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

Abstract

BackgroundIn 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 methodsA 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).ResultsIn 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).ConclusionCentral 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).

Mismatch repair deficiency identifies patients with high‐intermediate–risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: A prognostic biomarker

“…This emphasizes that the difference in recurrence and RFS is not driven by (preventable) vaginal recurrences, but that MMR status can identify patients who are at risk for clinically significant recurrences. Combining this with the previously reported randomized trials in a similar population that had high distant recurrence rates despite receiving aggressive adjuvant treatment, more effective therapy is urgently needed.…”

Reproducibility of lymphovascular space invasion (LVSI) assessment in endometrial cancer

“…Levels of reproducibility of these tumour characteristics are similar to our results for LVSI assessment. None of the previous studies specifically focused on LVSI assessment, but there are two studies that report on reproducibility of LVSI in EC . LVSI and other tumour characteristics were reviewed as part of an upfront pathology review before randomisation in the PORTEC‐3 trial .…”

“…None of the previous studies specifically focused on LVSI assessment, but there are two studies that report on reproducibility of LVSI in EC . LVSI and other tumour characteristics were reviewed as part of an upfront pathology review before randomisation in the PORTEC‐3 trial . A high rate of interobserver agreement between the original pathology report and central pathology review was found for LVSI (κ = 0.72).…”

Incorporation of molecular characteristics into endometrial cancer management

“…These microscopy‐based diagnoses are the current standard and serve as important input for (adjuvant) treatment decisions. However, considerable interobserver variation, in particular in high‐grade EC, is recognised, and centralised review prior to trial inclusion has pointed out that the therapeutic consequences are not negligible . This situation prompted research into the incorporation of robust diagnostic markers, which yields novel narrowly defined diagnostic entities.…”