The Stockholm III Trial on Different Preoperative Radiotherapy Regimens in Rectal Cancer

Study Overview
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Brief Summary
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Preoperative radiotherapy (RT) is recommended to many patients with localised rectal cancer, not previously treated with pelvic RT. However, the optimum fractionation, the timing of surgery and the best use of concomitant chemotherapy remains controversial. There are theoretical reasons to believe that radiotherapy given in larger fractions during a shorter period of time might result in more late side effects than giving a conventional, more protracted RT in patients with rectal cancer. In addition, the optimum timing of surgery after RT, with respect to postoperative morbidity, mortality and potential downsizing of the tumour is not known. To address these questions, a prospective randomized multicenter trial was initiated, the Stockholm III trial, in which patients with primarily resectable rectal cancer were randomized to short-course preoperative RT (5x5 Gy) followed by surgery within one week or after 4-8 weeks or long-course preoperative RT(25x2 Gy) followed by surgery after 4-8 weeks.

Detailed Description
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840 participants (men and women) with a biopsy verified adenocarcinoma of the rectum scheduled for an open abdominal procedure were enrolled at 18 Swedish Hospitals during 1998-2013. In the initial protocol patients were randomly assigned (1:1:1) between three different RT courses; 5x5 Gy with surgery within 1 week (SRT), 5x5 Gy with surgery after 4-8 weeks (SRT-delay) or 25x2 Gy during 5 weeks without concomitant chemotherapy and surgery after 4-8weeks (LRT-delay). After a protocol amendment on May 21, 1999, participating hospitals could choose to randomise patients to just the short-course radiotherapy arms (1:1) or to all three arms. Randomisation was done by telephone by the Regional Cancer Centre in Stockholm, Sweden, after assessing inclusion and exclusion criteria. Computer generated randomisation lists were constructed by use of permuted block technique (block size of six for the three- arm randomisation, block size of four for the two-arm randomisation) and stratified by participating center. Investigators and patients were not masked to treatment. Follow-up was recommended at 3-, 6- and 12 months after surgery, and yearly thereafter. Although follow-up according to national guidelines with a minimum follow-up at 1 and 3 years was allowed. Patient data was also collected from the Swedish ColoRectal Cancer Register (SCRCR) and medical records. Primary outcome: 1. Time to local recurrence. Secondary outcomes: Recurrence-free survival Frequency of postoperative complications Frequency of tumour regression

Official Title
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A Prospective Randomized Trial on Different Preoperative Radiotherapy Regimens in Rectal Cancer, Stockholm III.

Conditions
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Rectal Cancer

Intervention / Treatment
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* Radiation: Short-course RT
* Radiation: Long-course RT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy confirmed clinically resectable rectal adenocarcinoma within 15 cm from the anal verge Planned for bowel resection with an abdominal procedure. Informed consent. Exclusion Criteria: Distant metastases Locally advanced unresectable tumors Planned for local excision Previous radiotherapy to the abdominal or pelvic region Severe ischemic heart disease or symptoms of severe arteriosclerosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1. Short-course RT (5x5 Gy) + surgery within 1 week (SRT)<br>RT=Preoperative radiotherapy Gy=Gray | Radiation: Short-course RT<br>* Preoperative radiotherapy (RT) given 5 times 5 Gray during five consecutive days, preferably Monday - Friday, with a four-field box technique, including the primary tumour and the primary and secondary lymph nodes in the pelvis.<br>|
| Active Comparator: 2. Short-course RT (5x5 Gy) + surgery after 4-8 weeks (SRT-delay)<br>RT=Preoperative radiotherapy Gy= Gray | Radiation: Short-course RT<br>* Preoperative radiotherapy (RT) given 5 times 5 Gray during five consecutive days, preferably Monday - Friday, with a four-field box technique, including the primary tumour and the primary and secondary lymph nodes in the pelvis.<br>|
| Active Comparator: 3. Long-course RT (25x2 Gy) + surgery after 4-8 weeks (LRT-delay)<br>RT= Preoperative radiotherapy Gy= Gray | Radiation: Long-course RT<br>* Preoperative radiotherapy (RT) given 2 Gy in 25 fractions during 5 weeks, total dose 50 Gy with a four-field box technique, including the primary tumour and the primary and secondary lymph nodes in the pelvis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Local Recurrence. | Local recurrence was defined as tumour growth below the level of the sacral promontory, related to the previous rectal cancer, and diagnosed radiographically with MRI, CT, or both, or clinically (preferably with histological confirmation). A diagnosis of local recurrence was confirmed and reported by the patient-responsible physician to the Swedish ColoRectal Cancer Registry (SCRCR), a nationwide validated national registry. Local recurrence was measured both as first and any event occurring during follow-up (censoring date March 30 2015), when all patients had been followed for at least 2 years. | From date of randomisation until date of local recurrence or date of death from any cause, whichever came first, assessed up to end of follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Postoperative complications was defined as any cardiovascular event, infectious, neurological or surgical complications occurring within 30 days after surgery, or during the same hospital admission, validated from medial records. Overall postoperative complication was defined as having at least one postoperative complication. Participants were grouped based on type of preoperative radiotherapy (RT) regimen (eg short- or long course) and overall treatment time (OTT), defined as time between start of RT and surgery. Participants receiving short-course RT were categorised into four different groups; Group A: OTT 7 days, Group B: OTT 8-13 days, Group C: OTT 5-7 weeks, Group D: OTT 8-13 weeks. Participants receiving long-course RT were categorised into two different groups; Group E: OTT 9-11 weeks, Groups F: OTT 12-14 weeks. | From surgery until 30 days postoperatively. | 
| Tumour Regression Based on the Dworak Grading Scoring System | Tumour regression (TRG) was assessed using the Dworak grading scoring system, ranging from scores 0 to 4 with higher scores indicating better tumour regression. Definition of scores; 0 = no regression, 1 = dominant tumour mass with obvious fibrosis and/or vasculopathy, 2 = dominantly fibrotic changes with few tumour cells or groups (easy to find), 3 = very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucous substance, 4 = no tumour cells, only fibrotic mass (total regression or complete response). All available microscopy slides were assessed by one pathologist, blinded to treatment. | At the time of surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal cancer, Preoperative radiotherapy, Timing of Surgery, Prognosis