Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer
S M de Boer, B G Wortman, T Bosse, M E Powell, N Singh, H Hollema, G Wilson, M N Chowdhury, L Mileshkin, J Pyman, D Katsaros, S Carinelli, A Fyles, C M McLachlin, C Haie-Meder, P Duvillard, R A Nout, K W Verhoeven-Adema, H Putter, C L Creutzberg, V T H B M Smit, for PORTEC Study Group, S M de Boer, B G Wortman, T Bosse, M E Powell, N Singh, H Hollema, G Wilson, M N Chowdhury, L Mileshkin, J Pyman, D Katsaros, S Carinelli, A Fyles, C M McLachlin, C Haie-Meder, P Duvillard, R A Nout, K W Verhoeven-Adema, H Putter, C L Creutzberg, V T H B M Smit, for PORTEC Study Group
Abstract
Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.
Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).
Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).
Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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References
- Creutzberg CL, van Putten WL, Koper PC. et al. 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(9213): 1404–1411.
- 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(3): 744–751.
- 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(9658): 137–146.
- Colombo N, Creutzberg C, Amant F. et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Radiother Oncol 2015; 117(3): 559–581.
- Straughn JM, Huh WK, Orr JW Jr. et al. Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy. Gynecol Oncol 2003; 89(2): 295–300.
- Greven KM, Randall M, Fanning J. et al. Patterns of failure in patients with stage I, grade 3 carcinoma of the endometrium. Int J Radiat Oncol Biol Phys 1990; 19(3): 529–534.
- 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. JCO 2004; 22: 1234–1241.
- Bosse T, Peters EE, Creutzberg CL. et al. Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer—a pooled analysis of PORTEC 1 and 2 trials. Eur J Cancer 2015; 51(13): 1742–1750.
- Manion E, Cohen MB, Weydert J.. Mandatory second opinion in surgical pathology referral material: clinical consequences of major disagreements. Am J Surg Pathol 2008; 32(5): 732–737.
- de Boer SM, Powell ME, Mileshkin L. et al. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2016; 17(8): 1114–1126.
- Tavassoli FA, Devilee P, World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon: IARC Press, 2003.
- Cohen J. A coefficient of agreement for nominal scales. Educ Psychol Meas 1960; 20(1): 37–46.
- Landis JR, Koch GG.. The measurement of observer agreement for categorical data. Biometrics 1977; 33(1): 159–174.
- Chafe S, Honore L, Pearcey R, Capstick V.. An analysis of the impact of pathology review in gynecologic cancer. Int J Radiat Oncol Biol Phys 2000; 48(5): 1433–1438.
- Khalifa MA, Dodge J, Covens A. et al. Slide review in gynecologic oncology ensures completeness of reporting and diagnostic accuracy. Gynecol Oncol 2003; 90(2): 425–430.
- 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(9717): 816–823.
- Scholten AN, van Putten WL, Beerman H. et al. Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review. Int J Radiat Oncol Biol Phys 2005; 63(3): 834–838.
- Scholten AN, Smit VT, Beerman H. et al. Prognostic significance and interobserver variability of histologic grading systems for endometrial carcinoma. Cancer 2004; 100(4): 764–772.
- Lax SF, Kurman RJ, Pizer ES. et al. A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis. Am J Surg Pathol 2000; 24(9): 1201–1208.
- Alkushi A, Abdul-Rahman ZH, Lim P. et al. Description of a novel system for grading of endometrial carcinoma and comparison with existing grading systems. Am J Surg Pathol 2005; 29(3): 295–304.
- Han G, Sidhu D, Duggan MA. et al. Reproducibility of histological cell type in high-grade endometrial carcinoma. Mod Pathol 2013; 26(12): 1594–1604.
- Gilks CB, Oliva E, Soslow RA.. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol 2013; 37(6): 874–881.
- Thomas S, Hussein Y, Bandyopadhyay S. et al. Interobserver variability in the diagnosis of uterine high-grade endometrioid carcinoma. Arch Pathol Lab Med 2016; 140(8): 836–843.
- McCluggage WG, Hirschowitz L, Wilson GE. et al. Significant variation in the assessment of cervical involvement in endometrial carcinoma: an interobserver variation study. Am J Surg Pathol 2011; 35(2): 289–294.
- Stelloo E, Nout RA, Osse EM. et al. Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 2016; 22(16): 4215–4224.
- Talhouk A, McConechy MK, Leung S. et al. Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer 2017; 123(5): 802–813.
Source: PubMed