Rectal Cancer
Conditions
Keywords
Rectal cancer, Preoperative radiotherapy, Timing of Surgery, Prognosis
Brief summary
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
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: 1. Recurrence-free survival 2. Frequency of postoperative complications 3. Frequency of tumour regression
Interventions
RADIATIONShort-course RT
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.
RADIATIONLong-course RT
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.
Sponsors
Swedish Cancer Society
The Swedish Research Council
Karolinska Institutet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Local Recurrence. | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | From surgery until 30 days postoperatively. | 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. |
| Tumour Regression Based on the Dworak Grading Scoring System | At the time of surgery. | 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. |
Countries
Sweden
Participant flow
Recruitment details
Patients were recruited from 18 hospitals in Sweden between 1998-2013 and initially randomly assigned (1:1:1) to three different arms; Short-course radiotherapy with surgery within 1 week (SRT) or after 4-8 weeks (SRT-delay), or Long-course radiotherapy with surgery after 4-8 weeks (LRT-delay). After a protocol amendment in 1999 hospitals could choose to randomise patients to all three arms or only short-course treatment arms (SRT or SRT-delay, 1:1). Patients could only be randomised to one arm.
Pre-assignment details
Of 8122 eligible patients, 385 were assigned to the three-armed randomisation and 455 to the two-armed randomisation, resulting in 840 participants included in the study.
Participants by arm
| Arm | Count |
|---|---|
| Three-arm Randomisation: SRT Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | 129 |
| Three-arm Randomisation: SRT-delay Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | 128 |
| Three-arm Randomisation: LRT-delay Participants included in the three-armed randomisation and allocated to long-course preoperative radiotherapy (25x5 Gy) and surgery after 4-8 weeks. | 128 |
| Two-arm Randomisation: SRT Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | 228 |
| Two-arm Randomisation: SRT-delay Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | 227 |
| Total | 840 |
Baseline characteristics
| Characteristic | Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Two-arm Randomisation: SRT | Two-arm Randomisation: SRT-delay | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 67 years | 67 years | 66 years | 67 years | 67 years | 67 years |
| Sex: Female, Male Female | 48 Participants | 49 Participants | 55 Participants | 91 Participants | 93 Participants | 336 Participants |
| Sex: Female, Male Male | 81 Participants | 79 Participants | 73 Participants | 137 Participants | 134 Participants | 504 Participants |
| Tumour height from anal verge 0-5 centimeter | 50 Participants | 57 Participants | 31 Participants | 78 Participants | 68 Participants | 284 Participants |
| Tumour height from anal verge 11-15 centimeter | 30 Participants | 21 Participants | 35 Participants | 58 Participants | 63 Participants | 207 Participants |
| Tumour height from anal verge 6-10 centimeter | 49 Participants | 49 Participants | 60 Participants | 91 Participants | 95 Participants | 344 Participants |
| Tumour height from anal verge Missing | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 5 Participants |
| Type of Surgery Abdominal perineal excision | 47 Participants | 53 Participants | 24 Participants | 75 Participants | 79 Participants | 278 Participants |
| Type of Surgery Anterior Resection | 79 Participants | 68 Participants | 93 Participants | 139 Participants | 136 Participants | 515 Participants |
| Type of Surgery Hartmann's | 3 Participants | 6 Participants | 8 Participants | 14 Participants | 12 Participants | 43 Participants |
| Type of Surgery Local excision | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Type of Surgery No resection | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| ypStage I | 38 Participants | 55 Participants | 37 Participants | 58 Participants | 83 Participants | 271 Participants |
| ypStage II | 43 Participants | 31 Participants | 46 Participants | 75 Participants | 55 Participants | 250 Participants |
| ypStage III | 48 Participants | 31 Participants | 37 Participants | 86 Participants | 76 Participants | 278 Participants |
| ypStage IV | 0 Participants | 7 Participants | 5 Participants | 7 Participants | 6 Participants | 25 Participants |
| ypStage Missing | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 5 Participants |
| ypStage Stage x | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 51 / 129 | 43 / 128 | 49 / 128 | 110 / 357 | 108 / 355 |
| other Total, other adverse events | 65 / 129 | 48 / 128 | 50 / 128 | 188 / 357 | 144 / 355 |
| serious Total, serious adverse events | 0 / 129 | 7 / 128 | 6 / 128 | 1 / 357 | 23 / 355 |
Outcome results
Primary
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.
Time frame: 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.
Population: Participants were analysed according to intention to treat.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Three-arm Randomisation: SRT | Time to Local Recurrence. | 28.3 months |
| Three-arm Randomisation: SRT-delay | Time to Local Recurrence. | 22.1 months |
| Three-arm Randomisation: LRT-delay | Time to Local Recurrence. | 33.3 months |
| Two-arm Randomisation: SRT | Time to Local Recurrence. | 35.1 months |
| Two-arm Randomisation: SRT-delay | Time to Local Recurrence. | 17.2 months |
| Pooled Short-course RT: SRT | Time to Local Recurrence. | 33.4 months |
| Pooled Short-course RT: SRT-delay | Time to Local Recurrence. | 19.3 months |
Comparison: The effect of treatment regimen on local recurrence as first event in the three-armed group comparison (n = 385) was estimated with proportional hazards regression, stratified by participating centre.p-value: 0.5290% CI: [0.06, 2.56]Log Rank
Comparison: The effect of treatment regimen on recurrence-free survival in the three armed randomisation comparison (n = 385) was estimated with proportional hazards regression, stratified by participating centre.p-value: 0.9295% CI: [0.64, 1.35]Log Rank
Comparison: The effect of treatment regimen on local recurrence as first event in the pooled short-course RT comparison (n = 712) was estimated with proportional hazards regression, stratified by participating centre.p-value: 0.5990% CI: [0.36, 2.27]Log Rank
Comparison: The effect of treatment regimen on recurrence-free survival in the pooled short-course RT comparison (n = 712) was estimated with proportional hazards regression, stratified by participating centre.p-value: 0.3995% CI: [0.69, 1.18]Log Rank
Secondary
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.
Time frame: From surgery until 30 days postoperatively.
Population: Participants were analysed as treated and grouped based on type of preoperative radiotherapy (RT) and overall treatment time (OTT).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Three-arm Randomisation: SRT | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Overall postoperative complications | 45 Participants |
| Three-arm Randomisation: SRT | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | No postoperative complication | 55 Participants |
| Three-arm Randomisation: SRT-delay | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Overall postoperative complications | 138 Participants |
| Three-arm Randomisation: SRT-delay | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | No postoperative complication | 109 Participants |
| Three-arm Randomisation: LRT-delay | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Overall postoperative complications | 82 Participants |
| Three-arm Randomisation: LRT-delay | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | No postoperative complication | 110 Participants |
| Two-arm Randomisation: SRT | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Overall postoperative complications | 63 Participants |
| Two-arm Randomisation: SRT | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | No postoperative complication | 97 Participants |
| Two-arm Randomisation: SRT-delay | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Overall postoperative complications | 16 Participants |
| Two-arm Randomisation: SRT-delay | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | No postoperative complication | 36 Participants |
| Pooled Short-course RT: SRT | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | Overall postoperative complications | 28 Participants |
| Pooled Short-course RT: SRT | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. | No postoperative complication | 31 Participants |
Comparison: The association between postoperative complications and short-course RT by overall treatment time was assessed using logistic regression analysis.p-value: 0.28995% CI: [0.4, 1.32]Regression, Logistic
Comparison: The association between postoperative complications and short-course RT by overall treatment time was assessed using logistic regression analysis.p-value: 0.00995% CI: [0.3, 0.84]Regression, Logistic
Comparison: The association between postoperative complications and short-course RT by overall treatment time was assessed using logistic regression analysis.p-value: <0.00195% CI: [0.23, 0.65]Regression, Logistic
Comparison: The association between postoperative complications and long-course RT by overall treatment time was assessed using logistic regression analysis.p-value: 0.52195% CI: [0.39, 6.37]Regression, Logistic
Secondary
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.
Time frame: At the time of surgery.
Population: Participants grouped based on allocated treatment and analysed as-treated. Only participants with available microscopy slides were included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Three-arm Randomisation: SRT | Tumour Regression Based on the Dworak Grading Scoring System | TRG 4 | 4 Participants |
| Three-arm Randomisation: SRT | Tumour Regression Based on the Dworak Grading Scoring System | Not assessable | 0 Participants |
| Three-arm Randomisation: SRT | Tumour Regression Based on the Dworak Grading Scoring System | TRG 2 | 50 Participants |
| Three-arm Randomisation: SRT | Tumour Regression Based on the Dworak Grading Scoring System | TRG 0 | 29 Participants |
| Three-arm Randomisation: SRT | Tumour Regression Based on the Dworak Grading Scoring System | TRG 3 | 2 Participants |
| Three-arm Randomisation: SRT | Tumour Regression Based on the Dworak Grading Scoring System | TRG 1 | 233 Participants |
| Three-arm Randomisation: SRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 0 | 20 Participants |
| Three-arm Randomisation: SRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 4 | 29 Participants |
| Three-arm Randomisation: SRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 1 | 124 Participants |
| Three-arm Randomisation: SRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 2 | 92 Participants |
| Three-arm Randomisation: SRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | Not assessable | 4 Participants |
| Three-arm Randomisation: SRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 3 | 16 Participants |
| Three-arm Randomisation: LRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | Not assessable | 1 Participants |
| Three-arm Randomisation: LRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 0 | 4 Participants |
| Three-arm Randomisation: LRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 1 | 42 Participants |
| Three-arm Randomisation: LRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 2 | 37 Participants |
| Three-arm Randomisation: LRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 3 | 7 Participants |
| Three-arm Randomisation: LRT-delay | Tumour Regression Based on the Dworak Grading Scoring System | TRG 4 | 3 Participants |
Comparison: The association between pathological complete response (pCR), eg no signs of viable tumour or metastatic nodes (T0N0) and overall survival (OS) was assessed using Cox-regression model.p-value: 0.04695% CI: [0.26, 0.99]Regression, Cox