In High-Risk Endometrial Cancer, Adding Chemo No Help, but…

Roxanne Nelson, BSN, RN

October 02, 2017

SAN DIEGO — In women with early-stage, high-risk endometrial cancer, adding chemotherapy to radiation therapy was not superior to the standard treatment of radiation alone, according to new findings.

In a head-to-head trial of two adjuvant strategies, vaginal cuff brachytherapy  plus chemotherapy (VCB/C) was compared with the standard of pelvic radiation therapy (PXRT).

However, the rates of recurrence-free and overall survival were not improved with VCB/C compared with PXRT. In addition, there was a great risk for pelvic and para-aortic nodal recurrence in patients who received brachytherapy and chemotherapy, explained lead author, Marcus Randall, MD, a professor of radiation medicine at the University of Kentucky, Lexington.

Dr Randall presented his findings here during a plenary session at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting.

"Pelvic radiation therapy remains an appropriate, and probably preferable, treatment for high-risk, early-stage endometrial carcinoma," Dr Randall said. "But we need better treatment strategies to address the risk for systemic disease to further improve outcomes for these patients."

He explained that the management of high-risk, early-stage endometrial cancer is controversial, and adjuvant pelvic radiation therapy has become standard for those at significant risk for local recurrence after surgery.

Most local recurrences occur at the vaginal cuff, and about 1 in 5 high-risk patients develop metastatic disease.  "Combination chemotherapy has demonstrated improved outcomes in more advanced disease, and there has been a trend toward increased use of vaginal brachytherapy," he said. "Data suggests similar excellent ability to limit cuff recurrences compared to external radiation therapy."

Some physicians have begun treating high-risk patients with early-stage disease using VCB/C. Therefore, a head-to-head study was needed.

But the jury is still out with regard to the use of chemotherapy in this setting, observed one expert, who was not involved with the study.

"But the way the study was designed — we can conclude that we don't know the true benefit of chemotherapy in this population," said Sushil Beriwal, MD, deputy director of radiation services at the Cancer Center at the University of Pittsburgh Medical Center, Pennsylvania.

"The radiation therapy was different in the two arms," Dr Beriwal said. "One arm got 5 weeks of radiation therapy for 5 weeks and the other arm got brachytherapy, so they thought that the radiation toxicity would be higher in the other arm but it didn't turn out to be the case."

No Differences Between Groups

The GOG-249 was a phase 3 randomized trial designed to determine whether VCB/C could increase recurrence-free survival. The secondary objectives included comparisons of overall survival, patterns of failure, and adverse events.

This was not an equivalency study, Dr Randall explained, but was designed to test whether VCB/C was superior to PXRT.

A total of 601 patients were enrolled in the study; 74% had stage I disease and 89% underwent lymphadenectomy. Histologic types were as follows: endometrioid in 71%, serous in 15%, and clear-cell carcinomas in 5%. The median patient age was 63 years, and all patients had undergone hysterectomy before receiving radiation therapy or chemoradiation therapy.

Women in the PXRT group (n = 301) received a median radiation dose of 45 Gy delivered with intensity-modulated radiation therapy or standard four-field techniques over 5 weeks, while the VBC/C cohort (n = 300) was treated with high- or low-dose rate vaginal cuff brachytherapy with paclitaxel (175 mg/m2 for 3 hours) and carboplatin (area under the curve, 6 - 21 days). Most patients completed therapy: 91% in the PXRT group and 87% in the VBC/C group.

At a median follow-up of 53 months, the 3-year, relapse-free survival rate was 82% for both groups. Overall survival at 3 years was 91% for PXRT and 88% for VCB/C.

Vaginal and distant failure did not significantly differ between the two study groups; the estimated 5-year rates of vaginal and distant recurrences were, respectively, 2.5% and 18% for both groups.

Dr Randall also pointed out that there was no significant treatment heterogeneity between the two groups with respect to the survival outcomes.

However, the cumulative incidence of pelvic or para-aortic nodal recurrence at 5 years in the VCB/C group (9.2%; 25 recurrences, 20 in the pelvis) was twice as high as in the PXRT cohort (4.4%; 12 recurrences, 6 in the pelvis) (hazard ratio, 0.47; 95% confidence interval, 0.24 - 0.94).

Acute toxicity was significantly greater in the VCB/C group, while late toxicity was similar between both groups. Grade 3 or higher adverse events were reported in 187 patients in the VCB/C group vs only 32 in the PXRT group.

Severe late effects were similar in both groups (35 events in the VCB/C group vs 37 events in the PXRT group).

Value of Chemo Still Unclear

Commenting on the study, Vishal Gupta, MD, associate professor of radiation oncology at the Icahn School of Medicine at Mount Sinai in New York City, noted that "surprisingly, chemotherapy did not reduce the rate of distant metastases, which was 18% in both arms. Even patients with high-risk histologies, including papillary serous carcinoma and clear cell carcinoma, did not benefit from chemo."

Surprisingly, chemotherapy did not reduce the rate of distant metastases. Dr Vishal Gupta

"It is unclear if more cycles of chemotherapy would result in a difference, but it is unlikely to be tested in this patient population," he said.  "Another unexpected finding was that among patients receiving EBRT [external-beam radiation therapy], those receiving IMRT [intensity-modulated radiation therapy] had more acute and late toxicity compared to 3D [three-dimensional] conformal radiation therapy.  Intensity-modulated radiation therapy was expected to reduce acute and late toxicity, but this study found the opposite."

Dr Randall has disclosed financial relationships with the American Cancer Society, Peloton Therapeutics, Threshold Pharmaceuticals,  and V Foundation for Cancer Research and a family member's relationship with Threshold Pharmaceuticals. Dr Gupta and Dr Beriwal have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract LBA-1.  Presented September 25, 2017.

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