Add-On Chemo Boosts Survival in High-Risk Endometrial Cancer

Adjuvant chemoradiotherapy improved overall survival for women with locally advanced endometrial cancer compared with radiation alone, a post-hoc analysis of the phase III PORTEC-3 trial found.

With adjustment for stratification factors, overall survival (OS) at 5 years was 81.4% in the chemoradiotherapy group compared with 76.1% in the group receiving radiotherapy alone (adjusted HR 0.70, 95% CI 0.51-0.97, P=0.034), reported Stephanie de Boer, MD, of Leiden University Medical Center in the Netherlands, and colleagues.

And in their study of over 600 patients with stage I-III endometrial cancer, failure-free survival (FFS) at 5 years was 76.5% with chemoradiotherapy versus 69.1% with radiation alone (HR 0.70, 95% CI 0.52-0.94, P=0.016).

“These updated results of the PORTEC-3 trial, with a longer median follow-up of 72 months and with 75% of participants having reached 5 years of follow-up, showed a significant improvement in both overall and failure-free survival with chemoradiotherapy versus radiotherapy alone for high-risk endometrial cancer,” they wrote in the Lancet Oncology.

For first site of recurrence, distant metastases were the most common, with a 5-year probability of 21.4% versus 29.1% for the chemoradiotherapy and radiation-alone groups, respectively (HR 0.74, 95% CI 0.55-0.99, P=0.047). Isolated pelvic and vaginal recurrences were rare, with no significant differences seen between groups.

“In the aftermath of these potentially practice-changing results, additional questions are raised,” Marcus Randall, MD, of the University of Kentucky in Lexington, wrote in an accompanying editorial. Do the findings apply to all subgroups? Would chemotherapy alone be sufficient in the adjuvant setting? Is there a “preferred way” to combine chemotherapy with radiation?

“Taking into account the statistical limitations of subgroup analyses,” he said, “the therapeutic benefit of combined chemotherapy and radiotherapy (vs radiotherapy alone) appeared to remain confined to patients with stage III disease and those with serous carcinomas of all stages.”

For the stage III patients, 5-year OS and FFS were both significantly improved for the chemoradiotherapy group versus radiation-alone group:

• OS: 78.5% vs 68.5% (HR 0.63, 95% CI 0.41-0.99, P=0.043)
• FFS: 70.9% vs 58.4% (HR 0.61, 95% CI 0.42-0.89, P=0.011)

For stage I-II disease, survival outcomes modestly favored the combined adjuvant treatment numerically, but neither of the differences were significant:

• OS: 83.8% vs 82.0%
• FFS: 81.3% vs 77.3%

The study investigators noted that “the minimal benefit in failure-free survival and overall survival in stage I-II endometrial cancer achieved with chemoradiotherapy does not seem to justify the increased frequency of adverse events, impaired quality of life, and longer treatment duration of combined treatment for these patients.”

Patients with serous histology also appeared to benefit more from the addition of chemotherapy in the post-hoc analysis. After adjusting for stratification factors, OS at 5 years was 71.4% versus 52.8% in the chemoradiotherapy and radiotherapy groups, respectively (HR 0.48, 95% CI 0.24-0.96, P=0.037). And FFS at 5 years was 59.7% versus 47.9% (HR 0.42, 95% CI 0.22-0.80, P=0.008).

For the question of whether chemotherapy might be sufficient alone in the adjuvant setting, Randall pointed to two NRG/GOG trials.

In stage I-II disease, Randall noted that in NRG/GOG 249 patients treated with chemotherapy plus vaginal cuff brachytherapy had no improvement in overall or relapse-free survival compared with those treated with pelvic radiotherapy alone.

“However, the incidence of nodal failure was significantly higher in the absence of pelvic radiation therapy, and acute toxicity was greater in the vaginal cuff brachytherapy group,” he wrote.

Most recently, the phase III GOG 258 trial demonstrated similar outcomes between chemoradiotherapy and chemotherapy alone as adjuvant treatment for women with stage III-IVA endometrial cancer. At 5 years, 59% of women in the chemotherapy arm were estimated to be alive and relapse-free compared with 58% in the chemotherapy-alone arm.

But Randall noted that while the combined therapy did not improve recurrence-free survival or OS, “nodal and vaginal failures were significantly lower when radiotherapy was given.”

Finally, he asked whether the chemoradiotherapy approach taken in both PORTEC-3 and GOG 258 was indeed the best option.

“When NRG/GOG 258 was designed, there was vigorous debate about the combined modality group, with various investigators favoring a sandwich regimen typically involving three cycles of chemotherapy, followed by involved-field radiotherapy, and then additional chemotherapy,” he wrote, adding that “multiple studies (retrospective and prospective) have demonstrated the safety and efficacy of the so-called sandwich approach.”

From 2006 to 2013, the PORTEC-3 trial randomized 660 patients 1:1 to either radiotherapy alone or chemoradiotherapy. Radiotherapy consisted of 48.6 Gy in 1.8 Gy fractions given 5 days per week, while chemoradiotherapy consisted of two cycles of 50 mg/m² cisplatin given intravenously during radiotherapy, and then four cycles of intravenous carboplatin AUC5 plus paclitaxel 175 mg/m².

Adverse events (AEs) of grade ≥2 were significantly more frequent in the combined adjuvant therapy group, occurring in 38% of women versus 23% in the radiation-alone group (P=0.002), with 5-year neuropathy rates occurring in 6% versus 0%, respectively.

Grade 3 AEs were similar between the chemoradiotherapy and radiation-alone groups (8% vs 5%, P=0.24), with hypertension being the most common event (2% in each group). Only one grade 4 AE was reported (in the chemoradiotherapy arm), and there were no treatment-related deaths.