Resolving the Confusion Surrounding Adjuvant Radiation in Endometrial Cancer

This article is a review of The Role of Adjuvant Radiation in Endometrial Cancer.

Published analyses combining groups of patients with different risk profiles have created confusion surrounding patient selection for adjuvant treatment after surgery for endometrial cancer. As a result, no randomized trial has demonstrated a survival benefit with the addition of adjuvant radiation. Further confusion occurs because some patients have had pelvic lymph node dissection, which not only affects complication rates following radiation, but has uncertain benefit for patients.

In their review, Diavolitsis et al separate patients into “low-risk,” “intermediate-risk,” and “high-risk” disease. Low-risk patients are defined as those with stages IA/IB disease and G1 or G2 histology. There is fairly uniform agreement in the literature that adjuvant radiation of any type would have minimal impact on outcome for these patients.

Intermediate-Risk Disease
Intermediate-risk patients are not as well defined. The five randomized trials that were cited in this review had different criteria for inclusion, as stated by Diavolitsis et al.[1-5] The outcomes of all these trials demonstrated a reduction in local recurrence with either external-beam radiation therapy (EBRT) or vaginal brachytherapy (VBT). None of these trials suggest a survival benefit with the addition of either modality. However, several of these trials included a substantial number of “low-risk” patients that could have diluted the power needed to detect a significant impact on survival.

As Diavolitsis et al point out, subgroup analysis of the Gynecologic Oncology Group (GOG)-99 trial demonstrated a “high-intermediate” risk group and a “low-intermediate” risk group, which enabled the identification of a higher-risk group of patients who seemed to benefit from external-beam irradiation.[4] It is also important to note that GOG-99 is the only trial that mandated pelvic lymphadenectomy, and these “high-intermediate” risk patients seemed to benefit from radiation even though they had pathologically negative nodes.

A meta-analysis done in 2007 demonstrated a trend toward reduction in the risk of death in patients with multiple high-risk factors (including G3 histology and stage IC disease) with EBRT treatment.[6] So the majority of patients with intermediate-risk disease defined as IBG2/G3 or ICG1/G2 are unlikely to benefit from external-beam irradiation, and this appears to be confirmed in the Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-2 trial.[2] I agree that VBT will decrease local recurrence and provide an improved therapeutic ratio.

High-Risk Disease
High-risk disease is defined as including patients with stage IIB, IIIA, IIIC, ICG3 and papillary serous/clear cell histology. Papillary serous histology has a different recurrence pattern from other histologies in that it tends to fail more outside the pelvis. In addition, among patients with a particular stage of endometrioid cancer it has been demonstrated that prognosis is also dependent on histologic grade, depth of myometrial extension, and number of extrauterine sites involved. For example, in one paper, patients with stage IIIA disease who had G1 disease in only one extrauterine site had a 5-year disease-free survival of 100% with pelvic irradiation alone.[7] Thus, published reports of small groups of patients including those with these characteristics treated with whole-abdominal irradiation can give the erroneous impression that this treatment is necessary and/or beneficial.[8,9] Certainly GOG-122, which randomized stage III/IV patients to whole-abdominal irradiation or chemotherapy, suggested that chemotherapy benefited this higher-risk group of patients.[10]

A recent publication about ASTEC (A Study in the Treatment of Endometrial Cancer) reported on over 900 women with stage I and II disease who were randomized to EBRT or no EBRT. VBT was optional in either arm.[11] No benefit was observed for the group that received EBRT in terms of survival. Fewer first failures in the pelvis were observed with EBRT. Once again, all risk groups were eligible. However, when patients in the high-risk group was separated out, there still seemed to be no survival advantage for EBRT. About half of the “high-risk group” included patients with papillary serous histology, which further complicates the interpretation of this study.

Investigators have shown an interest in combining radiation with chemotherapy for these patients because neither modality alone has yielded optimal outcomes. At the American Society of Clinical Oncology (ASCO) 2007 annual meeting, Hogberg et al presented a trial of 372 patients randomized to radiation alone or chemotherapy and radiation.[12] Patients included those with high-risk pelvicconfined disease. There appeared to be a benefit for patients who received both chemotherapy and radiation compared to radiation alone. Results are pending from GOG-184, which was a phase III trial combining radiation and chemotherapy that has reached accrual. PORTEC-3 is currently accruing high-risk patients (IBG3 with lymphovascular invasion; IC/IIG3; IIIA or IIIC) to a randomization of external-beam radiation or chemotherapy and external-beam radiation.

In recommending adjuvant therapy for these patients, one needs to consider all pathologic and patient-related factors. Patients with ICG3 disease who have had a substantial lymph node dissection are at increased risk for bowel obstruction and lymphedema following EBRT. VBT may be recommended for this reason. Combining chemotherapy with VBT or EBRT should be considered for patients with poor prognostic findings.

Treatment Strategies
There is no question that externalbeam radiation therapy increases the incidence of normal tissue toxicity compared to vaginal brachytherapy. The particular technique of administering external-beam irradiation was shown to affect the incidence of complications in the PORTEC-1 report when a four-field treatment technique resulted in fewer sequelae than a two-field technique.[3]

The Radiation Therapy Oncology Group recently completed accruing a group of endometrial cancer patients treated with intensity-modulated radiation therapy (IMRT) with the hope of decreasing normal tissue toxicity for patients who may benefit from pelvic irradiation-results are pending. My bias for patients who have highrisk features such as lymphovascular space invasion with G2 or G3 disease, deep myometrial penetration, and older age has been to treat the pelvis using IMRT if a lymph node dissection has been performed.

Whether lymph node dissections are therapeutic or merely prognostic has been debated. A recent phase III trial comparing endometrial cancer patients who received systematic lymphadenectomy to those without lymphadenectomy demonstrated improved staging and an increased complication rate with lymphadenectomy, with no improvement in disease-free or overall survival.[13] ASTEC investigators have completed a trial to compare outcome of patients who had lymphadenectomies to that of patients who did not, and there appeared to be no therapeutic benefit for those patients undergoing lymphadenectomy for either recurrence or survival.[14] The role of positronemission tomography/computed tomography for imaging these patients needs to be better defined.

Conclusions
The goal of any treatment is to decrease the risk of recurrence or death without increasing the risk of normal tissue toxicity. This can only be accomplished by selecting appropriate patients for treatment, optimizing imaging, determining appropriate surgical procedures, employing optimal radiation technique (external-beam vs vaginal brachytherapy; conventional radiation vs IMRT), and continued investigation of systemic drugs alone or in combination with radiation. Hopefully, as level 1 evidence accumulates, better decisions will be made for these patients.

References:

1. Aalders J, Abeler V, Kolstad P, et al: Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: Clinical and histologic study of 540 patients. Obstet Gynecol 56:419-427, 1980.
2. Nout RA, Putter H, Jürgenliemk-Schulz IM, et al: Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial (abstract LBA5503). J Clin Oncol 26:(15S):293s, 2008.
3. Creutzberg CL, van Putten WL, Koper PC, et al: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: Multicentre randomized trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355:1404-1411, 2000.
4. Keys HM, Roberts JA, Brunetto VL, et al: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 92:744-751, 2004.
5. Orton J, Blake P, on behalf of ASTEC/EN.5 collaborators: Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN.5 trial (abstract 5504). J Clin Oncol 25(18S):275s, 2007.
6. Johnson N, Cornes P: Survival and recurrent disease after postoperative radiotherapy for early endometrial cancer: Systematic review and meta-analysis. BJOG 114:1313-1320, 2007.
7. Greven KM, Lanciano RM, Corn B, et al: Pathologic stage III endometrial carcinoma. Prognostic factors and patterns of recurrence. Cancer 71:3697-3702, 1993.
8. Smith RS, Kapp DS, Chen Q, et al: Treatment of high-risk uterine cancer with whole abdominopelvic radiation therapy. Int J Radiat Oncol Biol Phys 48:767-778, 2000.
9. Small W, Mahadevan A, Roland P, et al: Whole-abdominal radiation in endometrial carcinoma: An analysis of toxicity, patterns of recurrence, and survival. Cancer J 6:394- 400, 2000.
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 24:36-44, 2006.
11. ASTEC/EN.5 Study Group, Blake P, Swart AM, Orton J, et al: Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): Pooled trial results, systematic review, and meta-analysis. Lancet 373:137-146, 2009.
12. Hogberg T, Rosenberg P, Kristensen G, et al: A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991) (abstract 5503). J Clin Oncol 25(18S):274s, 2007.
13. Panici PB, Basile S, Maneschi F, et al: Systematic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: Randomized clinical trial. J Natl Cancer Inst 100:1707-1716, 2008.
14. ASTEC study group, Kitchener H, Swart AM, Qian Q, et al: Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): A randomized study. Lancet 373:125-136, 2009.