Drug Combination Halts Tumor Growth Better Than Single Agent
Main Category: Breast CancerAlso Included In: Biology / Biochemistry; Endocrinology
Article Date: 02 May 2007 - 7:00 PDT
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Treatment with three drugs that inhibit the human epidermal growth factor receptor (HER) stops HER2-positive breast cancer tumor growth in mice better than treatment with just one or two of the drugs.
Grazia Arpino, M.D., Ph.D., of Baylor College of Medicine in Houston, and colleagues measured tumor growth in mice with human breast cancer tumors that overexpress HER2. Some mice received one of three HER inhibitors - pertuzumab, trastuzumab, or gefitinib - or a combination of two or three of the drugs. The mice also received different combinations of hormonal therapy, including estrogen supplements, estrogen withdrawl, and tamoxifen.
A combination of all three HER inhibitors was more effective at slowing tumor growth than a single drug or combination of two drugs. The tumors grew after 49 days in mice that received all three drugs, compared with 21 days for mice in the estrogen-only group and 28 days for mice that got estrogen and pertuzumab. The addition of tamoxifen to any of the three drugs also inhibited tumors growth in the mice, but after two months the tumors grew resistant to the treatment. In mice treated with all three HER inhibitors plus tamoxifen or estrogen withdrawal, most tumors completely disappeared and did not progress for more than 189 days after treatment.
"These results support the hypothesis that acquired resistance to the individual agents is the result of [an] incomplete blockade of this complex network at the receptor level and not activation of a different survival pathway," the authors write.
Contact: Kimberlee Barbour
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Other highlights in the May 2 JNCI
Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at http://jnci.oxfordjournals.org/.
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Journal of the National Cancer Institute
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Drug Combination Halts Tumor Growth Better Than Single Agent?
posted by Gregory D. Pawelski on 6 May 2007 at 6:30 amCombination 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.
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