Two independent phase II studies have shown that the combination of carboplatin and docetaxel (Taxotere®; Aventis Pharmaceuticals, Inc.; Bridgewater, NJ) is active in the first-line treatment of metastatic breast cancer. Based on these promising results of combining trastuzumab with chemotherapy, nonanthracycline alternatives were investigated, with many of them incorporating platinum agents. There is also a great deal of information and HER positive women who receive this regimen with Herceptin. Experience with this combination is still limited, even with triple negative disease.
With Herceptin: The Breast Cancer International Research Group (BCIRG) conducted two pilot phase II trials of patients with advanced breast cancer overexpressing or with amplified HER2, in which trastuzumab was administered in combination with carboplatin/docetaxel or cisplatin/docetaxel. One prior chemotherapy regimen for metastatic breast cancer was allowed in the study of carboplatin/docetaxel but not in the study of cisplatin/docetaxel . Docetaxel (75 mg/m2) was administered followed by either carboplatin (AUC 6) or cisplatin (75 mg/m2) on day 1 of a 3-week cycle. Up to eight cycles were administered. Trastuzumab was administered at a loading dose of 4 mg/kg on the first day of the first cycle and then continued at a weekly dose of 2 mg/kg for 1 year or until disease progression.
Both regimens were active, but it is important to recognize that the two studies were not identical with respect to the patient populations enrolled. The overall response rates were 79% (95% CI = 66%–88%) for the cisplatin/docetaxel/trastuzumab group and 58% (95% CI = 40%–70%) for the more heavily pretreated carboplatin/docetaxel/trastuzumab group . In the subgroup of patients in whom HER2 gene amplification was analyzed by fluorescent in situ hybridization (FISH), the response rates were numerically higher in the cisplatin/docetaxel/trastuzumab group (77% versus 64%), but the median time to progression was longer in the carboplatin/docetaxel/trastuzumab group, (17.0 versus 12.7 months) In the subgroup of patients with FISH-negative disease for HER2, the response rate was n = 16/19 (84%) for the cisplatin study and n = 7/17 (41%) for the carboplatin trial. Grade 3/4 thrombocytopenia was more common with the carboplatin regimen, but gastrointestinal, renal, and neurosensory toxicities occurred more frequently with the cisplatin regimen. Grade 3/4 renal toxicity, ototoxicity, neurosensory toxicity, and constipation were not observed with the carboplatin regimen. One patient in each group developed congestive heart failure. These studies showed that adding trastuzumab to a platinum/taxane combination is active in HER2-overexpressing advanced breast cancer, leading to high response rates and notable times to progression, forming the basis for further phase II and phase III clinical trials as outlined below. The regimens containing cisplatin and carboplatin showed similar activities, but nonhematologic toxicities appeared to be less frequent with the carboplatin regimen.
The benefit of adding carboplatin to paclitaxel and trastuzumab in the first-line treatment of HER2-overexpressing metastatic breast cancer was further shown in results from an ongoing phase III study. A total of 191 patients were randomly assigned to treatment with paclitaxel (175 mg/m2 infused over 3 hours) either with or without carboplatin (AUC of 6 mg/ml minute). Treatment was repeated q3w for up to six cycles. Trastuzumab was administered at a loading dose of 4 mg/kg followed by weekly doses of 2 mg/kg until disease progression. Nearly half the patients had received prior adjuvant chemotherapy, and 66% had 3+ IHC for HER2. Updated data indicate that the group receiving carboplatin had a significantly higher response rate (52% versus 36%, p = 0.03) and a longer median time to progression (10.3 versus 7.0 months, p = 0.016) than the group receiving only paclitaxel and trastuzumab. A similar advantage of carboplatin was observed in the subgroup with HER2 scored as 3+ by immunohistochemistry: the response rates were 57% versus 37% (p = 0.03) and the median times to progression were 14 versus 7.1 months (p = 0.007). The study was not powered statistically to show a survival advantage between treatments, but at the latest update, the median overall survival time was 42.1 months (range 1.8–45.7) with paclitaxel/carboplatin/trastuzumab versus 33.3 months (range 1.8–45.7) with paclitaxel/trastuzumab (p = 0.41). In the 3+HER2 patients, the paclitaxel/carboplatin/trastuzumab group showed a trend for longer median survival (42 months [range 5.6–51.8] versus 29 months [range 1.8–55.3], p= 0.15) .
As expected, the addition of a third drug to paclitaxel and trastuzumab resulted in greater myelosuppression; grade 4 neutropenia (36% versus 12%, p 0.01) and grade 3 thrombocytopenia (9% versus 1%, p 0.01) were significantly more common with carboplatin/paclitaxel/trastuzumab than with paclitaxel/trastuzumab. Fatigue (10% versus 4%), anemia (5% versus 2%), and nausea (6% versus 1%) also occurred somewhat more frequently. Thus, these preliminary results suggest that adding carboplatin to paclitaxel and trastuzumab provides a statistically and clinically significant higher response rate and longer time to progression than paclitaxel and trastuzumab in patients with a high degree of HER2 overexpression, as well as an important trend toward better survival, all associated with a very modest increase in myelosuppression.
In conclusion, this regimen is supported by Phase III data and should be considered standard of care.
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