Single Application Brachytherapy in Cervical Cancer

Study Overview
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Brief Summary
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The purpose of the study is to evaluate safety and feasibility of single brachytherapy application with dose delivery in multiple fractions. Study will be conducted in Phase I/II clinical trial setting with strict Image guidance protocol.This study is expected reduce treatment duration and to increase ease and acceptability of brachytherapy in patients along with significant saving of resources

Detailed Description
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Brachytherapy for cervical cancers has evolved a long way from the era of Manchester based point A prescription to volume-based prescription in the current era of 3 Dimensional (3D) imaging. Advancement in imaging technology and widespread availability of this technology has allowed most centers worldwide to incorporate Image guided brachytherapy as a routine part of their clinical practice. The primary advantage of 3D image guided brachytherapy is that it allows the dose given by brachytherapy to conform to the anatomy of each individual patient while reducing the doses to organs at risk (OAR) (1). This technique has shown to improve local control rates and also reduce the rates of moderate to severe morbidity in multiple single institutional series (2-6). However, treatment related urinary and gastrointestinal late morbidity is still a significant problem with the 3 year actuarial incidence of intermediate to major morbidity (Grade≥2) being 30% and 29% for urinary and gastrointestinal side effects, respectively and Major morbidity (Grade≥3) is seen in 7% and 8%, respectively [An intErnational study on MRI guided BRachytherapy in locally Advanced CErvical cancers (EMBRACE) study 2014, work in progress(7)]. Most important factor determining late toxicities in radiotherapy is dose per fraction and total dose (total BEDGy3) rather than rate of dose accumulation or number of applications, which is evident from many trials of HDR brachytherapy. The dose per fraction in the protocol of 9Gy, 7Gy and 7Gy HDR is effective in terms of local control rates and toxicities which has been published(8,9). Our study is designed to evaluate the feasibility to deliver complete course of HDR brachytherapy in a single application while achieving dose constraints to OARs and keeping in account inter-fraction variation of doses to OAR's. In the protocol proposed here, The Investigators intend to deliver fractionated treatments in a strict image based and quality controlled environment to minimize the doses to OAR's. Also if the constraints are not achieved, patients would be offered Standard brachytherapy regimen. This would ensure that the anticipated late toxicities would be minimized. This study is expected to decrease overall treatment time and increase the ease and acceptability of brachytherapy in patients and with significant saving of resources while maintaining disease control rates and toxicity rates similar to standard protocols.

Official Title
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A Feasibility and Safety Study of Single Application Multi-fractionated High Dose Rate (HDR) Brachytherapy in Locally Advanced Cervical Cancer

Conditions
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Cervical Cancer

Intervention / Treatment
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* Radiation: Single application multi-fraction brachytherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically diagnosed invasive cervical cancer (squamous carcinoma, adenosquamous carcinoma, adenocarcinoma) International Federation of Gynecology and Obstetrics (FIGO) stage 2b-4a after thorough clinical examination and work-up investigation Suitable for radical radiation therapy with/without chemotherapy, and also for brachytherapy boost Accepts the Informed consent process and signs the form on his/her will. Exclusion Criteria: Patients with vesico-vaginal fistula or recto-vaginal fistula at diagnosis Patients at high risk of anaesthesia and patients with phobia /contra-indications to undergo MRI Patients not suitable for brachytherapy Metastatic disease beyond iliac on standard imaging Vault cancers/recurrence Previous history of pelvic radiation Non-compliance to treatment Medical or psychological illness precluding treatment protocol
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
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I/ Phase II single arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single application brachytherapy<br>After external beam radiotherapy with or without chemotherapy as per standard, each study patient will undergo single application brachytherapy to deliver 3 High Dose Rate (HDR) fractions [1st, 2nd and 3rd fractions of doses 9 Gy, 7 Gy and 7 Gy respectively] keeping 6-12 hours of interval. All patients will undergo an inter-fraction Computed Tomography (CT) scan before delivery of second fraction. Plan will be re-optimized to reduce the dose to Organs at Risk (OAR's), only if the dose exceeds the dose constraints. Dose constraints being exceedingly hard in 1st fraction or before 2nd fraction even after re-planning will deem patient non-feasible but optimization will be done to give preference to OAR's while accepting some compromise in target doses. | Radiation: Single application multi-fraction brachytherapy<br>* Single application brachytherapy procedure to deliver high dose rate fractions of 9Gy, 7Gy and 7Gy with 6-12 hours apart under strict image guidance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants achieving specified dosimetric constraints | Number of participants achieving protocol specified dosimetric constraints will be measured, these dosimetric constraints are considered as a measure of safety. If not more than 20% of participants fail to achieve dosimetric constraints, trial will be considered feasible. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events as assessed by CTCAE v 4.0 | To assess toxicity outcomes in terms of treatment related late Gastrointestinal (GI) / Genitourinary (GU) / Vaginal toxicities (grade 3 or more) | 2 years | 
| Local control rate | Status of local disease at 2 years after treatment | 2 years | 
| Percentage Inter-fraction dose variation | To evaluate inter fraction dose variation for organs at risk | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical cancer, Image guided Brachytherapy, single application