Pelvic Radiation Therapy for Early Endometrial Cancer: Careful Selection Is Key

Despite a number of randomized trials evaluating the benefit of pelvic radiation in endometrial cancer, the management of the intermediate-risk subgroup remains highly controversial. In her article in this issue of ONCOLOGY, Dr. Eifel has provided a thorough and insightful review of the topic.[1] She describes the major issues in the published literature, and the emerging confusion that complicates medical decision making, as she eloquently builds a solid case in support of adjuvant pelvic radiation therapy for selected patients. In the six adjuvant trials comparing adjuvant whole-pelvic radiation therapy to either vaginal brachytherapy or observation, there is a consistent lack of an overall survival benefit, despite demonstrated improvements in pelvic control.[2-7] As Dr. Eifel emphasizes, these trials were all inadequately powered, given that they consistently enrolled patients with low-risk disease. This was largely attributable to incorrect assignment of pathologic grades by local investigators and community pathologists, grades which were later recognized to be lower on central pathology review. As a result, these study patients had a very low risk of failure, so the number needed to treat (NNT) in order to show an overall benefit of pelvic radiotherapy was much larger than appreciated, in essence diluting the intermediate-risk study population.

The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-2 trial showed that both survival and vaginal recurrence rates were the same regardless of whether adjuvant whole pelvic radiation or vaginal brachytherapy was used. There was, however, a modest increase in pelvic recurrences outside the vaginal cuff in exchange for a much lower morbidity with vaginal brachytherapy compared to whole pelvic radiation treatment.[6] Given that upstaging is so common, one might propose vaginal brachytherapy as the most appropriate choice for this high-intermediate–risk subgroup, given that a significant number are actually lower risk. In terms of pelvic recurrences, the morbidity of pelvic radiation in this lower-risk subset is not worth its incremental benefit over vaginal brachytherapy.

It is certainly compelling that when both surgical staging and central pathology review are employed, the survival benefit conferred by radiation in carefully selected patients begins to emerge.[5] However, given the heterogeneity of nodal management strategies, as well as the differences in pathology experience across the United States, this selective use of radiation therapy may not be a realistic goal. Unfortunately, our clinical results for “high-intermediate” patients will continue to look more like the PORTEC-2 results, where the value of pelvic radiation is washed out or diluted by the erroneous inclusion of low-risk patients. Thus, at this time it may be appropriate to reserve pelvic radiation for those with deep invasion plus other risk factors, where the higher morbidity associated with radiation is an acceptable price to pay for superior pelvic control. Dr. Eifel also mentions the possibility of multimodality trials. It is worth noting that the recently closed Gynecologic Oncology Group (GOG) 249 study-a randomized trial that included patients with higher-risk histologies and compared whole-pelvic radiation therapy to vaginal cuff brachytherapy followed by 3 cycles of carboplatin and taxol chemotherapy-may provide further clarification of who may benefit most from pelvic radiation. The shift in management of certain subgroups, such as stage II patients who have had a type I hysterectomy, to a chemotherapy-plus-vaginal-brachytherapy approach may demonstrate, on patterns-of-failure analysis, that pelvic radiation is crucial in lowering pelvic recurrences. However, we will not have the data to fuel that debate for years to come. One other interesting area in terms of multimodality therapy is the sequencing of treatment, where centers may choose to start with radiation, to end with radiation, or to sandwich radiation between cycles of chemotherapy. No phase III data exist to support the patterns of failure or benefits of different sequencing patterns, so this will continue to be another area of heated debate.

The use of a nomogram to help quantify the risk of a heterogeneous group of patients is exciting, and has been embraced in other clinical sites such as breast cancer. One hopes that the nomogram introduced this year by Alhilli et al will be validated soon, enabling its use in clinical practice.[8] It is hoped that future prognostic markers, such as aneuploidy or genetic mutations, will become available to help guide individualized patient care and truly enable us to select those patients with the most to gain from adjuvant treatment. The review by Dr. Eifel not only outlines the relevant studies and available data, but it also interprets them in a comprehensible way, highlighting reasonable evidence-based management recommendations. Given the prevalent upstaging seen in community practice, one should employ caution in use of pelvic radiation in any intermediate-risk patients besides those with deep invasion plus other risk factors, owing to the potentially unfavorable risk-to-benefit ratio for radiation use in other populations of patients with endometrial cancer. Future directions, including nomograms, multi-modality approaches, and more individualized patient care based on genomic profiles, may help to tailor each patient’s therapy to her individual risk. However, our current state of knowledge is well summarized in Dr. Eifel’s review.

Disclosures:

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.

References:

1. Eifel PJ. The value of pelvic radiation therapy after hysterectomy for early endometrial cancer. Oncology (Williston Park). 2013;27:990-9.

2. Aalders J, Abeler V, Kolstad P, et al. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol. 1980;56:419-27.

3. 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. 2009;373:137-46.

4. 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.

5. 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. 2004;92:744-51.

6. Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375:816-23.

7. Sorbe B, Horvath G, Andersson H, et al. External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma-a prospective randomized study. Int J Radiat Oncol Biol Phys. 2012;82:1249-55.

8. Alhilli MM, Podratz KC, Dowdy SC, et al. Risk-scoring system for the individualized prediction of lymphatic dissemination in patients with endometrioid endometrial cancer. Gynecol Oncol. 2013 Jul 9. [Epub ahead of print]