Standard Dose Versus High Dose of Radiotherapy in Rectal Preservation With Chemo-radiotherapy in Rectal Cancer Patients (WW3)

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Cancer of Rectum
• Intervention / Treatment: Radiation: 50.4 Gy to the tumor and elective volume; Drug: Capecitabine 825 mg/m2 twice daily on weekdays; Radiation: 62 Gy to the clinical tumor volume and 50.4 Gy to the elective volume

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.

• Study Type: Interventional
• Enrollment (Estimated): 111
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lars H Jensen, MD, PhD; Phone Number: +45 7940 6802; Email: lars.henrik.jensen@rsyd.dk

Study Locations

• Denmark
  • Aalborg, Denmark
    • Recruiting
    • Aalborg University Hospital
  • Copenhagen, Denmark
    • Recruiting
    • Copenhagen University Hospital, Righshospitalet and Bispebjerg Hospital
  • Næstved, Denmark
    • Not yet recruiting
    • Zealand University Hospital, Næstved
  • Roskilde, Denmark
    • Not yet recruiting
    • Zealand University Hospital, Roskilde
  • Vejle, Denmark
    • Recruiting
    • Department of Oncology, Vejle Hospital
    • Contact: Lars H Jensen, MD, PhD; Email: lars.henrik.jensen@rsyd.dk

Participation Criteria

Eligibility Criteria

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

Description

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

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
Active Comparator: A: Standard chemoradiotherapy; 50.4 Gy to the tumor and elective volume. The dose is given in 28 fractions on weekdays concomitantly with capecitabine 825 mg/m2 twice daily on weekdays.	Radiation: 50.4 Gy to the tumor and elective volume; Standard radiotherapy; Drug: Capecitabine 825 mg/m2 twice daily on weekdays; Standard chemotherapy
Experimental: B: High-dose radiotherapy; 62 Gy to the clinical tumor volume and 50.4 Gy to the elective volume. The dose is given in 28 fractions on weekdays concomitantly with capecitabine 825 mg/m2 twice daily on weekdays	Drug: Capecitabine 825 mg/m2 twice daily on weekdays; Standard chemotherapy; Radiation: 62 Gy to the clinical tumor volume and 50.4 Gy to the elective volume; Experimental radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rectal preservation at two years	Presence of a full-length rectum, i.e. no rectal resection.; Absence of rectal tumor, malignant lymph nodes or any other tumor deposit or recurrence within the pelvis based on clinical examination, CT and MR; No stoma because of side effects to treatment or rectal dysfunction	2 years after start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete response within four months from start of radiotherapy		4 months
Locoregional recurrence (within the pelvis)		At least yearly up to 5 years
Relapse free survival		At least yearly up to 5 years
Overall survival		At least yearly up to 5 years
Colostomy-free survival		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	QLQ is a 30-question assessment of quality of life. Twenty-eight questions are assessed on a scale of 1 (Not at all) to 4 (Very much); 2 questions are assessed on a scale of 1 (very poor) to 7 (excellent). Score range 0- 100. In the function scales, score 100 is best (more function). In the symptom scales, score 100 is worst, (more symptoms). The colorectal cancer module QLQ-CR29 should always be complemented by QLQ-C30. It contains four functional scales and 18 symptom scales. Some scales are dependent on gender and some are for patients with or without a stoma. There are 19 individual items assessed on a scale of 1 (Not at all) to 4 (Very much). Scores are totaled from each item to form the scales, and then normalized to 0-100.	Up to 5 years
Frequency of grade 3-4 toxicity according to CTCAE v4		Up to 5 years

Collaborators and Investigators

• Sponsor: Vejle Hospital
• Investigators: Principal Investigator: Lars H Jensen, MD, PhD, Department of Oncology, Vejle Hospital - University Hospital of Southern Denmark

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2020
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: September 17, 2019
• First Submitted That Met QC Criteria: September 17, 2019
• First Posted (Actual): September 19, 2019

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: June 2, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• 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; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: WW3

Drug and device information, study documents

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