Page 966 - Basic _ Clinical Pharmacology ( PDFDrive )

952 SECTION VIII Chemotherapeutic Drugs

The use of combination chemotherapy is important for several almost always results in a loss in the capacity to cure the tumor
reasons. First, it provides maximal cell kill within the range of effectively before a reduction in the antitumor activity is observed.
toxicity tolerated by the host for each drug as long as dosing is Although complete remissions may continue to be observed with
not compromised. Second, it provides a broader range of interac- dose reductions down to as low as 20% of the optimal dose, resid-
tion between drugs and tumor cells with different genetic abnor- ual tumor cells may not be entirely eliminated, thereby allowing
malities in a heterogeneous tumor population. Finally, it may for eventual relapse. Because toxicities are usually associated with
prevent and/or slow the subsequent development of cellular drug anticancer drugs, it is often appealing for clinicians to avoid acute
resistance. Of note, these same concepts apply to the therapy of toxicity by simply reducing the dose and/or by increasing the time
chronic infections, such as HIV and tuberculosis. interval between each cycle of treatment. However, such empiric
Certain principles have guided the selection of drugs in the modifications in dose represent a major cause of treatment failure,
most effective drug combinations, and they provide a paradigm especially in patients with drug-sensitive tumors.
for the development of new drug therapeutic programs. A positive relationship between dose intensity and clinical
efficacy has been documented in several solid tumors, including
1. Efficacy: Only drugs known to have some level of clinical effi-
cacy when used alone against a given tumor should be selected advanced ovarian, breast, lung, and colon cancers, as well as in
for use in combination. If available, drugs that produce com- hematologic malignancies, such as the lymphomas. At present,
plete remission in some fraction of patients are preferred to there are three main approaches to dose-intense delivery of che-
those that produce only partial responses. motherapy. The first approach, dose escalation, involves increas-
2. Toxicity: When several drugs of a given class are available and ing the doses of the respective anti-cancer agents. The second
strategy is administration of anti-cancer agents in a dose-intense
are equally effective, a drug should be selected on the basis of manner by reducing the interval between treatment cycles, while
toxicity that does not overlap with the toxicity of other drugs the third approach involves sequential scheduling of either
in the combination. Although such selection leads to a wider single agents or combination regimens. Each of these strategies is
range of adverse effects, it minimizes the risk of a lethal effect presently being applied to the treatment of a wide range of solid
caused by multiple insults to the same organ system by differ- cancers, including breast, colorectal, and NSCLC, and in general,
ent drugs and allows dose intensity to be maximized. such dose-intense regimens have significantly improved clinical
3. Optimum scheduling: Drugs should be used in their optimal outcomes.
dose and schedule, and drug combinations should be given at
consistent intervals. Because long intervals between cycles
negatively affect dose intensity, the treatment-free interval DRUG RESISTANCE
between cycles should be the shortest time necessary for recov-
ery of the most sensitive normal target tissue, which is usually A fundamental problem in cancer chemotherapy is the develop-
the bone marrow. ment of cellular drug resistance. Primary or inherent resistance
4. Mechanism of interaction: There should be a clear under- refers to drug resistance in the absence of prior exposure to avail-
standing of the biochemical, molecular, and pharmacokinetic able standard agents. The presence of inherent drug resistance was
mechanisms of interaction between the individual drugs in a first proposed by Goldie and Coleman in the early 1980s and was
given combination, to allow for maximal antitumor effect. thought to result from the genomic instability associated with the
Omission of a drug from a combination may allow overgrowth development of most cancers. For example, mutations in the p53
by a tumor clone sensitive to that drug alone and resistant to tumor suppressor gene occur in up to 50% of all human tumors.
other drugs in the combination. Preclinical and clinical studies have shown that loss of p53 func-
5. Avoidance of arbitrary dose changes: An arbitrary reduc- tion leads to resistance to radiation therapy as well as resistance
tion in the dose of an effective drug in order to add other less to a wide range of anti-cancer agents. Defects in the mismatch
effective drugs may reduce the dose of the most effective agent repair enzyme family, which are tightly linked to the development
below the threshold of effectiveness and destroy the ability of of familial and sporadic colorectal cancer, are associated with
the combination to cure disease in a given patient. resistance to several unrelated anti-cancer agents, including fluo-
ropyrimidines, thiopurines, and cisplatin/carboplatin. In contrast
Dosage Factors to primary resistance, acquired resistance develops in response to
exposure to a given anti-cancer agent. Experimentally, drug resis-
Dose intensity is one of the main factors limiting the ability of tance can be highly specific to a single drug and is usually based
chemotherapy or radiation therapy to achieve cure. As described on a specific change in the genetic machinery of a given tumor
in Chapter 2, the dose-response curve in biologic systems is usu- cell with amplification or increased expression of one or more
ally sigmoidal in shape, with a threshold, a linear phase, and a pla- genes. In other instances, a multidrug-resistant phenotype occurs,
teau phase. For chemotherapy, therapeutic selectivity is dependent associated with increased expression of the MDR1 gene, which
on the difference between the dose-response curves of normal and encodes a cell surface transporter glycoprotein (P-glycoprotein,
tumor tissues. In experimental animal models, the dose-response see Chapter 5). This form of drug resistance leads to enhanced
curve is usually steep in the linear phase, and a reduction in dose drug efflux and reduced intracellular accumulation of a broad
when the tumor is in the linear phase of the dose-response curve range of structurally unrelated anti-cancer agents, including