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The addition of carboplatin to paclitaxel prolonged overall survival and progression-free survival, and proved to be noninferior to the standard combination of paclitaxel and ifosfamide in patients with uterine carcinosarcoma.
The addition of carboplatin to paclitaxel prolonged overall survival (OS) and progression-free survival (PFS), and proved to be noninferior to the standard combination of paclitaxel and ifosfamide in patients with uterine carcinosarcoma, according to data from the phase 3 GOG-0261 trial (NCT00954174) published in the Journal of Clinical Oncology.1
Results showed that paclitaxel plus carboplatin (n = 228) resulted in a median OS of 37 months vs 29 months with paclitaxel plus ifosfamide (n = 221; adjusted hazard ratio [aHR], 0.87; 90% CI, 0.70-1.075). Although the P value for the stratified test (< .01) rejects the null hypothesis of inferiority of paclitaxel/carboplatin in favor of noninferiority, in a one-tailed test, the regimen was not found to be statistically superior to paclitaxel/ifosfamide (P = .14). Furthermore, those in the investigative arm experienced a median PFS of 16 months vs 12 months in the control arm (aHR = 0.735; 95% CI, 0.58-0.93; P < .001).
In the 101 patients with ovarian carcinosarcoma, paclitaxel plus carboplatin (n = 44) resulted in a median OS of 30 months vs 25 months with paclitaxel/ifosfamide (n = 46; aHR = 1.15; 95% CI, 0.67-1.95). Here, neither inferiority nor inferiority were ruled out. Additionally, the investigative arm experienced a median PFS of 14.6 months vs 10.3 months in the control arm (aHR = 1.01; 95% CI, 0.61-1.67).
“These results establish a new standard regimen–[paclitaxel and carboplatin]—for women with [uterine carcinosarcoma] of all stages and especially for stage III patients,” lead study author Matthew A Powell, MD, and colleagues wrote in the paper. “Toxicity was as predicted and manageable. Identifying and targeting the molecular aberrations in these tumors should lead to further improvements in treatment.”
After a 2013 Cochrane review of published and unpublished data from the phase 3 GOG-108 (NCT02470585), GOG-150 (NCT03038100), and GOG-161 (NCT00003128) trials found that those who received paclitaxel plus ifosfamide experienced longer OS and PFS in patients with uterine carcinosarcoma vs those who received radiotherapy or single-agent ifosfamide, the combination regimen was established as the standard of care for this population.2 However, paclitaxel plus ifosfamide has 3 notable limitations: a 3-day infusion makes it difficult to administer, it requires the use of growth factor support, and it is associated with a greater risk for central neurologic toxicity than other chemotherapy regimens, particularly in older patients.
Since the late 1990s, paclitaxel plus carboplatin has been the standard regimen for those with epithelial ovarian carcinoma; it is also the standard regimen for those with endometrial carcinoma. The combination has previously been examined in smaller studies of patients with ovarian carcinosarcoma and uterine carcinosarcoma and showcased efficacy that compared favorably with ifosfamide-based regimens.
The international, open-label, noninferiority phase 3 GOG-0261 trial sought to evaluate the OS and PFS in uterine and ovarian carcinosarcoma. To be eligible for enrollment, patients needed to have chemotherapy-naïve uterine or ovarian carcinosarcoma of all stages or recurrent disease, be at least 18 years of age, and have a Gynecologic Oncology Group (GOG) performance status of 0 to 2.
Patients also must have recovered from the effects of recent surgery, radiotherapy, or other therapies, absence of active infection, and not be receiving any hormonal therapy directed at the malignant tumor at least 1 week before to protocol chemotherapy. They were also required to have acceptable bone marrow, renal, hepatic, and neurologic function.
Patients in the investigative arm were administered intravenous (IV) paclitaxel at 175 mg/m2 over 3 hours, plus IV carboplatin once on day 1 of each 3-week cycle for 6 to 10 cycles. Notably, the initial dose of paclitaxel was reduced to 135 mg/m2 if the patient had prior whole pelvic radiotherapy, and it could be increased if the patient tolerated the lower dose.
Those in the control arm were given IV ifosfamide at a daily dose of 1.6 g/m2 on days 1 to 3, plus IV and/or oral mesna plus paclitaxel at 135 mg/m2 via 3-hour infusion on day 1, plus granulocyte-colony stimulating factor support (filgrastim [Neupogen] or pegfilgrastim [Neulasta]) on days 4 to 6 of each 3-week cycle for 6 to 10 cycles. Paclitaxel and ifosfamide dosage could be increased or decreased, if needed, based on nadir counts. The initial dose of ifosfamide was reduced to 1.2 g/m2 if the patient received prior whole pelvic radiotherapy.
The primary end point of the study was OS, measured from the date of random assignment to the date of death from any cause or the date of last contact. Secondary end points included PFS, adverse effects (AEs), quality of life, and neurotoxicity.
Within the cohorts of patients with uterine carcinosarcoma (n = 449), the median age for the investigative and control arms were 65 and 64 years, respectively. Among all patients, 63% were White, 93.8% were non-Hispanic, 59.7% had a GOG performance status of 0, 47.9% had stage III or IV disease, 67.9% did not have measurable disease, and 86% did not receive prior radiotherapy.
Additional data showed that in a subset of patients with uterine carcinosarcoma who had stage III or IV disease, those who received the investigative regimen experienced a longer OS (HR, 0.74; 95% CI, 0.54-1.01) and PFS (HR, 0.65; 95% CI, 0.48-0.88) than those who were given the control arm; however, the difference was only noted to be statistically significant with regard to PFS. Among a subset of patients with uterine carcinosarcoma and stage III disease only, those in the investigative arm had longer OS and PFS vs those in the control arm, according to unadjusted Kaplan-Meier plots. Again, however, this difference was only significant for PFS.
No new safety signals were reported with either regimen. Specifically, 82% of patients in the investigative arm experienced grade 3 to 5 hematologic AEs vs 50% of those in the control arm (P < .01). Additionally, grade 3 to 5 neurologic AEs were reported in 7% of patients in the paclitaxel/carboplatin arm vs 12% of those in the paclitaxel/ifosfamide arm (P > .10).
“This open-label, randomized, phase 3 therapeutic noninferiority clinical trial shows that paclitaxel/carboplatin is not inferior to paclitaxel/ifosfamide in terms of OS and PFS and significantly increases PFS duration for patients with uterine carcinosarcoma,” the study authors concluded. “Findings were similar but not statistically significant in the smaller ovarian carcinosarcoma cohort…These results establish that paclitaxel/carboplatin should be used as a standard regimen for patients with uterine carcinosarcoma and should be considered for treating patients with ovarian carcinosarcoma.”