The Stockholm III Trial on Different Preoperative Radiotherapy Regimens in Rectal Cancer
Sponsor
Karolinska Institutet (Other)
Overall Status
Completed
CT.gov ID
NCT00904813
Collaborator
Swedish Cancer Society (Other), The Swedish Research Council (Other)
840
18
3
232.9
46.7
0.2
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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:
- Time to local recurrence.
Secondary outcomes:
-
Recurrence-free survival
-
Frequency of postoperative complications
-
Frequency of tumour regression
Study Design
Study Type:
Interventional
Actual Enrollment
:
840 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Prospective Randomized Trial on Different Preoperative Radiotherapy Regimens in Rectal Cancer, Stockholm III.
Study Start Date
:
Nov 1, 1998
Actual Primary Completion Date
:
Feb 1, 2015
Actual Study Completion Date
:
Mar 31, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: 1. Short-course RT (5x5 Gy) + surgery within 1 week (SRT) RT=Preoperative radiotherapy Gy=Gray |
Radiation: Short-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.
|
| Active Comparator: 2. Short-course RT (5x5 Gy) + surgery after 4-8 weeks (SRT-delay) RT=Preoperative radiotherapy Gy= Gray |
Radiation: Short-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.
|
| Active Comparator: 3. Long-course RT (25x2 Gy) + surgery after 4-8 weeks (LRT-delay) RT= Preoperative radiotherapy Gy= Gray |
Radiation: Long-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.
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mora Hospital | Mora | Dalarna | Sweden | |
| 2 | Danderyds Hospital | Danderyd | Stockholm | Sweden | |
| 3 | Norrtälje Hospital | Norrtälje | Stockholm | Sweden | |
| 4 | Södertälje Hospital | Södertälje | Stockholm | Sweden | |
| 5 | Eskilstuna Hospital | Eskilstuna | Sweden | ||
| 6 | Falun Hospital | Falun | Sweden | ||
| 7 | Gävle Sjukhus | Gävle | Sweden | ||
| 8 | Helsingborg Hospital | Helsingborg | Sweden | ||
| 9 | Linköping University Hospital | Linköping | Sweden | ||
| 10 | MAS University Hospital | Malmö | Sweden | ||
| 11 | Vrinnevi Hospital | Norrköping | Sweden | ||
| 12 | Karolinska University Hospital | Stockholm | Sweden | 17176 | |
| 13 | Ersta Hospital | Stockholm | Sweden | ||
| 14 | South Hospital | Stockholm | Sweden | ||
| 15 | St Görans Hospital | Stockholm | Sweden | ||
| 16 | Norrlands Universitetssjukhus | Umeå | Sweden | ||
| 17 | Uppsala University Hospital | Uppsala | Sweden | ||
| 18 | Visby Hospital | Visby | Sweden |
Sponsors and Collaborators
- Karolinska Institutet
- Swedish Cancer Society
- The Swedish Research Council
Investigators
- Principal Investigator: Anna Martling, Professor, Karolinska Institutet
Study Documents (Full-Text)
None provided.More Information
Publications
- Pettersson D, Cedermark B, Holm T, Radu C, Påhlman L, Glimelius B, Martling A. Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg. 2010 Apr;97(4):580-7. doi: 10.1002/bjs.6914.
- Pettersson D, Glimelius B, Iversen H, Johansson H, Holm T, Martling A. Impaired postoperative leucocyte counts after preoperative radiotherapy for rectal cancer in the Stockholm III Trial. Br J Surg. 2013 Jun;100(7):969-75. doi: 10.1002/bjs.9117. Epub 2013 Apr 2.
- Pettersson D, Lörinc E, Holm T, Iversen H, Cedermark B, Glimelius B, Martling A. Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br J Surg. 2015 Jul;102(8):972-8; discussion 978. doi: 10.1002/bjs.9811.
Responsible Party:
Anna Martling,
Professor, Senior Consultant Surgeon,
Karolinska Institutet
ClinicalTrials.gov Identifier:
NCT00904813
Other Study ID Numbers:
- 98/240
First Posted:
May 20, 2009
Last Update Posted:
May 7, 2021
Last Verified:
Apr 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by Anna Martling,
Professor, Senior Consultant Surgeon,
Karolinska Institutet
Additional relevant MeSH terms:
Study Results
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 Detail | 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. |
| Arm/Group Title | Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Two-arm Randomisation: SRT | Two-arm Randomisation: SRT-delay |
|---|---|---|---|---|---|
| Arm/Group Description | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Participants included in the three-armed randomisation and allocated to long-course preoperative radiotherapy (25x5 Gy) and surgery after 4-8 weeks. | Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. |
| Period Title: Overall Study | |||||
| STARTED | 129 | 128 | 128 | 228 | 227 |
| COMPLETED | 129 | 128 | 128 | 228 | 227 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Two-arm Randomisation: SRT | Two-arm Randomisation: SRT-delay | Total |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Participants included in the three-armed randomisation and allocated to long-course preoperative radiotherapy (25x5 Gy) and surgery after 4-8 weeks. | Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Total of all reporting groups |
| Overall Participants | 129 | 128 | 128 | 228 | 227 | 840 |
| Age (years) [Median (Full Range) ] | ||||||
| Median (Full Range) [years] |
67
|
67
|
66
|
67
|
67
|
67
|
| Sex: Female, Male (Count of Participants) | ||||||
| Female |
48
37.2%
|
49
38.3%
|
55
43%
|
91
39.9%
|
93
41%
|
336
40%
|
| Male |
81
62.8%
|
79
61.7%
|
73
57%
|
137
60.1%
|
134
59%
|
504
60%
|
| Tumour height from anal verge (Count of Participants) | ||||||
| 0-5 centimeter |
50
38.8%
|
57
44.5%
|
31
24.2%
|
78
34.2%
|
68
30%
|
284
33.8%
|
| 6-10 centimeter |
49
38%
|
49
38.3%
|
60
46.9%
|
91
39.9%
|
95
41.9%
|
344
41%
|
| 11-15 centimeter |
30
23.3%
|
21
16.4%
|
35
27.3%
|
58
25.4%
|
63
27.8%
|
207
24.6%
|
| Missing |
0
0%
|
1
0.8%
|
2
1.6%
|
1
0.4%
|
1
0.4%
|
5
0.6%
|
| Type of Surgery (Count of Participants) | ||||||
| Anterior Resection |
79
61.2%
|
68
53.1%
|
93
72.7%
|
139
61%
|
136
59.9%
|
515
61.3%
|
| Abdominal perineal excision |
47
36.4%
|
53
41.4%
|
24
18.8%
|
75
32.9%
|
79
34.8%
|
278
33.1%
|
| Hartmann's |
3
2.3%
|
6
4.7%
|
8
6.3%
|
14
6.1%
|
12
5.3%
|
43
5.1%
|
| Local excision |
0
0%
|
1
0.8%
|
0
0%
|
0
0%
|
0
0%
|
1
0.1%
|
| No resection |
0
0%
|
0
0%
|
3
2.3%
|
0
0%
|
0
0%
|
3
0.4%
|
| ypStage (Count of Participants) | ||||||
| I |
38
29.5%
|
55
43%
|
37
28.9%
|
58
25.4%
|
83
36.6%
|
271
32.3%
|
| II |
43
33.3%
|
31
24.2%
|
46
35.9%
|
75
32.9%
|
55
24.2%
|
250
29.8%
|
| III |
48
37.2%
|
31
24.2%
|
37
28.9%
|
86
37.7%
|
76
33.5%
|
278
33.1%
|
| IV |
0
0%
|
7
5.5%
|
5
3.9%
|
7
3.1%
|
6
2.6%
|
25
3%
|
| Stage x |
0
0%
|
3
2.3%
|
1
0.8%
|
1
0.4%
|
6
2.6%
|
11
1.3%
|
| Missing |
0
0%
|
1
0.8%
|
2
1.6%
|
1
0.4%
|
1
0.4%
|
5
0.6%
|
Outcome Measures
| Title | Time to Local Recurrence. |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants were analysed according to intention to treat. |
| Arm/Group Title | Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Two-arm Randomisation: SRT | Two-arm Randomisation: SRT-delay | Pooled Short-course RT: SRT | Pooled Short-course RT: SRT-delay |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Participants included in the three-armed randomisation and allocated to long-course preoperative radiotherapy (25x5 Gy) and surgery after 4-8 weeks. | Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the two-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Participants assigned to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week pooled from the three-armed and two-armed randomisation. | Participants assigned to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks pooled from the three-armed and two-armed randomisation. |
| Measure Participants | 129 | 128 | 128 | 228 | 227 | 357 | 355 |
| Median (Full Range) [months] |
28.3
|
22.1
|
33.3
|
35.1
|
17.2
|
33.4
|
19.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Three-arm Randomisation: SRT, Three-arm Randomisation: SRT-delay, Three-arm Randomisation: LRT-delay |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | In the initial protocol treatment groups were deemed non-inferior if the upper limit of a two-sided 90% CI for the hazard ratio did not exceed 1.7. With a cumulative incidence of local recurrence at 15%, a sample size of 840 participants were determined to provide a power of 80%. However, due to lower recurrence rate, the trial was re-powered in the amendment 1999 to deem non-inferiority at an HR not exceeding 2.5 or 3.6 depending on the frequency of local recurrence. | |
| Statistical Test of Hypothesis | p-Value | 0.52 |
| Comments | The threshold for statistical significance was p=0.05. | |
| Method | Log Rank | |
| Comments | An overall p-value was calculated. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.38 | |
| Confidence Interval |
(2-Sided) 90% 0.06 to 2.56 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | SRT was used as reference group. Estimation described above is for SRT-delay. For LRT-delay HR (90% CI) was 1.22 with lower limit: 0.33, and upper limit: 3.45. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Three-arm Randomisation: SRT, Three-arm Randomisation: SRT-delay, Three-arm Randomisation: LRT-delay |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | In the initial protocol treatment groups were deemed non-inferior if the upper limit of a two-sided 90% CI for the hazard ratio did not exceed 1.7. With a cumulative incidence of local recurrence at 15%, a sample size of 840 participants were determined to provide a power of 80%. However, due to lower recurrence rate, the trial was re-powered in the amendment 1999 to deem non-inferiority at an HR not exceeding 2.5 or 3.6 depending on the frequency of local recurrence. | |
| Statistical Test of Hypothesis | p-Value | 0.92 |
| Comments | The threshold for statistical significance was p=0.05. | |
| Method | Log Rank | |
| Comments | An overall p-value was calculated. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.93 | |
| Confidence Interval |
(2-Sided) 95% 0.64 to 1.35 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | SRT was used as reference group (1.00). Estimation described above is for SRT-delay. For LRT-delay HR (95% CI) was 0.99 with lower limit: 0.68, and upper limit: 1.42. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Pooled Short-course RT: SRT, Pooled Short-course RT: SRT-delay |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | In the initial protocol treatment groups were deemed non-inferior if the upper limit of a two-sided 90% CI for the hazard ratio did not exceed 1.7. With a cumulative incidence of local recurrence at 15%, a sample size of 840 participants were determined to provide a power of 80%. However, due to lower recurrence rate, the trial was re-powered in the amendment 1999 to deem non-inferiority at an HR not exceeding 2.5 or 3.6 depending on the frequency of local recurrence. | |
| Statistical Test of Hypothesis | p-Value | 0.59 |
| Comments | The threshold for statistical significance was p=0.05. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.91 | |
| Confidence Interval |
(2-Sided) 90% 0.36 to 2.27 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | SRT was used as reference group (1.00). Estimation described above is for SRT-delay. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Pooled Short-course RT: SRT, Pooled Short-course RT: SRT-delay |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | In the initial protocol treatment groups were deemed non-inferior if the upper limit of a two-sided 90% CI for the hazard ratio did not exceed 1.7. With a cumulative incidence of local recurrence at 15%, a sample size of 840 participants were determined to provide a power of 80%. However, due to lower recurrence rate, the trial was re-powered in the amendment 1999 to deem non-inferiority at an HR not exceeding 2.5 or 3.6 depending on the frequency of local recurrence. | |
| Statistical Test of Hypothesis | p-Value | 0.39 |
| Comments | The threshold for statistical significance was p=0.05. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.90 | |
| Confidence Interval |
(2-Sided) 95% 0.69 to 1.18 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | SRT was used as reference group. Estimation described above is for SRT-delay. | |
| Title | Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time. |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants were analysed as treated and grouped based on type of preoperative radiotherapy (RT) and overall treatment time (OTT). |
| Arm/Group Title | Group A: Short-course RT and OTT 7 Days | Group B: Short-course RT and OTT 8-13 Days | Group C: Short-course RT and OTT 5-7 Weeks | Group D: Short-course RT and OTT 8-13 Weeks | Group E: Long-course RT and OTT 9-11 Weeks | Group F: Long-course RT and OTT 12-14 Weeks |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants treated with short-course preoperative radiotherapy (5x5 Gy) with overall treatment time of 7 days. | Participants treated with short-course preoperative radiotherapy (5x5 Gy) with overall treatment time of 8-13 days. | Participants treated with short-course preoperative radiotherapy (5x5 Gy) with overall treatment time of 5-7 weeks. | Participants treated with short-course preoperative radiotherapy (5x5 Gy) with overall treatment time of 8-13 weeks. | Participants treated with long-course preoperative radiotherapy (25x2 Gy) with overall treatment time 9 -11 weeks. | Participants treated with long-course preoperative radiotherapy (25x2 Gy) with overall treatment time 12 - 14 weeks. |
| Measure Participants | 100 | 247 | 192 | 160 | 52 | 59 |
| Overall postoperative complications |
45
34.9%
|
138
107.8%
|
82
64.1%
|
63
27.6%
|
16
7%
|
28
3.3%
|
| No postoperative complication |
55
42.6%
|
109
85.2%
|
110
85.9%
|
97
42.5%
|
36
15.9%
|
31
3.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Three-arm Randomisation: SRT, Three-arm Randomisation: SRT-delay |
|---|---|---|
| Comments | The association between postoperative complications and short-course RT by overall treatment time was assessed using logistic regression analysis. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.289 |
| Comments | The threshold of statistical significance was p=0.05. | |
| Method | Regression, Logistic | |
| Comments | Model was adjusted for sex, age over 75 years, type of surgery and ASA fitness grade. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.40 to 1.32 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Group B was used as the reference group. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Three-arm Randomisation: SRT-delay, Three-arm Randomisation: LRT-delay |
|---|---|---|
| Comments | The association between postoperative complications and short-course RT by overall treatment time was assessed using logistic regression analysis. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.009 |
| Comments | The threshold for statistical significance was p=0.05. | |
| Method | Regression, Logistic | |
| Comments | Model was adjusted for sex, age over 75 years, type of surgery and ASA fitness grade. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.5 | |
| Confidence Interval |
(2-Sided) 95% 0.30 to 0.84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Group B was used as the reference group. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Three-arm Randomisation: SRT-delay, Two-arm Randomisation: SRT |
|---|---|---|
| Comments | The association between postoperative complications and short-course RT by overall treatment time was assessed using logistic regression analysis. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | The threshold for statistical significance was p-value=0.05. | |
| Method | Regression, Logistic | |
| Comments | Model was adjusted for sex, age over 75 years, type of surgery and ASA fitness grade. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.39 | |
| Confidence Interval |
(2-Sided) 95% 0.23 to 0.65 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Group B was used as the reference group. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Two-arm Randomisation: SRT-delay, Pooled Short-course RT: SRT |
|---|---|---|
| Comments | The association between postoperative complications and long-course RT by overall treatment time was assessed using logistic regression analysis. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.521 |
| Comments | The threshold for statistical significance was p-value = 0.05. | |
| Method | Regression, Logistic | |
| Comments | Model was adjusted for sex, age over 75 years, type of surgery and ASA fitness grade. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.58 | |
| Confidence Interval |
(2-Sided) 95% 0.39 to 6.37 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Group E was used as the reference group. | |
| Title | Tumour Regression Based on the Dworak Grading Scoring System |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants grouped based on allocated treatment and analysed as-treated. Only participants with available microscopy slides were included in the analysis. |
| Arm/Group Title | Short-course RT: SRT | Short-course RT: SRT-delay | Long-course RT: LRT-delay |
|---|---|---|---|
| Arm/Group Description | Participants treated with short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants treated with short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Participants treated with long-course preoperative radiotherapy (25x5 Gy) and surgery after 4-8 weeks. |
| Measure Participants | 318 | 285 | 94 |
| TRG 0 |
29
22.5%
|
20
15.6%
|
4
3.1%
|
| TRG 1 |
233
180.6%
|
124
96.9%
|
42
32.8%
|
| TRG 2 |
50
38.8%
|
92
71.9%
|
37
28.9%
|
| TRG 3 |
2
1.6%
|
16
12.5%
|
7
5.5%
|
| TRG 4 |
4
3.1%
|
29
22.7%
|
3
2.3%
|
| Not assessable |
0
0%
|
4
3.1%
|
1
0.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Three-arm Randomisation: SRT, Three-arm Randomisation: SRT-delay, Three-arm Randomisation: LRT-delay |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.046 |
| Comments | The threshold for statistical significance was p=0.05. | |
| Method | Regression, Cox | |
| Comments | Model adjusted for age, sex and type of surgery. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.51 | |
| Confidence Interval |
(2-Sided) 95% 0.26 to 0.99 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | No pCR was used as reference group. | |
Adverse Events
| Time Frame | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Serious adverse events: Acute radiation-induced toxicity was not assessed in such manner that specific terms can be separated. | |||||||||
| Arm/Group Title | Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Pooled Short-course RT: SRT | Pooled Short-course RT: SRT-delay | |||||
| Arm/Group Description | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week. | Participants included in the three-armed randomisation and allocated to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks. | Participants included in the three-armed randomisation and allocated to long-course preoperative radiotherapy (25x5 Gy) and surgery after 4-8 weeks. | Participants assigned to short-course preoperative radiotherapy (5x5 Gy) and surgery within 1 week pooled from both three-armed and two-armed randomisation. | Participants assigned to short-course preoperative radiotherapy (5x5 Gy) and surgery after 4-8 weeks pooled from both three-armed and two-armed randomisation. | |||||
All Cause Mortality |
||||||||||
| Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Pooled Short-course RT: SRT | Pooled Short-course RT: SRT-delay | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 51/129 (39.5%) | 43/128 (33.6%) | 49/128 (38.3%) | 110/357 (30.8%) | 108/355 (30.4%) | |||||
Serious Adverse Events |
||||||||||
| Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Pooled Short-course RT: SRT | Pooled Short-course RT: SRT-delay | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/129 (0%) | 7/128 (5.5%) | 6/128 (4.7%) | 1/357 (0.3%) | 23/355 (6.5%) | |||||
| Gastrointestinal disorders | ||||||||||
| Acute radiation-induced toxicity | 0/129 (0%) | 7/128 (5.5%) | 6/128 (4.7%) | 1/357 (0.3%) | 23/355 (6.5%) | |||||
Other (Not Including Serious) Adverse Events |
||||||||||
| Three-arm Randomisation: SRT | Three-arm Randomisation: SRT-delay | Three-arm Randomisation: LRT-delay | Pooled Short-course RT: SRT | Pooled Short-course RT: SRT-delay | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 65/129 (50.4%) | 48/128 (37.5%) | 50/128 (39.1%) | 188/357 (52.7%) | 144/355 (40.6%) | |||||
| Surgical and medical procedures | ||||||||||
| Reoperation | 11/129 (8.5%) | 7/128 (5.5%) | 7/128 (5.5%) | 43/357 (12%) | 37/355 (10.4%) | |||||
| Any postoperative complication | 65/129 (50.4%) | 48/128 (37.5%) | 50/128 (39.1%) | 188/357 (52.7%) | 144/355 (40.6%) | |||||
| Any surgical complication | 40/129 (31%) | 33/128 (25.8%) | 30/128 (23.4%) | 128/357 (35.9%) | 100/355 (28.2%) | |||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Anna Martling |
|---|---|
| Organization | Karolinska Institutet |
| Phone | +46851770000 |
| anna.martling@ki.se |
Responsible Party:
Anna Martling,
Professor, Senior Consultant Surgeon,
Karolinska Institutet
ClinicalTrials.gov Identifier:
NCT00904813
Other Study ID Numbers:
- 98/240
First Posted:
May 20, 2009
Last Update Posted:
May 7, 2021
Last Verified:
Apr 1, 2021