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

Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT): A Prospective Randomized Swedish Phase II Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Radiation: Radiation therapy

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.

• Study Type: Interventional
• Enrollment (Estimated): 254
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexander Valdman, MD, PhD; Phone Number: +46(0)700021317; Email: alexander.valdman@sll.se

Study Locations

• Sweden
  • Solna
    • Stockholm, Solna, Sweden, 17176
      • Recruiting
      • Karolinska University Hospital, Theme Cancer, Dept of Pelvic cancer
      • Contact: Tone Fokstuen, MD, PhD; Phone Number: +46 724 69 48 26; Email: tone.fokstuen@sll.se
      • Principal Investigator: Tone Fokstuen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Proton therapy; 5 x 5 Gy External radiation therapy with Protons	Radiation: Radiation therapy; 5 x 5 Gy external radiation therapy
Active Comparator: Photon therapy; 5 x 5 Gy External radiation therapy with Photons	Radiation: Radiation therapy; 5 x 5 Gy external radiation therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to five years after treatment
Differences in patient reported outcomes (PRO)	Differences in patient reported outcomes (PRO) between treatment arms in the preoperative period, the postoperative period, and overall	Baseline, Day 1-5, 2 and 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months
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	From week 3 until week 20 of the trial
Tumour regression grading (mrTRG)	Radiological assessment and comparison of tumour regression grading (mrTRG) between treatment arms	Baseline to response evaluation week 16-17 of the trial
Cost effectiveness analysis measured by QALY	Health economic comparison between proton and photon treatment. Cost effectiveness analysis measured by QALY	Time from randomization up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	Disease free survival after proton vs. photon treatment	Time from randomization until first recurrence, local/regional/systemic or death
Overall survival	Overall survival after proton vs. photon treatment	Time from randomization until death
Quality of Life (QLQ-C30)	Quality of life after proton vs. photon treatment (QLQ-C30)	Baseline, 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months
Difference in postoperative complications	Difference in postoperative complications between study arms measured by LARS score	From week 17-20 of the trial up to 5 years
Clinical complete remission (cCR)	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	From start of treatment up to 1 year
Incidence of acute lumbar plexus neuralgia	Difference between treatment arms in acute lumbar plexus neuralgia grade 1-3 measured as a change from baseline according to CTCAE 5.0	From baseline until week 4 of the trial
Exploratory: Concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells	Difference between treatment arms in concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells after given radiotherapy	Postoperative pathology from week 17 until week 24 of the trial
Exploratory: Difference in concentrations of CEA (carcinoembryonic antigen) between treatment arms	Change from baseline in concentrations of circulating CEA (carcinoembryonic antigen) between treatment arms	CEA measurements at baseline, week 3, 6, 9 and 12 of the trial

Collaborators and Investigators

• Sponsor: Alexander Valdman
• Investigators: Principal Investigator: Alexander Valdman, MD, PhD, Department of Radiotherapy, Karolinska University Hospital, Stockholm, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: August 18, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Proton therapy; Preoperative radiation; Short-course; Primary adenocarcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: PRORECT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No