Avoidance of arbitrary dose changes: An arbitrary reduction in the dose of an effective drug in order to add other less effective drugs may reduce the dose of the most effective agent below the threshold of effectiveness and destroy the ability of the combination to cure disease in a given patient.
Dose intensity is one of the main factors limiting the ability of chemotherapy or radiation therapy to achieve cure. As described in Chapter 2, the dose-response curve in biologic systems is usually sigmoidal in shape, with a threshold, a linear phase, and a plateau phase. For chemotherapy, therapeutic selectivity is dependent on the difference between the dose-response curves of normal and tumor tissues. In experimental animal models, the dose-response curve is usually steep in the linear phase, and a reduction in dose when the tumor is in the linear phase of the dose-response curve almost always results in a loss in the capacity to cure the tumor effectively before a reduction in the antitumor activity is observed. Although complete remissions may continue to be observed with dose reductions down to as low as 20% of the optimal dose, residual tumor cells may not be entirely eliminated, thereby allowing for eventual relapse. Because toxicities are usually associated with anticancer drugs, it is often appealing for clinicians to avoid acute toxicity by simply reducing the dose and/or by increasing the time interval between each cycle of treatment. However, such empiric modifications in dose represent a major cause of treatment failure, especially in patients with drug-sensitive tumors.
A positive relationship between dose intensity and clinical efficacy has been documented in several solid tumors, including advanced ovarian, breast, lung, and colon cancers, as well as in hematologic malignancies, such as the lymphomas. At present, there are three main approaches to dose-intense delivery of chemotherapy. The first approach, dose escalation, involves increasing the doses of the respective anti-cancer agents. The second strategy is administration of anti-cancer agents in a dose-intense manner by reducing the interval between treatment cycles, while the third approach involves sequential scheduling of either single agents or combination regimens. Each of these strategies is presently being applied to the treatment of a wide range of solid cancers, including breast, colorectal, and NSCLC, and in general, such dose-intense regimens have significantly improved clinical outcomes.
A fundamental problem in cancer chemotherapy is the development of cellular drug resistance. Primary or inherent resistance refers to drug resistance in the absence of prior exposure to available standard agents. The presence of inherent drug resistance was first proposed by Goldie and Coleman in the early 1980s and was thought to result from the genomic instability associated with the development of most cancers. For example, mutations in the p53 tumor suppressor gene occur in up to 50% of all human tumors. Preclinical and clinical studies have shown that loss of p53 function leads to resistance to radiation therapy as well as resistance to a wide range of anti-cancer agents. Defects in the mismatch repair enzyme family, which are tightly linked to the development of familial and sporadic colorectal cancer, are associated with resistance to several unrelated anti-cancer agents, including fluoropyrimidines, thiopurines, and cisplatin/carboplatin. In contrast to primary resistance, acquired resistance develops in response to exposure to a given anti-cancer agent. Experimentally, drug resistance can be highly specific to a single drug and is usually based on a specific change in the genetic machinery of a given tumor cell with amplification or increased expression of one or more genes. In other instances, a multidrug-resistant phenotype occurs, associated with increased expression of the MDR1 gene, which encodes a cell surface transporter glycoprotein (P-glycoprotein, see Chapter 5). This form of drug resistance leads to enhanced drug efflux and reduced intracellular accumulation of a broad range of structurally unrelated anti-cancer agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins, and even small molecule inhibitors, such as imatinib.