Adjuvant therapy for women with high-risk endometrial carcinoma
Authors: Sean C Dowdy, Gretchen E Glaser
Journal: The Lancet Oncology (2018)

Identification of optimal therapy for patients with high-risk endometrial carcinoma has been frustrated by near-dichotomous paradigms of surgical treatment in the international community and a scarcity of level 1 data to inform adjuvant treatment. For example, at a meeting of the European Society for Medical Oncology–European Society of Gynaecological Oncology–European Society for Radiotherapy and Oncology Endometrial Consensus Conference Working Group, 14 recommendations were supported by level 1 or 2 evidence out of 50 nonsurgical treatment topics.1Colombo N Creutzberg C Amant F et al.ESMO-ESGO-ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up.Radiother Oncol. 2015; 117: 559-581Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar However, the emergence of successful international cooperatives will accelerate the pace of innovation and learning worldwide, which will be welcome news indeed for both treating clinicians and patients who suffer from endometrial cancer. In The Lancet Oncology, the third successive randomised trial of endometrial cancer treatment is presented by Stephanie M de Boer and colleagues2de Boer SM Powell ME Mileshkin L Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.Lancet Oncol. 2018; (published online Feb 12.)http://dx.doi.org/10.1016/S1470-2045(18)30079-2Summary Full Text Full Text PDF PubMed Scopus (387) Google Scholar and the PORTEC group on behalf of seven participating countries. The PORTEC-3 investigators randomly assigned patients with high-risk endometrial cancer to pelvic radiotherapy alone or adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy), a regimen based on the phase 2 RTOG-9708 trial.3Greven K Winter K Underhill K Fontenesci J Cooper J Burke T Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer.Gynecol Oncol. 2006; 103: 155-159Summary Full Text Full Text PDF PubMed Scopus (227) Google Scholar 5-year failure-free survival favoured the chemoradiotherapy group with a 7% difference between the groups. However, inclusion criteria were necessarily based on a historical and relatively unsophisticated stratification system that consolidates disparate stages and histological subtypes into a single high-risk group. Analysed separately, patients with stage III disease obtained the greatest benefit from chemoradiotherapy, with a more than 11% absolute improvement in failure-free survival (hazard ratio [HR] 0·66, 95% CI 0·45–0·97, p=0·031)—a clinically relevant finding that exceeds the 10% improvement used to design the trial. The 9% improvement in 5-year overall survival in patients with stage III disease was smaller than the study was designed to detect (adjusted p=0·074). These results are similar to the pooled results of the NSGO 9501/EORTC 55991 and MaNGO-ILIADE 3 trials showing improved failure-free survival but non-significantly higher overall survival (p=0·07) for patients receiving radiotherapy sequentially with adjuvant chemotherapy compared with radiotherapy alone.4Hogberg T Signorelli M de Oliveira CF et al.Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer—results from two randomised studies.Eur J Cancer. 2010; 46: 2422-2431Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar Detailed qualitative data from PORTEC-3 have been previously published, serving to contextualise these survival improvements.5de Boer SM Powell ME Mileshkin L et al.Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial.Lancet Oncol. 2016; 17: 1114-1126Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar Treatment-related toxicity was worse in the chemoradiotherapy group, with 60% of patients experiencing grade 3 or worse adverse events compared with 12% in those receiving radiotherapy alone. These differences disappeared by 24 months, but grade 2 toxicity remained higher in the chemotherapy group at 5 years, mostly due to neuropathy. Considered together, the significant improvement in failure-free survival seen in patients with stage III disease seems to justify the accompanying toxicity. On multivariable analysis, only being older than 70 years was associated with treatment effect, and providers should council elderly patients of this potential benefit of chemoradiotherapy. This is an important consideration, recognising that in the USA, patients older than 70 years are 50% less likely than their younger counterparts to receive adjuvant chemotherapy or radiotherapy after surgery.6Fader AN Habermann EB Hanson KT Lin JF Grendys EC Dowdy SC Disparities in treatment and survival for women with endometrial cancer: a contemporary national cancer database registry analysis.Gynecol Oncol. 2016; 143: 98-104Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar Although lymph node assessment was not required, it was done in the majority of patients, was not associated with failure-free survival, and rates were identical in both groups. The findings of PORTEC-3 should therefore be relevant to all practices, irrespective of surgical paradigm. By contrast with the benefit conferred to stage III patients, the addition of chemotherapy did not improve outcomes for stage I or II patients. Although PORTEC-3 might have been underpowered to identify differences in failure-free survival in this subgroup, the small magnitude of benefit does not seem to justify the accompanying increase in adverse events, impairment in long-term quality of life, and longer treatment duration. The use of radiotherapy alone is supported by unpublished results of GOG-249,7The ASCO PostASTRO 2017: GOG-249 confirms adjuvant pelvic radiation as standard of care for high-risk, early-stage endometrial cancer.http://www.ascopost.com/News/58092Google Scholar in which high-risk stage I or II patients were randomly assigned to radiotherapy or chemotherapy and vaginal brachytherapy. Chemotherapy did not improve failure-free survival, overall survival, or the incidence of distant recurrences, but resulted in twice the incidence of nodal recurrence and significantly more grade 3 or worse adverse events than did radiotherapy alone. The ongoing ENGOT-EN2-DGCG/EORTC-55102 trial evaluating the role of chemotherapy versus observation in patients with high-risk, node-negative endometrial cancer will be pivotal given the conflicting efficacy of chemotherapy observed for uterine serous carcinoma in PORTEC-3, the pooled analysis of NSGO-9501, EORTC-5599, and MaNGO-ILIADE 3 trials, and the GOG-122 trial.2de Boer SM Powell ME Mileshkin L Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.Lancet Oncol. 2018; (published online Feb 12.)http://dx.doi.org/10.1016/S1470-2045(18)30079-2Summary Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 4Hogberg T Signorelli M de Oliveira CF et al.Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer—results from two randomised studies.Eur J Cancer. 2010; 46: 2422-2431Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 8Randall ME Filiaci VL Muss H et al.Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.Proc Am Soc Clin Oncol. 2006; 24: 36-44Crossref PubMed Scopus (777) Google Scholar Most recurrences of endometrial cancer manifested as distant metastases in PORTEC-3, and although this type of recurrence was less common with chemoradiotherapy, the difference did not achieve statistical significance. Unpublished results of GOG-258,9Matei D Filiaci VL Randall M et al.A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked, advanced endometrial carcinoma.Proc Am Soc Clin Oncol. 2017; 35 (abstr 5505.)Google Scholar which randomly assigned patients to the same chemoradiotherapy regimen as that used in PORTEC-3 or to chemotherapy alone, showed fewer distant recurrences in the chemotherapy group at the expense of more vaginal and nodal recurrences and no difference in failure-free survival or estimated 5-year overall survival.9Matei D Filiaci VL Randall M et al.A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked, advanced endometrial carcinoma.Proc Am Soc Clin Oncol. 2017; 35 (abstr 5505.)Google Scholar Future trials should investigate regimens to maximise the local control advantages of radiotherapy with distant control improvements seen with chemotherapy for patients with high-risk endometrial cancer. Continued assessment of toxicity, quality of life, and cost will be paramount to define optimal adjuvant therapy. We declare no competing interests. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trialAdjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. Full-Text PDF Open Access