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Preoperative versus postoperative chemoradiotherapy for rectal cancer

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JOURNAL CLUB
GERMAN RECTAL CANCER TRIAL

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Preoperative versus postoperative chemoradiotherapy for rectal cancer

  1. 1. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group Volume 351:1731-1740 October 2004 GERMAN RECTAL CANCER TRIAL
  2. 2. HOW WE DISCUSS ANY CLINICAL TRIAL • BACKGROUND • RATIONALE • AIM • OBJECTIVES:ENDPOINTS • TRIAL METHODOLOGY • RESULTS • CONCLUSION • DISCUSSION
  3. 3. BACKGROUND OF THE STUDY In Rectal Cancer
  4. 4. LR following non TME Surgery averages approx. 25-30%
  5. 5. Total Mesorectal Excision (TME): Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004
  6. 6. ADJUVANT THERAPY Chemotherapy Radiation therapy CTRTRT alone
  7. 7. Adjuvant Chemoradiation Therapy Study Description Outcome GITSG (1988) Gastrointenstinal study group 4 arm trial S/S+RT/S+CT/S+CRT 227 patients B2 , 10 yr OS 45 % vs 27%,LRR 10% vs 25% Significant benefit with CRT NCCTG 79-47-51 (NEJM 1991) Stage II –III RT alone or CRT (5FUX2> 5FU +RT> 5FUX2) (50% APR) 5-yr LR 14% (CRT) vs 25% 5-yr DM 29% vs 46% 5-yr OS 55% vs 45% NSABP R-01(1988) 3 arm RCT 500 patientsPT3/T4N+ S/S+CT/S+RT S+CT: Improved DFS& OS S+RT: Reduction in LRR 16% vs 25 % favouring RT No survival benefit NSABP -02 (1999) 2 arm RCT Postop CT (5FU or MOF) postop CRT PORT : no benefit on DFS or OS, reduced the at 5 yr-LRR (13% to 8%) (P = .02). Post-op CT: benefit in DFS at 5 yr (55% vs 47%; P = .009), 5-year OS (65% vs 62%; P = .17).
  8. 8. Postoperative Treatment In Rectal Cancer 1990 NIH Consensus Statement: • Combined postoperative chemotherapy and radiation improves local control and survival in patients with stage II and III rectal cancer and is recommended
  9. 9. Preoperative treatment Preoperative RT alone Pre-operative chemoradiotherapy
  10. 10. Preoperative approach  Pre-operative RT : rationale o Tumour downstaging and improve resection, o Better tolerance than postoperative RT o Sphincter preservation
  11. 11. Short Course Preoperative Radiotherapy
  12. 12. Preoperative chemo-RT Rationale  improved compliance of preop RT  Reduced toxicity of Preop chemo-RT than post op  RT more effective pre op due to oxygenation  Tumour downstaging and improve resection,  Sphincter preservation  Reduced local recurrence  survival benefit
  13. 13. Preoperative chemoradiotherapy Trial N (pt.) Randomisation Median F/U LR OS French study cT3-4 cN+ 733 Pre op CRT 45 Gy + 5FU & LV f/b Sx Preop RT f/b Sx - 5yr 8.1% Vs 16.5% P - 0.048 5yr NSS EORTC 22921 4arm study 1011 1.Pre op RT Sx+/- CT 2. Pre op CRTSx +/-CT 10.4 Yrs (7.8- 13.1) 10yrs 22.4% vs 11.8% vs 14.5% vs 11.7% P –0.0017 10yr 49%vs 50.7%vs 51.8%vs 48.4% P – 0.91 Sauer R et al. German CAO/ARO/AIO-94 JCO 2012 Bosset J et.al. EORTC 22921 Lancet Oncol 2014
  14. 14. Aim of the study • To compare preoperative chemoradiotherapy with postoperative chemoradiotherapy for the management of locally advanced rectal cancer
  15. 15. OBJECTIVE ENDPOINTS • Primary endpoints of the study are  5-year overall-survival,  Local control  distant control • secondary endpoints include  rate of curative (R0) resections  sphincter saving procedures  toxicity of radio chemotherapy  surgical complications  quality of life.
  16. 16. Trial Methodology • Enrolled patients February 1995 - September 2002. Eligibility criteria • Histopathologically confirmed, resectable adenocarcinoma with the inferior margin within 16 cm from the anal verge.  ERUS(endorectal USG) and CT scan of the abdomen and pelvis were performed to rule out TNM stage I tumors and distant metastases. Exclusion criteria: • Age > 75 years of age. • Previously had cancer other than nonmelanoma skin cancer. • Previously received chemotherapy. • Previously received Pelvic radiotherapy • Contraindications to chemoradiotherapy.
  17. 17. Randomization • After written informed consent had been obtained, eligible patients were randomly assigned to receive either postop CTRT or preop CTRT • Randomization was performed by the study center in Erlangen, Germany with stratification according to Surgeon. • Beginning in October 1998, prerandomization according to the double- consent design of Zelen was permitted at the request of 16 of the 26 participating centers.
  18. 18. According to this design, informed consent is sought after the patient is told the result of randomization that is whether pt. is in control group or intervention group and, as suggested by the term “double,” the result of randomization is disclosed to patients in both groups. According to this design, data must be analysed according to the result of randomization and any decisions made by patients to receive the alternative treatment must be disregarded with respect to the analysis ARM1:Post-op chemo-RT ARM2:Pre-op chemo-RT
  19. 19. Arm 1:Post-op chemo-RT Arm 2:Pre-op chemo-RT
  20. 20. RADIATION THERAPY Technique:  Three or 4-field box technique.  Include the entire tumor bed, the perirectal, presacral and the internal iliac nodal groups.  superior border: L5/S1 junction.  Inferior border: bottom of the obturator foramen after LAR or includes the perineal scar after APR resection.  Anteriorly: dorsal wall of the bladder  Posteriorly: the sacrum has to be included.  The lateral margins : 1–2 cm lateral of the linea terminalis. Dose:  ARM A:POST-OP RT: 50.4Gy/28# @1.8Gy/#,5#/week. To pelvis.+5.4Gy/3# boost to tumour bed  ARM B:PREOP RT :50.40 Gy/28# @1.8Gy/#,5#/week. to pelvis
  21. 21. CHEMOTHERAPY ADJUVANT CHEMOTHERAPY • Four cycles of bolus 5FU (500mg/m2 /day, 5d/week, every 4wks) were started 4 weeks after surgery in preop ARM B or 4weeks after post-op Chemo-rt in ARM A CONCURRENT CHEMOTHERAPY • During the first and fifth weeks of radiotherapy, 5FU was given as a 120-hour continuous infusion at a dose of 1000 mg per square meter per day
  22. 22. SURGERY • Total mesorectal excision(TME) was performed in all the patients according to a standardized technique. • To rule out potential bias with respect to the quality of surgery and the commitment to sphincter preservation, patients were stratified according to surgeon • Assessment of the intended surgical procedure before randomization (i.e., whether sphincter preservation was deemed possible or not) was included to evaluate the efficacy of preoperative chemoradiotherapy in permitting sphincter- sparing surgery in patients with low-lying tumors.
  23. 23. FOLLOW-UP & ASSESSMENT OF TOXICITY • DURING THERAPY:  patients were monitored weekly for signs of acute toxic effects. • AFTER THERAPY:  Patients were followed at 3-month intervals for 2 years and then at 6- month intervals for 3 years.  long-term toxic effects were assessed at 1, 3 and 5-years. • FOR CHEMOTHERAPY  Acute and long-term toxic effects were graded according to a German classification system (correspond to WHO criteria). • FOR RADIOTHERAPY  RTOG and EORTC criteria for acute and late toxicity used
  24. 24. Statistical analysis: sample size calculation • The primary end point was overall survival. • The study was designed to have 80 percent power to detect an absolute difference of 10 % in 5-year OS rate, with a two-sided alpha level of 0.05. • The sample size required to detect this difference was 340 patients per group. • Because an estimated 15 percent dropout rate was expected, the enrolment period was extended to the end of September 2002, at which point 823 patients had been enrolled • Secondary end points were DFS, LR and DR, postoperative complications, acute and long-term toxic effects, and sphincter preservation. • All eligible and consenting patients were included in the analyses according to the intention-to-treat principle. • End points were measured beginning at the time of randomization.
  25. 25. Statistical test  Chi-square tests were used to compare proportions.  Survival anlysis were carried out by the K-M method.  The Kaplan-Meier survival curve is defined as the probability of surviving in a given length of time while considering time in many small intervals.  The Cox proportional-hazards model was used to calculate hazard ratios and 95 % CI.  Hazard ratio is measure of how often a particular event happens in one group compared to another group, over time  Intention to treat analysis  Once randomized always analysed  A two-sided P value ≤ 0.05 was considered to indicate statistical significance.
  26. 26. RESULTS First results were published after median Follow up of 45.8 months.
  27. 27. Significantly more patients in the preop chemo-RT group than in the postop chemo-RT group had tumours located 5 cm or less from the anal verge Most of baseline characteristics of 799 patients were similar in the two groups
  28. 28. 823 patients from 26 hospitals Randomisation 402 pts POST-OP CHEMORT421 pts PREOP CHEMORT 16 pts not included in analysis  5 pts withdrew consent  11 pts not meet inclusion 8 pts not included in analysis  4 pts withdrew consent  4 pts not meet inclusion 405 pts assigned & evaluated in pre op treatment group 394 pts assigned & evaluated in post op treatment group 9 pts requested a change in treatment group (signf) 19 patients requested a change in treatment group 415 pts treated according to the preoperative protocol 384 pts treated according to the postoperative protocol
  29. 29. COMPLIANCE TO TREAMENT • In the preoperative-treatment group, 92 percent received the prescribed radiotherapy and 89 percent completed preoperative chemoradiotherapy as planned. • In the postoperative-treatment group, 28 percent were excluded from receiving postoperative chemoradiotherapy according to the protocol specifications, either because of stage I disease (18 percent) or because of intraoperatively detected distant metastases or postoperative complications or death (10 percent).
  30. 30. PROTOCOL VIOLATION Protocol violations occurred more frequently in the postoperative-treatment group and were mainly due to patients’ refusal to receive radiotherapy or chemotherapy
  31. 31. Histopathological tumour staging • After preoperative chemoradiotherapy, there was a significant shift toward earlier TNM stages (P<0.001): • 8 percent of the patients in this group had a complete response, only 25 percent (as compared with 40 percent in the postoperative-treatment group) had positive lymph nodes (TNM stage III)
  32. 32. The rates of complete resection and sphincter sparing surgery did not differ between the group TYPE OF SURGERY
  33. 33. among 194 patients with tumours that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiotherapy
  34. 34. Postoperative morbidity did not differ significantly between the groups. • In-hospital mortality was 0.7 percent in the preoperative chemoradiotherapy group and 1.3 percent in the postoperative- treatment group P=0.41). • overall rate of postop complications:36 percent in the preoperative- treatment group and 34 percent in the post operative treatment group (P=0.68). • rate of anastomotic leakage 11 percent in the preoperative and 12 percent in the postoperative-treatment group (P=0.77). • rates of delayed sacral-wound healing 10 percent in the preoperative vs. 8 percent in the postoperative P=0.10 • postop bleeding 3 percent vs. 2 percent p=0.50 • Postop ileus 2 percent vs. 1 percent, respectively; P=0.26
  35. 35. Toxicity of chemoradiotherapy The overall rates of acute and long term side effects were lower with the preoperative than with the postoperative (27% vs 40%) especially with respect to acute and chronic diarrhea and the development of strictures at the anastomotic site.
  36. 36. Overall survival: HR for death 0.96 , 95 % CI OS at five years was 76 percent in the preoperative- treatment group and 74 percent in the postoperative- treatment group (P=0.80) OS among the 799 Patients Randomly Assigned to Preoperative or Postoperative Chemoradiotherapy, According to an Intention-to-Treat Analysis. Follow-up data were available for 781 patients.
  37. 37. DFS: HR 0.87 , 95 % CI 68 percent in the preoperative-treatment group and 65 percent in the postoperative-treatment group (P=0.32) verall Survival (Panel A) and Disease-free Survival (Panel B) among the 799 Patients Randomly Assigned to Preoperative or Postoperative Chemoradiotherapy, According to an Intention-to-Treat Analysis. Follow-up data were available for 781 patients. DFS among the 799 Patients Randomly Assigned to Preoperative or PostoperativeChemoradiotherapy, According to an Intention-to-Treat Analysis. Follow-up data were available for 781 patients.
  38. 38. Local recurrences The cumulative incidence of local recurrences at five years was 6 percent in the group assigned to preoperative chemoradiotherapy and 13 percent in the group assigned to postoperative chemoradiotherapy (P=0.006)
  39. 39. Distant recurrences The cumulative incidence of distant recurrences at five years was 36 percent in the preoperative-treatment group and 38 percent in the postoperative-treatment (P=0.84)
  40. 40. Update analysis- 11 years follow up J Clin Oncol 30, 2012
  41. 41. OS benefit: non significant The overall survival at 10 years in the intention-to-treat population was 59.6% (95% CI, 54.9% to 64.7%) in the preoperative arm and 59.9% (95% CI, 55.2% to 65.1%) in the postoperative arm (P=0.85)
  42. 42. Local Recurrence: significant
  43. 43. LR Preop CRT Post op CRT Post op:no CRT
  44. 44. Multivariate Cox regression analysis for local recurrence revealed that • incomplete local resection (R1) • not receiving CRT at all were significantly associated with a higher LR risk
  45. 45. Distant Recurrence: not significant
  46. 46. forest plot analysis showed increased HRs for local recurrences for almost all subgroups for patients actually treated with postoperative as compared with preoperative CRT with the strongest difference in patients who had surgery involving intersphincteric or APR
  47. 47. CONCLUSION • In conclusion, although no survival benefit was achieved with preoperative as compared with postoperative chemoradiotherapy, • Trial suggest that preoperative chemoradiotherapy is the preferred treatment for patients with locally advanced rectal cancer, given that it is associated with  superior overall compliance rate,  an improved rate of local control,  reduced toxicity,  increased rate of sphincter preservation in patients with low-lying tumors.
  48. 48. DISCUSSION
  49. 49. COMPLIMENT • RCT comparing preop chemoradiotherapy with that of postoperative chemort for rectal cancer were initiated in the United States by the RTOG (trial 94-01) and the NSABP(protocol R-03). • Unfortunately, both studies suffered from low enrolment and were closed prematurely. • preop chemoradiotherapy, given as planned (i.e., without any modification or dose reduction) in most of the patients assigned to this group (89 percent), significantly reduced rates of local failure and acute and long- term toxic effects. • Among patients with tumors judged by the surgeon to require an abdominoperineal excision, the rate of sphincter-preserving surgery was more than doubled after preoperative chemoradiotherapy. • Postponing surgery for a six-week course of neoadjuvant treatment plus a six-week interval to allow tumor shrinkage and recovery from side effects did not result in an increased rate of surgical complications or an increased incidence of tumor progression.
  50. 50. Comment  With the increasing use of preoperative treatment in patients with rectal cancer, accurate staging is needed to avoid unnecessary treatment of early-stage tumors.  Our trial was designed to show an absolute difference of 10 percentage points in overall survival between standard postoperative and preoperative chemoradiotherapy. • However the results show no statistically significant difference in the incidence of distant recurrence or in the rates of disease-free or overall survival could be demonstrated. • Given that the rate of local recurrence with preoperative chemoradiotherapy and total mesorectal excision was only 6 percent, it is possible that further progress in the prevention of distant recurrences might be accomplished with more effective chemotherapy
  51. 51. Criticism: lack of data • The study reported by Sauer et al. is commendable in that it confirms the theoretical advantages of adding preoperative chemotherapy to preoperative radiotherapy for the treatment of rectal cancer. • However table 1 shows lack of proper data maintenance • The reason for this lack of data is unclear, especially since the enrolment criteria specifically include this measurement.
  52. 52. • in 75 patients distance of the tumor from the anal verge was unknown (may have included anal canal & sigmoid colon cancer) • in about one fourth of the patients,stage was unknown; • in about 7 percent, the nodal status was unknown. Criticism: lack of data
  53. 53. According to Table 2 92 percent and 89 percent of the patients assigned to preoperative chemoradiotherapy received full doses of radiotherapy and chemotherapy, respectively, as compared with 54 percent and 50 percent of the patients assigned to postoperative chemoradiotherapy. Criticism: protocol violation & compliance
  54. 54. Criticism: protocol violation & compliance • Results show that preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, significantly improves local control • However, the improved rate of local control achieved with the preoperative approach could have resulted from the higher percentage of patients in that group who received full doses of radiotherapy and chemotherapy • thus may not constitute clear evidence that the preoperative strategy reduces local failure. • This observation could be extended to other end points examined, considering that the authors found no statistically significant difference in the incidence of distant recurrences or in the rates of disease-free and overall survival between the two groups
  55. 55. Criticism: sphincter preservation • Sauer et al. conclude that preoperative chemoradiotherapy increases the rate of sphincter preservation. • However, the trial was not designed to address this issue. • The benefit with respect to sphincter preservation was found only in the subgroup of patients in whom abdominoperineal resection was deemed necessary. • There was no stratification according to this factor. • The analysis of sphincter preservation was performed not according to the intention-to-treat principle but according to the actual treatment given. • More patients in the postoperative-treatment group than in the preoperative- treatment group requested a change in their assigned treatment (19 patients vs. 9 patients, P=0.05). • This difference may explain, at least in part, the imbalance in the numbers of patients who underwent abdominoperineal resection (116 in the preoperative- treatment group and 78 in the postoperative-treatment group).
  56. 56. • The authors do not mention two randomized trials(EORTC & MRC ) designed to investigate whether shrinkage of tumors after preoperative radiotherapy, with or without chemotherapy, increases the rate of anterior resection in both, the difference in the rate of sphincter preservation was statistically nonsignificant • The surgeon's willingness to modify the operation in cases with tumor shrinkage is of pivotal importance in this respect.
  57. 57. Criticism: over treatment in stage 1 & 4  in the postoperative-chemoradiotherapy group 18% pt were found to have stage I disease, and about 10 percent were found intraoperatively to have distant metastases Because of the randomized assignment to treatment, it is reasonable to assume that there were similar percentages of patients with stage I and stage IV disease — patients who were not likely to derive any benefit from chemoradiotherapy — in the preoperative group were also treated  These pt. can be spared by unnecessary toxic effects if post op Chemo RT chosen
  58. 58. Traditionally, patients with stage I disease and patients with distant metastases have been considered ineligible for postoperative radiotherapy. The Swedish Rectal Cancer Trial, however, demonstrated that preoperative radiotherapy significantly improved local control even in patients with stage I rectal cancer. Preoperative radiotherapy may also be beneficial for patients with early-stage tumors within the lower part of the rectum when sphincter-preserving surgery is attempted. Likewise, for those with stage IV disease, survival times have been dramatically increased in recent years through the use of more effective systemic chemotherapy. Thus, sustained local control has become important in this group of patients too. Over treatment in stage 1 & 4:may be required
  59. 59. THANK YOU

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