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Radiotherapy before or after surgery improves survival in people with rectal cancer
TREATMENT
Radiotherapy before or after surgery improves survival in people with rectal cancer Abstracted from: Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet 2001; 358: 1291^1304.
BACKGROUND A large number of trials have examined e¡ects of adjuvant and neo-adjuvant radiotherapy in people with rectal cancer. Results of individual trials may be limited by low power or poor methods. Publication bias may also compromise reliability. Systematic review and meta-analysis of high-quality trials may yield more reliable evidence about pre- and post-operative radiotherapy in people with rectal cancer.
colonic cancer; were poorly randomized, or if co-interventions were di¡erent among groups.
OBJECTIVE To examine the e¡ectiveness of preand post-operative radiotherapy for reducing local recurrence risk and death from rectal cancer.
MAIN RESULTS Radiotherapy reduced overall annual mortality and annual cancer-related mortality compared with surgery alone (p=0.002 for overall annual mortality; absolute risk for cancer-related death in 1 year 45% with radiotherapy + surgery vs 50% with surgery alone, p=0.0003). Both pre-operative radiotherapy and post-operative radiotherapy reduced annual risk of local recurrence compared with surgery alone (see Tables 1^3; relative risk reduction for local recurrence 46% with pre-operative radiotherapy vs surgery alone, p=0.00001; relative risk reduction for local recurrence 37% with post-operative radiotherapy vs surgery alone, p=0.002). Pre-operative radiotherapy did not signi¢cantly improve rates of curative resection compared
METHOD Systematic review and meta-analysis. INCLUSION/EXCLUSION CRITERIA Twentytwo trials begun prior to 1987, with 8507 people were included.Trials were included if they adequately randomized participants with rectal cancer to either pre- or post-operative radiotherapy and no radiotherapy, with adequate concealment of allocation and no di¡erences in co-interventions among randomized groups. Trials were excluded if they examined e¡ects in people with Table 1 Rectal cancer recurrence rates with pre-operative radiotherapy and with surgery alone
ANALYSIS Comparisons between pre-operative radiotherapy, post-operative radiotherapy and no radiotherapy for rectal cancer. OUTCOMES Local tumor recurrence; death.
Table 2 Rectal cancer recurrence rates with post-operative radiotherapy and with surgery alone
Pre-operative radiotherapy %
Surgery alone %
Odds reduction %
Dukes’stage Stage A Stage B Stage C
4 10 13
11 20 28
64 53 58
Dukes’stage Stage A Stage B Stage C
Age group (years) o55 55 to 64 65 to 74 75+
15 7 9 10
24 16 23 19
50 60 63 49
Sex Men Women
9 11
20 22
58 55
Age Group (years) o55 55 to 64 65 to 74 75+ Sex Men Women
Radiotherapy schedule Short (5 days or less) Long (45 days)
8 13
21 20
64 39
Radiotherapy Schedule Short (5 days or less) Long (45 days)
1363- 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. Allrights reserved doi:10.1054/ebon.5, available online at http://www.idealibrary.com.on
Post-operative radiotherapy %
Surgery alone %
Odds reduction %
0 11 14
0 14 22
F 31 41
16 8 14 14
19 18 17 24
22 60 18 49
13 11
17 19
29 47
12
18
37
Evidence-based Oncology (2002) 3, 93^95
93
Table 3 Comparison of rectal cancer survival and recurrence rates with surgery alone or surgery plus pre- or post-operative radiotherapy Outcome
Surgery alone %
Surgery plus radiotherapy %
Absolute di¡erence %
p-value
Overall survival at 5 years 10-year survival Rectal cancer deaths at 5 years Non-rectal cancer deaths at 5 years Any recurrence at 5 years
42.1 25.3 51.9 14.6 52.9
2.9 1.6 8.3 3.3 (harm) 7
o 0.05 4 0.05 0.00002 0.001 o0.00001
Isolated local recurrence at 5 years
22.2
9.7
o0.00001
Any recurrence at 5 years
53.8
Isolated local recurrence at 5 years
22.9
45.0 26.9 43.6 17.9 45.9 (pre-operative) 12.5 (pre-operative) 50.3 (post-operative) 15.3 (post-operative)
3.5
0.1
7.6
0.0002
Note: Relative and absolute risks cannot be calculated since numbers on which percentages are based are not provided. 95% con¢dence intervals are in parentheses.
with no pre-operative radiotherapy (absolute risk for curative resection 85% with pre-operative radiotherapy vs 86% with no pre-operative radiotherapy). Trials examining e¡ects of pre-operative radiotherapy were heterogeneous. Heterogeneity was accounted for by di¡erent doses among trials. Subgroup analysis suggested that pre-operative radiotherapy doses had to be over 30 Gy to be e¡ective and were more e¡ective in younger, high-risk people. AUTHORS’ CONCLUSIONS Pre-operative radiotherapy (BED 30 Gy) reduces the risk of local cancer recurrence and death, especially for young, high-risk people. Short schedules seem at least as e¡ective as longer ones. Post-operative radiotherapy reduces local recurrence.
Commentary Several large trials have found that peri-operative radiotherapy improves outcomes in people with rectal cancer. However, much controversy has remained, in particular about the magnitude of benefit, about appropriate schedules and about benefits in different subgroups. The present systematic overview helps to clarify some of these questions. Most importantly, the review has found that preoperative radiotherapy reduces local failure rates and rectal cancer-related mortality in dose-dependent manner and that at comparable doses (BED 30 Gy) preoperative radiotherapy improves outcomes compared with postoperative therapy. Short preoperative schedules may reduce recurrence more than longer schedules (odds reduction for recurrence 64% with schedules 5 days vs 39% with schedules 45 days, significance not reported). However, the review found that mortality unrelated to rectal cancer increased in the first year following radiotherapy, particularly with high-dose radiotherapy (BED 37.5 Gy) to large tissue volumes. Overall survival was, therefore, only marginally
94
Evidence-based Oncology (2002) 3, 93^95
METHOD NOTES Individual trials were too short to rule out a long-term overall survival bene¢t, particularly since radiotherapy doses were inadequate in many cases. Sources of funding: Imperial Cancer Research and the European Biomed Programme; University of Birmingham Clinical Trials; Clinical Trial Service Unit atthe University of Oxford. Correspondence to: CCCG Secretariat, University of Birmingham Clinical Trials Unit, Park Grange, 1 Somerset Road, Edgbaston, Birmingham, B152RR, UK.
prolonged in preoperative trials examining doses greater than BED 30 Gy. The relevance of appropriate radiotherapy techniques was emphasized in the report. The review gives no information about the relative effects of the three most commonly used strategies: preoperative radiotherapy over one week (Swedish 5 5 Gy schedule); preoperative radiotherapy over 5 weeks with or without postoperative chemotherapy, or postoperative radiochemotherapy over 5 weeks together with chemotherapy for 6 months in people with stages II and III disease. It was previously claimed that only postoperative radiochemotherapy improved survival, but the results of this review and a previous one based only upon published data,1 suggest that benefits may extend to preoperative radiotherapy. Similarly, the study does not examine effects of combining radio(chemo)therapy with more modern surgical techniques, such as total mesorectal excision, which has improved failure rates and may improve survival compared with the type of surgery used in trials initiated prior to 1987. One trial examining effects of radiotherapy prior to total mesorectal excision has
recently found that the combination reduced local failure rates compared with standard surgical techniques (absolute risk of local failure after 5 5 Gy preoperatively 8.2% vs 2.4% at 2 years; relative risk reduction 71%, po0.001).2 More extensive surgery such as total mesorectal excision may reduce the number and size of tumor cell deposits to be targeted by radiotherapy.3 In common with findings from other studies, combining total mesorectal surgery with radiotherapy did not increase postoperative mortality, suggesting that appropriate radiation techniques do not increase the risk of early rectal cancer-unrelated deaths. This meta-analysis, the findings of the total mesorectal excision trial and the NSABP-R02 trial4 have influenced the standard of care at many sites worldwide. It is not possible to judge the relative importance of the meta-analysis alone for this change. The NSABP-R02 trial found that the radiotherapy component of postoperative radiochemotherapy was not of importance for the survival gain, although it decreased local failure rates by 43% (from 14% to 8%, p=0.02). Bengt Glimelius, MD, PhD University Hospital, Uppsala and Radiumhemmet, Stockholm, Sweden
Literature cited 1. Camma C,Giunta M, Fiorica F, Pagliaro L,Craxi A,Cottone M. Preoperative radiotherapy for respectable rectal cancer: a meta-analysis. JAMA 2000; 284: 1008 ^1015. 2. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, WiggersT, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, Leer JW, van deVelde CJ. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638 ^ 466. 3. Glimelius B, Isacsson U. Preoperative radiotherapy for rectal cancer^ is 5 5 Gy a good or a bad schedule? Acta Oncol 2001; 40: 958 ^967. 4. Wolmark N, Wieand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, Wexler M, Prager D, Cruz AB Jr, Gordon PH, Petrelli NJ, Deutsch M, Mamounas E,Wickerham DL, Fisher ER, Rockette H, Fisher B.Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R- 02. J Natl Cancer Inst 2000; 92: 388 ^396. Level and Quality of Evidence (seeTable): 1b
Evidence-based Oncology (2002) 3, 93^95
95
Radiotherapy before or after surgery improves survival in people with rectal cancer Abstracted from: Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet 2001; 358: 1291^1304.
BACKGROUND A large number of trials have examined e¡ects of adjuvant and neo-adjuvant radiotherapy in people with rectal cancer. Results of individual trials may be limited by low power or poor methods. Publication bias may also compromise reliability. Systematic review and meta-analysis of high-quality trials may yield more reliable evidence about pre- and post-operative radiotherapy in people with rectal cancer.
colonic cancer; were poorly randomized, or if co-interventions were di¡erent among groups.
OBJECTIVE To examine the e¡ectiveness of preand post-operative radiotherapy for reducing local recurrence risk and death from rectal cancer.
MAIN RESULTS Radiotherapy reduced overall annual mortality and annual cancer-related mortality compared with surgery alone (p=0.002 for overall annual mortality; absolute risk for cancer-related death in 1 year 45% with radiotherapy + surgery vs 50% with surgery alone, p=0.0003). Both pre-operative radiotherapy and post-operative radiotherapy reduced annual risk of local recurrence compared with surgery alone (see Tables 1^3; relative risk reduction for local recurrence 46% with pre-operative radiotherapy vs surgery alone, p=0.00001; relative risk reduction for local recurrence 37% with post-operative radiotherapy vs surgery alone, p=0.002). Pre-operative radiotherapy did not signi¢cantly improve rates of curative resection compared
METHOD Systematic review and meta-analysis. INCLUSION/EXCLUSION CRITERIA Twentytwo trials begun prior to 1987, with 8507 people were included.Trials were included if they adequately randomized participants with rectal cancer to either pre- or post-operative radiotherapy and no radiotherapy, with adequate concealment of allocation and no di¡erences in co-interventions among randomized groups. Trials were excluded if they examined e¡ects in people with Table 1 Rectal cancer recurrence rates with pre-operative radiotherapy and with surgery alone
ANALYSIS Comparisons between pre-operative radiotherapy, post-operative radiotherapy and no radiotherapy for rectal cancer. OUTCOMES Local tumor recurrence; death.
Table 2 Rectal cancer recurrence rates with post-operative radiotherapy and with surgery alone
Pre-operative radiotherapy %
Surgery alone %
Odds reduction %
Dukes’stage Stage A Stage B Stage C
4 10 13
11 20 28
64 53 58
Dukes’stage Stage A Stage B Stage C
Age group (years) o55 55 to 64 65 to 74 75+
15 7 9 10
24 16 23 19
50 60 63 49
Sex Men Women
9 11
20 22
58 55
Age Group (years) o55 55 to 64 65 to 74 75+ Sex Men Women
Radiotherapy schedule Short (5 days or less) Long (45 days)
8 13
21 20
64 39
Radiotherapy Schedule Short (5 days or less) Long (45 days)
1363- 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. Allrights reserved doi:10.1054/ebon.5, available online at http://www.idealibrary.com.on
Post-operative radiotherapy %
Surgery alone %
Odds reduction %
0 11 14
0 14 22
F 31 41
16 8 14 14
19 18 17 24
22 60 18 49
13 11
17 19
29 47
12
18
37
Evidence-based Oncology (2002) 3, 93^95
93
Table 3 Comparison of rectal cancer survival and recurrence rates with surgery alone or surgery plus pre- or post-operative radiotherapy Outcome
Surgery alone %
Surgery plus radiotherapy %
Absolute di¡erence %
p-value
Overall survival at 5 years 10-year survival Rectal cancer deaths at 5 years Non-rectal cancer deaths at 5 years Any recurrence at 5 years
42.1 25.3 51.9 14.6 52.9
2.9 1.6 8.3 3.3 (harm) 7
o 0.05 4 0.05 0.00002 0.001 o0.00001
Isolated local recurrence at 5 years
22.2
9.7
o0.00001
Any recurrence at 5 years
53.8
Isolated local recurrence at 5 years
22.9
45.0 26.9 43.6 17.9 45.9 (pre-operative) 12.5 (pre-operative) 50.3 (post-operative) 15.3 (post-operative)
3.5
0.1
7.6
0.0002
Note: Relative and absolute risks cannot be calculated since numbers on which percentages are based are not provided. 95% con¢dence intervals are in parentheses.
with no pre-operative radiotherapy (absolute risk for curative resection 85% with pre-operative radiotherapy vs 86% with no pre-operative radiotherapy). Trials examining e¡ects of pre-operative radiotherapy were heterogeneous. Heterogeneity was accounted for by di¡erent doses among trials. Subgroup analysis suggested that pre-operative radiotherapy doses had to be over 30 Gy to be e¡ective and were more e¡ective in younger, high-risk people. AUTHORS’ CONCLUSIONS Pre-operative radiotherapy (BED 30 Gy) reduces the risk of local cancer recurrence and death, especially for young, high-risk people. Short schedules seem at least as e¡ective as longer ones. Post-operative radiotherapy reduces local recurrence.
Commentary Several large trials have found that peri-operative radiotherapy improves outcomes in people with rectal cancer. However, much controversy has remained, in particular about the magnitude of benefit, about appropriate schedules and about benefits in different subgroups. The present systematic overview helps to clarify some of these questions. Most importantly, the review has found that preoperative radiotherapy reduces local failure rates and rectal cancer-related mortality in dose-dependent manner and that at comparable doses (BED 30 Gy) preoperative radiotherapy improves outcomes compared with postoperative therapy. Short preoperative schedules may reduce recurrence more than longer schedules (odds reduction for recurrence 64% with schedules 5 days vs 39% with schedules 45 days, significance not reported). However, the review found that mortality unrelated to rectal cancer increased in the first year following radiotherapy, particularly with high-dose radiotherapy (BED 37.5 Gy) to large tissue volumes. Overall survival was, therefore, only marginally
94
Evidence-based Oncology (2002) 3, 93^95
METHOD NOTES Individual trials were too short to rule out a long-term overall survival bene¢t, particularly since radiotherapy doses were inadequate in many cases. Sources of funding: Imperial Cancer Research and the European Biomed Programme; University of Birmingham Clinical Trials; Clinical Trial Service Unit atthe University of Oxford. Correspondence to: CCCG Secretariat, University of Birmingham Clinical Trials Unit, Park Grange, 1 Somerset Road, Edgbaston, Birmingham, B152RR, UK.
prolonged in preoperative trials examining doses greater than BED 30 Gy. The relevance of appropriate radiotherapy techniques was emphasized in the report. The review gives no information about the relative effects of the three most commonly used strategies: preoperative radiotherapy over one week (Swedish 5 5 Gy schedule); preoperative radiotherapy over 5 weeks with or without postoperative chemotherapy, or postoperative radiochemotherapy over 5 weeks together with chemotherapy for 6 months in people with stages II and III disease. It was previously claimed that only postoperative radiochemotherapy improved survival, but the results of this review and a previous one based only upon published data,1 suggest that benefits may extend to preoperative radiotherapy. Similarly, the study does not examine effects of combining radio(chemo)therapy with more modern surgical techniques, such as total mesorectal excision, which has improved failure rates and may improve survival compared with the type of surgery used in trials initiated prior to 1987. One trial examining effects of radiotherapy prior to total mesorectal excision has
recently found that the combination reduced local failure rates compared with standard surgical techniques (absolute risk of local failure after 5 5 Gy preoperatively 8.2% vs 2.4% at 2 years; relative risk reduction 71%, po0.001).2 More extensive surgery such as total mesorectal excision may reduce the number and size of tumor cell deposits to be targeted by radiotherapy.3 In common with findings from other studies, combining total mesorectal surgery with radiotherapy did not increase postoperative mortality, suggesting that appropriate radiation techniques do not increase the risk of early rectal cancer-unrelated deaths. This meta-analysis, the findings of the total mesorectal excision trial and the NSABP-R02 trial4 have influenced the standard of care at many sites worldwide. It is not possible to judge the relative importance of the meta-analysis alone for this change. The NSABP-R02 trial found that the radiotherapy component of postoperative radiochemotherapy was not of importance for the survival gain, although it decreased local failure rates by 43% (from 14% to 8%, p=0.02). Bengt Glimelius, MD, PhD University Hospital, Uppsala and Radiumhemmet, Stockholm, Sweden
Literature cited 1. Camma C,Giunta M, Fiorica F, Pagliaro L,Craxi A,Cottone M. Preoperative radiotherapy for respectable rectal cancer: a meta-analysis. JAMA 2000; 284: 1008 ^1015. 2. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, WiggersT, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, Leer JW, van deVelde CJ. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638 ^ 466. 3. Glimelius B, Isacsson U. Preoperative radiotherapy for rectal cancer^ is 5 5 Gy a good or a bad schedule? Acta Oncol 2001; 40: 958 ^967. 4. Wolmark N, Wieand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, Wexler M, Prager D, Cruz AB Jr, Gordon PH, Petrelli NJ, Deutsch M, Mamounas E,Wickerham DL, Fisher ER, Rockette H, Fisher B.Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R- 02. J Natl Cancer Inst 2000; 92: 388 ^396. Level and Quality of Evidence (seeTable): 1b
Evidence-based Oncology (2002) 3, 93^95
95