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

ASTEC/EN.5 Study Group, P Blake, Ann Marie Swart, J Orton, H Kitchener, T Whelan, H Lukka, E Eisenhauer, M Bacon, D Tu, M K B Parmar, C Amos, C Murray, W Qian, J Sandercock, K James, M Carey, A Branson, C H Buckley, E Eisenhauer, C W Redman, J Shepherd, G Dunn, P Heintz, J Yarnold, P Johnson, M Mason, R Rudd, P Badman, S Begum, N Chadwick, S Collins, A Cradduck, K J Goodall, J Jenkins, K Law, P Mook, C Goldstein, B Uscinska, C Goudreau, T Williams, D Soroka, E Elliott, H Deans, T K Sarkar, L T Tan, J Clarke, R J McClelland, V Barley, P Cornes, J D Graham, C Goodfellow, S Tahir, S Davidson, D Cole, B Lavery, A Flavin, K Hayat, M Hocking, C J R Irwin, P Dyson, D Guthrie, J J Nicoll, S E Pearson, D Guthrie, M Persic, F N Daniel, D Yiannakis, A Lamont, P Murray, A Cook, R Counsell, A Horne, J S Morgan, A Rathmell, B Lavery, S Khanna, R Jyothirmayi, J Summers, P K Hoskin, A Allerton, M J Ostrowski, J Scoble, S Chan, M Quigley, V Laurence, M J Lind, R Dealey, I Fernando, T N Latief, J Mould, A Stevens, P Blake, C L Harmer, K Harrington, S Oates, R Agrawal, S Awwad, G H Newman, P Cornes, G Rees, A Hindley, G Skailes, M Powell, R A Cooper, C J Orton, R I Rothwell, G Khoury, E M Low, P Flynn, O Freites, S El-Sharkawi, O A Adeyemi, E M Murray, M McCormack, G Tobias, M Adams, L Hanna, V Cowie, S Pledge, D J Radstone, K Karolewski, M Klimek, P Blecharz, M Baekelandt, L Hansen, J Kaern, M Onsrud, H Oksefjell, M Scheistroen, K Sundfoer, D McConnell, P Ghatage, R Grimshaw, J Carson, S Filice, P Bessette, A Nabid, M Roy, M Duclos, L Portelance, L Souhami, P Drouin, P Gauthier, J Dubuc, M Jolicoeur, T V Nguyen, K Chan, C Johanson, E Friedman, M Patel, S Voruganti, A Fyles, L Manchul, M Milosevic, M Carey, J Radwan, D D'Souza, J Gilchrist, A Hammond, K Schneider, B Lada, M Anthes, P Tai, P Craighead, K Arthur, G Dundas, C Parsons, P Lim, F Wong, M Quinn, J Krook, ASTEC/EN.5 Study Group, P Blake, Ann Marie Swart, J Orton, H Kitchener, T Whelan, H Lukka, E Eisenhauer, M Bacon, D Tu, M K B Parmar, C Amos, C Murray, W Qian, J Sandercock, K James, M Carey, A Branson, C H Buckley, E Eisenhauer, C W Redman, J Shepherd, G Dunn, P Heintz, J Yarnold, P Johnson, M Mason, R Rudd, P Badman, S Begum, N Chadwick, S Collins, A Cradduck, K J Goodall, J Jenkins, K Law, P Mook, C Goldstein, B Uscinska, C Goudreau, T Williams, D Soroka, E Elliott, H Deans, T K Sarkar, L T Tan, J Clarke, R J McClelland, V Barley, P Cornes, J D Graham, C Goodfellow, S Tahir, S Davidson, D Cole, B Lavery, A Flavin, K Hayat, M Hocking, C J R Irwin, P Dyson, D Guthrie, J J Nicoll, S E Pearson, D Guthrie, M Persic, F N Daniel, D Yiannakis, A Lamont, P Murray, A Cook, R Counsell, A Horne, J S Morgan, A Rathmell, B Lavery, S Khanna, R Jyothirmayi, J Summers, P K Hoskin, A Allerton, M J Ostrowski, J Scoble, S Chan, M Quigley, V Laurence, M J Lind, R Dealey, I Fernando, T N Latief, J Mould, A Stevens, P Blake, C L Harmer, K Harrington, S Oates, R Agrawal, S Awwad, G H Newman, P Cornes, G Rees, A Hindley, G Skailes, M Powell, R A Cooper, C J Orton, R I Rothwell, G Khoury, E M Low, P Flynn, O Freites, S El-Sharkawi, O A Adeyemi, E M Murray, M McCormack, G Tobias, M Adams, L Hanna, V Cowie, S Pledge, D J Radstone, K Karolewski, M Klimek, P Blecharz, M Baekelandt, L Hansen, J Kaern, M Onsrud, H Oksefjell, M Scheistroen, K Sundfoer, D McConnell, P Ghatage, R Grimshaw, J Carson, S Filice, P Bessette, A Nabid, M Roy, M Duclos, L Portelance, L Souhami, P Drouin, P Gauthier, J Dubuc, M Jolicoeur, T V Nguyen, K Chan, C Johanson, E Friedman, M Patel, S Voruganti, A Fyles, L Manchul, M Milosevic, M Carey, J Radwan, D D'Souza, J Gilchrist, A Hammond, K Schneider, B Lada, M Anthes, P Tai, P Craighead, K Arthur, G Dundas, C Parsons, P Lim, F Wong, M Quinn, J Krook

Abstract

Background: Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer.

Methods: Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40-46 Gy in 20-25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5).

Findings: After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1.05 (95% CI 0.75-1.48; p=0.77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1.04; 95% CI 0.84-1.29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6.1%.

Interpretation: Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity.

Trial registration: ClinicalTrials.gov NCT00002807.

Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Kaplan-Meier plots for outcome measure EBRT=external beam radiotherapy.
Figure 3
Figure 3
Isolated vaginal or pelvic initial recurrence EBRT=external beam radiotherapy.
Figure 4
Figure 4
Effect of external beam radiotherapy on subgroups defined as at high and intermediate risk of recurrence and on women who had lymphadenectomy or no lymphadenectomy as part of initial surgery EBRT=external beam radiotherapy. O–E=observed minus expected. Outer bars=99% CI. Inner bars=95% CI.
Figure 5
Figure 5
Meta-analysis EBRT=external beam radiotherapy. HR=hazard ratio.

References

    1. Kong A, Simera I, Collingwood M, Williams C, Kitchener H, on behalf of Cochrane Gynaecological Cancer Group Adjuvant radiotherapy for stage I endometrial cancer: systematic review and meta-analysis. Ann Oncol. 2007;18:1595–1604.
    1. Aalders J, Abeler V, Kolstad P. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol. 1980;56:419–427.
    1. Soderini A, Sardi J. Role of adjuvant radiotherapy in intermediate risk (Ib G2-3-IC) endometriod carcinoma after extended staging surgery. Preliminary reports of a randomised trial. Int J Gynecol Cancer. 2003;13(suppl 1):78.
    1. Keys HM, Roberts JA, Brunetto VL. 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;92:744–751.
    1. Creutzberg CL, van Putten WL, Koper PC. Surgery and postoperative radiotherapy versus surgery alone for patients with stage 1 endometrial carcinoma: multi centre trial. PORTEC study group. Lancet. 2000;355:1404–1411.
    1. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynecol. 1989;96:889–892.
    1. Standards and Minimum Datasets for Reporting Cancers . Minimum dataset for the histopathological reporting of atypical hyperplasia and adenocarcinoma in endometrial biopsy and curettage specimens and for endometrial cancer in hysterectomy specimens. Royal College of Pathologists; 2001.
    1. Early Breast Cancer Trialists' Collaborative Group Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. N Engl J Med. 1995;333:1444–1455.
    1. Royston P, Parmar MK. Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects. Stat Med. 2002;21:2175–2197.
    1. Lefebvre C, Clarke M. Identifying randomised trials. In: Egger MSG, Altman DG, editors. Systematic reviews in healthcare: meta-analysis in context. 2nd edn. BMJ Publishing Group; London: 2001. pp. 69–87.

Source: PubMed

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