Chapter 9: Targeted Therapy

BACKGROUND

Chemotherapy has been the mainstay of systemic treatment of cancer for nearly 75 years. Chemotherapy can be broadly classified as either cytotoxic (killing rapidly dividing cells) or cytostatic (preventing further replication of rapidly dividing cells). However, chemotherapy is not specific to cancer cells, and will also affect normal cells which have high turnover, such as those in the gastrointestinal tract (leading to inflammation and sloughing of the GI tract), hair follicles (leading to alopecia), and in the bone marrow (leading to anemia, thrombocytopenia, and leukopenia). Many of the targeted therapies we use and will discuss in this chapter are cytostatic drugs, and implemented to retard growth, while traditional chemotherapies—such as alkylating agents and antimetabolites—are cytotoxic and lead to apoptosis of the affected cells.

Goodman and Gilman's use of nitrogen mustard in the treatment of Hodgkin's lymphoma and Farber's use of folate analogues for acute lymphoblastic leukemia (ALL)—both cytotoxic therapies—opened the door to chemotherapy in the mid-1940s.^1,2 The next step in the treatment of what were considered incurable malignancies came with the premise of combination chemotherapy, whereby several different drugs—each aimed at affecting phases in the cell cycle—were used simultaneously.³ Within a matter of months, ALL went from being an incurable disease to demonstrating prolonged remission and even cure. The concept of combinatorial chemotherapy was expanded to treat a variety of hematological and solid tumors in both children and adults. Today, combination cytotoxic chemotherapy remains the mainstay of treatment for the majority of malignancies.

Adjuvant therapy was the next major step toward our understanding of chemotherapy in the treatment of cancer with the goal to eliminate micrometastatic disease after “curative” resections. As postulated in the "cell-kill" hypothesis,⁴ the more abundant the tumor the less likely chemotherapy would be able to induce a cure. Fisher's use of adjuvant therapy for breast cancer patients after radical mastectomy revolutionized the collective approach to the treatment of cancer.⁵ Rather than depending on "curative" resection alone, he used adjuvant chemotherapy to treat circulating tumor cells to prevent future metastases and recurrences. Since their pivotal study, and the subsequent influence of the National Surgical Adjuvant Breast Project (NSABP), an overwhelming number of clinical trials implementing combination chemotherapy have been employed in both the adjuvant and neoadjuvant setting. It was classically thought that if only the right combination of chemotherapeutic drugs for a particular malignancy could be identified, then a large-scale cure would be attainable. However, in most cases, chemotherapy is largely an extender of survival more than it is a modality of cure. Moreover, the morbidity associated with chemotherapy, as a single agent or in combination, can be debilitating, as patients often cannot tolerate the dosage or duration prescribed. More specific targeted therapy was needed.

The search for molecular targets which would allow greater precision toward tumor cells without causing damage to healthy cells began, not surprisingly, with the treatment of breast cancer. ...