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At the 20th Annual Chemotherapy Foundation Symposium in New York, N.Y., this past November there were numerous presentations about advances in chemotherapy clinical trials that used triplets -- combinations of three chemotherapy agents as opposed to more conventional single or double agent therapy. BenchMarks summarizes several presentations that revolve around two newer classes of drugs, called taxanes and platinums [see sidebar], which make up many of the new triplets. BenchMarks also talked to Elise Kohn, M.D., principal investigator, Laboratory of Pathology, National Cancer Institute, to get her perspective on clinical trial design and drug choice.

Colorectal Cancer
Mace Rothenberg, M.D., Vanderbilt-Ingram Cancer Center, Nashville, Tenn.: Platinum agents are used primarily because they form DNA adducts that can interrupt the cancer process. Oxaliplatin (a newer platinum) binds in a different place on DNA than cisplatin or carboplatin (2 older platinums) and it's a larger and bulkier compound, thus it's harder to separate from the DNA once it's bound. The main difference between oxaliplatin and the other platinum compounds is the spectrum of cytotoxicity, or ability to induce cell death. For colorectal cancer, oxaliplatin has shown activity against six cell lines whereas the other two platinum drugs haven't shown activity. Of particular note are some recent trials showing 20-month survival for advanced colorectal cancer patients using oxaliplatin in different combinations with other drugs, which is a significant survival advantage.

Bladder Cancer
Maha Hussain, M.D., University of Michigan Comprehensive Cancer Center, Ann Arbor, Mich.: We've evaluated gemcitabine in combination with paclitaxel and carboplatin in patients with advanced urothelial (the epithelium, or lining of the bladder) cancer. This combination demonstrated an encouraging level of activity even in patients with visceral metastasis. Carboplatin allowed the use of this triplet in patients who may not have tolerated cisplatin-based therapy, although a high level of activity is also reported with the combination of gemcitabine, paclitaxel and cisplatin. The overall and complete response rates and median survivals with these triplets (even in patients with visceral disease) suggest the potential for improved outcome. However, this will have to be established by randomized trials such as the current intergroup (EORTC/SWOG, two cooperative cancer consortiums) trial, which is evaluating gemcitabine, paclitaxel and cisplatin relative to gemcitabine and cisplatin. Non-platinum based combinations, such as gemcitabine plus paclitaxel, have also emerged as promising doublets. This combination is currently being evaluated by SWOG in elderly patients.

Breast Cancer
Nicholas J. Robert, M.D., U.S. Oncology Breast Committee, Fairfax, Va.: In treating advanced breast cancer patients, we try to build on experience in other solid tumors where combinations of paclitaxel and carboplatin are familiar treatments. We've found this combination to be active, well-tolerated, with no cardiotoxicity and good response rates. When looking at women who were Her2 positive, we wanted to see if carboplatin added to the effect of Herceptin and if the combination produced improved outcomes. A phase III study of triplet therapy of carboplatin, docetaxel and Herceptin showed a 64 percent response rate and time to progression of 17 months, which is 10 months better than other combinations.

In a Phase III trial of carboplatin, paclitaxel, and Herceptin presented at the San Antonio Breast Conference in December 2002, Robert found that the triplet of Herceptin, paclitaxel and carboplatin versus the doublet of Herceptin plus paclitaxel was clearly superior with a 52% versus 36% response rate and a 11.2 month versus 6.9 month time to progression, both significant differences. Additionally, adverse event profiles were found to be comparable between the two groups with the exception of more neutropenia and thrombocytopenia in the triplet group.

Mark Pegram, M.D., UCLA School of Medicine, Jonsson Comprehensive Cancer Center, Los Angeles, Calif.: We've looked at various drugs in breast cancer patients who overexpress the Her2 protein (who are thus commonly referred to as being Her2 positive). We found that although the drug of choice for treating Her2 positive patients is the molecularly targeted drug Herceptin, when testing the efficacy of a doublet, the synergy between it and a class of drugs called anthracyclines increased the risk of cardiomyopathy. So we then looked at docetaxel and Herceptin, which was a better choice of taxanes than paclitaxel. It turns out that taxanes such as docetaxel or paclitaxel induce apoptosis (cell death) that augments the benefit of Herceptin. We also have some evidence that the triplet of taxotere (another taxane) plus a platinum drug plus herceptin shows efficacy. We are testing this hypothesis in a randomized clinical trial and the early results look promising.

Ovarian and Cervical Cancer
Dr. Elise Kohn, M.D., Medical Ovarian Cancer Clinic, Medical Oncology Clinical Research Unit, and principal investigator, Laboratory of Pathology, NCI: I think there are no tried and true criteria for choosing how to use single agent versus doublets or triplets in chemotherapy treatment of patients not enrolled in chemotherapy trials. I think it's important to realize that every patient is different and some of the work we're trying to do at NCI is to allow us to optimize decision making for those situations. In designing a clinical trial, we use preclinical and clinical data to drive logical and presumptively safe combinations to test for efficacy and safety. The final guidelines for determination of how to use these combinations in general practice is based upon those results and the gold standard is the results of randomized trials comparing the new approach to existing standards. How do we guide patients to their treatment decisions between standard and experimental therapy? Sometimes a patient may be eligible for more than one trial and that may give them the opportunity to discuss with one or with multiple physicians what the philosophy and requirements of the trial are and what opportunities exist. Once a patient is involved in one of our trials, if an intervention doesn't optimally affect her cancer, we do go ahead and discuss not just clinical trial options but we always discuss what options are there for the patient in the community setting as well. We don't always know all the clinical trial options for a patient at any given time so we can't give them a global review but part of our core consent process is to be sure that the patient understands that she has multiple other options.

Several of the trials I'm involved with are molecularly targeted trials. I think whether people are doing molecularly targeted trials (like with the new drug Gleevec that has shown excellent early efficacy in some cancers) or more conventional chemotherapy is a choice that varies widely. I don't think we've proven that molecularly targeted drugs are equivalent or better than conventional chemotherapy or that we've learned how to use them optimally yet. We're still trying to improve our clinical trial design and translational objectives to allow us to learn that. I think right now that these agents should be used in clinical trial settings so that we learn how to use them properly and that we shouldn't be 'ad-libbing' them as a community.

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