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![Is RAPIDO a new normal for
locally advanced rectal cancer?
DR KANHU CHARAN PATRO
MD,DNB[RADIATION ONCOLOGY],FAROI,PDCR,CEPC,MBA
HOD, RADIATION ONCOLOGY
MGCHRI, VISAKHAPATNAM,INDIA
12/17/2020 1](https://image.slidesharecdn.com/rapidotrial-201217113551/75/RAPIDO-TRIAL-RECTUM-1-2048.jpg)
![Locating the study
Type Phase lll randomized
Institution Multicentric [UK and USA]-54
Period June 21, 2011 to June 2, 2016
Total number patients 1. 920
2. Experimental group (462)
3. Standard of care group (450)
Clinical Trial registration NCT01558921
Median follow up 4·6 years
Analysis type ITT
12/17/2020 14](https://image.slidesharecdn.com/rapidotrial-201217113551/75/RAPIDO-TRIAL-RECTUM-14-2048.jpg)
![1. CAPOX
1. Capecitabine 1000 mg/m² orally twice daily on days 1–14,
2. Oxaliplatin 130 mg/m² IV on day 1
3. Chemotherapy-free interval between days 15–21
2. FOLFOX
1. Oxaliplatin 85 mg/m² IV on day 1, leucovorin [ folinic acid] 200 mg/m² IV
on days 1 and 2,
2. Followed by bolus fluorouracil 400 mg/m² IV and fluorouracil 600 mg/m²
IV for 22 h on days 1 and 2,
3. Chemotherapy-free interval between days 3–14
Chemotherapy protocols
12/17/2020 21](https://image.slidesharecdn.com/rapidotrial-201217113551/75/RAPIDO-TRIAL-RECTUM-21-2048.jpg)
![Shorter duration of chemo
1. Fewer weeks of chemotherapy (18 weeks
preoperatively vs 24 weeks postoperatively) could
also have contributed to better compliance in the
experimental group than in the standard of care
group, and did not result in reduced efficacy.
2. Justification for a reduced number of chemotherapy
cycles has emerged in several adjuvant colon cancer
trials, [SCOT TRIAL] showing that 3 months of
CAPOX is noninferior to 6 months of CAPOX in terms
of disease-free survival.
12/17/2020 42](https://image.slidesharecdn.com/rapidotrial-201217113551/75/RAPIDO-TRIAL-RECTUM-42-2048.jpg)
Uploaded byKanhu Charan
RAPIDO TRIAL RECTUM
The RAPIDO trial tested a new experimental treatment for locally advanced rectal cancer that involved short-course radiotherapy followed by chemotherapy before surgery, compared to the standard treatment of long-course chemoradiotherapy followed by surgery and then chemotherapy. The results showed that the experimental treatment led to a lower rate of disease-related treatment failures and distant metastases, along with a doubled rate of pathologic complete responses, without increasing toxicities or compromising survival rates. This provides evidence that the experimental approach may be a new standard of care for high-risk locally advanced rectal cancer.
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RAPIDO TRIAL RECTUM
- 1. Is RAPIDO anew normal for locally advanced rectal cancer? DR KANHU CHARAN PATRO MD,DNB[RADIATION ONCOLOGY],FAROI,PDCR,CEPC,MBA HOD, RADIATION ONCOLOGY MGCHRI, VISAKHAPATNAM,INDIA 12/17/2020 1
- 2. Rectal cancer And PreoperativeInduction therapy followed by Dedicated Operation (RAPIDO) trial 12/17/2020 2
- 3. Lancet Oncology 2020Published Online December 7, 2020 12/17/2020 3 Geke A.P. Hospers, MD, Professor at the University Medical Center Groningen in the Netherlands
- 4.
- 5. • INFERENCE- Theobserved decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. • Therefore, the experimental treatment can be considered as a new standard of care in high- risk locally advanced rectal cancer • Result Median follow-up was 4·6 years, the cumulative probability of disease- related treatment failure was 23·7% in the experimental group versus 30·4% in the standard of care group (HR 0·75, p=0·019) 12/17/2020 5 Result in short
- 6. Issues • Local control •Metastasis rate • Organ preservation • Optimal sequence 12/17/2020 6
- 7.
- 8. Setting the stage •Long course/short course RT f/b SX and chemo is the standard for locally advanced rectal cancer • Preoperative chemoradiotherapy aims to downstage tumours, leading to improved locoregional control with local recurrence rates of approximately 5–9%. • However, unfortunately the occurrence of distant metastases has not decreased accordingly • Systemic relapses remain a major problem in locally advanced rectal cancer • RAPIDO trial aimed to reduce distant metastases without compromising locoregional control. • This trial is based on the Dutch M1-trial in which patients with metastatic primary rectal cancer received short-course radiotherapy f/b chemotherapy 12/17/2020 8
- 9. This approach mightresult in a decreased number of distant metastases without increasing the risk of locoregional failure, ultimately improving survival outcomes Based on the Dutch M1-trial The hypothesis 12/17/2020 9
- 10. Aim and objective Decreasednumber of distant metastases without increasing the risk of locoregional failure, ultimately improving survival outcome 12/17/2020 10
- 11. The DUTCH M1trial 12/17/2020 11
- 12. 1. The 2-yearoverall survival rate was 80% 2. The 2-year recurrence rate was 64% after R0 resection The DUTCH M1 trial result 12/17/2020 12
- 13. Primary end point oDisease-related treatment failure at 3 years Secondary end point o Completion rate of neoadjuvant treatment, o Toxicity o R0 resection rate o Pathological complete response rate o Surgical complications within 30 days o Quality of life (in patients alive without disease related treatment failure, 3 years after surgery), o Functional outcome, o Overall survival (time from randomization to death from any cause) The end points 12/17/2020 13
- 14. Locating the study TypePhase lll randomized Institution Multicentric [UK and USA]-54 Period June 21, 2011 to June 2, 2016 Total number patients 1. 920 2. Experimental group (462) 3. Standard of care group (450) Clinical Trial registration NCT01558921 Median follow up 4·6 years Analysis type ITT 12/17/2020 14
- 15. Inclusions and exclusions InclusionsExclusions 1. 18 years or older, 2. Biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma 3. Distal extension less than 16 cm from the anal verge. 4. Pelvic MRI with at least one of the following high-risk criteria was required: - Clinical tumor (cT) stage cT4a or cT4b, - Extramural vascular invasion - Nodal (cN) stage cN2, -involved mesolectal fascia - Enlarged lateral lymph nodes considered to be metastatic 1. Extensive growth of the rectal tumor into the cranial part of the sacrum or the lumbosacral nerve roots 2. presence of metastatic disease or recurrent rectal cancer 12/17/2020 15
- 16. Inclusions • Clinical TumorcT4a Or cT4b, • Extramural Vascular Invasion, • Clinical Nodal Stage cN2, • Involved Mesorectal Fascia • Enlarged Lateral Lymph Nodes 12/17/2020 16
- 17. RECTAL CANCER MRI-FORMAT FOR RADIOLOGIST BASED ON RAPIDO STUDY 8th MAY 2021/RECTUM 1. Primary I. Tumor height from the anorectal junction II. Morphology of the tumor III. Depth of extramural spread IV. Presence or absence of extramural vascular invasion and grading V. Mesorectal fascia involvement VI. Breach of the peritoneal reflection by the tumor, 2. Node I. Presence or absence of Mesorectal or extramesorectal lymph node metastases II. Mesorectal lymph nodes with a short axis diameter of more than 10 mm and round III. Short axis of 5–9 mm and meeting at least two criteria of round shape, I. Irregular border, II. Heterogeneous signal intensity IV. with an irregular border or heterogeneous signal intensity, or both, or round lymph nodes with a short axis diameter of more than 10 mm, or a combination of these factors, were considered to be metastatic. 12/17/2020 17
- 18. Experimental arm NART- 5Gy/5#,max8 days 6 cycles of CAPOX / 9 cycles of FOLFOX4 Dedicated surgery –TME 2–4 weeks 12/17/2020 18
- 19. Standard arm +/- Adjuvant8 cycles of CAPOX / 12 cycles of FOLFOX4 Dedicated Surgery – TME after 6-10 weeks of last fraction NART – 50.4Gy/28# or 50Gy/25# ,with concurrent oral Capecitabine 825mg/m2 BD 12/17/2020 19
- 20. Trial population 12/17/2020 20 920 468452 468 441 423 398 PER Consent PER ITT Per protocol Experiment Standard
- 21. 1. CAPOX 1. Capecitabine1000 mg/m² orally twice daily on days 1–14, 2. Oxaliplatin 130 mg/m² IV on day 1 3. Chemotherapy-free interval between days 15–21 2. FOLFOX 1. Oxaliplatin 85 mg/m² IV on day 1, leucovorin [ folinic acid] 200 mg/m² IV on days 1 and 2, 2. Followed by bolus fluorouracil 400 mg/m² IV and fluorouracil 600 mg/m² IV for 22 h on days 1 and 2, 3. Chemotherapy-free interval between days 3–14 Chemotherapy protocols 12/17/2020 21
- 22. Radiotherapy protocols Experimental arm• Short-course radiotherapy (5 × 5 Gy) • Administered over a maximum of 8 days Standard arm • 28 daily fractions of 1・8 Gy up to 50・4 Gy or 25 # of 2・0 Gy up to 50・0 Gy, as per the decision of the treating physician and hospital policy, with concomitant twice-daily oral capecitabine 825 mg/m2. • Optional field reduction was recommended after 45 Gy (1・ 8 Gy schedule) or 46 Gy (2・0 Gy schedule), Target volume • In both groups, the clinical target volume for radiotherapy included the entire mesorectum with the primary tumor and relevant regional lymph nodes; an additional boost dose was optional. • The clinical target volume of the boost was the assessable tumor with a 1 cm margin within the same anatomical compartment as where the tumor is located. 12/17/2020 22
- 23. Surgery procedures • Surgerywas done according to total mesorectal excision principles; a partial mesorectal excision was accepted for proximal tumours. • Open and laparoscopic approaches were allowed and at the surgeon’s discretion. • The completeness of resection was assessed using the residual tumor classification • Pathological assessment of the resected sample was done according to national guidelines of each participating country and included standardized work up and reporting. • The involvement of circumferential resection margins, quality of the sample, and complete tumor response (yes or no) were recorded. • Quality of the resection was assessed at two different levels for abdominoperineal excision (mesorectum and anal canal) and at one level for anterior resection (mesorectum) 12/17/2020 23
- 24. Follow up • Clinicalassessments at 6, 12, 24, 36, and 60 months after surgery, including CEA measurement • Chest x-ray or CT of the thorax and ultrasound or CT of the abdomen at 12 and 36 months as a minimum • Total colonoscopy was obligatory within the first year unless done preoperatively and Colonoscopy was mandatory 60 months postoperatively • On indication, other diagnostics (eg, PET CT scan) were allowed, to confirm or detect recurrent disease 12/17/2020 24
- 25. Statistical Analysis Statistics IBMSPSS Statistics (version 25.0) Aim To detect a decrease in 3-year cumulative probability of disease-related treatment failure from 30% to 22·5%, corresponding to a hazard ratio (HR) of 0·715 Power 80% Alpha error 0.05 Analysis type ITT Comparison Kaplan Meier Compared - χ² test Student’s t test or the Mann-Whitney U test(continuous data) 12/17/2020 25
- 26. Baseline characteristics ofpatient 12/17/2020 26
- 27.
- 28.
- 29.
- 30.
- 31. Overall survival After amedian follow-up of 4・6 years, no difference in overall survival was observed, but might be revealed with longer follow-up that will continue until 10 years after randomization, according to the trial protocol 12/17/2020 31
- 32.
- 33.
- 34. Pathological response- DOUBLE 12/17/202034 Experimental Standard
- 35. Watch and waitpolicy Total patients 912 Parameter Experimental arm Standard arm Patients 462 450 Watch and wait policy 14 11 Local 1 1 Distant 2 1 Local and distant 0 1 12/17/2020 35
- 36. Expected adverse events 1.Diarrhea 2. Neurological defect 3. Wound related event 12/17/2020 36 There were more grade ≥ 3 toxicities during preoperative treatment in the experimental arm, including more neurologic toxicity (4.3% vs 0.2%), more vascular disorders (8.5% vs 4.1%), and more diarrhea (17.6% vs 9.3%)
- 37.
- 38.
- 39. Summary of theresults • 7% lower disease-related treatment failure: 30.4% vs 23.9% • 7% lower distant metastases rate: 26.8% vs 20.0% • Doubling in pathologic complete response rate: 14% vs 28% • Similar 3-year overall survival: 89% in each • No unexpected toxicity • No differences in surgical or postoperative complications or QOL 12/17/2020 39
- 40.
- 41. Discussion • Shorter durationchemotherapy-the SCOT • The lower rate of distant metastasis- the POLISH ll • The more CR rate- the STELLAR • The timing of chemotherapy-the PORODIGE 23 • The efficacy- the STOCKHOLM lll12/17/2020 41
- 42. Shorter duration ofchemo 1. Fewer weeks of chemotherapy (18 weeks preoperatively vs 24 weeks postoperatively) could also have contributed to better compliance in the experimental group than in the standard of care group, and did not result in reduced efficacy. 2. Justification for a reduced number of chemotherapy cycles has emerged in several adjuvant colon cancer trials, [SCOT TRIAL] showing that 3 months of CAPOX is noninferior to 6 months of CAPOX in terms of disease-free survival. 12/17/2020 42
- 43. Chemo duration-The SCOTtrial 12/17/2020 43
- 44.
- 45. Met rate-The POLISHll trial 12/17/2020 45
- 46. Met rate-The POLISHll trial 12/17/2020 46 Experimental arm Standard arm POLISH ll 30% 27% RAPIDO 20% 26.8%
- 47. CR-The STELLAR trial 12/17/202047 1. Staged by MRI, were randomized to either experimental or control group. 2. The experimental group included SCRT (25 Gy/ 5 fractions/ 5 days) followed by 4 courses of CAPOX before surgery, and 3. Control group consisted of preoperative LCRT (50Gy/ 25 fractions/ 35 days with concurrent capecitabine). 4. Radical resection under TME principles was performed 6-8 weeks after neoadjuvant treatment, 5. Then 2 or 6 courses of CAPOX was prescribed as the postoperative adjuvant chemotherapy in experimental or control group • Pathological complete response (pCR) rates were 46.7% (7/15) and 10.5% (2/19) • The updated results supported proceeding of STELLAR trial based on acceptable acute toxicity and surgical complications, and high CR rate in patients with SCRT followed by chemotherapy was stable with increasing cases
- 48. Timing of chemo-ThePRODIGE 23 12/17/2020 48
- 49. PRODIGE 23: Efficacy (Primaryand Key Secondary Endpoints) Conroy. ASCO 2020. Abstr 4007. 12/17/2020 49
- 50. pCR rate-Stockholm llltrial 12/17/2020 50
- 51. • pCR wasseen in 1 (0.3%), 29 (10.4%) and 2 (2.2%) patients in SRT, SRT-delay and LRT-delay, respectively • The pCR were associated with superior survival. • pCR vs no-pCR Hazard Ratio (95% Confidence Interval) OS: 0.51 (0.26-0.99) p = 0.046, • TTR: 0.27 (0.09-0.86) p = 0.027 pCR rate-Stockholm lll trial 12/17/2020 51
- 52. Organ preservation-the OPRAstudy 12/17/2020 52
- 53. Organ preservation-the OPRAstudy 12/17/2020 53
- 54. Surgery – timeinterval-GRECCAR-6 12/17/2020 54 A longer waiting period may be associated with higher morbidity and more difficult surgical resection.
- 55.
- 56.
- 57.
- 58. Wait and watchdatabase? 12/17/2020 58
- 59. • Retrospective, multicenterregistry study • 793 patients in the IWWD with clinical complete response who had been managed by a watch and-wait strategy • Median follow-up was 55·2 month • The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8–90·9), for 3 years was 97·3% (95·2–98·6), and for 5 years was 98·6% (97·6–100·0). • The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3–95·9), for 3 years was 97·8% (96·6–99·3), and for 5 years was 96·6% (94·0–98·9). Wait and watch database? 12/17/2020 59
- 60.
- 61. • As suggestedby Bahadoer and colleagues, an interim restaging MRI scan after three cycles of chemotherapy can potentially identify this group of patients who are non-responders to preoperative treatment, thus potentially prompting an earlier surgery than planned, and thus possibly improving overall survival outcomes • The GRECCAR-6 trial, which investigated the effect of time to surgery after radiotherapy, did not find any benefit in rates of pathological complete response beyond 7 weeks after radiotherapy. But no additional chemotherapy • The increase in pathological CR observed in the RAPIDO protocol is probably due to the effect of additional chemotherapy after initial radiotherapy. • The PRODIGE 23 trial is the only other trial to our knowledge that has shown promising results Although this induction regimen was well tolerated in this trial setting, the generalized tolerability of mFOLFIRINOX in the population remains unknow Comments 12/17/2020 61
- 62. • Strand treatmentis not standard of care • Boost dose improves • Chemotherapy before surgery after or before CRT • Some patients can be observed for organ preservation approach if CR by clinoco- radiological • Oxaliplatin adds some benefit • Rationalization can be done to shortcut the hospital visit What we learnt? 12/17/2020 62
- 63. Limitlessness of thisstudy • Phase lll randomized • Good patient population • Multicentric • Study of QOL- awaited 12/17/2020 63
- 64. Limitedness of thisstudy • Absence of a central review of baseline MRIs • Alteration of the primary endpoint during a trial is undesirable • Chemotherapy is not similar in both arms • No standardized Radiotherapy techniques • Overall survival at 3 years • Not all patients in standard arm received adjuvant chemo 12/17/2020 64
- 65. COVID-19 implications • Decreasein the number of treatment days spent in health-care facilities • 12 days in the experimental group versus 25–28 days in the standard of care group for the preoperative period on the basis of typical treatment regimens. • If adjuvant chemotherapy is given (8 treatment days in 24 weeks if CAPOX, 24 days if FOLFOX4), the reduction is even in time spent in hospital minimizes the risk 12/17/2020 65
- 66. Conclusion 1. RAPIDO trialshows that short-course radiotherapy followed by 18 weeks of chemotherapy before surgery decreases the probability of disease related treatment failure in high risk locally advanced rectal cancer reducing the probability of distant metastases 2. High rate of pathological complete response – organ preservation 3. High compliance and tolerability 4. Hence, this treatment could be considered as a new standard of care for patients with high-risk locally advanced rectal cancer 12/17/2020 66
- 67. Acknowledgement 1. Dr SayanPaul 2. Dr P Vijay Ananda Reddy 3. Chartrounds India 4. Dr K.Keerthiga 5. Audience • Google 12/17/2020 67
Editor's Notes
- #50 CRT, chemoradiotherapy; ITT, intention-to-treat; MFS, metastasis-free survival; NS, not significant; TME, total mesorectal excision.