Chemotherapy Approaches in the Management of Cancers

Cancer chemotherapy has principally been used in the management of advanced or metastatic disease, following failed local therapies, or in disease for which no alternative therapy is effective. Chemotherapy is curative for several advanced human cancers, such as gestational trophoblastic disease, certain hematologic malignancies, or germ cell testicular cancer. However, most common solid tumors are not curable with current chemotherapeutic regimens when metastatic (Table 2.1).

The roles of chemotherapy are manifold: induction chemotherapy denotes its use as primary therapy when there is no alternative treatment available or subsequently suitable even with tumor response, such as in hematologic malignancies, where disease is systemic. As an adjunct in combined modality therapy, chemotherapy is adjuvant when systemic treatment is applied after the tumor has been controlled by an alternative modality, such as surgery and/or radiotherapy, or neoadjuvant (primary) chemotherapy when localized cancer will otherwise not be optimally managed if systemic chemotherapy is not used before definitive local therapy.

Dose Intensity Versus Dose Density

Multiple laboratory experiments have established the proportionate dose-response curve, such that log kill is greater for the regimen with a higher dose intensity (i.e., by increasing the dose level delivered over a standard time interval). The slope of the curve is often steeper for tumors with a higher growth fraction. This observation underlies one of the principles in cancer chemotherapy—the administration of the highest possible dose of drugs in the shortest possible time intervals. The latter is typically limited by the recovery period of host organ function, such as the gastrointestinal tract and, in particular, the bone marrow, and thus explains the familiar 14- to 28-day intervals between cycles of therapy.

Progress in understanding of tumor growth kinetics has led to the emergence of new concepts in the schedules and

TABLE 2.1. Responses of tumors to chemotherapy.

Curable

Prolonged survival

Palliative/minimal

Hodgkin's lymphoma Non-Hodgkin's lymphoma

(e.g., Burkitt's, diffuse large cell]

Acute leukemias Testicular cancer Ovarian cancer Choriocarcinoma Childhood cancers (e.g., rhabdomyosarcoma, Wilm's tumor, Ewing's sarcoma]

Non-Hodgkin's lymphoma

(e.g., follicular] Bladder cancer Breast cancer Lung cancer Colorectal cancer Oligodendrogliomas

Multiple myeloma Chronic leukemias Malignant melanoma Renal cell carcinoma Glioblastoma multiforme Pancreatic carcinoma Hepatocellular carcinoma Head and neck cancers Esophageal carcinoma Gastric carcinoma Prostate carcinoma dosing of cytotoxic agents. Dose intensity refers to the dose level or total amount of drug received over a fixed unit of time. It is a function of the magnitude of the dose level. Achieving a certain effective dose level is analogous to the concentration-dependent killing of some antibiotics, such as aminoglycosides, wherein increasing bactericidal activity is achieved with exposure to a higher dose until a threshold concentration of maximal efficacy is achieved. Dose intensity is an important concept derived from the well-observed steep dose-response effect of chemotherapy agents demonstrated in randomized trials such as in germ cell tumors.11

However, achieving a higher dose intensity by administration of higher dose levels of chemotherapy is hampered by concomitant increase in frequency and severity of toxicities. In addition, this concept may not be applicable in metastatic solid tumors, when tumor burden is largest. This restriction is illustrated by the negative results of myeloablative doses of chemotherapy compared to conventional chemotherapy in women with metastatic breast carcinoma.12 Moreover, it has been observed in vitro that one of the important determinants of cytotoxicity is the duration of drug exposure beyond a threshold drug concentration. Indeed, there may be a readily tolerable minimal dose level for tumors, as implied in a recent trial by the Cancer and Leukemia Group B (CALGB) trial. In that study, there was no survival benefit to the administration of a more dose-intense regimen of 5-fluorouracil, adri-amycin, and cyclophosphamide (FAC) in the adjuvant setting among women whose tumors did not express the HER/2 neu oncoprotein.13

In contrast, dose density refers to the total amount of drug received over a variable given period of time. To illustrate, giving 2x amount of drug in cycles of y days (A) is twice more dose intense than x drug in y days (B), whereas B is less dose dense than x drug given in y/2 days (C). C is as dose intense and dose dense as A. Simply, dose density is a function of frequency of dose administration within a treatment cycle. Dose density is analogous to the time-dependent killing activity of penicillins and cephalosporins wherein bactericidal activity is directly related to the time of exposure above the minimum inhibitory concentration (MIC), after which it becomes independent of drug concentration. A tumor thus relapses when subtotal eradication upon initial drug administration leads to tumor growth and development of drug resistance in between treatment cycles when the interval between therapy is prolonged. The dose-dense therapy may inhibit tumor regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy. Dose-dense strategy is the logical conclusion derived from the Norton-Simon model of tumor growth and drug response. Moreover, recent preclinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs, so-called "metronomic" dosing, may affect tumor endothelium and inhibit tumor angiogenesis, thus resulting in a better therapeutic index with reduced significant side effects (e.g., myelo-suppression) involving other tissues. In solid tumors, this may be exemplified by the successful use of weekly paclitaxel in metastatic breast cancer.14

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