agents, either singly or, more effectively, in combination for treating childhood and adult malignancies. He introduced actinomycin D for the treatment of metastatic and localized Wilms tumour".

Cytotoxic drugs remain a principal component of many cancer treatment protocols. Today, cytotoxic antineoplastic drugs are FDA approved to cure cancer, to prolong life, or to provide palliation when reducing tumor size can relieve pain or other distressing symptoms. Cytotoxic drugs work primarily by interfering with completion of the cell replication cycle.

When a cell cannot pass through all phases of the cell cycle the result may be programmed cell death known as apoptosis or necrosis. Cytotoxics have their greatest effect on cells and cancers that have rapid replication rates. Certain cancers as well as healthy hair follicle cells, bone marrow cells, and cells lining the mouth and gut replicate frequently making them more susceptible to the effects and side effects of cytotoxic medicines. Other healthy tissues like muscle, heart, brain, and bone replicate less often and are therefore less effected by cytotoxic drugs. Unfortunately, the usefulness of all cytotoxic regimens are limited by the side effects on healthy cells.

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The three goals of cytotoxic chemotherapy are 1) cure cancer, 2) prolong life, 3) provide palliation when cancer cannot be cured or controlled.

"The majority of curable cancers are uncommon tumours such as childhood cancers, leukaemias, lymphomas and testicular tumours. Other cancers are partially responsive but the impact of chemotherapy on survival in advanced solid tumours is less (although important). These include cancer of the breast, SCLC, ovarian cancer and cancer of the colon." "The overall contribution of chemotherapy to cure is relatively small".

"Single-drug chemotherapy may cure selected cancers (eg, choriocarcinoma, hairy cell leukemia). More commonly, multidrug regimens incorporating drugs with different mechanisms of action and different toxicities are used to increase the tumor cell kill, reduce dose-related toxicity, and decrease the probability of drug resistance. These regimens can provide significant cure rates (eg, in acute leukemia, testicular cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, and, less commonly, solid tumors such as small cell lung cancer and nasopharyngeal cancer). Multidrug regimens typically are given as repetitive cycles of a fixed combination of drugs. The interval between cycles should be the shortest one that allows for recovery of normal tissue."

Cytotoxic chemotherapy differs significantly from either surgery or radiation because it almost always acts systemically, damaging cells in the process of replication, throughout the body. This feature of cytotoxic drugs is important because chemotherapy can reach cancer cells that may have spread to other parts of the body. However, when cytotoxic drugs attack all cells that are in the process of reproducing, these drugs don’t distinguish between normal cells and cancer cells. As a result, both cancer cells and normal cells may be destroyed or damaged, leading to potentially serious side effects. The goal of cancer chemotherapy is to cure or control cancer by destroying cancer cells while sparing normal cells and minimizing toxic side effects.

Cytotoxic drugs are predominantly systemic treatments that affect replicating cells whether healthy or malignant.