Which is the best foot to put forward in recurrent ovarian cancer?

In the primary chemotherapy treatment of ovarian carcinoma, both the Gynecologic Oncology Intergroup consensus statement and the National Comprehensive Cancer Network guidelines recommend the combination of a platinum agent and a taxane as the primary chemotherapy regimen. However, this widely accepted recommendation conflicts with 2 prior studies. A phase 3 randomized trial by the Gynecologic Oncology Group of Protocol 132 compared 3 regimens in primary treatment: 1) a platinum compound (cisplatin), 2) a taxane (paclitaxel), and 3) the combination of both agents. That study demonstrated no significant difference between single-agent cisplatin (progression-free survival [PFS], 16.4 months) and the cisplatin/paclitaxel combination (PFS, 14.1 months). Furthermore, although single-agent paclitaxel was inferior (PFS, 10.8 months; P< .001) because of presumed crossover, there was no difference in survival between the 3 treatment arms. That study raised the question of whether sequential therapy would be equally effective and potentially less toxic than combination therapy. Similarly, the International Collaborators on Ovarian Neoplasms (ICON) conducted a randomized trial (ICON3) comparing the combination of carboplatin and paclitaxel with single-agent carboplatin or combined cisplatin, doxorubicin (Adriamycin), and cyclophosphamide (CAP). In that study, there was no difference in PFS or survival between the 2 treatment arms, suggesting that, like in the Gynecologic Oncology Group study of Protocol 132, platinum was the principal agent in first-line chemotherapy. This followed ICON2, which demonstrated equivalency between carboplatin and the CAP combination in primary treatment. Unfortunately, because of ineffective screening, the vast majority of patients with ovarian carcinoma (70%) present initially with advanced-stage disease. Despite surgery and platinum/taxane chemotherapy, most patients ( 80%) will develop a recurrence. In the setting of recurrent ovarian cancer, treatment is palliative. However, survival after recurrence in ovarian cancer can be quite long, depending on the original PFS, and the overall survival is approximately 2.5 to 3.0 times the PFS. In the setting of recurrent disease, the likelihood of a response to second-line, platinum-based chemotherapy positively correlates with PFS. That is, the longer the PFS, the higher the response rate to second-line, platinum-based therapy and the longer the overall survival. On the basis of retrospective outcome data, the definitions of platinum resistance (patients with a treatment free interval [TFI]<6 months) and platinum sensitivity (patients with a TFI>6 months) proposed by Markman and Hoskins are widely accepted. Because of the lack of randomized data in the setting of platinumsensitive, recurrent ovarian cancer, considerable controversy and variations in practice patterns exist. In the last 8 years 2 randomized trials—ICON4, comparing carboplatin/paclitaxel with carboplatin or CAP, and OV 2.5, comparing carboplatin/gemcitabine with carboplatin—have demonstrated the superiority of carboplatin combinations in platinum-sensitive ovarian carcinoma. A third, more recent trial comparing carboplatin/pegylated liposomal doxorubicin with carboplatin/paclitaxel demonstrated an improved PFS with less severe chemotherapy complications, particularly neuropathy and alopecia, with the carboplatin/pegylated liposomal doxorubicin combination. A fourth large trial comparing single-agent versus combination nonplatinum agents in both platinum-sensitive and platinum-resistant ovarian carcinoma demonstrated a PFS benefit but not a survival benefit of the combination in the platinum-sensitive cohort alone. Finally, an older, small phase 3 trial by Cantu et al. compared single-agent paclitaxel versus CAP for patients with platinum-sensitive, relapsed ovarian cancer. The design of that trial required crossover to the opposite regimen with progression.