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

• ClinicalTrials.gov Identifier: NCT04525989
• Recruitment Status: Recruiting
• First Posted: August 25, 2020
• Last Update Posted: August 16, 2022
• Sponsor: Alexander Valdman
• Information provided by (Responsible Party): Alexander Valdman, Karolinska University Hospital

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.

Condition or disease	Intervention/treatment	Phase
Rectal Cancer	Radiation: Radiation therapy	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 254 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 20, 2021
• Estimated Primary Completion Date: March 2028
• Estimated Study Completion Date: March 2028

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Incidence of acute grade 2-5 gastrointestinal toxicity [ Time Frame: From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial) ]
   The incidence of acute preoperative grade 2-5 gastrointestinal toxicity according to CTCAE v5.0 associated with proton vs. photon radiotherapy

Secondary Outcome Measures :

1. Incidence of grade >2 hematologic and non-hematologic toxicity [ Time Frame: Baseline up to five years after treatment ]

   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.

2. Differences in patient reported outcomes (PRO) [ Time Frame: Baseline, Day 1-5, 2 and 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months ]
   Differences in patient reported outcomes (PRO) between treatment arms in the preoperative period, the postoperative period, and overall
3. Proportion of patients being able to undergo full dose neoadjuvant chemotherapy [ Time Frame: From week 3 until week 20 of the trial ]
   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
4. Tumour regression grading (mrTRG) [ Time Frame: Baseline to response evaluation week 16-17 of the trial ]
   Radiological assessment and comparison of tumour regression grading (mrTRG) between treatment arms
5. Cost effectiveness analysis measured by QALY [ Time Frame: Time from randomization up to 5 years ]
   Health economic comparison between proton and photon treatment. Cost effectiveness analysis measured by QALY

Other Outcome Measures:

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

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Alexander Valdman, MD, PhD; +46(0)700021317; alexander.valdman@sll.se

Locations

Sweden

Karolinska University Hospital, Theme Cancer, Dept of Pelvic cancer; Recruiting

Stockholm, Solna, Sweden, 17176

Contact: Tone Fokstuen, MD, PhD +46 724 69 48 26 tone.fokstuen@sll.se

Principal Investigator: Tone Fokstuen, MD, PhD

Sponsors and Collaborators

Alexander Valdman

Investigators

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

More Information

• Responsible Party: Alexander Valdman, MD, PhD, Senior Consultant Radiation Oncologist, Karolinska University Hospital
• ClinicalTrials.gov Identifier: NCT04525989
• Other Study ID Numbers: PRORECT
• First Posted: August 25, 2020
• Last Update Posted: August 16, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alexander Valdman, Karolinska University Hospital:

Proton therapy; Preoperative radiation; Short-course; Primary adenocarcinoma

Additional relevant MeSH terms:

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases