RAPIDO Trial

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomized, open-label, phase 3 trial

1. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomized, open-label, phase 3 trial MBBS (SIMS, Gold medalist), BSc, MRCPS (Glasgow), MRCS (Edinburgh), FCPS (Surgery), FCPS (Surgical Oncology), European Board (FEBS Surgical Oncology), FICS (General Surgery), FICS (Surgical Oncology), Associate FACS (General Surgery). Fellowship in Surgical Oncology (Shaukat Khanum Memorial Cancer Hospital, Lahore) JIBRAN MOHSIN Surgical Oncologist / Assistant Professor of Surgery (Akhtar Saeed Medical & Dental College, Lahore)

2. R ectal cancer A nd P reoperative I nduction therapy followed by D edicated O peration (RAPIDO) trial Lancet Oncol 2020 (7 th December ) Impact factor 41.316 5 th among 242 journal s in oncology globally ( 2020  Journal Citation Reports ® , Clarivate 2021) 184 Citations

3. Abbreviations CCR Complete Clinical Response MRI Magnetic Resonant Imaging CRM Circumferential Resection Margins PCR Pathological Complete Response CRT Chemoradiotherapy PME Partial Mesorectal Excision ECOG Eastern Cooperative Oncology Group RT Radiotherapy EMVI Extramural Vascular Invasion SCRT Short Course Radiotherapy LARC Locally Advanced Rectal Cancer TME Total Mesorectal Excision LNs Lymph Nodes TNM Tumor –Node- Metastases LRR Locoregional Recurrence TNT Total Neoadjuvant Therapy MRF Mesorectal Fascia

4. Outline Introduction Methods Study design and participants Randomization and masking Procedures Outcomes Statistical analysis Registration and Funding Results Discussion Conclusion Critical Appraisal

5. Introduction Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, RAPIDO trial aimed to reduce distant metastases without compromising locoregional control.

6. Introduction Standard of care (LARC): CRT  TME (6-8 W)  ± Adjuvant Chemo CRT: Improved locoregional control (LRR 5-9 %) 1,2 Unchanged distant metastases Stockholm III trial 3 SCRT (downstaging)  Delayed Surgery Adjuvant Chemotherapy 2,4,5 Inconclusive evidence Intent: Reduce systemic relapses Suboptimal compliance Braendengen M, Tveit KM, Berglund A, et al. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 2008; 26: 3687–94. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23. Erlandsson J, Holm T, Pettersson D, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre , randomised , non-blinded, phase 3, non-inferiority trial. Lancet Oncol 2017; 18: 336–46. Gerard J-P, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24: 4620–25. Breugom AJ, van Gijn W, Muller EW, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo) radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol 2015; 26: 696–701.

7. Introduction Surgery Safely delayed after SCRT Window for preoperative chemotherapy (increased compliance) 6,7 Hypothesis: Decreased distant metastases (Preop chemo) No increased risk of locoregional failure (SCRT) Improved Survival Outcome 6. Radu C, Berglund A, Pahlman L, Glimelius B. Short-course preoperative radiotherapy with delayed surgery in rectal cancer - a retrospective study. Radiother Oncol 2008; 87: 343–49. 7. Nilsson PJ, van Etten B, Hospers GAP, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer 2013; 1 3: 279.

8. Introduction Dutch M1-trial 8 Metastatic primary rectal cancer SCRT  6 x (Capecitabine, Oxaliplatin, Bevacizumab)  Surgery (6-8 W) 84 % Compliance 47 % Downstaging 26 % PCR Similar reports form Sweden 6 6. Radu C, Berglund A, Pahlman L, Glimelius B. Short-course preoperative radiotherapy with delayed surgery in rectal cancer - a retrospective study. Radiother Oncol 2008; 87: 343–49. 8. van Dijk TH, Tamas K, Beukema JC, et al. Evaluation of short course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer. Ann Oncol 2013; 24: 1762–69.

9. Introduction Objective: To reduce disease-related treatment failure at 3 years Data on Compliance, toxicity and postoperative complications Previously published 9 Primary endpoint after median follow-up of 4.6 years Published in this article 9. van der Valk MJM, Marijnen CAM, van Etten B, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75–83.

10. Methods Study Design Investigator-driven, multicentric, open label, randomized, controlled, phase 3 trial Settings 54 hospitals and radiotherapy centers in 7 countries Netherlands, Sweden, Spain, Slovenia, Denmark, Norway and USA Coordinated by Clinical Research Centre (Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands)

11. Methods Inclusion Criteria (Tumor) Biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma Distal extension < 16 cm from anal verge Pelvic MRI (≥ 1 high-risk criteria, TNM-5) 10 cT4a or cT4b cN2 EMVI Involved MRF (tumor/lymph node ≤ 1 mm) Enlarged lateral LNs (metastatic) 10. Valentini V, Aristei C, Glimelius B et al. Multidisciplinary rectal cancer management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol 2009; 92: 148–63.

12. Methods Inclusion Criteria (Patient) Age ≥ 18 years Mentally / Physically fit for chemotherapy (ECOG 0-1) Assessed for staging within 5 weeks before randomization Available for follow-up Written informed consent Comorbidities permitted Labs Hb: Clinically acceptable TLC ≥ 4 x 10 9 cells per L Platelets ≥ 100 x 10 9 per L Bilirubin < 35 µmol/L Renal clearance ≥ 50 mL/min

13. Methods Exclusion Criteria Extensive growth of rectal tumor (surgery never possible) cranial part of sacrum Lumbosacral nerve roots Metastatic or recurrent disease Watch-and-wait strategy (Surgery mandatory) Ethical considerations Good clinical practice guidelines Declaration of Helsinki Central evaluation: medical ethics committee of University Medical Centre Groningen (Netherlands) Participating centers: Boards of directors or local ethics committees

14. Methods Randomization Recruited at participating hospitals before start of any treatment Randomly assigned (1:1) : Experimental group vs standard of care group ProMISe data management system (version 4.0) Stratified and randomly varying block design Each block size randomly chosen to contain 2 to 4 allocations

15. Methods Stratification Institution ECOG Performance status (0 or 1) cT stage (cT2-cT3 or cT4) cN stage ( cN - or cN +) Masking Patients and clinical staff not masked (nature of intervention) All investigators (masked to treatment assignment for the primary endpoint until prespecified number of events reached)

16. Methods Procedures High-resolution 3D T2-weighted sequence MRI (before and after preoperative treatment) Minimal MRI reports features: Tumor height from anorectal junction Morphology of tumor Depth of extramural spread EMVI ± MRF involvement Breach of peritoneal reflection (extra) Mesorectal LN metastases ± (Next slide) Response to preoperative treatment (restaging)

17. Methods Metastatic Lymph Node Metastatic extramesorectal LN Mesorectal 11 Extra- mesorectal Short axis diameter Other Features > 10 mm Round shape + + 5-9 mm At least 2 of the following Round shape Irregular border Heterogenous MRI signal intensity + Irregular border or Heterogenous MRI signal intensity or both + 11. Brown G, Richards CJ, Bourne MW, et al. Morphologic predictors of lymph node status in rectal cancer with use of high-spatial resolution MR imaging with histopathologic comparison. Radiology 2003; 227: 371–77.

18. Experimental Group Standard of care Group Short-course radiotherapy 5 x 5 Gy max 8 days Radiotherapy 50.4 Gy (1.8 Gy x 28 daily fractions) 50.0 Gy (2.0 Gy x 25 fractions) Optional field reduction (last fractions to tumor bed): After 45 Gy (1.8 Gy schedule) or 46 Gy (2.0 Gy schedule) Methods

19. Experimental Group Standard of care Group Chemotherapy (Duration 18 W) Within at least 4 weeks (Preferably 11-18 days) after last radiotherapy fraction Regimens: 6 x CAPOX Capecitabine: 1000 mg/m 2 oral twice daily (days 1-14) Oxaliplatin: 130 mg/m 2 IV (day 1) Interval (days 15-21) 9 x FOLFOX4 Oxaliplatin: 85 mg/m 2 IV (day 1) Leucovorin ( folinic acid): 200 mg/m 2 IV (days 1 and 2) Fluorouracil: bolus (400 mg/m 2 IV) and infusion (600 mg/m 2 IV for 22 h) (days 1 and 2) Interval (days 3-14) Chemotherapy Capecitabine: 825 mg/m 2 oral twice daily (concomitant) Methods

20. Experimental Group Standard of care Group Surgery TME Principles After 2-4 weeks Surgery TME Principles After 6-10 weeks of last radiotherapy fraction Adjuvant Chemotherapy (center protocol) (within 6-8 W) 8 x CAPOX 12 x FOLFOX4 Methods

21. Methods Clinical Target Volume (RT) Entire mesorectum with primary tumor + relevant regional LNs Boost (optional) Assessable tumor with a 1 cm margin within same anatomical compartment as where tumor was located Toxicity CTCAE (Common Terminology Criteria for Adverse Events) version 4 ≥ 25 % dose reduction (previous cycle) Monitoring Experimental: before all cycles Standard of Care: weekly Post-operative Complications: Clavien - Dindo Classification 12 12. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: 205–13.

22. Methods Surgery TME Principles vs PME (proximal tumors) Open vs laparoscopic (surgeon choice) Pathological assessment Residual tumor classification 13 (completeness of resection) National guidelines (standardized workup and reporting) CRM ± Quality of sample/resection (APR – mesorectum + anal canal)(AR – mesorectum) Complete tumor response ± 13. Wittekind C, Compton C, Quirke P, et al. A uniform residual tumor (R) classification: integration of the R classification and the circumferential margin status. Cancer 2009; 115: 3483–88.

23. Methods Serious Adverse Event Any untoward medical occurrence or effect that at any dose results in death is life-threatening (at the time of the event); requires admission to hospital or extension of ongoing hospital stay; results in persistent or clinically significant disability or incapacity; is a congenital anomaly or birth defect; or is a new event of the trial likely to affect the safety of the participants, such as an unexpected outcome of an adverse reaction, lack of efficacy of a study drug used for the treatment of a life-threatening disease, and major safety finding from a newly completed animal study.

24. Methods Standardized , minimal follow-up schedule C linical assessments (including CEA) 6, 12, 24, 36, and 60 months Total colonoscopy (mandatory) within the first year (unless done preoperatively) 60 months (mandatory) CXR/US abdomen or CT thorax/abdomen (mandatory) 12 and 36 months (minimum). Other diagnostics (e.g., PET-CT) as indicated for recurrent disease

25. Methods Functional outcome and health-related quality of life (QoL) (PUBLISHED ELSEWHERE) Indication: No disease-related treatment failure event within 36 months after surgery (measured once) European Organization for Research and treatment of Cancer (EORTC) QoL questionnaires: QoL questionnaire for patients with cancer (QLQ-C30), QoL questionnaires for patients with colorectal cancer (QLQ-CR29; supplemented with questions related to sexual functioning from the prostate cancer [QLQ-PR25] and endometrial cancer [QLQ-EN24] modules) and QoL questionnaire to assess chemotherapy-induced peripheral neuropathy (QLQ-CIPN20). L ow anterior resection syndrome (LARS) scores 14 14. Bryant CLC, Lunniss PJ, Knowles CH, Thaha MA, Chan CLH. Anterior resection syndrome. Lancet Oncol 2012; 13: e403–08.

26. Methods Outcomes Primary endpoint = disease-related treatment failure (not centrally reviewed) Locoregional failure (1 st occurrence) Locally progressive disease leading to an unresectable tumor Local R2 resection Local recurrence after R0-R1 resection (CCR and W/W strategy locoregional regrowth  R0/R1 resection )(≠ locoregional regrowth) Distant metastasis, New primary colorectal tumor, or Treatment-related death.

27. Methods Reported elsewhere 9. van der Valk MJM, Marijnen CAM, van Etten B, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75–83. Outcomes Secondary endpoints Completion rate of neoadjuvant treatment , R0 resection rate (resection margin of >1 mm), Pathological complete response rate (no residual tumor at pathological assessment after surgery), Overall survival (time from randomization to death from any cause), and Locoregional failure / distant metastases (not protocolized) Toxicity*, 9 Surgical complications within 30 days*, 9 Functional outcome*, and Quality of life *.

28. Methods Changes to Protocol -1 Primary endpoint Disease-free Survival (DFS)  Disease-related treatment failure 1 year before end of inclusion period DFS: used for adjuvant treatment, Patients were not disease free at randomization and some will never become disease free Approved M edical ethics committee and DSMB – Data Safety Monitoring Board

29. Methods Changes to Protocol -2 Change in hypothesis Decrease in events from 50% to 40% to decrease in the probability of primary endpoint events from 30% to 22.5 % (experimental treatment) At Median follow-up > 3 years Lower than anticipated number of primary end point events and 452 required events never reachable Reasons Alteration of the endpoint (death due to other reasons and a new primary tumor, other than colorectal, are not events), A finite period of follow-up (statistical programs assume endless follow-up), and Possibly better overall outcomes than projected.

30. Methods (Statistical analyses) 3-year cumulative probability of reduction of primary endpoint events from 30% to 22.5% Hazard ratio (HR) = 0.715 2- sided log-rank test with 280 events would achieve 80% power 2- sided α significance level of 0.05 OS, locoregional failure and distant metastases (intention-to-treat) R0 resection, PCR (patients with resection) _________________________________________________________________________________ Surgical complications (curative intent surgery within 6 months) QoL (resection  no primary event  full response to questionnaire) Toxicity (all patients with allocated treatment)

31. Methods Statistical analyses IBM SPSS Statistics (version 25.0) Proportions: compared using the χ2 test Continuous data : Student’s t test or the Mann-Whitney U test (depending on distribution) Median values ( IQR) and means (SDs). R (version 3.6.1) for Survival analyses Kaplan-Meier method (intention-to-treat basis)

32. Methods . Statistical analyses Locoregional failure analyses : all patients with(out) distant metastases included Distant metastases analyses : all patients with(out) locoregional failure included Patients who were alive and disease free at last follow-up: censored . Median follow-up : calculated using R everse Kaplan-Meier method p values for all survival analyses : calculated on the basis of (cause specific) log-rank tests.

33. Methods Statistical analyses Sensitivity analyses effect of timing of disease staging (i.e., time-related bias), adjust for stratification factors, Hospital policy on adjuvant chemotherapy within the standard of care group Effect on the endpoints (disease-related treatment failure, distant metastases, and locoregional failure) Starting point for all analyses: date of randomization Significance threshold for all p values: 0.05

34. Methods Registration EudraCT (2010-023957-12) and ClinicalTrials.gov (NCT01558921) Role of the funding source Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network. Funders : no role in study design, data collection, data analysis, data interpretation, or writing of the report. C orresponding author : full access to all data and final responsibility for the decision to submit for publication.

35. Study Profile

36. Study Profile (Continued)

37. Baseline characteristics (eligible patients)

38. Baseline characteristics (eligible patients) Continued

39. Results Inclusion Period : June 21, 2011, and June 2, 2016 Database lock : 19 June 2020. Median follow-up: 4.6 years (IQR 3.5 – 5.5). Median time between randomization and surgery 25.5 weeks (IQR 24.0 – 27.9)  experimental group 15.9 weeks (14.6 – 17.6)  standard of care group.

40. Results Cumulative probability of disease-related treatment failure (3 years: 23.7 % vs 30.4 % )

41. Results Cumulative probability of distant metastases (3 years: 20.0 % vs 26.8 % )

42. Results Cumulative probability of locoregional failure (3 years: 8.3 % vs 6.0 % )

43. Results Sensitivity analyses adjusting for possible time-related bias and separately for stratification factors showed similar results as the original analyses

44. Results Number of surgeries with curative intent and disease-related treatment failures

45. Results Pathological Outcomes

46. Experimental Group Standard of Care Preop Postop Median time (end of RT  start of chemo) 14 days (IQR 12-17) - Optional field reduction 23 % External beam boost < 1% 2 % Dose reduction of chemotherapy 44 % 6 % 34 % Regime chemotherapy 99 % (CAPOX) Results

47. Experimental Group Standard of Care Preop Postop Premature stoppage of chemotherapy 15 % 9 % 37 % Reason for stoppage of chemotherapy Toxicity Disease Progression Noncompliance Withdrew from study Unknown 14 % < 1% < 1% < 1% < 1% 7% < 1% - - 1% 32% 1% 1 % 1 % 1 % Type of surgery approach (open /lap) P=0.31 Type of resection (TME vs PME for proximal tumors) ( APR vs AR) P=0.56 Results

48. Experimental Group Standard of Care Preop Postop Adverse Events (Grade 3 or high) 48 % 25 % 34 % Serious Adverse events 38 % 34 % 34 % Most common Serious Adverse Event Chemotherapy Diarrhea (9%) Diarrhea (3%) Infection (4%) Surgery Wound-related events Results

49. Results Overall Survival (3 years: 89.1 % vs 88.8 % )

50. Results Adverse Events

51. Results Adverse Events

52. Results Mortality Experimental Group Standard of Care Overall 17 % 18 % Rectal cancer related 79 % 82 % Second primary tumor 8% 9 % Treatment related 5 % Cardiac arrest (1) PE (1) Infection (2) 5% PE (1) Neutropenic sepsis (1) Aspiration (1) Suicide (Severe depression) (1) Others 5% 5 % Unknown 4% -

53. Results Subgroup analyses of primary endpoint as per baseline characteristics Consistently in favor of the experimental group. 28 /54 (52%) centers opted for adjuvant chemotherapy in the standard of care group. 3-year probability unchanged disease-related treatment failure (p=0.32). distant metastases (28.5% vs 24.4% ; p=0.34) and locoregional failure ( 7.2 % vs 4.3 %; p=0.20)

54. Discussion DISEASE-RELATED TREATMENT FAILURE Significantly lower probability in experimental group at 3 years. Mainly due to low rate of distant metastases Better compliance to preoperative chemotherapy 9 Short duration 18 W vs 24 W non inferiority of 3 months vs 6 months of adjuvant chemo 15,16 Earlier (18 W) start of chemotherapy – more effective eradication of micro metastases Not affected by hospital policy regarding the adjuvant chemotherapy Suggestive of low efficacy of adjuvant chemotherapy 17,18 9. van der Valk MJM, Marijnen CAM, van Etten B, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75–83. 15. Iveson TJ, Kerr RS, Saunders MP, et al. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised , phase 3, non-inferiority trial. Lancet Oncol 2018; 19: 562–78. 16. Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 2018; 378: 1177–88. 17. Bujko K, Glimelius B, Valentini V, Michalski W, Spalek M. Postoperative chemotherapy in patients with rectal cancer receiving preoperative radio(chemo)therapy: a meta-analysis of randomized trials comparing surgery ± a fluoropyrimidine and surgery + a fluoropyrimidine ± oxaliplatin. Eur J Surg Oncol 2015;16:200-07. 18. Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16: 200–07.

55. Discussion Polish II Study 19 - RCT (515 LARC) (SCRT + Chemo vs CRT) RAPIDO trial Chemo Regime 3 x FOLFOX4 6 x CAPOX or 9 x FOLFOX4 3-year cumulative incidence of distant metastases Experimental = 30 % Standard = 27 % (p=0.25) Experimental = 20.0 % Standard = 26.8 % (P=0.0048) Standard group: Enrollment of similar patient populations Experimental group: Difference due to duration of preoperative chemotherapy STELLAR TRIAL 20 (Affect of number of chemotherapy cycles on outcome) MRI – staged non metastatic LARC SCRT + 4 x CAPOX  Surgery  2 x CAPOX 19. Bujko K, Wyrwicz L, Rutkowski A, et al. Long-course oxaliplatin based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol 2016; 27: 834–42. 20. Jin J, Liu S, Zhu Y, et al. The updated results for the phase 3 study of 5×5 Gy followed by chemotherapy in locally advanced rectal cancer (STELLAR trial). Int J Radiat Oncol Biol Phys 2017; 99: e157.

56. Discussion 3 year probability of locoregional failure Similar to previously published data 1,2,4,21 Longer duration between RT and surgery (median time 25.5 weeks vs 15.9 weeks) Increased downstaging Increased PCR Disadvantage if little or no response (high ypT4 – 9 vs 6 %- in experimental group, progression on preop therapy ; early response imaging advised  change in therapy) Braendengen M, Tveit KM, Berglund A, et al. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 2008; 26: 3687–94. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23. 4. Gerard J-P, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24: 4620–25. 21. Peeters KCMJ, Marijnen CAM, Nagtegaal ID, et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007; 246: 693–701.

57. Discussion Stockholm III trial 22 (less advanced rectal cancer) RAPIDO trial Intermediate-risk rectal 23 cancer (4 consecutive series) PCR SCRT  Delayed Surgery ( 10.4 %) LCRT (2.2 %) Experimental group: 28 % Standard group: 14 % (Potential opportunity for organ preservation (watch-and-wait strategy) 26 CRT (18 %) CRT + 6 x modified FOLFOX6  surgery (38%) Interval between RT and surgery 4-8 weeks > 18 weeks Chemotherapy (no of cycles) - + -/+ Increase PCR  Local control / Survival Benefit (OS)?? 24,25 22. Erlandsson J, Lorinc E, Ahlberg M, et al. Tumour regression after radiotherapy for rectal cancer - results from the randomized Stockholm III trial. Radiother Oncol 2019; 135: 178–86. 23. Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre , phase 2 trial. Lancet Oncol 2015; 16: 957–66. 24. Marco MR, Zhou L, Patil S, et al. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: final results of a multicenter phase II trial. Dis Colon Rectum 2018; 61: 1146–55. 25. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11: 835–44. 26. van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 2018; 391: 2537–45.

58. Discussion Overall Survival No difference at 4.6 years median follow up Need of longer follow up (10 years) Optimal timing of chemotherapy in TNT ?? RT 1 st : control of local progression Chemo 1 st : early control of micro metastases PRODIGE 23 trial 27 (chemo ±  CRT  TME surgery chemo) Significantly increased 3-year DFS, metastasis-free survival, PCR rate 27. Conroy T, Lamfichekh N, Etienne P-L, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: final results of PRODIGE 23 phase III trial, a UNICANCER GI trial. Proc Am Soc Clin Oncol 2020; 38: 4007 ( abstr ).

59. Discussion Optimal timing of chemotherapy in TNT ?? CRT  Chemo (vs Chemo  CRT) 28 Fewer adverse events, better compliance to CRT, High PCR Long-term oncological results awaited Currently preferred 28. Fokas E, Allgauer M, Polat B, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ ArO /AIO-12. J Clin Oncol 2019; 37: 3212–22.

60. Discussion Serious Adverse events Diarrhea and neurological toxicity More in experimental group Due to preop CAPOX and longer period between chemo and surgery No effect on surgery. 9 9. van der Valk MJM, Marijnen CAM, van Etten B, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75–83.

61. Discussion SCRT vs CRT Merit: Short Duration, minimal delay in start of preop chemo Lower efficacy?? No RCT on anti-tumor or down staging effect with similar delay surgery Increased tumor-cell kill effect (5 fractions vs 25 fractions) – Stockholm III 22 Long-term morbidity (not comparable) SCRT: + 29 CRT: Less studied 2 RCT: no difference (3-5 years) 30,31 Cautions AP portals /3D Conformal RT vs IMRT /Volume modulated arc therapy Reduction in target volume vs volume used in trials that tested long-term effects of RT in rectal cancer 22. Erlandsson J, Lorinc E, Ahlberg M, et al. Tumour regression after radiotherapy for rectal cancer - results from the randomized Stockholm III trial. Radiother Oncol 2019; 135: 178–86. 29. Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Late adverse effects of radiation therapy for rectal cancer - a systematic overview. Acta Oncol 2007; 46: 504–16. 30. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol 2012; 30: 3827–33. 31. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006; 93: 1215–23.

62. Discussion Limitations Alteration of primary end-point Absence of central review of baseline MRI and primary endpoint Short-duration follow up (OS benefit?)

63. Discussion In Context of COVID-19 Pandemic Decreased hospital stay (less risk and implement of social distancing) 32 Experimental 12 days Standard: Preoperative: 25-28 days Postoperative: 8 days (CAPOX ) or 24 days (FOLFOX4) 32. Marijnen CAM, Peters FP, Rodel C, et al. International expert consensus statement regarding radiotherapy treatment options for rectal cancer during the COVID 19 pandemic. Radiother Oncol 2020; 148: 213–15.

64. Conclusion High-risk LARC SCRT  18 W chemo  surgery (vs CRT +/- Adjuvant chemo) Decreased probability of disease related treatment failure Mainly by reducing the probability of distant metastases. High PCR  Potential for organ preservation Suggested new standard of care fo r High risk LARC (s upported by high compliance and tolerability) Future research : early assessment of tumor response to systemic therapy  increase efficacy by further decrease in distant metastases.

65. Critical Appraisal Research Question _______________________________________________ Is the study’s research question relevant? Does the study add anything new? What type of research question does the study pose?

66. Critical Appraisal Is the basic study design v a l i d for a randomised controlled trial? _____________________________________________________________________ Did the study address a clearly focused (PICO) research question? (study design – research question) Was the assignment of participants to interventions randomised? (method, systemic bias, masking) We r e a l l participants w ho e n t e r e d t he study a cc o u n t e d f or a t i t s c o ncl us i o n? (intention-to-treat, stopped early?, original protocol followed?) Does the study test a stated hypothesis?

67. Critical Appraisal Was the study methodologically sound? _____________________________________________________________________ Were the participants ‘blind’ to intervention they were given? Were the investigators ‘blind’ to the intervention they were giving to participants? Were the people assessing/analysing outcome/s ‘blinded’? Were the study groups similar at the start of the randomised controlled trial? Apart from the experimental intervention, did each study group receive the same level of care (that is, were they treated equally)? (clearly defined protocol, equal follow up)

68. Critical Appraisal W h a t a r e t he re s u l t s? _____________________________________________________________________ Were the effects of intervention reported comprehensively? (power, statistical tests, p value, bias, incomplete data) Was the precision of the estimate of the intervention or treatment effect reported? (Confidence Interval) Do the benefits of the experimental intervention outweigh the harms and costs? Do the data justify the conclusions? Are there any conflicts of interest?

69. Critical Appraisal Wi l l t he resu l t s h e l p l o c all y ? _____________________________________________________________________ Can the results be applied to your local population/in your context? Would the experimental intervention provide greater value to the people in your care than any of the existing interventions?

70. THANK YOU