Endometrial cancer is the most common gynecologic cancer, but there has been little consensus about the appropriate indications for adjuvant therapy. One reason for the lack of consensus is the absence of randomized studies in endometrial cancer that report an overall survival benefit. This may be attributed to the frequency of comorbidities in women with endometrial cancer, which increases the risk of death from causes other than cancer. Furthermore, many trials have “lumped” patients with diverse risk factors, raising questions about the applicability of study findings to subsets of patients meeting the eligibility criteria.
Despite these limitations, there have been many large studies conducted in endometrial cancer that provide insights into the best treatment recommendations to improve disease-free survival and quality of life. ASTRO developed evidence-based guidelines on the role of postoperative adjuvant therapy in endometrial cancer as a resource for the oncology community.1 In July 2015, these guidelines were endorsed by ASCO, which determined that the recommendations from the ASTRO guideline were clear, thorough, and based on the most relevant scientific evidence.2 The ASCO-endorsed guidelines are summarized in this issue of The ASCO Post.
Key Points
The ASTRO guidelines were developed through a systematic multistep process that included: (1) identifying five key questions to be addressed; (2) convening a panel of multidisciplinary experts, including radiation oncologists, gynecology oncologists, and medical oncologists; (3) performing a comprehensive literature review; (4) organizing a series of conference calls to discuss each key question; (5) formulating a literature discussion and summary recommendations for each of the key questions; (6) revising recommendations based on feedback from the panel, three independent expert reviewers, and the public; (7) assessing the level of consensus among the panelists using a modified Delphi approach; and (8) scoring the quality of the evidence using the American College of Physicians’ strength-of-evidence rating.
The first key question in the ASTRO guidelines addressed which patients do not require radiation therapy. The panel recommended observation for patients with minimally invasive grade 1 to 2 endometrioid endometrial cancers without other risk factors following hysterectomy. Best available evidence supported the use of vaginal cuff brachytherapy for patients with grade 1 or 2 cancer and > 50% myometrium invasion or grade 3 cancer and < 50% myometrium invasion.
Pelvic radiation is recommended for patients with deeply invasive high-grade disease, cervix invasion, or local extension into adjacent tissues, including the nodes. The guidelines panel thought that there was limited evidence for the use of brachytherapy after pelvic radiation.
Finally, the guidelines addressed the optimal integration of radiation therapy and chemotherapy. Concurrent chemoradiotherapy followed by adjuvant chemotherapy for patients with locally advanced disease was recommended, although it was acknowledged that evidence in support of a particular sequencing strategy was limited. The panel also noted that pathologic risk factors for local or distant recurrence might identify patients for whom chemotherapy or radiotherapy alone could be considered.
ASCO Endorsement and Noted Discrepancies
The ASCO endorsement panel favorably reviewed the methodology of the ASTRO guideline and performed an updated literature review, which did not reveal any new evidence warranting modification of the guidelines. The ASCO endorsement reprinted the ASTRO guidelines statements, with the addition of supplementary qualifying statements.
With regard to the recommendation for combined-modality treatment in locally advanced disease, the ASCO endorsement added the note that “the best evidence for this population supports the use of chemotherapy, but consideration of external-beam radiation is reasonable.” However, the available data comparing radiation with chemotherapy include three randomized trials: Maggi et al,3 Susumu et al,4 and Randall et al,5 the first two of which reported no significant difference in outcome. The third study, GOG 122, would have also reported similar rates of survival in both arms, apart from the process of stage adjustment that was performed in the analysis to rebalance the number of stage IV patients in the two arms.
Selective adjustment of risk factors in the arms of a trial negates the purpose of a randomized trial, which is designed to avoid selection bias, and limits the value of this study in measuring the impact of chemotherapy. In fact, the only randomized trial in endometrial cancer that reported an improvement in progression-free survival with chemotherapy delivered chemotherapy in combination with external-beam radiation.6 This finding suggests that perhaps chemotherapy is particularly effective when delivered in combination with pelvic radiation.
Additionally, the ASCO panel added the following supplementary qualifying statement: “Chemotherapy may be considered in certain patients with high-risk early-stage endometrial cancer.” Although retrospective studies suggest that patients with serous cancer may benefit from chemotherapy, there are no randomized trials demonstrating that chemotherapy improves outcome in early-stage endometrial cancer. In fact, the GOG 249 study, which has been reported only in abstract form, compared pelvic radiation with vaginal cuff brachytherapy and chemotherapy; the investigators found no difference in progression-free survival but higher rates of acute toxicity in patients treated with chemotherapy.
Future Outlook
The ASCO-endorsed ASTRO guidelines will hopefully improve the consistency of treatment recommendations for women with endometrial cancer across the United States. The areas of debate regarding the role of chemotherapy in early and advanced endometrial cancer may find more clarity with the publication of critical trials, including PORTEC-3, GOG 249, and GOG 258. ■
Disclosure: Drs. Klopp, Eifel, and Visvanathan reported no potential conflicts of interest.
References
1. Klopp A, Smith BD, Alektiar K, et al: The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 4:137-144, 2014.
2. Meyer LA, Bohlke K, Powell MA, et al: Postoperative radiation therapy for endometrial cancer: American Society of Clinical Oncology clinical practice guideline endorsement of the American Society for Radiation Oncology evidence-based guideline. J Clin Oncol 33:2908-2913, 2015.
3. Maggi R, Lissoni A, Spina F, et al: Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: Results of a randomised trial. Br J Cancer 95:266-271, 2006.
4. 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. Gynecol Oncol 108:226-233, 2008.
5. 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 24:36-44, 2006.
6. 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 46:2422-2431, 2010.
Dr. Klopp is Associate Professor and Dr. Eifel is Professor, Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston. Dr. Viswanathan is Associate Professor, Radiation Oncology, Harvard Medical School, and Attending Physician, Radiation Oncology, Dana-Farber Cancer Institute, Boston.
