Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

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 (2 cycles of cisplatin 50 mg/m2 in week 1 and 4 of RT, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required prior to 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 United Kingdom (n=900), and for 1226/1295 (95%) matching review and original reports were available. 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the United Kingdom, 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, http://ift.tt/HkCGY7) and with ClinicalTrials.gov (NCT00411138).