Feasibility of the Maastro Applicator in Rectal Cancer

Study Overview
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Brief Summary
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The goal of this interventional pilot trial is to confirm that Maastro endoluminal HDR ( High Dose Radiation) contact brachytherapy boosting is feasible and may increase the chance of functional organ sparing of the rectum in patients with rectal cancer. Participants will be treated with chemoradiotherapy and an endoluminal boost with the Maastro applicator.

Detailed Description
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The goal of this clinical trial is to confirm that Maastro endoluminal HDR contact brachytherapy boosting is feasible and may increase the chance of functional organ sparing of the rectum in patients with rectal cancer. If at least 7 out of 10 planned Maastro applicator treatment series (3 fractions per series) can be conducted successfully from a procedural point of view the treatment will be considered feasible. The study intervention will be similar to the study treatment of arm B of the OPERA trial. Opposed to the treatment in arm B of the OPERA trial, the endoluminal boost will be given using HDR brachytherapy with the Maastro applicator instead of a CXRT (Contact X-ray Radiotherapy) device. The dose profile of the Maastro applicator is similar to the dose profile of CXRT device. As in the OPERA trial patients will be stratified based on tumor size. As the diameter of the treatment field of the largest Maastro applicator (there are two sizes) equals 2.5 cm we will stratify for tumor diameter < 2.5 cm v ≥ 2.5 cm. In the OPERA trial patients were stratified for a tumor diameter of < 3.0 cm v ≥ 3.0 cm as currently the largest applicator diameter for the CXRT device is 3.0 cm (currently available applicators: 2.0, 2.5 and 3.0 cm). The endoluminal boost will consist of 3 fractions with a dose equivalent to 30 Gy per fraction prescribed at the surface of the applicator. The 3 boost fractions will be delivered over a 4-week time period (week 1-2-4). Conform OPERA protocol, patients with a tumor size < 2.5 cm will receive an upfront endoluminal HDR contact boost followed by concurrent chemoradiotherapy (25x1.8 Gy combined with capecitabine 825 mg/m2 bd on radiotherapy days). Patients with a tumor size ≥ 2.5 cm will first undergo concurrent chemoradiotherapy (25x1.8 Gy combined with capecitabine 825 mg/m2 bd on radiotherapy days) to first shrink the tumor and will receive the endoluminal HDR contact boost afterwards in order to eventually fit the tumor surface in the surface of the Maastro applicator.

Official Title
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Introduction of the Maastro Applicator for Endoluminal Boosting in Rectal Cancer: a Pilot Study

Conditions
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Rectal Cancer, Feasibility, Toxicity, Quality of Life, Radiation Toxicity, Radiation Proctitis, Brachytherapy, Complete Response

Intervention / Treatment
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* Device: Maastro applicator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age and capable of giving informed consent. Adenocarcinoma of the rectum classified cT (clinical Tumor) 2-3b, < 5 cm largest diameter and < ½ circumference (MRI staging), N0-N1 (any node < 8 mm diameter), M0 Operable patient Tumor accessible to the Maastro applicator with a distance from the lower tumor border to the anal verge ≤10 cm No comorbidity preventing treatment Adequate birth control for women of child-bearing potential Follow-up possible. Exclusion Criteria: Tumor extending into the anal canal. Stop of anti-coagulants (except ≤100 mg aspirin/day) is medically contraindicated. Presence of coagulation disorder resulting in an increased bleeding risk. Prior pelvic radiation therapy (excluding the abovementioned neoadjuvant treatment). Prior surgery or chemotherapy for rectal cancer (excluding the abovementioned neoadjuvant treatment). Inflammatory bowel disease (IBD). (Systemic) treatment possibly causing rectal or genitourinary toxicity for a separate active malignancy. World Health Organization performance status (WHO-PS) ≥ 3. Life expectancy of < 6 months. Pregnant women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: A single arm prospective interventional pilot trial in 10 patients with feasibility and safety checks and early stopping/intermission rules
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maastro applicator in combination with chemoradiotherapy<br>The intervention is similar to the treatment of arm B of the published OPERA trial, however the endoluminal boost will be given using the Maastro applicator instead of a CXRT device. | Device: Maastro applicator<br>* The dose profile of the Maastro applicator is similar to the dose profile of a CXRT device. Patients will be stratified based on tumor size. The cut-off is set at the maximum diameter of the treatment surface of the Maastro applicator. The boost consists of 3 fractions with a dose equivalent to 30 Gy per fraction prescribed at the surface of the applicator. The 3 boost fractions will be delivered over a 4-week time period. Patients with a tumor size < 2.5 cm will receive an upfront boost followed by concurrent chemoradiotherapy (25x1.8 Gy combined with capecitabine 825 mg/m2 bd on radiotherapy days). Patients with a tumor size ≥ 2.5cm will first undergo concurrent chemoradiotherapy (25x1.8 Gy combined with capecitabine 825 mg/m2 bd on radiotherapy days) and will afterwards receive the boost.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical feasibility of the Maastro boosting technique. | If at least 7 out of 10 planned Maastro applicator treatment series (3 fractions per series) can be conducted successfully from a procedural point of view the treatment will be considered feasible. | During treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Maastro applicator endoluminal HDR contact brachytherapy boosting in functional organ sparing of the rectum | Percentage of patients with a persistent clinical complete response with good rectal function (no irreversible G2 or higher toxicity that does not respond to treatment) at 3 years. (number of patients with a complete response AND no persistent G2 or higher rectal toxicity) / (total number of patients) * 100% | 3 years follow-up | 
| Percentage of planned interventional Maastro procedures that could be conducted successfully from a procedural point of view. | (procedures conducted successfully from a procedural point of view according to the checklist, please refer to appendix A) / (total number of procedures) * 100% | During treatment | 
| Duration of the application procedure. | Time from insertion of the proctoscope to finalising removal of the proctoscope in minutes. | During treatment | 
| Percentage of patients with G3 or higher rectal toxicity up to 3 months after treatment potentially attributable to endoluminal HDR contact brachytherapy. | Doctor reported CTCEA (Common Terminologie Criteria for Adverse Events) v. 5 G3 or higher rectal toxicity not present before the start of treatment and occurring up to 3 months after treatment potentially attributable to endoluminal radiotherapy. (number of patients with new G3 or higher rectal toxicity up to 3 months after treatment) / (total number of patients) * 100% | 3 months follow-up | 
| Clinical complete response rate up to 3 years after treatment. | Clinical response will be assessed using the watch and wait protocol which is part of standard clinical care at MUMC+ ( Maastricht Medical University Center). Data will be reported at 3 months, 6 months, 1 year, 2 years and 3 years of follow-up. (number of patients with a cCR) / (total number of patients) * 100% | 3 years follow-up | 
| Rectal toxicity scored according to CTCAE v. 5 up to 3 years after treatment. | Both patient and doctor reported rectal toxicity scored according to CTCEA v. 5 will be determined before each application procedure, weekly during chemoradiotherapy, 1 week after treatment and 1, 3, 6, 12, 18, 24 and 36 months after treatment. | 3 years follow-up | 
| Genitourinary toxicity scored according CTCAE v. 5 up to 3 years after treatment. | Both patient and doctor reported genitourinary toxicity scored according to CTCEA v. 5 will be determined before each application procedure, weekly during chemoradiotherapy, 1 week after treatment and 1, 3, 6, 12, 18, 24 and 36 months after treatment. | 3 years follow-up | 
| Health status and quality of life as measured by QLQ (quality of life questionnaire)-C30 up to 3 years after treatment. | Patients will fill out the validated health status and quality of life questionnaire QLQ-C30 after inclusion (at baseline) and 1, 3, 6, 12, 18, 24 and 36 months after treatment. | 3 years follow-up | 
| Health status and quality of life as measured by QLQ-CR29 (Colo Rectal) up to 3 years after treatment. | Patients will fill out the validated health status and quality of life questionnaire QLQ-CR29 after inclusion (at baseline) and 1, 3, 6, 12, 18, 24 and 36 months after treatment. | 3 years follow-up | 
| Health status and quality of life as measured by EQ-5D (EuroQol Five Dimensions Health Questionnaire) up to 3 years after treatment. | Patients will fill out the EQ-5D-5L after inclusion (at baseline) and 1, 3, 6, 12, 18, 24 and 36 months after treatment. | 3 years follow-up | 
| Long-term rectal functional outcome as measured by LARS 9 Low Anterior Resection Syndrome) score up to 3 years after treatment. | Patients will fill out the LARS questionnaire after inclusion (at baseline) and 1, 3, 6, 12, 18, 24 and 36 months after treatment. | 3 years follow-up | 
| Local recurrence rate up to 5 years after treatment. | Local recurrence rate is defined as the rate of rectal recurrences at the site of the initial primary tumor. Local recurrence rate will be registered up to 5 years after treatment by consulting the hospital patient file. (number of patients with a local recurrence) / (total number of patients) * 100% | 5 years follow-up | 
| Locoregional recurrence rate up to 5 years after treatment. | Locoregional recurrence rate is defined as the rate of recurrences in the rectum and the regional pelvic lymph node areas. Locoregional recurrence rate will be registered up to 5 years after treatment by consulting the hospital patient file. (number of patients with a locoregional recurrence) / (total number of patients) * 100% | 5 years follow-up | 
| Metastatic rate up to 5 years after treatment. | Metastatic rate is defined as the rate of distant metastasis. Metastatic rate will be registered up to 5 years after treatment by consulting the hospital patient file. (number of patients with distant metastases) / (total number of patients) * 100% | 5 years follow-up | 
| Salvage surgery rate after treatment. | The percentage of patients undergoing salvage surgery will be determined. Both TME and local excision rate will be reported separately and combined. The reason for surgery (e.g. local recurrence, patient's wish, unacceptable toxicity) if available and the pathologic outcome (e.g. pCR) will also be reported for patients undergoing surgery. Salvage surgery rate will be registered up to 5 years after treatment by consulting the hospital patient file. (number of patients undergoing salvage surgery) / (total number of patients) * 100% | 5 years follow-up | 
| Overall and disease specific survival rate up to 5 year after treatment. | Both overall survival rate and disease specific survival rates will be reported. Survival rate will be registered up to 5 years after treatment by consulting the hospital patient file. 100% - (number of patients having died within 5 years after treatment [due to any causes or due to rectal cancer] / total number of patients * 100%) | 5 years follow-up | 
| The diagnostic value of clinical response assessment using digital rectal examination, endoscopy and MRI after endoluminal radiation boosting using the Maastro applicator. | Clinical response will be assessed using the watch and wait protocol which is part of standard clinical care at MUMC+. According to this protocol tumor response is assessed using a digital rectal examination, sigmoidoscopy and MRI (including T2 and DWI). This combined modality approach has been reported to have a specificity of 97% and a sensitivity of 71% for the detection of complete tumor response after neoadjuvant (chemo)radiotherapy. The exact diagnostic value of this multimodality approach has not been validated in the setting of an endoluminal boost with the Maastro applicator. We will evaluate the diagnostic value by relating the test results to a persistent clinical complete response at 1 and 2 years, residual tumor (yes/no) in the resection specimen in case of salvage surgery and a clinical local recurrence in case of refusal of salvage surgery. | during follow-up | 
| Complications within the first 30 days after completion of salvage total mesorectal excision (TME) surgery up to 3 years after treatment. | Complications within the first 30 days after completion or salvage TME surgery will be scored according to the classification of surgical complications by Clavien-Dindo (16). Complications will be registered up to 3 years after treatment by consulting the hospital patient file. | 3 years follow-up |