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Rectal cancer Preoperative Radiotherapy- Short vs long course

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preoperative radiotherapy and chemotherapy in locally advanced cancer rectum, short course radiotherapy versus long course CTRT

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Rectal cancer Preoperative Radiotherapy- Short vs long course

  1. 1. Journal club Rectal Cancer: Preoperative Management Presenter: Dr. Gaurav Kumar
  2. 2. Introduction
  3. 3. Local Recurrence Following Surgery Alone: Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004
  4. 4. MDTSurgery Radiation Therapy Systemic Therapy Imaging Psychologist & Rehabilitation Need for Multidisciplinary approach
  5. 5. Pre-op RT vs. surgery alone Swedish Rectal Cancer Trial (NEJM 1997;336:980 ): 1168 patients randomised to 25 Gy (5x5) PRT or no RT. Surgery alone Preop. RT Rate of local recurrence 27% 11% p<0.001 5-year overall survival 48% 58% p=0.004 Dutch Colorectal Cancer Group (Kapiteijn E. NEJM 2001;345:638): 1861 patients randomised TME vs PRT+TME TME PRT+TME Recurrence rate 2.4% 8.2% OS ns ns
  6. 6. Pre-op vs. post-op Chemo RT Randomized trial of the German Rectal Cancer study Group (Sauer R et al. N Engl J Med 2004;351:1731-40): – cT3 or cT4 or node-positive rectal cancer – 50.4 Gy (1.8 Gy per day) – 5-FU: 1000 mg/m2 per day (d1-5) during 1. and 5. week Preop CRT Postop CRT Patients N=415 N=384 5 y. OS 76% 74% p=0.8 5 y. local relapse 6% 13% p=0.006 G3,4 toxic effects 27% 40% p=0.001 • Increase in sphincter-preserving surgery with preop Th.
  7. 7. MRC CR07/NCIC-CTG C016 (Sebag-Montefiore et al. 2009): 1350pt. with resectable rectal cancer randomized ▫ 25 Gy/5# + Surgery (TME) ▫ Surgery (TME) + (45 Gy & 5 FU) Preop RT Postop CRT 5 y. OS 80.8% 78.7% 5 y. local relapse 4.4% 10.6% DFS 79.5% 74.5% Pre-op RT vs. post-op Chemo RT cont.
  8. 8. Preop short course RT vs long course CTRT Polish Study (Br J Surg. 2006): 316 pts with resectable T3-4 rectal cancer, no sphincter involvement, tumor palpable on DRE (1999-2002). – RT  short-course RT with 5 Gy/d x 5 days + Surgery (TME) – CRT  50.4 Gy (1.8 Gy /# over 5.5 weeks) + bolus 5-FU 325 mg/m²/d + LV x 5 days 1st and 5th wks of RT + Surgery (TME) Preop SCRT Preop LCRT 5 y. OS 67.2% 66.2% 5 y. local relapse 9.0% 14.2% DFS 58.4% 55.6%
  9. 9. Trial details:
  10. 10. Material & methods  Registered under Clinical Trials.gov  Eligibility: Primary/locally recurrent rectal cancers cT4/palpably fixed cT3 Adenocarcinoma Age </= 75 years WHO PS </= 2 Fit for Surgery/Chemotherapy Written consent  Exclusion: M1 disease Medical comorbidities- Not fit for Sx/CT Peripheral neuropathy- As oxaliplatin is used
  11. 11. Material & methods cont.  Workup: Clinical history & examination Colonoscopy/Rectoscopy Pelvic MRI/CT Abdomen/Chest CT (or CXR) Blood counts/Clinical chemistry Study Groups  Group A: 5x5 Gy RT (week 1) 1 week gap Consolidation Chemotherapy with FOLFOX4 2 weekly x 3 4 - 5 weeks gap Surgery  Group B: Long course CTRT (RT- 50.4Gy/28# & CT- 5-FU+Leucovorin bolus week 1st and 5th of RT + Oxaliplatin weekly/5 cycles) 6 weeks gap Surgery 12 wks 12 wks
  12. 12. Chemotherapy details Group A: Cosolidation Chemotherapy 1st chemotherapy week 3 (RT- week 1, No concurrent) 2nd chemotherapy week 5 3rd chemotherapy week 7 Regimen: FOLFOX4 q2wkly Inj. Oxaliplatin @85 mg/m² D1 Inj. 5-FU400 mg/m² bolus D1,D2 & 600 mg/m² CI D1,2 Inj. Leucovorin 200 mg/m² D1,2 before 5-FU Group B: Cocurrent chemotherapy Week 1 & 5 of RT- Inj. 5-FU @ 325 mg/m² x 5 days (Bolus) Inj. Leucovorin @ 20 mg/m² x 5days (Bolus) Weekly with RT - Inj. Oxaliplatin @ 50 mg/m²
  13. 13. Radiotherapy details Group A: Short course RT 5 Gy x 5# (1 week) followed by consolidation CT Group B: Long course RT 50.4 Gy/28# (6 weeks) with concurrent Surgery details Both Groups: Resection attempted regardless of clinical response R1 – Cancer cells within 1 mm of Sx margin R2 – Pathological proof of cancer cells at Sx margin (Not mere perop finding) Postop complications defined – within 30 days of Sx Acute toxicity: NCI CTCAE v 3 scale Late toxicity: RTOG/EORTC scale (1 month after Sx)
  14. 14. Follow up: 3 monthly x 2years 6 monthly thereafter Follow up method: Physical examination Serum CEA Abdomen + Pelvic CT at 1 year & 2 year CT thorax/CXR at 1 year & 2 year * Routine MRI not mandatory for inclusion criteria * Oxaliplatin initially included in both groups based on a retrospective study published at that time but was left to physician discretion from 2012 (RCTs proved no benefit from oxaliplatin in preop RT setting) *Overall preoperative treatment time: </= 7 weeks for both groups
  15. 15. Statistics  Primary End point: R0 resection  Secondary End points: Overall survival DFS Locoregional failure rates Distant relapse rate pathological CR Acute & Late toxicities Postoperative complications Sample size calculation: Assumption that R0 rate after conventional CTRT to be 75% To detect 10 % benefit in R0 rates (significance level 0.05 and power 80 %) 540 participants
  16. 16. Stats cont.  Categorical variables compared : chi-square/Fischer exact/ Mann-whitney U- test  Survival : Kaplan Meier method  DFS : local/distant/death – whichever occurred earlier  Acute toxicity/ compliance measured as treatment progressed  Randomisation : By telephone to a data centre independent from investigator  Stratification : According to cT3/cT4/recurrent tumours Institution based *Statistician blinded to treatment group assigned * Accural : 2008-2014
  17. 17. Results
  18. 18. Acute toxicity/Adherence to treatment 5x5 Gy RT + CT n=256 (%) Long course CTRT n=259 (%) P-value Oxaliplatin use Yes No Preop CT not given 183 (72) 72 (28) 01 166 (64) 93 (36) 0.062 Grade of toxicity 0 1 2 3 4 Toxic deaths 65 (25) 72 (28) 57 (22) 49 (19) 10 (4) 03 (1) 45 (17) 59 (23) 94 (36) 42 (16) 12 (5) 07 (3) 0.006 Radiotherapy dose reduction 0 20 (8) <0.001 Radiotherapy time prolongation >/= 1 wk 0 12(5) <0.001
  19. 19. 5x5 Gy RT + CT n=256 (%) Long course CTRT n=259 (%) P-value Chemotherapy dose reduction Yes (Toxicity) Yes (Organizational/unknown cause) Yes (Cancer progression) No CT not given No data 51 (20) 05 (2) 01 (0.5) 197 (77.5) 1 1 66 (26) 05 (2) 0 188 (73) 0 0 0.15 Chemotherapy cycle delay, no dose reduction Yes (Toxicity) Yes (Organizational/unknown cause) No CT not given No data 43 (17) 13 (5) 198 (78) 1 1 NA - - - - - Radiotherapy +/- CT dose reduction/delay Yes No 95 (37) 161 (63) 87 (34) 172 (66) 0.4
  20. 20. Acute toxicity cont.  Median interval between start of RT & Surgery Group A: 12.4 weeks Group B: 12.4 weeks  Median overall time of preoperative treatment Group A: 6.6 weeks Group B: 5.5 weeks (p=<0.001)  Median interval between start of RT(5x5 Gy) and 1st consolidation chemotherapy = 9 days
  21. 21. Acute Toxicity profile Group A (5x5 Gy) (%) Group B (50.4 Gy/28#) (%) P-value Acute toxicity (Total) 75 83 0.006 Acute toxicity (Grade III-IV) 23 21 Diarrhoea low high 0.001 Neutropenia high low 0.032 Neutropenic fever 2 3 NS Toxic deaths 2 5 0.09
  22. 22. Late toxicity Group A (5x5 Gy) (%) Group B (50.4 Gy/28#) (%) P-value Late complications Death due to complication Grade 3-4 Grade 1-2 No complication No data NA (R2, LR, Tumor not resected, P/o deaths) 1 (0.5) 15 (8) 19 (11) 143 (80) 5 78 2 (1) 10 (6) 25 (15) 135 (79) 7 75 0.54 Death In patient with cancer From treatment complication From inter-current illness Unknown cause 64 (25) 52 6 4 2 84 (33) 67 13 2 2
  23. 23. Oncological outcome Group A (5x5 Gy) (%) Group B (50.4 Gy/28#) (%) Locoregional status No tumor resection/R2 resection Pelvic recurrence after R0/R1 Locoregional control No data (LFU) 42 (16) 35 (13) 184 (70) 0 54 (22) 18 (7) 179 (71) 3 Distant metastasis Yes [as firs event] No No data (LFU) 75 (29) [60(23)] 186 (71) 0 62 (25) [58 (23)] 189 (75)
  24. 24. Overall Survival
  25. 25. Cumulative Local failure
  26. 26. Oncological outcome cont. Group A (5x5 Gy) (%) Group B (50.4 Gy/28#) (%) P-value Overall Survival (3 years) 73 65 0.046 DFS (3 years) 53 52 NS Cumulative local failure (3 years) 22 21 0.82 Cumulative distant failure (3 years) 30 27 0.25 Radical rescue surgery (Combined for local & distant failure) 6 5 NS
  27. 27. Surgery & Pathology
  28. 28. Group A (5x5 Gy) N=261 (%) Group B (50.4 Gy/28#) N=254 (%) P-value Postoperative Complication Postoperative deaths (30 days) Anastomotic dehisence (Re-Surgery required) Other complications (Re-Surgery required) Treated conservatively No complications No data NA (Tumor not resected) 0 13 (6) 18 (8) 31 (15) 152 (71) 6 41 4 8 (4) 14 (7) 23 (12) 148 (75) 7 49 0.18 Surgery & Pathology cont.
  29. 29. Surgery & Pathology cont.
  30. 30. Surgery & Pathology cont.
  31. 31. Discussion
  32. 32. Short course RT + CT Long course CTRT R0 resection rate DFS Local failure rate Distant metastasis rate Postoperative complication Late complication Overall survival No difference between the groups Better in short course preop RT
  33. 33. Six key results of the study in favour of Short course RT with consolidation chemotherapy  Improved patient survival  Lower toxicity  Greater convenience  Lower cost  Patient preference  Logistic advantage for high burden centre
  34. 34.  Similar distant& local failures in both groups Survival with recurrences higher in Short course group (OS higher) Hypothesis: Long lasting Antitumor immune response activated due to large fraction size of RT ▪ Low rate of acute preop toxicity in short course group Reason: Sequential RT & CT in short course, so overlapping toxicity low More flexibility in short course with chemotherapy delivery
  35. 35. Limitations of the study  5-FU bolus used instead of continuous infusion/capecitabine (standard of care) * 2 RCTs have proven equal efficacy of bolus and continuous infusion 5-FU in P/O RT  Lack of MRI for staging purpose * Economic reasons & long waiting list  Short follow up  Imbalance of oxaliplatin use in two groups * difference of imbalance however is only 4%
  36. 36. Related articles
  37. 37. No difference in OS, RFS, Distant recurrences and late toxicity between short course and long course
  38. 38. Equivalent tumor down staging in short course if surgery delayed to 4-8 weeks
  39. 39. No difference in Local control/OS/ Short term QOL between short and long course RT
  40. 40. Long term health related QOL similar in short course vs long course RT groups
  41. 41. Thank You
  42. 42. The German Study: A Shifting Concept
  43. 43. German study cont.
  44. 44. German trial cont. 10 - Year Radiotherapy + Sx Surgery P Local recurrence 5% 11% < 0.0001 Overall Survival 48% 49% 0.86 Cancer specific deaths 17% 22% 0.04

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