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Weekly Dose-dense Paclitaxel-Carboplatin for Recurrent Ovarian Cancer
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Using a "dose-dense" regimen of paclitaxel and carboplatin in heavily pre-treated, platinum- resistant ovarian cancer patients, a UK oncology group demonstrated that a more protracted treatment schedule (six months) was both tolerable and associated with an impressive overall response rate (60%). The findings provide rationale for a randomized clinical trial to examine this approach for relapsed ovarian cancer, particularly for those who relapse within a year of completing initial platinum-based treatment.
Source: Sharma R, et al. Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer. Br. J Cancer. 2009;100:707-712.
In the treatment of recurrent ovarian cancer, it is acknowledged that a return to a platinum-based regimen may be an effective approach, particularly if the interval since the last platinum treatment is a year or more.1 Under that circumstance, the response rate might approach 60%. However, in patients relapsing after original platinum treatment within six months, the response rate is significantly lower (10-15%).1
In the current report, Sharma et al report a retrospective series of 20 patients with a diagnosis of epithelial ovarian cancer that were treated with "dose-dense" scheduling of carboplatin/paclitaxel having relapsed within six months from a platinum-based regimen. The median age of the patients enrolled was 61 years (range 40-74 years), and the median number of prior therapies was three (range 1-8). Carboplatin AUC 3 and paclitaxel 70 mg/m2 were administered on days 1, 8, and 15 every four weeks, with the intent to deliver six cycles of chemotherapy. Baseline CT imaging of the chest, abdomen, and pelvis was carried out prior to the commencement of therapy and after every two cycles. Blood samples for full blood count, biochemistry, liver function tests, and serum CA125 tests were taken prior to the commencement of therapy and before each treatment. Tumor response was assessed after every two cycles with repeat CT chest, abdomen, pelvis, and by CA125 (GCIG criteria).2,3 Data regarding the planned and delivered weekly dose intensity of treatment, the overall treatment dose delivered, toxicity, and clinical outcome were collected.
Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anemia (5%). One patient experienced grade 4 neutropenia. No grade 3 or 4 thrombocytopenia was reported. Fatigue, nausea, and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months, and overall survival was 13.3 months. The dynamics of response-to-dose-dense therapy were as rapid as with front-line therapy within the same patient.
There have been several efforts to develop effective and well-tolerated chemotherapy options for patients who have platinum-resistant ovarian cancer. A number of agents, including topotecan, gemcitabine, liposomal doxorubicin, paclitaxel, and vinorelbine have been reported but response rates are generally less than 20%.4,5 Thus evolved the interest in applying novel dose and scheduling paradigms reintroducing platinum in association with paclitaxel or other drugs, and several "dose-dense" regimens were developed. For example, van der Burg et al6 reported a response rate of 46% in patients with a platinum-free interval (PFI) of < 4 months, with weekly cisplatin (50-70 mg/m2) and daily oral etoposide for six weekly cycles followed by maintenance oral etoposide. Subsequently, weekly paclitaxel was found to have activity in platinum-resistant ovarian cancer, and combinations of these two agents were shown to improve both response rate and survival. The current retrospective analysis is of added value as it demonstrates that a dose-dense regimen can be highly effective, with acceptable toxicity in this heretofore difficult group of patients.
1. Markman M, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9:389-393.
2. Therasse P, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216.
3. Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol. 2003;21: 187s-193s.
4. Gordon AN, et al. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004;95:1-8.
5. Mutch DG, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25:2811-2818.
6. van der Burg ME, et al. Weekly cisplatin and daily oral etoposide is highly effective in platinum pretreated ovarian cancer. Br J Cancer. 2002;86:19-25.