Drug Combination Halts Tumor Growth Better Than Single Agent

Drug Combination Halts Tumor Growth Better Than Single Agent?

Combination chemotherapy has not always produced greater degrees of clinical benefit than single agent therapy. When two or more drugs are given, there is a greater probability that at least one of the drugs will be active. Then there is the potential for true synergery, where the whole is greater than the sum of the parts.

Most classic drug combinations are only additive or at most, minimally synergistic. Examples of merely additive drug combinations are cisplatin/5FU, cisplatin/Taxol, and cisplatin/etoposide. However, some newer combinations show greater degrees of synergy, including cisplatin/topotecan, gemcitabine/platinum, and gemcitabine/alkylators.

The profound synergy between gemcitabine/platinum in vitro has been confirmed in the clinic in a number of settings. The similar degree of synergy between gemcitabine and alkylating agents suggest that these combinations should be explored in clinical settings in which alkylating agents are known to be important.

True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases are merely additive, where the whole equals the sum of its parts, and not synergistic. In hematologic neoplasms (leukemia, lymphoma, multiple myeloma), true synergy is very common.

In cases where drugs are only additive and not synergistic, nothing is learned by testing the drugs in combination over what is learned by testing them separately. So drugs in combination are only tested in cases where there is the realistic possibility of seeing true synergy.

Such solid tumor drug combinations as Cyclophosphamide + Doxorubicin or Carboplatin + Taxol are virtually always only additive and not synergistic. Cisplatin plus Etoposide is virtually never synergistic in non-small cell lung cancer, but is synergistic 25% - 50% of the time in small cell lung cancer. Gemcitabine + Cisplatin is very often synergistic. Vinorelbine + Mitomycin c or Mitoxantrone is occasionally synergistic, as is Irinotecan + Cisplatin.

The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.

The era of empiric, aggressive, multi-agent cytotoxic chemotherapy for first-line/recurrent/refractory adult solid tumors should come to an end.

More emphasis should be put on matching treatment to patient, through the use of individualized genetic and cellular pre-testing, having more respect for minimal partial response or stable disease, when it can be achieved through use of the least toxic and mutagenic drug regimens, and reserve the use of higher dose therapy or aggressive combination chemotherapy to those patients with tumor biologies most amenable to attack and destroy by these aggressive treatments.

Cell Function Analysis

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