Standard Dose Versus High Dose of Radiotherapy in Rectal Preservation With Chemo-radiotherapy in Rectal Cancer Patients

Official title

Randomized Trial of Standard Dose Versus High Dose of Radiotherapy in Rectal Preservation With Chemo-radiotherapy to Patients With Early Low and Mid Rectal Cancer: The Watchful Waiting 3 Trial (WW3)

Overview

In recent years, an increasing number of retrospective and prospective observational studies have indicated that a subset of rectal cancer patients may avoid surgery if they can achieve a complete response to chemoradiotherapy. Prospective trials, including the previous Danish Watchful Waiting trials (NCT00952926, NCT02438839) in early rectal cancer have demonstrated high levels of organ preservation with dose-escalation, but it is unclear whether this was primarily due to tumor stage or dose level. The aim of the present study is to investigate if a higher dose of radiotherapy is superior compared to a standard dose in patients with early rectal cancer undergoing chemoradiotherapy with curative intent.

Detailed description

The main curative treatment modality for rectal cancer is surgery, potentially combined with chemotherapy and radiotherapy to lower the risk of local recurrence. In recent years, an increasing number of retrospective and prospective observational studies have indicated that a subset of patients may avoid surgery altogether if they can achieve a complete response to chemoradiotherapy. These studies have mainly focused on locally advanced tumors with a high risk of local recurrence. Smaller, less advanced tumors appear to respond better to chemoradiotherapy, but the optimal treatment for non-surgical management has not been established. Prospective trials, including the previous Danish Watchful Waiting trials (NCT00952926, NCT02438839) in early rectal cancer have demonstrated high levels of organ preservation with dose-escalation, but it is unclear whether this was primarily due to tumor stage or dose level. High-level evidence is currently absent for the question of radiotherapy dose, especially in early stage cancers.

The aim of the present study is to investigate if a higher dose of radiotherapy is superior compared to a standard dose in patients with early rectal cancer undergoing chemoradiotherapy with curative intent.

Interventions

• Radiation 50.4 Gy to the tumor and elective volume
  Standard radiotherapy
• Radiation 62 Gy to the clinical tumor volume and 50.4 Gy to the elective volume
  Experimental radiotherapy
• Drug Capecitabine 825 mg/m2 twice daily on weekdays
  Standard chemotherapy

Primary outcome measures

• Rectal preservation at two years [Time frame: 2 years after start of treatment]

Secondary outcome measures (7)

• Rate of complete response within four months from start of radiotherapy [Time frame: 4 months]
• Locoregional recurrence (within the pelvis) [Time frame: At least yearly up to 5 years]
• Relapse free survival [Time frame: At least yearly up to 5 years]
• Overall survival [Time frame: At least yearly up to 5 years]
• Colostomy-free survival [Time frame: At least yearly up to 5 years]
• Quality of life as assessed ny the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) CR29+C30 [Time frame: Up to 5 years]
• Frequency of grade 3-4 toxicity according to CTCAE v4 [Time frame: Up to 5 years]

Eligibility criteria

Inclusion criteria

• Histopathologically verified adenocarcinoma of the rectum
• MDT conference finds patient a candidate for rectal resection
• Clinical tumor category cT1-3
• MRI findings

• Maximal cross-sectional size of 4.5 cm (axial plane relative to the rectum)
• Lowest edge of tumor located at or below the peritoneal reflection on MRI
• Performance status 0-2
• Age ≥ 18 years
• Eligible for radiotherapy and capecitabine according to investigator, including

• Adequate function of bone marrow (neutrophils ≥ 1.5 x 10\^9/l and thrombocytes ≥ 100 x 10\^9/l)
• Adequate function of liver (ALAT < 2.5 x upper limit of normal, bilirubin < 2.5 x upper limit of normal)
• Adequate kidney function (Serum creatinine < 1.5 x upper limit of normal or measured GFR > 30 ml/min)
• Fertile women must present a negative pregnancy test and use secure contraceptives during and three months after treatment
• Written and orally informed consent

Exclusion criteria

• Previous surgical treatment of the present cancer, including transanal excision of tumor
• Other malignant disease within the past five years except non-melanoma skin cancer and premalignant lesions such as carcinoma in situ
• Distant metastases verified by imaging or biopsy, i.e. cM1
• Previous radiation treatment of the pelvis
• Pregnant or breastfeeding women.
• Existing colostomy or ileostomy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Denmark · 5 centers

• Aalborg University Hospital — Aalborg
• Copenhagen University Hospital, Righshospitalet and Bispebjerg Hospital — Copenhagen
• Zealand University Hospital, Næstved — Næstved
• Zealand University Hospital, Roskilde — Roskilde
• Department of Oncology, Vejle Hospital — Vejle

Identifiers

NCT: NCT04095299 · WW3

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗