CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).

Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.

The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.

Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.

“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.

Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.

Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m² in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m² in 3-week intervals, or to receive radiotherapy alone.

Median follow-up was 60.2 months.

“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.

Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.

A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.

“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.

In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.

In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.

“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.

The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.

Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.

However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.

Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.

“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.

Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.

“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.

Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.

sworcester@frontlinemedcom.com

PORTEC-3: Possible benefit with combined CT/RT in high-risk endometrial cancer