Primary Chemoradiation VS. Neoadjuvant Chemotherapy Followed By Surgery As Treatment Strategy For LAVC

Study Overview
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Brief Summary
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A phase 2 randomised controlled trial will be performed in which the efficacy and safety of standard treatment (primary chemoradiation; consisting of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for six weeks) and experimental treatment (NACT; consisting of carboplatin and paclitaxel in a 3-weekly scheme) will be compared in 98 patients with LAVC, registered from eight national medical centres.

Official Title
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Primary Chemoradiation VS. Neoadjuvant Chemotherapy Followed By Surgery As Treatment Strategy For Locally Advanced Vulvar Carcinoma

Conditions
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Locally Advanced Vulvar Carcinoma, Squamous Cell Carcinoma of the Vulva

Intervention / Treatment
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* Drug: Paclitaxel and Carboplatin
* Combination Product: Chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman ≥ 18 years Signed and written informed consent. Histologically-confirmed primary or recurrent squamous cell carcinoma vulvar cancer FIGO stage II - IVa, T2 or higher, any N, M0. Local tumour through which the size or localization implies requirement of treatment through primary chemoradiation or surgery consisting of extensive surgery (meaning surgery damaging pelvic organs or exenterative surgery). This can imply; T2 or larger tumour with (irresectable) groin metastases T2 or larger tumour with involvement of the urethra or anal sphincter World Health Organization performance status of 0-2 Adequate haematological function defined by platelet count >100x10E9/L, absolute leukocyte >3X10E9/L or neutrophil count (ANC) >1.5x10E9/L, and hemoglobin >6.0 mmol/L Adequate hepatic function defined by a total bilirubin level ≤1.5x the upper limit of normal (ULN) range and ASAT and ALAT levels ≤2.5x ULN for all subjects Adequate renal function defined by an estimated creatinine clearance ≥50mL/min according to the Cockroft-Gault formula (or local institutional standard method) Beta HCG level of 14 mIU/mL or below for women of childbearing potential Highly effective contraception for patients if the risk of conception exists Exclusion Criteria: Patients with highly suspicious or positive metastases to the pelvic lymph nodes Any psychiatric condition that would prohibit the understanding or rendering of informed consent Prior radiotherapy to the pelvis or groin area limiting full dose chemoradiation according to protocol Existing neuropathy which will hinder the intake of chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Primary chemoradiation<br>Patients included in the standard treatment arm will receive a combination of weekly cisplatin combined with 30 fractions of external beam radiotherapy on the primary tumour with a total dose of 64.5 Gy. Cisplatin will be given for six weeks intravenously with a dose of 40 mg/m2, if possible on the first day of the week. On day 1 until day 5 the patient will receive external beam radiotherapy. This will be repeated for a six-week period. | Combination Product: Chemoradiation<br>* According to standard treatment.<br>|
| Experimental: NACT (3-weekly carboplatin and paclitaxel) followed by surgery<br>Patients included in the experimental arm will be treated with intravenous infusion of paclitaxel 175 mg/m2, followed by carboplatin 5 area under the curve (AUC). This will be administered in a 3-weekly scheme with preferably 3 and a maximum of 4 courses, with evaluation after two courses of chemotherapy by physical examination. NACT will be subsequently followed by radical surgery in responding patients. A four to six weeks interval after the last course of chemotherapy needs to be respected before surgery, to allow sufficient physical recovery. | Drug: Paclitaxel and Carboplatin<br>* Paclitaxel 175 mg/m2, followed by carboplatin 5 area under the curve (AUC). This will be administered in a 3-weekly scheme.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loco-regional control after 24 months per completed treatment including salvage treatment | Proportion of patients free from local-regional progression | 24 months after completed treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-related treatment failure | Patients without an event will be censored at their last date of contact. The Kaplan-Meier method will be used to estimate freedom from disease-related failure. Difference between the two main treatment arms, NACT vs. chemotherapy, will be tested using a log-rank test. Incidences of disease-related failure will be reported based on the Kaplan-Meier estimates, together with confidence intervals for the hazard ratio using both 90 and 95% confidence levels. | 24 months after completed treatment | 
| Disease free survival |  | 24 months after completed treatment | 
| Patterns of recurrence of disease | Type of recurrence after treatment: local, regional or distant recurrence | 24 months after completed treatment | 
| Overall survival |  | 24 months after completed treatment | 
| Treatment related death |  | 24 months after completed treatment | 
| Prevention of trimodal treatment | Proportion of patients that don't need adjuvant surgery (arm 1) and number of patients that don't need adjuvant radiotherapy (arm 2) | 24 months after completed treatment | 
| Functional organ preservation | Proportion of patients for who an organ-sparing surgery is possible | 24 months after completed treatment | 
| Short term and long term complications | According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | 24 months after completed treatment |