Paclitaxel-Carboplatin Established as Standard of Care for Uterine Carcinosarcoma

Median overall survival (OS) and progression-free survival (PFS) in uterine carcinosarcoma (UCS) both improved with paclitaxel and carboplatin as compared with a standard-of-care regimen, a randomized trial showed.

OS improved from 29 months with paclitaxel and ifosfamide to 37 months with paclitaxel and carboplatin, a difference that met statistical criteria for noninferiority but not superiority. PFS improved significantly with paclitaxel and carboplatin (16 vs 12 months with paclitaxel-ifosfamide; P<0.01).

Toxicity profiles differed between the two regimens, but the frequency and severity of treatment-related toxicities were similar, reported Matthew A. Powell, MD, of Washington University in St. Louis, and coauthors, writing in the Journal of Clinical Oncology.

“In clinical practice, simplification with carboplatin and paclitaxel is already happening. Even as this trial was going on, more and more evidence was announcing that carboplatin-paclitaxel was the right thing to use,” Powell told MedPage Today.

“It became our standard for all endometrial cancer. With the GOG-0209 trial, we started treating newly diagnosed ovarian cancer the same way,” he added. “This combination seems to work well for both ovarian and uterine cancers, regardless of whether they’re the rare subtype called carcinosarcoma.”

The rationale for using ifosfamide came from historical evidence indicating that molecular and biological features of UCS were similar to those of sarcomas, and ifosfamide was a classic therapy for sarcomas.

“When you look at it under a microscope, it looks like a sarcoma, but in reality it’s just a really broken epithelial tumor,” said Powell. He explained that molecular characteristics of UCS resemble an epithelial cancer that’s lost its ability to suppress certain genes, “so stromal elements or sarcoma-looking elements show up in the histopathology.”

For newly diagnosed uterine and ovarian cancers, the worst outcomes are associated with the rarest forms of the disease: UCS and ovarian carcinosarcoma (OCS). UCS accounts for 5% of all uterine cancers but for 15% of uterine cancer mortality. Similarly, OCS accounts for 1-4% of ovarian cancers but is associated with significantly worse 5-year survival.

A Cochrane Review of three randomized phase III trials showed better survival and less toxicity in patients with UCS treated with paclitaxel-ifosfamide as compared with single-agent ifosfamide, which led to adoption of the combination as the standard for UCS. Powell and coauthors cited three limitations of the regimen: it’s difficult to administer, it needs growth factor support, and it carries increased neurologic toxicity.

Paclitaxel and carboplatin has been standard treatment for epithelial ovarian cancer since the 1990s and became the standard for endometrial cancer following the GOG-0209 trial, the authors continued. The combination became standard for OCS after several small studies demonstrated the regimen’s activity. The GOG-0232 trial subsequently showed that paclitaxel-carboplatin had clinical activity comparable to ifosfamide-containing regimens for similar patients.

Powell and colleagues continued the evaluation of paclitaxel-carboplatin for UCS in the GOG-0261 randomized trial, the current study, which included patients with UCS or OCS. Investigators in the multicenter study randomized 449 patients with UCS and 90 patients with OCS to paclitaxel paired with either carboplatin or ifosfamide. The primary endpoint was OS, and the trial was statistically powered to demonstrate noninferiority.

The primary analysis showed that patients treated with paclitaxel-carboplatin had a non-significant 13% reduction in the OS hazard versus the group treated with paclitaxel-ifosfamide (95% CI 0.70-1.075). The PFS hazard was 27% lower in the paclitaxel-carboplatin arm and met statistical criteria for superiority (95% CI 0.58-0.93, P<0.01).

In the OCS subgroup, patients in the paclitaxel-carboplatin arm had a median OS of 30 months and median PFS of 15 months, as compared with 25 and 10 months, respectively, for the paclitaxel-ifosfamide arm. The analysis lacked precision to demonstrate statistical significance.

No new safety signals arose with either regimen. Hematologic toxicity was more common with paclitaxel-carboplatin, attributable in large part to patients in that arm not receiving growth factor support. Paclitaxel-ifosfamide was associated with more confusion and neurologic toxicity, known side effects of ifosfamide. Renal toxicity and genitourinary bleeding also occurred more often with ifosfamide.

Though powered for noninferiority, the trial clearly established paclitaxel-carboplatin as the preferred treatment for UCS, according to authors of an accompanying editorial.

“Found to be noninferior to IP [ifosfamide-paclitaxel], yet easier to administer in the outpatient setting and harboring a significantly safer toxicity profile, CP [carboplatin-paclitaxel] has become a new standard for patients with UCS,” wrote Dario R. Roque, MD, and Daniela Matei, MD, the Northwestern Feinberg School of Medicine and Robert Lurie Cancer Center in Chicago.

“The high level of activity induced by CP suggests that the epithelial carcinoma component of UCS is the main tumor driver, contrary to previous theories speculating that UCS represents either the collision of adjacent carcinoma and sarcoma elements or the divergence of a common progenitor into two elements,” they added.