Adjuvant Chemoradiation May Be Considered for High-Risk Endometrial Cancer

By Marilynn Larkin

NEW YORK (Reuters Health) – Adjuvant chemotherapy given during and after pelvic radiation for high-risk endometrial cancer improves failure-free, but not overall, survival at five years and may be discussed as an alternative to radiation alone, researchers suggest.

Dr. Stephanie M. de Boer of Leiden University Medical Center in the Netherlands and colleagues conducted PORTEC-3, an open-label, randomized, phase 3 trial involving 103 centers internationally.

Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both); endometrioid-type stage II or III; or stage I to III with serous or clear-cell histology.

A total of 660 participants (median age, 62) were randomly assigned to receive radiation alone (48.6 Gy in 1.8 Gy fractions given five days per week) or radiation and chemotherapy (two cycles of cisplatin 50 mg/m2 given during radiation, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2).

As reported online February 12 in The Lancet Oncology, five-year overall survival was 81.8% with chemoradiation versus 76.7% with radiation alone (a statistically nonsignificant difference); five-year failure-free survival was 75.5% versus 68.6% (a significant difference).

Grade 3 or worse adverse events during treatment occurred in 60% of women who received chemoradiation versus 12% of those who received radiation alone. Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiation than after radiation in (8% of patients vs. 1% at three years).

Most deaths were due to endometrial cancer, though in four patients (two in each group), the cause of death was uncertain. One death in the radiation group was due to either disease progression or late treatment complications; two deaths in the chemoradiation group and one in the radiation group were due to either intercurrent disease or late treatment-related toxicity.

The authors conclude that “women with high-risk endometrial cancer should be individually counseled about this combined treatment.”

Dr. de Boer and Dr. Carien Creutzberg, also of Leiden University Medical Center, told Reuters Health in a joint email, “Patients with stage III cancer had the greatest benefit with chemoradiation because of their higher risk of disease recurrence; for these patients, combined treatment should be considered to maximize failure-free survival.”

“Nevertheless,” they add, “the improvement in failure-free survival after chemoradiation should be weighed against the severity and duration of toxicity of combined treatment for each patient, especially since overall survival was not significantly improved.”

“The PORTEC-3 trial results cannot be seen outside of the context of the results of the GOG-258 trial, which were reported at ASCO 2017 (https://bit.ly/2F3UAO1) and those of GOG-249 reported at ASTRO 2017 (https://bit.ly/2EZpFWN),” they noted.

“Together the trials show excellent pelvic control and relapse-free survival rates with radiation therapy alone for women with stage I-II endometrial cancer with high-risk features,” they said, “and highest relapse-free survival and pelvic control rates with the combination of chemotherapy and radiation.”

Dr. Sean Dowdy of Mayo Clinic in Rochester, Minnesota, coauthor of a related editorial, told Reuters Health by email, “A great strength of this study is that qualitative outcomes were published previously (https://bit.ly/2GR5Ldk). Chemoradiation resulted in higher grade 3 toxicity (60% vs. 12%). While these differences disappeared at 24 months, excess grade 2 toxicity persisted five years after treatment.”

“For this reason, patients with stage III disease should review risks and benefits with their provider to determine the most appropriate treatment regimen,” he concluded.

Dr. David Miller, a professor at UT Southwestern Medical Center’s Simmons Cancer Center in Dallas commented, “Quality of life, by definition, is subjective. But, it should be an important part of the discussion with patients as they weigh the risk and benefits of any toxic intervention such as surgery, radiation, and/or chemotherapy.”

“A 5% increase in survival may be worth a 48% increase in severe toxicity to some,” he said by email. “But, is it if the patient then requires a cane or walker for mobility?”

“Costs are often a consideration,” he noted, “especially in the many patients with incomplete or no insurance. We now call that financial toxicity, (and) it also needs to be part of the discussion with patients.”

Like the authors and editorialist, Dr. Miller said, “This study should not be considered in isolation, but as part of an evolving body of scientific data.”

“GOG-122 (https://bit.ly/2sYOywc) showed that chemotherapy was better than whole-abdomen radiation,” he said. “While PORTEC-3 showed that chemotherapy might improve radiation in Stage III patients, GOG-258 reported that radiation did not improve upon (results achieved by) chemotherapy.”

“There appears to be little compelling survival data to support combining chemotherapy and radiation therapy,” Dr. Miller stressed. “That leads to the obvious conclusion that we should select one or the other. What should be the criteria?”

“If surgical staging and/or imaging highly suggests that the tissue at risk for recurrence could be contained in a radiation field, then that might be the best treatment,” he proposed. “Whereas, if findings suggest that the tissues at risk can’t be contained in a radiation field, then chemotherapy should be better.”

SOURCES: https://bit.ly/2EXnYFD and https://bit.ly/2EWmStq

Lancet Oncol 2018.

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