Dose-Escalated Intensity Modulated Radiation Therapy in Patients with Locally Advanced Vulvar Cancer- Does It Increase Response Rate?

Abstract

The management for locally-advanced vulvar cancer includes preoperative and definitive chemoradiotherapy. By increasing dose from 47.6Gy to 57.6Gy, GOG 205 safely increased clinical (cCR) and pathologic complete response (pCR) to 64% and 50% from 48% and 31% in GOG 101. Intensity modulated radiotherapy (IMRT) has improved the tolerability of radiotherapy in vulvar cancer, such that the ongoing GOG 0279 is examining further dose-intensification to 64Gy with concurrent gemcitabine and cisplatin. The aim of the current study is to assess the response of dose-escalated IMRT in locally-advanced vulvar cancer. We performed a retrospective review of patients treated with dose-escalated (≥54Gy) IMRT from 2012-2018 for locally-advanced vulvar cancer. Patients treated with preoperative (n=30, 67%) or definitive intent (n=15, 33%) were included, while patients treated with adjuvant radiotherapy were excluded. Concurrent chemotherapy with weekly cisplatin (40mg/m2) was administered in 93%. Median dose to the vulva was 66.8 Gy (IQR: 66.0 Gy to 68.0 Gy) for definitive and 59.4 Gy (IQR: 58.0 Gy-61.2 Gy) for preoperative IMRT. Toxicity was graded using CTCAE v4.03. Predictors of disease free survival (DFS) were analyzed using the Kaplan Meier method with log rank test between groups and a parsimonious multivariate Cox multivariate model. p16 status was not analyzed as a variable, due to missing data for p16 in 69%. Of the included 45 patients: median age was 67 years, 60% were ≥ cT2, 53% were node-positive on PET imaging, and 57% were ≥ FIGO Stage IIIA. The overall rate of cCR was 78%, with a pCR rate for preoperative patients of 63%. At a median follow-up of 18 months (IQR: 7.7 – 33.7), the 2-year DFS was 65% (95%CI 49%-81%) for all patients, 84% (95%CI 62%-100%) for definitive IMRT, and 58% (95%CI 39%-78%) for preoperative IMRT. pCR was a significant predictor of DFS on both univariate [2-year DFS 83% (95%CI 65%-100%) versus 21% (95%CI 0%-46%), p <0.01] and on multivariate analysis (HR 0.28, 95% CI 0.08-0.96). There was no significant difference in DFS by RT dose, age, clinical nodal status, SUV, or presence of lichen sclerosis on multivariate analysis. Median treatment duration was 46 days (IQR: 45-50 days), with a treatment break required in 4 patients, 3 for reasons unrelated to RT and 1 for febrile neutropenia. Grade 3 acute RT toxicity was seen in 14 (31%) patients and consisted mainly of radiation dermatitis, pain, and GI. Grade 3 late RT toxicity was seen in 3 (7%) of patients: vaginal stricture (n=2) and perineal pain (n=1). Dose-escalated IMRT for locally advanced vulvar cancer was well tolerated with acceptable acute and chronic effects, with minimal treatment interruptions. cCR and pCR rates compared favorably with published data. pCR is a strong predictor of DFS and may serve as a viable endpoint for future clinical trial design in locally-advanced vulvar cancer.