Multimodality Therapy for High-Risk Endometrial Cancer: Balancing the Courses While Keeping All Options on the Table

October 15, 2013

As advances in treatment strategies continue to focus on individualization of therapy, the identification of disease subsets is crucial to strategizing optimal therapeutic approaches.

Oncologists have made great strides over the past several decades in the multidisciplinary management of many malignancies, often by more effectively optimizing and integrating surgery, radiotherapy (RT), and systemic therapy. Significant progress in defining patterns of relapse and tumor biology across subpopulations of patients at risk for local and/or systemic relapse have helped to individualize cancer therapy in different tumor types. More recently, incorporating targeted approaches to pathway-specific abnormalities (eg, human epidermal growth factor receptor 2 [HER2], epidermal growth factor receptor [EGFR], BRAF) have potentiated progress in multiple tumor sites, including melanoma, stomach, prostate, breast, and lung cancers.[1-7] Optimizing multimodality treatment approaches across endometrial cancer subsets has been the subject of ongoing research, and critical review of past data and their shortcomings is important to keep treatment options in perspective and moving forward in the most optimal direction. The review by Dr. Patricia Eifel in this issue of ONCOLOGY[8] provides a critical overview of current adjuvant modalities.

As Dr. Eifel articulates in her article, controversy over optimal adjuvant radiation treatment approaches in endometrial cancer patients is, in part, the result of studies that have failed to answer the question of efficacy of adjuvant radiation in populations that stand to benefit the most from treatment, not only those with early-stage disease, but also patients with advanced endometrial cancer.[9,10] Additionally, published prospective trials comparing the relative benefits of chemotherapy (CT) and RT alone as adjuvant management in high-risk groups have not helped us to ascertain how to maximize outcomes with combinations of each modality while achieving manageable toxicity. These trials have shown conflicting results, again possibly because of patient selection factors and differences in trial design. Three recent prospective trials in patients with intermediate- and high-risk disease have compared adjuvant CT to RT.[10-12]

In the phase III Gynecologic Oncology Group (GOG)-122 trial,[10] patients with stage III and optimally debulked (defined as no single site of residual tumor greater than 2 cm) stage IV disease were randomized to RT (n = 202) or to doxorubicin-cisplatin CT every 3 weeks for 8 cycles (n = 194). All endometrial carcinoma histologies were eligible, including clear cell (3.5% of patients in the RT arm and 5.2% of those in the CT arm) and papillary serous (RT/CT arms: 21.3%/20.6%). The RT was delivered with conventional techniques prior to an era in which more accurate CT-based 3D treatment planning was routinely used; patients were treated with 30 Gy in 20 fractions to the whole abdomen (a dose not expected to control gross peritoneal disease up to 2 cm) with a pelvic boost of 15 Gy in 8 fractions +/− a boost to the para-aortic lymph node (PALN). At a median follow-up of 74 months, there was significant improvement in progression-free survival (PFS) (50% vs 38%, P = .007) and overall survival (OS) (55% vs 42%, P = .004) in favor of the CT arm. An analysis of the patterns of failure showed a lower rate of failure in the pelvis in patients receiving RT rather than CT (13% vs 18%, respectively) and lower rates of distant failure in patients receiving CT rather than RT (18% vs 22%, respectively). Acute grade 3 or higher hematologic toxicity was significantly worse in the CT arm than in the RT arm (88% vs 14%, respectively), and grade 3 or higher gastrointestinal toxicity in the CT vs RT arms was 20% vs 13%, respectively.

A trial from Japan randomized 385 patients with surgically staged IC to IIIC (> 50% myometrial invasion, 25% stage III) endometrial carcinoma (the majority had positive lymph nodes, without PALN sampling) to either pelvic RT (at 45–50 Gy over 4–6 weeks) or to CT with cyclophosphamide, doxorubicin, and cisplatin every 4 weeks for a median of 3 cycles (range, 1–7 cycles).[12] Patients with nonendometrioid histologies were excluded. At 5 years, there was no statistical difference in PFS or OS between arms (with PFS of 83.5% vs 81.8% in the RT vs CT groups, respectively; and an OS rate of 85.3% in the RT group vs 86.7% in the CT group). There were no significant differences between arms in the incidence of grade 3 or higher overall toxicity (1.6% with RT vs 4.7% with CT:), which is markedly reduced with volume-directed RT and more limited use of CT than was reported in the GOG-122 trial.

Finally, a trial from Milan, Italy randomized 345 patients with surgically staged IC–II (> 50% myometrial invasion), grade 3, and stage III endometrial carcinoma to pelvic or extended-field RT (45–50 Gy) vs adjuvant CT (cisplatin at a dose of 50 mg/m2, doxorubicin at 45 mg/m2, and cyclophosphamide at 600 mg/m2 × 5 cycles).[11] Importantly, similar to the Japanese trial and different from the GOG study, clear cell and papillary serous histologies were excluded. With a median follow-up of 95.5 months, there was no difference in 3-year, 5-year, or 7-year OS between the arms (at rates of 78%, 69%, and 62%, respectively, in the RT arm; and 76%, 66%, 62%, respectively, in the CT arm). PFS was also not statistically different between arms. There was a nonsignificant reduction in initial relapse locally in patients receiving RT (with rates of local relapse being 7% in the RT arm vs 11% in the CT arm) as well as a nonsignificant reduction in metastases in patients receiving CT compared with RT (16% vs 21%, respectively). Rates of late grade 3 or higher genitourinary and gastrointestinal toxicity on the RT arm were 5% and 16%, respectively. In this study, the more moderate CT regimen chosen (whose aggressiveness was midway between that of the regimens used in the GOG-122 and Japanese trials) was reflected in the incidence of acute grade 3 or higher hematologic toxicity in the CT arm (41%). These studies illustrate the impact that patient selection and regimens used have on relapse, survival, and toxicity outcomes.

With a disease-free survival (DFS) rate of only 50% in the superior arm (CT) of the GOG-122 study, investigators have since sought to optimize an approach in this group of high-risk patients to include both RT and CT. Owing to concerns about toxicity, sequential rather than concomitant regimens were initially tested. One randomized phase III trial was designed by including a treatment regimen of surgery followed by volume-directed RT, and then randomized 552 patients to 6 cycles of cisplatin and doxorubicin, with or without paclitaxel.[13] At 36 months, recurrence-free survival was 64% vs 62% in the arms with vs without paclitaxel, respectively. Two additional combined randomized trials and other single-institution retrospective series have reported results with sequential treatment for this high-risk group.[14-17] Hogberg et al reported results in 534 patients with high-risk (as defined by the International Federation of Gynecology and Obstetrics [FIGO]) stage I–III endometrial cancer treated with surgery and adjuvant RT +/− CT, with an improvement in PFS in the CT arm.[16] Alvarez-Secord et al retrospectively reviewed 356 patients with stage III and IV endometrial cancer treated adjuvantly with RT alone, CT alone, or sequential combination therapy.[14] Patients in the CT-alone arm had significantly worse 3-year PFS and OS (19% and 33%, respectively, P < .001) compared with those in the RT-alone arm (59% and 70%) and the combined-therapy arm (62% and 79%). Similarly, Geller et al reported excellent 5-year PFS and OS rates of 74% and 79%, respectively, in 23 high-risk endometrial cancer patients (78% stage III) treated with sandwich CT and RT.[15]

Concerns about toxicity have led to a number of investigations of sequential vs concurrent combined treatment (chemoradiotherapy, or CRT) approaches in patients with endometrial cancer. The Radiation Therapy Oncology Group (RTOG) performed a phase II trial of CT (cisplatin at 50 mg/m2 in weeks 1 and 4) concurrent with RT (45 Gy to the pelvis followed by a vaginal brachytherapy cuff boost) followed by additional adjuvant CT with cisplatin and paclitaxel for 4 cycles in 46 patients with stage IB–IIIC disease, with resulting 4-year DFS and OS rates of 81% and 85%, respectively, and a reasonable 21% rate of late grade 3 or higher overall toxicity.[18] An additional retrospective series from Japan, in 76 women with stage III and IV endometrial cancer treated adjuvantly with CT alone, RT alone, or CRT, with a median follow-up of 54 months, showed a statistically significant improvement in OS in the CRT arm compared with the CT arm (P = .03), and a trend towards improved OS in the CRT arm compared with the RT arm (P = .052).[19] Finally, the use of intensity-modulated radiation therapy (IMRT) to treat extended fields has been shown to reduce radiation doses to critical organs[20,21] and to be both safe and effective, resulting in a 15% rate of grade 3 or higher toxicity when delivered in combination with concurrent cisplatin chemotherapy.[22] This approach of CRT followed by additional CT in high-risk endometrial cancer patients is under investigation in the cooperative group setting.

As advances in treatment strategies continue to focus on individualization of therapy, the identification of disease subsets-through the use of predictive molecular markers that define pathway-specific abnormalities and their subsequent biologic behavior-is crucial to strategizing optimal therapeutic approaches. Further work will be required to accurately define these molecular subsets in endometrial cancer, with the goal of facilitating optimal integration of cytotoxic chemotherapy, external beam radiation, brachytherapy, and biologic agents in a manner that utilizes the strengths of each of these therapeutic modalities to the greatest advantage.


The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-14.

2. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84.

3. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-65.

4. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-84.

5. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-71.

6. Ryan CJ, Molina A, Griffin T. Abiraterone in metastatic prostate cancer. N Engl J Med. 2013;368:1458-9.

7. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-97.

8. Eifel PJ. The value of pelvic radiation therapy after hysterectomy for early endometrial cancer. Oncology (Williston Park). 27:990-9.

9. Creutzberg CL, van Putten WL, Warlam-Rodenhuis CC, et al. Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial. J Clin Oncol. 2004;22:1234-41.

10. Randall 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. J Clin Oncol. 2006;24:36-44.

11. Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Brit J Cancer. 2006;95:266-271.

12. Susumu N, Sagae S, Udagawa Y, et al. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecologic Oncol. 2008;108:226-33.

13. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Gynecologic Oncol. 2009;112:543-52.

14. Alvarez 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. Gynecologic Oncol. 2007;107:285-91.

15. Geller 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. Gynecologic Oncol. 2010;118:19-23.

16. Hogberg 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;46:2422-31.

17. Nelson G, Randall M, Sutton G, et al. FIGO stage IIIC endometrial carcinoma with metastases confined to pelvic lymph nodes: analysis of treatment outcomes, prognostic variables, and failure patterns following adjuvant radiation therapy. Gynecol Oncol. 1999;75:211-4.

18. Greven 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;103:155-9.

19. Nakayama K, Nagai Y, Ishikawa M, et al. Concomitant postoperative radiation and chemotherapy following surgery was associated with improved overall survival in patients with FIGO stages III and IV endometrial cancer. Int J Clin Oncol. 2010;15:440-6.

20. Ahmed RS, Kim RY, Duan J, et al. IMRT dose escalation for positive para-aortic lymph nodes in patients with locally advanced cervical cancer while reducing dose to bone marrow and other organs at risk. Int J Radiat Oncol Biol Phys. 2004;60:505-12.

21. Portelance L, Chao KS, Grigsby PW, et al. Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys. 2001;51:261-6.

22. Salama JK, Mundt AJ, Roeske J, Mehta N. Preliminary outcome and toxicity report of extended-field, intensity-modulated radiation therapy for gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2006;65:1170-6.