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Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT) (PRORECT)

Primary Purpose

Rectal Cancer

Status
Recruiting
Phase
Not Applicable
Locations
Sweden
Study Type
Interventional
Intervention
Radiation therapy
Sponsored by
Alexander Valdman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring Proton therapy, Preoperative radiation, Short-course, Primary adenocarcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Inclusion Criteria - Primary tumour characteristics

  • Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge detected using a rigid rectoscope.
  • Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:

    • Clinical stage (c) T4b, i.e. infiltration of an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to TNM version 8).
    • cT4a, i.e. peritoneal involvement.
    • Extramural vascular invasion (EMVI+).
    • N2-status regarded as metastatic according to ESGAR consensus criteria
    • Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal fascia.
    • Metastatic lateral nodes (lat LN+) according to ESGAR consensus criteria

Inclusion Criteria - General

  • Staging done within 6 weeks before start of radiotherapy. No contraindications to chemotherapy with CAPOX including adequate blood counts, (within 5 weeks prior to randomisation):

    • white blood count ≥4.0 x 10*9/L
    • platelet count ≥100 x 10*9/L
    • clinically acceptable haemoglobin levels
    • creatinine levels indicating renal clearance of ≥50 ml/min
    • bilirubin ˂35 µmol/l.
  • ECOG performance score ≤1
  • Patient is considered to be mentally and physically fit for chemotherapy with CAPOX as judged by the oncologist.
  • Age ≥18 years
  • Written informed consent.
  • Adequate potential for follow-up.

Exclusion Criteria:

  • Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
  • Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis.
  • Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
  • Known DPD deficiency.
  • Any contraindications to MRI (e.g. patients with pacemakers).
  • Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
  • Concurrent uncontrolled medical conditions.
  • Any investigational treatment for rectal cancer within the past month.
  • Pregnancy or breast feeding.
  • Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
  • Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
  • Patients with symptoms of peripheral neuropathy.
  • Patients with pacemaker or ICD
  • Patients with bilateral hip protheses

Sites / Locations

  • Karolinska University Hospital, Theme Cancer, Dept of Pelvic cancerRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Proton therapy

Photon therapy

Arm Description

5 x 5 Gy External radiation therapy with Protons

5 x 5 Gy External radiation therapy with Photons

Outcomes

Primary Outcome Measures

Incidence of acute grade 2-5 gastrointestinal toxicity
The incidence of acute preoperative grade 2-5 gastrointestinal toxicity according to CTCAE v5.0 associated with proton vs. photon radiotherapy

Secondary Outcome Measures

Incidence of grade >2 hematologic and non-hematologic toxicity
The incidence of grade >2 hematologic (blood count, febrile neutropenia) and non-hematologic toxicity (general, genitourinary, gastrointestinal, skin) associated with protocol treatment, assessed by CTCAE v5.0 in the preoperative period, the postoperative period, and overall. Patient reported side-effects will be assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, the QLQ-C30, version 3. The QLQ-C30 will be supplemented with the disease specific module (rectal-cancer) QLQ-CR29. During radiotherapy, daily reported symptoms will be investigated by a newly developed symptom scale, Radiotherapy related symptom assessment scale (RSAS). The questionnaire includes 13 items specific for current diagnose. The RSAS is a validated instrument for assessing symptom intensity and distress in patients with different cancer disease undergoing radiotherapy, with psychometric properties within the expected range.
Differences in patient reported outcomes (PRO)
Differences in patient reported outcomes (PRO) between treatment arms in the preoperative period, the postoperative period, and overall
Proportion of patients being able to undergo full dose neoadjuvant chemotherapy
Differences between treatment arms in proportion of patients being able to undergo full dose neoadjuvant chemotherapy i.e. at least 4 cycles of CAPOX or 6 cycles of FOLFOX
Tumour regression grading (mrTRG)
Radiological assessment and comparison of tumour regression grading (mrTRG) between treatment arms
Cost effectiveness analysis measured by QALY
Health economic comparison between proton and photon treatment. Cost effectiveness analysis measured by QALY

Full Information

First Posted
August 18, 2020
Last Updated
August 15, 2022
Sponsor
Alexander Valdman
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1. Study Identification

Unique Protocol Identification Number
NCT04525989
Brief Title
Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT)
Acronym
PRORECT
Official Title
Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT): A Prospective Randomized Swedish Phase II Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 20, 2021 (Actual)
Primary Completion Date
March 2028 (Anticipated)
Study Completion Date
March 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Alexander Valdman

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
To investigate a potential toxicity benefit of preoperative radiation therapy with protons compared to conventional photon beam radiation therapy in patients with locally advanced rectal cancer.
Detailed Description
The aim of this study is to investigate whether proton beam radiotherapy in locally advanced rectal cancer can offer meaningful reductions in acute gastrointestinal toxicity compared to standard treatment with photons which may improve patient's tolerability of neoadjuvant chemotherapy. There are currently no published clinical reports evaluating the use of proton therapy in the upfront treatment of locally advanced rectal cancer. There are further no published randomized trials comparing radiotherapy with photon vs proton in locally advanced rectal cancer. This is a prospective randomized trial, initially run at the limited number of centres but later expanded to other centres participating in the Skandion network. Patients will be treated with short course 5 x 5 Gy radiation scheme with either photons (standard arm) or protons (Skandion clinic) followed by four to six cycles of combination chemotherapy (capecitabine and oxaliplatin) and surgery. The rectal tumour will be removed by TME/PME surgery or more extensive surgery if required because of tumour extent. All patients will receive at least 4 courses of CAPOX (Capecitabine b.i.d.1000 mg/m2 day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 every 3 weeks) week 3-14, followed by surgery at week 17-20.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rectal Cancer
Keywords
Proton therapy, Preoperative radiation, Short-course, Primary adenocarcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Prospective randomized
Masking
None (Open Label)
Allocation
Randomized
Enrollment
254 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Proton therapy
Arm Type
Experimental
Arm Description
5 x 5 Gy External radiation therapy with Protons
Arm Title
Photon therapy
Arm Type
Active Comparator
Arm Description
5 x 5 Gy External radiation therapy with Photons
Intervention Type
Radiation
Intervention Name(s)
Radiation therapy
Intervention Description
5 x 5 Gy external radiation therapy
Primary Outcome Measure Information:
Title
Incidence of acute grade 2-5 gastrointestinal toxicity
Description
The incidence of acute preoperative grade 2-5 gastrointestinal toxicity according to CTCAE v5.0 associated with proton vs. photon radiotherapy
Time Frame
From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial)
Secondary Outcome Measure Information:
Title
Incidence of grade >2 hematologic and non-hematologic toxicity
Description
The incidence of grade >2 hematologic (blood count, febrile neutropenia) and non-hematologic toxicity (general, genitourinary, gastrointestinal, skin) associated with protocol treatment, assessed by CTCAE v5.0 in the preoperative period, the postoperative period, and overall. Patient reported side-effects will be assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, the QLQ-C30, version 3. The QLQ-C30 will be supplemented with the disease specific module (rectal-cancer) QLQ-CR29. During radiotherapy, daily reported symptoms will be investigated by a newly developed symptom scale, Radiotherapy related symptom assessment scale (RSAS). The questionnaire includes 13 items specific for current diagnose. The RSAS is a validated instrument for assessing symptom intensity and distress in patients with different cancer disease undergoing radiotherapy, with psychometric properties within the expected range.
Time Frame
Baseline up to five years after treatment
Title
Differences in patient reported outcomes (PRO)
Description
Differences in patient reported outcomes (PRO) between treatment arms in the preoperative period, the postoperative period, and overall
Time Frame
Baseline, Day 1-5, 2 and 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months
Title
Proportion of patients being able to undergo full dose neoadjuvant chemotherapy
Description
Differences between treatment arms in proportion of patients being able to undergo full dose neoadjuvant chemotherapy i.e. at least 4 cycles of CAPOX or 6 cycles of FOLFOX
Time Frame
From week 3 until week 20 of the trial
Title
Tumour regression grading (mrTRG)
Description
Radiological assessment and comparison of tumour regression grading (mrTRG) between treatment arms
Time Frame
Baseline to response evaluation week 16-17 of the trial
Title
Cost effectiveness analysis measured by QALY
Description
Health economic comparison between proton and photon treatment. Cost effectiveness analysis measured by QALY
Time Frame
Time from randomization up to 5 years
Other Pre-specified Outcome Measures:
Title
Disease free survival
Description
Disease free survival after proton vs. photon treatment
Time Frame
Time from randomization until first recurrence, local/regional/systemic or death
Title
Overall survival
Description
Overall survival after proton vs. photon treatment
Time Frame
Time from randomization until death
Title
Quality of Life (QLQ-C30)
Description
Quality of life after proton vs. photon treatment (QLQ-C30)
Time Frame
Baseline, 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months
Title
Difference in postoperative complications
Description
Difference in postoperative complications between study arms measured by LARS score
Time Frame
From week 17-20 of the trial up to 5 years
Title
Clinical complete remission (cCR)
Description
Proportion of patients who reach a clinical complete remission (cCR), enter a watch-and-wait period and remain free of regrowth at least one year
Time Frame
From start of treatment up to 1 year
Title
Incidence of acute lumbar plexus neuralgia
Description
Difference between treatment arms in acute lumbar plexus neuralgia grade 1-3 measured as a change from baseline according to CTCAE 5.0
Time Frame
From baseline until week 4 of the trial
Title
Exploratory: Concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells
Description
Difference between treatment arms in concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells after given radiotherapy
Time Frame
Postoperative pathology from week 17 until week 24 of the trial
Title
Exploratory: Difference in concentrations of CEA (carcinoembryonic antigen) between treatment arms
Description
Change from baseline in concentrations of circulating CEA (carcinoembryonic antigen) between treatment arms
Time Frame
CEA measurements at baseline, week 3, 6, 9 and 12 of the trial

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Inclusion Criteria - Primary tumour characteristics Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge detected using a rigid rectoscope. Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically: Clinical stage (c) T4b, i.e. infiltration of an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to TNM version 8). cT4a, i.e. peritoneal involvement. Extramural vascular invasion (EMVI+). N2-status regarded as metastatic according to ESGAR consensus criteria Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal fascia. Metastatic lateral nodes (lat LN+) according to ESGAR consensus criteria Inclusion Criteria - General Staging done within 6 weeks before start of radiotherapy. No contraindications to chemotherapy with CAPOX including adequate blood counts, (within 5 weeks prior to randomisation): white blood count ≥4.0 x 10*9/L platelet count ≥100 x 10*9/L clinically acceptable haemoglobin levels creatinine levels indicating renal clearance of ≥50 ml/min bilirubin ˂35 µmol/l. ECOG performance score ≤1 Patient is considered to be mentally and physically fit for chemotherapy with CAPOX as judged by the oncologist. Age ≥18 years Written informed consent. Adequate potential for follow-up. Exclusion Criteria: Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen. Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis. Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years. Known DPD deficiency. Any contraindications to MRI (e.g. patients with pacemakers). Medical or psychiatric conditions that compromise the patient's ability to give informed consent. Concurrent uncontrolled medical conditions. Any investigational treatment for rectal cancer within the past month. Pregnancy or breast feeding. Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract. Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months. Patients with symptoms of peripheral neuropathy. Patients with pacemaker or ICD Patients with bilateral hip protheses
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alexander Valdman, MD, PhD
Phone
+46(0)700021317
Email
alexander.valdman@sll.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexander Valdman, MD, PhD
Organizational Affiliation
Department of Radiotherapy, Karolinska University Hospital, Stockholm, Sweden
Official's Role
Principal Investigator
Facility Information:
Facility Name
Karolinska University Hospital, Theme Cancer, Dept of Pelvic cancer
City
Stockholm
State/Province
Solna
ZIP/Postal Code
17176
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tone Fokstuen, MD, PhD
Phone
+46 724 69 48 26
Email
tone.fokstuen@sll.se
First Name & Middle Initial & Last Name & Degree
Tone Fokstuen, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No

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Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT)

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