The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.
Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.
Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.
“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.
The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.
The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.
Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.