With regard to overall survival (OS), paclitaxel and carboplatin was not inferior and demonstrated improved progression-free survival (PFS) when compared with paclitaxel and ifosfamide in patients with uterine carcinosarcoma. Toxicity and patient-reported quality-of-life profiles were similar for the two drug regimens. Dr. Matthew A. Powell of the Washington University School of Medicine in St Louis, MO, US and colleagues who published the findings from an open-label, randomised, phase III therapeutic non-inferiority study on 10 January 2022 in the Journal of Clinical Oncology wrote that paclitaxel and carboplatin should be standard treatment for uterine carcinosarcoma.
Standard treatment for patients with uterine carcinosarcoma is surgery (total hysterectomy or bilateral salpingo-oophorectomy), peritoneal washings, and retroperitoneal lymph node assessment. Developing and testing treatments has been hampered, as historically, uterine carcinosarcoma was treated with other sarcomas. However, recent evidence indicates that the carcinomatous components dictate tumour behaviour, and molecular studies demonstrated that the sarcomatous components are derived from the carcinomatous components through metaplastic transformation. In 2009, the FIGO mandated that uterine carcinosarcoma should be staged as an endometrial carcinoma.
GOG-0232 previously evaluated 55 patients with uterine carcinosarcoma treated with paclitaxel and carboplatin and found that 13% of patients had confirmed complete response and 41% had partial response. The overall response rate was 54% (95% confidence interval [CI] 37 to 67), which compared favourably with earlier ifosfamide-based regimens for similar patients.
Paclitaxel and ifosfamide regimen has important limitations: it is difficult to administer requiring 3 days of infusion, it requires the use of growth factor support and it is associated with a greater risk for central neurologic toxicity than other chemotherapy regimens, especially for older patients.
Given these limitations, the efficacy of paclitaxel and carboplatin in ovarian carcinoma, and the findings of small studies evaluating paclitaxel and carboplatin in patients with ovarian and uterine casrcinosarcomas, the GOG-0261 study team tested the null hypothesis that paclitaxel and carboplatin was inferior to paclitaxel and ifosfamide for patients with all stages of uterine and ovarian carcinosarcomas.
In the GOG-0261 study, adult patients with chemotherapy-naïve uterine or ovarian carcinosarcoma were randomly assigned to paclitaxel and carboplatin or paclitaxel and ifosfamide with 3-week cycles for 6 to 10 cycles. With 264 events in patients with uterine carcinosarcoma, the power for OS hybrid non-inferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on paclitaxel and ifosfamide with a type I error of 5% for a one-tailed test.
The study enrolled 536 patients with uterine carcinosarcoma and 101 patients with ovarian carcinosarcoma, with 449 and 90 eligible patients, respectively. Primary analysis was on patients with uterine carcinosarcoma from whom 40% had stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent disease. Among eligible patients with uterine carcinosarcoma, paclitaxel and carboplatin was assigned to 228 and paclitaxel and ifosfamide to 221 patients.
Paclitaxel and carboplatin was not inferior to paclitaxel and ifosfamide. The median OS was 37 versus 29 months (HR 0.87, 90% CI 0.70 to 1.075; p < 0.01 for non-inferiority, p > 0.1 for superiority). The median PFS was 16 versus 12 months (HR 0.73; p = < 0.01 for non-inferiority, p < 0.01 for superiority).
Toxicities were similar, except that more patients in the paclitaxel and carboplatin arm had haematologic toxicity and more patients in the paclitaxel and ifosfamide arm had confusion and genitourinary haemorrhage.
Among 90 eligible patients with ovarian carcinosarcoma, those in the paclitaxel and carboplatin arm had longer OS (30 versus 25 months) and PFS (15 versus 10 months) than those in the paclitaxel and ifosfamide arm, but these differences were not statistically significant.
The authors commented that their results establish paclitaxel and carboplatin as a new standard regimen for women with uterine carcinosarcoma of all stages and especially for stage III patients. Toxicity was as predicted and manageable. Identifying and targeting the molecular aberrations in these tumours should lead to further improvements in treatment.
In an accompanied editorial, professors Dario R. Roque and Daniela Matei of the Feinberg School of Medicine, Northwestern University in Chicago, IL, US wrote that uterine carcinosarcoma is a rare and highly aggressive histologic subtype representing less than 5% of all uterine cancers, but its fatality rate is substantially higher than in endometrial cancer. It contains both epithelial and sarcomatous components, had been historically classified as a subtype of uterine sarcoma and treated with sarcoma regimens, being excluded from clinical studies targeting the broader population of patients with uterine cancer. Treatment protocols are evolving, shifting from ifosfamide-based regimens with known activity in sarcoma to those more commonly used in the management of uterine (and ovarian) epithelial tumours.
Because of associated high toxicity, requirement for growth factor usage, and cumbersome multiple day dosing of ifosfamide, it became important to find an equally effective, but less toxic regimen. Found to be non-inferior to paclitaxel and ifosfamide, easier to administer in the outpatient setting and harbouring a significantly safer toxicity profile, paclitaxel and carboplatin has become the new standard for patients with uterine carcinosarcoma. Furthermore, high level of activity induced by paclitaxel and carboplatin suggests that the epithelial carcinoma component of uterine carcinosarcoma is the main tumour driver, contrary to previous theories speculating that uterine carcinosarcoma represents either the collision of adjacent carcinoma and sarcoma elements or the divergence of a common progenitor into two elements.
The editorialists emphasised that demonstration that carboplatin and paclitaxel regimen induces the same benefits in uterine carcinosarcoma as in endometrial cancer supports a one size fits all strategy and opens the door toward considering uterine carcinosarcoma under the same umbrella of new clinical studies enrolling patients with high-grade endometrial cancer. The pace of drug development for uterine carcinosarcoma has been slow until now and inclusion of patients with uterine carcinosarcoma into novel studies targeting the broader category of uterine cancer would accelerate the path to approval of new agents for this aggressive disease. A randomised phase III GOG-3031 study will evaluate paclitaxel and carboplatin plus dostarlimab versus paclitaxel and carboplatin plus placebo in patients with recurrent or primary advanced endometrial cancer, including those with uterine carcinosarcoma.
The study was supported by US National Cancer Institute grants to NRG Oncology.
- Powell MA, Filiaci VL, Hensley ML, et al. Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial. JCO; Published online 10 January 2022. DOI: 10.1200/JCO.21.02050
- Roque DR, Matei D. Paclitaxel and Carboplatin for Uterine Carcinosarcoma: A Path to Inclusion. JCO; Published online 19 January 2022. DOI: 10.1200/JCO.21.02667