Management of high-risk endometrial cancer: are we there yet?
Authors: Marcus Randall
Journal: The Lancet Oncology (2019)

Endometrial cancer is a diverse disease that includes varying stages and histologies. As a result, the design, completion, and interpretation of large randomised trials comparing adjuvant therapies for this disease, even when well conducted and well analysed, is problematic. This situation is especially true in the study of adjuvant therapy for advanced endometrial cancer, since many patients are diagnosed and treated surgically for early disease, with no indication for adjuvant treatment. The PORTEC Study Group is to be commended for its work in refining the use of adjuvant therapy across various types of non-metastatic endometrial cancer. In the PORTEC-3 study, eligible patients included those with stages II and III and high-risk stage I endometrioid endometrial cancer and stages I–III serous and clear cell histologies.1deBoer SM Powell ME Mileshkin L et al.Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.Lancet Oncol. 2019; (published online July 22.)http://dx.doi.org/10.1016/S1470-2045(19)30395-XSummary Full Text Full Text PDF Scopus (112) Google Scholar With more than 650 women enrolled, the combination of systemic chemotherapy and radiotherapy was shown to improve outcomes compared with radiotherapy alone. For example, 5-year overall survival was 81·4% (95% CI 77·2–85·8) with chemoradiotherapy versus 76·1% (71·6–80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51–0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5–80·7) versus 69·1% (63·8–73·8; HR 0·70 [0·52–0·94], p=0·016). In the aftermath of these potentially practice-changing results, additional questions are raised. First, do these findings apply broadly to all subgroups included in the study? In addition to the broad eligibility criteria of PORTEC-3 (ie, different tumour stages and histologies), many clinicopathological variables have prognostic significance, such as tumour grade, depth of myometrial invasion, patient age, lymphovascular space invasion (in the absence of positive lymph nodes), and the patient's general condition. Even within similar or identical subgroups, substantial differences exist among patients, such as extent of nodal dissection, which are potentially confounding variables. Whether or not the results from PORTEC-3 are generally applicable across patient subgroups remains unknown. However, taking into account the statistical limitations of subgroup analyses, 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. Second, is chemotherapy alone a sufficient form of adjuvant therapy? The Gynecologic Oncology Group (now NRG Oncology) did separate studies that overlap (in terms of patient eligibility) with PORTEC 3. In the NRG/GOG 249 study, investigators randomly assigned high-risk patients with stage I and II disease, including those with high-risk histologies, to chemotherapy plus vaginal cuff brachytherapy or pelvic radiotherapy with no chemotherapy. In the NRG/GOG 249 study, the chemotherapy plus vaginal cuff brachytherapy group did not show improved overall survival or relapse-free survival compared with the group that received 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.2Randall ME Filiaci V McMeekin DS et al.Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer.J Clin Oncol. 2019; 37: 1-9Crossref PubMed Scopus (95) Google Scholar In the NRG/GOG 258 trial, patients with stage III–IVA uterine cancer were randomly assigned to received adjuvant chemotherapy alone or combined chemotherapy with pelvic radiotherapy (and para-aortic radiotherapy if nodal metastases were present). Although recurrence-free survival and overall survival were not improved with the combined therapy, nodal and vaginal failures were significantly lower when radiotherapy was given.3Matei D Filiaci G Randall ME et al.Adjuvant chemotherapy/radiation for locally advancedendometrial cancer.N Engl J Med. 2019; 380: 2317-2326Crossref PubMed Scopus (124) Google Scholar In these and other previous studies of adjuvant therapy within the PORTEC-3 eligibility groups, locoregional failure has been a notable and often predominant failure pattern in the absence of pelvic radiotherapy. The apparent complementarity of chemotherapy (in limiting distant failure) and radiotherapy (in limiting local failure), is a consistent finding that is a reasonable basis for subsequent clinical investigation. Several studies support the use of combined modality therapy rather than monotherapy.4Chapman BV Swanick CW Ning MS et al.Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.Gynecol Oncol. 2019; 154: 22-28Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 5Alvarez Secord A Havrilesky LJ Bae-Jump V et al.The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer.Gynecol Oncol. 2007; 107: 285-291Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar Finally, is there a preferred way of combining chemotherapy with radiotherapy? In both PORTEC-3 and NRG/GOG 258, the combined chemotherapy plus radiotherapy schedule was based on a phase 2 regimen piloted by the Radiation Therapy Oncology Group, RTOG 9708.6Greven K Winter K Underhill K et al.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 (204) Google Scholar 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. The combined therapy approach taken in RTOG 9708 was ultimately chosen, because the data were prospectively obtained. However, multiple studies (retrospective and prospective) have demonstrated the safety and efficacy of the so-called sandwich approach.5Alvarez Secord A Havrilesky LJ Bae-Jump V et al.The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer.Gynecol Oncol. 2007; 107: 285-291Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 7Lupe K D'Souza DP Kwon JS et al.Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer.Gynecol Oncol. 2009; 114: 94-98Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 8Geller MA Ivy J Dusenbery KE et al.A single institution experience using sequential multi-modality adjuvant chemotherapy and radiation in the "sandwich" method for high risk endometrial carcinoma.Gynecol Oncol. 2010; 118: 19-23Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 9Geller MA Ivy JJ Ghebre R et al.A phase II study of carboplatin and docetaxel followed "sandwich" method for stage III, IV and recurrent endometrial cancer.Gynecol Oncol. 2011; 121: 112-117Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar Increasing evidence supports the use of upfront systemic therapy, when combined with radiotherapy, as a strategy to maximise both systemic and local control.10Goodman CR Hatoum S Seagle B-L et al.Association of chemotherapy and radiotherapy sequence with overall survival in locoregionally advanced endometrial cancer.Gynecol Oncol. 2019; 153: 41-48Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar Many clinicians often use this regimen as a preferred adjuvant approach in locally advanced endometrial cancer. Based on outstanding work done by the PORTEC Study Group and others, we have made good progress in improving outcomes for women with high-risk and locally advanced endometrial cancers. However, we are not there yet. I have received an honorarium from Isoray Medical within the past 2 years. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trialThis updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. Full-Text PDF Open Access