SECTION X: PROS AND CONS Radiation Therapy in Early Endometrial Cancers: Pro

Remi A. Nout, MD Carien L. Creutzberg, MD, PhD

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Surgery is the mainstay of treatment for patients with endometrial carcinoma (EC) and consists of total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO). The role of pelvic and para-aortic lymphadenectomy or lymph node sampling has been widely debated. Some authors argued that lymphadenectomy would obviate the need for radiation therapy (RT), others emphasized the added morbidity of lymphadenectomy and the fact that the survival benefit suggested in retrospective studies could be explained by selection bias and stage migration. Recently, two large randomized trials have been published, both not showing any survival benefit of lymphadenectomy (LA) for patients with stage I EC. Thorough LA did identify 13% microscopic nodal metastases in the LA group, as compared to 3% in the no-LA group. However, both survival and disease -free survival rates were identical in the two groups, as well as the patterns of relapse. Use of adjuvant RT or chemotherapy (CT) was not different between the groups. This can probably be explained by the fact that the major prognostic factors for endometrial carcinoma stage, histological type, age, grade, depth of invasion and lymph-vascular space invasion - are associated with risk of lymph node metastases, but also with early distant disease spread in the absence of lymph node metastases. Adjuvant RT for endometrial carcinoma has increasingly been tailored to risk factors. Based on staging studies and prospective and retrospective data, endometrial carcinoma has been classified as low-risk, intermediate risk and highrisk for lymph node metastases and/or early disease spread to the abdominal cavity and to distant sites. Low-risk are stage I, grade 1 or 2 EC of endometrioid histology with no or superficial myometrial invasion. High-risk are non-endometrioid histologies; stage I-II grade 3 EC with deep myometrial invasion, and stages III-IV. All others are intermediate risk EC; this group has further been refined with other factors to define a high-intermediate risk (HIR) group (see below). As most patients with endometrial carcinoma have early symptoms and are diagnosed at early stage, approximately 55% of the patients have a low (<4%) risk of disease recurrence. For such low-risk EC patients (stage I, grade 1 or 2
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with no or superficial myometrial invasion), relapse-free survival without further treatment is 95%, and there is consensus that adjuvant RT is not indicated. Four prospective randomized trials have been published that evaluated the role of external beam RT (EBRT) in intermediate-risk endometrial carcinoma (Table 1). The Norwegian trial, published in 1980, included 540 women with clinical stage 1 endometrial carcinoma (1). After hysterectomy and postoperative vaginal brachytherapy (60 Gy to the mucosal surface), patients were randomly assigned to additional EBRT (40 Gy in 2 Gy fractions) or observation. Although EBRT reduced vaginal and pelvic relapse rates (2% at 5 years versus 7% in the in the brachytherapy group), more distant metastases were found in the EBRT group (10% versus 5%), and survival was not improved (89% versus 91% at 5 years). The subgroup with grade 3 tumors with deep (>50%) myometrial invasion showed improved local control and survival after EBRT (18% versus 27% cancer-related deaths); however, there were too few patients in this category to reach significance. In the first Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, 715 patients with stage I endometrial carcinoma, grade 1 or 2 with deep (>50%) myometrial invasion or grade 2 or 3 with superficial (<50%) invasion were randomized after TAH-BSO to receive EBRT (46 Gy in 2 Gy fractions) or no additional treatment (NAT) (2). The 10-year locoregional relapse rates were 5% in the EBRT group and 14% in the control group (p < 0.0001). There was no significant survival difference between the treatment arms, with 10-year overall survival of 68% (EBRT) vs 73% (NAT, P=0.14) and endometrial cancer-related death rates of 10% and 8% (P = 0.47). Risk criteria for locoregional relapse were grade 3, age older than 60 years, and outer 50% invasion. Five-year survival after any relapse was 12% in the RT group and 48% in the control group (p<0.001). This was due to the fact that 75% of locoregional relapses in the NAT group were located in the vagina. After vaginal relapse, 5year actuarial survival was 64%; EBRT 38% vs NAT 70%, which shows the high salvage rates of vaginal relapse in patients not previously irradiated. In contrast, outcome after

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Radiation Therapy in Early Endometrial Cancers: Pro

Table 1. Randomized trials of adjuvant radiation therapy in stage I endometrial carcinoma.

Trial Norwegian 1968-1974 PORTEC 1990-1997 GOG-99 1987-1995 ASTEC/EN5 1996-2005 No. patients eligibility 540 Stage I 714 IB grade 2-3 IC grade 1-2 392 St IB, IC St II (occult) 905 St IAB g3, IC, St II, serous/cc Surgery TAH-BSO Randomization Brachytherapy vs. brachytherapy and pelvic RT NAT vs. pelvic RT NAT vs. pelvic RT NAT vs. pelvic RT Locoregional recurrence 7% vs. 2% at 5 years p<0.01 14% vs. 4% at 5 years p<0.001 12% vs. 3% at 2 years p<0.01 7%* vs. 4% at 5 years p=0.038 Survival 89% vs. 91% at 5 years p=NS 85% vs. 81% at 5 years p=0.31 86% vs. 92% at 4 years p=0.56 84% vs.84% at 5 years p=0.98 Severe complications NA

TAH-BSO

TAH-BSO and lymphadenectomy TAH-BSO +/- lymphadenectomy

3% GI at 5 years (actuarial) 8% GI at 2 years (crude) 3 vs. 7% gr 3/4

RT = radiation therapy; NAT = no additional treatment; NA = not available; GI = gastro-intestinal *51% of patients in the NAT arm of ASTEC/EN5 received vaginal brachytherapy; only isolated recurrence reported

pelvic and distant relapse was poor, with only 11% 5-year survival. The GOG-99 trial included 392 evaluable patients with stage IB, IC, or IIA endometrial carcinoma of any histological grade, who were randomized after TAH-BSO and lymphadenectomy to receive pelvic EBRT (50.4 Gy in 1.8 Gy fractions) or NAT (3). A high-intermediate risk group (HIR) was defined based on the prognostic factors age, histological grade, myometrial invasion, and the presence of lymphovascular space invasion (Table 2). The HIR group (33% of the study population) had a 2-year incidence of relapse in the NAT arm of 27%, in contrast to 6% for the LIR group (67% of patients). RT resulted in similar hazard reductions for the HIR and LIR subgroups (58% and 54%), but in absolute terms, the differences were greater for HIR patients, with a reduction of 4-year cumulative relapse from 27% (NAT) to 13% (RT). There was even a slight, although non-significant survival benefit: 4-year overall survival 86% for NAT and 92% for EBRT. The 2-year estimated vaginal and pelvic failure rate was 12% in the NAT group and 3% in the EBRT group, for a 58% hazard reduction by RT. These results are strikingly similar to those obtained in the PORTEC study without lymphadenectomy. However, the 4-year crude rate of severe complications in GOG-99 was 13% for patients who had received RT, compared to a 5-year actuarial rate of 3% in the PORTEC trial, which underlines the increased risk of toxicity when combining extended surgery with pelvic radiotherapy. In addition, GOG-99 has shown that the HIR factors are associated with increased risk of relapse, regardless of lymphadenectomy. GOG-99 and other studies have shown lymph-vascular space invasion to be strongly associated with risk of lymph node involvement, as well as relapse at distant sites and inferior outcome. In the pooled ASTEC and EN5 trials, 905 patients with stage I endometrial carcinoma with risk features (deep invasion or high grade) were randomly allocated to EBRT or NAT (4). There was no difference in overall survival (84% at

5 years in both groups), confirming the results of the PORTEC and GOG-99 trials. In the ASTEC/EN5 trial, brachytherapy was used at discretion of the centres and was used in both arms. As a consequence, 51% of the patients in the NAT arm received vaginal brachytherapy. This can explain the fact that the 5-year rates of isolated (not total) vaginal or pelvic recurrence was 6.1% in the NAT arm, compared to 3.2% in the EBRT arm (hazard ratio 0.46, p=0.02). Conclusions that can be drawn from these randomized trials of pelvic radiotherapy in stage I endometrial carcinoma are that EBRT provides a highly significant improvement of local control, but without survival advantage. Furthermore, mild adverse effects were recorded in 26% of EBRT patients in the PORTEC-1 trial, predominantly gastrointestinal (GI) toxicity. A large proportion of endometrial cancer patients has a very favourable prognosis, and should be observed after TAH-BSO. Radiation therapy is a very effective salvage treatment for vaginal relapse in patients not previously irradiated. The use of postoperative RT should therefore be limited to the group of patients at sufficiently high risk of locoregional relapse to warrant the risk of treatment associated morbidity. In the PORTEC study, patients with two of the three major risk factors grade 3, age 60 or over, and outer 50% myometrial invasion, were found to have an increased risk of locoregional relapse, and to have the highest absolute benefit of pelvic RT. The 10-year locoregional relapse rates in this HIR group were 4.6% in the RT group and 23.1% in the control group (Table 2). In the GOG-99 trial, similar high risk criteria were identified, with reduction of isolated 4-year local relapse in the HIR group from 13 to 5%. Because most relapses occur in the vagina, the use of vaginal brachytherapy alone has been advocated. Data from retrospective studies that used vaginal brachytherapy alone for stage I endometrial cancer have shown the 5-year risk of vaginal relapse to be 0% to 7%. As pelvic and distant failure rates would not be reduced with brachytherapy alone, most studies included only or mainly low-risk patients (grade 1-2 with no or superficial invasion). However, the re-

Radiation Therapy in Early Endometrial Cancers: Pro Table 2. Comparison of the high-intermediate (HIR) risk groups in stage I endometrial carcinoma in the PORTEC and GOG-99 trials, and risk reduction with radiation therapy
Risk groups PORTEC Risk factors: - Age - Grade - Myometrial invasion - Lymphovascular space invasion High-intermediate risk (HIR) group < 60 vs. > 60 Grade 1-2 vs. 3 <50% vs. >50% At least 2 of the 3 factors GOG-99 <50 vs.<70 vs. >70 Grade 1 vs. 2-3 <66% vs. >66% absent vs. present Any age and 3 factors Age >50 and 2 factors Age >70 and 1 factor 4-year relapse (any): RT: 13% NAT: 27% rel. risk 0.48 4-year isolated local relapse: RT: 5% NAT: 13% rel. risk 0.38

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Results for the HIR group

10-year locoregional relapse: RT: 5% NAT: 23% rel. risk 0.22 using GOG high risk criteria: RT: 8% NAT: 22% rel. risk 0.36

RT: radiation therapy; NAT: no additional treatment; rel. risk: relapse with RT compared with NAT

sults of the randomized trials for intermediate risk EC suggested that, in view of the absence of survival benefit with EBRT and of the fact that most recurrences were located in the vagina, vaginal brachytherapy (VBT) might also be effective for patients with high-intermediate risk features to obtain local control with fewer side effects than EBRT and better quality of life. This was the rationale for the randomized PORTEC-2 trial (2002-2006), which compared EBRT and VBT among 427 EC patients with high-intermediate risk features, both with regards to efficacy and health-related quality of life (HRQL). First results at a median follow-up of 3 years have shown VBT to be highly effective, while VBT patients had a better HRQL (5). This efficacy of VBT is in agreement with the low risk of local recurrence in the NAT group of the ASTEC/EN5 trial, which used VBT in 51% of NAT patients. High-risk EC are those of non-endometrioid histology, those with grade 3 endometrioid carcinoma with deep invasion, and advanced stage tumours. EBRT continues to be indicated for patients with high-risk EC to maximize pelvic control. However, the increased rates of early distant disease spread determine the inferior outcome for high-risk patients, and effective systemic therapies are needed to improve their prognosis. First randomized trials comparing adjuvant chemotherapy to EBRT did not show any difference in overall or disease-free survival. EBRT delayed pelvic relapse and chemotherapy delayed distant relapse, but the eventual relapse and survival rates were similar. Therefore, a logical step is to use combinations of chemotherapy and radiotherapy, currently standard treatment in many tumor

sites. Trials are needed to investigate whether such combined treatments will improve overall and disease free survival, and what the cost would be in terms of adverse effects and impact on quality of life. Preliminary results of a recent phase III trial of NSGO/EORTC using both chemotherapy and radiotherapy were promising, with 7% improvement of progression-free survival in the combined therapy arm (6). In the current phase III PORTEC-3 trial the survival benefit of combined chemotherapy and radiotherapy is being investigated. In PORTEC-3, which is an international Intergroup trial for high-risk endometrial carcinoma, patients are randomly allocated to EBRT alone or EBRT with concurrent (cisplatin 2 cycles) and adjuvant (carboplatin and paclitaxel, 4 cycles) chemotherapy. The central pathology review for this trial is done before randomization to confirm high-risk status of these patients. This international trial will determine the risks and benefits of such intensive treatment, evaluating survival and recurrence-free survival as well as adverse effects and impact on quality of life in this elderly patient group. In conclusion, adjuvant RT for patients with EC has become increasingly tailored to individual risk factors, thus sparing many patients with low-risk factors form the toxicities of adjuvant treatment. RT is a highly effective salvage treatment for the occasional patient with locoregional relapse. Four large randomized trials on the role of EBRT have reduced overtreatment among intermediate-risk EC patients, and have provided a sound basis for limiting adjuvant RT to those with high-intermediate risk features. GOG-99 has shown that such features should be used to tailor adjuvant treatment, regardless of lymphadenectomy. In the PORTEC-2 trial, the efficacy of VBT alone was evaluated in comparison to EBRT, and preliminary results showed VBT to have control rates similar to EBRT, with less impact on HRQL. VBT may well be regarded the treatment of choice for patients with HIR endometrial carcinoma. The 15% EC patients at high risk for distant metastases and cancer related death continue to receive EBRT. The current PORTEC-3 trial investigates if the addition of chemotherapy during and after RT improves their survival. HRQL in this trial will establish cost-benefit information for such intensified treatments.

Suggested References for Further Reading

1. Aalders J, Abeler V, Kolstad P, Onsrud M: Postoperative external ir-

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radiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56:419-427. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van den Bergh AC, van dS-B, Beerman H, van LM: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404-1411.

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Radiation Therapy in Early Endometrial Cancers: Pro Kroese MC, van Bunningen BN, Smit VT, Nijman HW, van den Tol PP, Creutzberg CL: Quality of Life After Pelvic Radiotherapy or Vaginal Brachytherapy for Endometrial Cancer: First Results of the Randomized PORTEC-2 Trial. J Clin Oncol 27 2009 (Epub ahead of print, June 22, 2009 as 10.1200/ JCO.2008.20.2424). 6. Hogberg T, Rosenberg P, Kristensen G, De Oliveira CF, de Pont Christensen R, Sorbe B, Lundgren C, Salmi T, Andersson H, Reed N. A randomized phase-III study on adjuvant treatment with radiation (RT) chemotherapy (CT) in early-stage highrisk endometrial cancer (NSGO-EC-9501/EORTC 55991). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I 25[18S], 5503. 2007. Ref Type: Abstract

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Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG: 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;92:744751. Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, Eisenhauer E, Bacon M, Tu D, Parmar MK, Amos C, Murray C, Qian W: 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;373:137-146. Nout RA, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, Mens JW, Slot A, Stenfert