Uploaded byBala Vellayappan
Rectal cancer
1) Pre-operative chemoradiotherapy remains the standard of care for stage 2-3 rectal cancer as it reduces local recurrence rates and allows for sphincter preservation. 2) For selected low-risk patients, de-intensified treatment with less surgery or radiation can be considered as local recurrence rates have reached low levels with current regimens. 3) High-risk patients still require trimodality treatment with chemotherapy, radiation, and surgery. 4) Biomarkers or functional imaging may help further select appropriate patients for de-intensified treatment. Distant metastases remain problematic and more effective systemic therapies are still needed.
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Rectal cancer
- 1. Austerity drive forrectal cancer : can we do with less ? Dr Bala Vellayappan MBBS, FRANZCR, MCI Consultant, Radiation Oncology, NCIS, NUH Asst. Prof, YYL SoM Dept Research Director
- 2. Disclosures • None • Iam a believer in the use of RT for rectal cancers
- 3. Frequently asked questionsat lower GI tumour board… 1. Is that 5 mm lung nodule metastatic disease? 2. Is it above or below the peritoneal reflection? 3. Is it stage 2 or 3? i.e are the LN involved?
- 4. Introduction • In Singapore,most common cancer overall. 1/3 present with stage III disease. Patel SG Curr Gastroenterol Rep 2018
- 5. How is rectalcancer different from colon cancer? Rectal cancer Colon cancer Patterns of local recurrence High : Rich lymphatics, and drainage to pelvic side walls Low : Local recurrence/anastomotic recurrence not common Patterns of distant recurrence Drainage along superior rectal vessel IVC>> Lung mets more common *Extra-peritoneal Drainage via portal vein >> Liver mets more common. More peritoneal dissemination Surgical approach Narrow pelvis limits surgical accessibility Surgery is considerably easier Benefit of RT Proven No strong evidence (ref INT 0130) Response to chemotherapy = =
- 6. Workup for rectalcancer • H + P • Full colonoscopy and biopsy (5% synchronous) • Baseline labs and CEA • T staging : Clinical exam and MRI • N staging : MRI (+- contrast), CT or PET/CT • M staging : CT TAP or PET/CT
- 7. MRI protocol • 3Tbetter than 1.5 T • Useful in assessing meso-rectal invasion and EMVI • NUH protocol : Ax T2, Sag T2, Cor T2, Ax DWI, Ax T1, Ax Lava Flex, Ax Lava pre • Point of controversy: Is contrast useful ?
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- 9. Traditional approach :Surgery alone high local recurrences Stage group Local failure rates T1-T2 N0 LF <10% T3N0, T1N1 LF 15– 35% Rationale for pelvic radiotherapy!T3-T4 or N1/2 LF 45 – 65% Local failure is debilitating and morbid. Limited ability to salvage. We must do everything we can to reduce local recurrences.
- 10. Where are wenow? 1. 2. 3a. 4. 3b.
- 11. Variations in thedelivery of RT 1. Pre-op vs post-op 2. Short-course vs long-course 3. Addition of oxaliplatin 4. 3D VS Intensity-modulated Radiation therapy (IMRT)
- 12. Variations in thedelivery of RT 1. Pre-op vs post-op 2. Short-course vs long-course 3. Addition of oxaliplatin 4. 3D VS IMRT
- 13. Pre-op(neoadjuvant) vs post-op(adjuvant) Pre-OP Post-OP Symptom relief Slow Quick Appropriate patient selection for RT 10-20% overtreatment (T2, N0) Pathologically staged = accurate Bowel toxicity Less Bowel flops into pelvis Wound complications More Less Anastomotic complications Less More Sphincter salvage Possible … Tumor Hypoxia Less More Patient compliance Better Potentially worse
- 14. German Rectal CancerStudy: Preop vs postop 823 Patients , EUS staged cT3/4,N0/+ Adenoca TME surgery postop CRT 55.8Gy Preop CRT 50.4Gy TME surgery • No difference in OS (76% vs. 74%. p=0.8) • Increased local control (6% vs. 13%. P=0.06) • Decreased G3/4 acute toxicity (27% vs. 40%. P=0.001) • 8% patients had complete pathological response • Improved sphincter preservation with pre- op Sauer NEJM 2004 R A N D O M I Z E
- 15. Variations in thedelivery of RT 1. Pre-op vs post-op 2. Short-course vs long-course 3. Addition of oxaliplatin 4. 3D VS IMRT
- 16. Pre-op : Short(25Gy in 1 week) or long (50Gy over 5 weeks ? Author Inclusion N Intervention Comparison Outcome Comments Bukjo 2004 T3 – T4 314 25 Gy / 5 # 50.4Gy/28# + 5FU No difference in sphincter preservation rate More acute toxicity in CRT group (18% vs. 3%) No difference in DFS (58% vs. 56%), local recurrence (9% vs. 14%), and late toxicity (10% vs. 7%) Ngan 2012 T3, Nx 326 25Gy /5# 50.4Gy/28# + capecitabine No diff in local recurrence (7.5 v 5.7%) No diff in OS (74 vs 70%) Subgroup : More recurrence in distal cancer with short course (12 % vs 3%) SHORT COURSE = LONG COURSE Low rectal cancers, CRM threatened LONG > SHORT
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- 18. Variations in thedelivery of RT 1. Pre-op vs post-op 2. Short-course vs long-course 3. Addition of oxaliplatin 4. 3D VS IMRT
- 19. Does addition ofconcurrent oxaliplatin improve outcome? STAR-01 ACCORD-12 NSABP-R04 CAO/ARO-04 PETACC-6 N 720 596 1608 1265 1094 RT dose 50.4 45 - 50 50.4 – 55.8 50.4 45 - 50 G3+ GI toxicity 7 v 24% 11 v 25% 7 v 15% 8 v 12% 6 v 18% yPCR 16% 13 v 19% 19 v 21% 13 v 17% 11.5 v 13% Spincter salvage 78% 75% 62% 88% 65 – 69% Gerard JCO 2010; Aschele JCO 2011; Rodel Lancet Oncol 2012; Roh JCO, 2014; Schmoll, PASCO, 2013
- 20. Variations in thedelivery of RT 1. Pre-op vs post-op 2. Short-course vs long-course 3. Addition of oxaliplatin 4. 3D VS IMRT
- 21. Do newer RTtechniques improve outcome? • IMRT in rectal cancer • Ability to conform radiation dose to primary rectal tumour and regional lymphatics • At the same time spares critical normal tissues such as • Bladder • Small bowel • Femoral heads • Potential for radiation dose escalation 3D RT
- 22. 3DCRT vs IMRTdosimetric comparison IMRT decreases dose to bladder, small bowel and femoral heads 3DCRT IMRT 3 D C R T I M R T
- 23. Journal of Cancer2017, p 3114 • Prospective single-arm Phase II design • IMRT 55Gy/25# with concurrent capecitabine • TME surgery 8 weeks post RT • Primary outcome : pCR • Secondary outcome : downstaging rate • n = 20 • 35% pCR, 65% downstaging. Spincter preservation 85%. 5% G3 toxicity (proctitis). 2 year OS 90%
- 24. Evolution of rectalcancer treatment APR Anterior resection TME surgery NIH Consensus statement : adjuvant RT + chemo for all T3, N+ Neoadjuvant therapy Long course Short course Individualised therapy TNT Distant recurrence Local recurrence ~30% 1920s 1960s 1980-90s 1990s 2000s 2010s Present <5%
- 25. Can we dowith less local therapy ?
- 26. Can we dowith less surgery (or no surgery)? • Potential scenario : • 1) Avoid surgery in patients who achieve a complete clinical response to pre-op therapy? i.e. watch and wait policy Rationale : • surgical complications ~30% • permanent or temp stoma • impaired bowel/bladder/sexual function
- 27. In the footstepsof ANAL cancer paradigm • Anal Cancer : APR surgery (before 1970s)Preop chemoRT (1970s)Definitive chemoRT (present) • Distal rectal cancer : APR (present) Preop chemoRT (present)definitive chemoRT (future)
- 28. Response is asurrogate for better biology Response Tumour Regression Grade (TRG) Outcome TRG 4 i.e pCR NO local recurrence. 86% 5y DFS TRG 2-3 4% local recurrence, 75% 5y DFS TRG 0-1 6% local recurrence, 63% 5y DFS Rodel JCO 2005
- 29. Brazilian data Inclusion • 361patients • 99 with clinical CR (27%) Treatment • Median followup 60 m Results • 5% local recurrence - mostly surgical salvage • mean interval to recurrence 52m • 0% pelvic recurrence, 8% distant mets • 5 ys OS 93% Habr-Gama J Gastrointest Surg 2006
- 30. NOM : selectionbias for better biology? • MSKCC retrospective review comparing patients in cCR and pCR • Are we doing patients with “better biology” a dis-service by omitting surgery?
- 31. • Median followup19 m • 26% had local recurrence (19 of 73) all surgically salvaged Smith ASCO GI 015
- 32. Challenges with NOM •Surgery still the only means of reliably detecting a pCR • Clinical response may not always correlate with pathological response • Clinical evaluation can be limited to distinuguish fibrosis from residual disease • Biopsy post chemoRT can be difficult to interpret • Committed patients for very close surveillance and early salvage in order not to compromise outcome increased healthcare cost at the expense of ?better QoL
- 33. Can we dowith less RT (or no RT?) • 1) In patients with negative margins after TME? (post-op RT) • 2) In patients with good response to systemic therapy?
- 34. N=1350 Operable Rectal cancer TME surgery Preoperative 25Gy/5# TMEsurgery Montefiore. Lancet Oncol 2009 Post operative chemoRT 45G/25# only if CRM <1mm. If CRM clear, no adjuvant therapy) R A N D O M I Z E Primary outcome : Local recurrence
- 35. Even with goodclean surgery, you can’t boot RT
- 36. Can we bootRT with effective chemotherapy?
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- 38. Do we needmore chemo? APR Anterior resection TME surgery NIH Consensus statement : adjuvant RT + chemo for all T3, N+ Neoadjuvant therapy Long course Short course Individualised therapy TNT Distant recurrence Local recurrence ~30% 1920s 1960s 1980-90s 1990s 2000s 2010s Present <5%
- 39. Conclusion Even at specialtycancer centers, a sizeable minority of patients with rectal cancer treated with curative-intent neoadjuvant chemoradiotherapy do not complete postoperative chemotherapy. Strategies to facilitate the ability to complete this third and final component of curative intent treatment are necessary. Adjuvant chemo completion rates are still suboptimal
- 40. 1) There isa still a problem of poor completion rates of adjuvant chemotherapy 2) Still 35% rates of DM – micrometastatic disease should be addressed earlier 3) LRR <5% are already close to optimal with current (C)RT regimens. We should not be trying too hard to tweak this further. 4) Adding more chemo or dose to chemoRT is unlikely to improve DFS/OS and only adds more toxicity. Total neoadjuvant therapy (TNT) : Rationale
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- 43. Polish II Phase3 RCT
- 44. Polish II :results Bukjo Ann Onc 2016
- 45. Pre-op SCRT +Chemo – RAPIDO Trial
- 46. TNT : Pre-opSCRT + Chemo Compliance to pre-op chemo is good – 80-100% Higher rates of pCR may allow omission of surgery Superiority over current standard still unproven
- 47. Case study :EA • 69, Lady, PS 0 • Ano-rectal mass. Extending 8cm into rectum. • No vaginal involvement • Biopsy : adenocarcinoma
- 48. IMRT with concurrentcapecitabine 45 Gy 50Gy
- 50. Conclusion • Pre-op chemoRTremains the standard of care for stage 2 – 3 rectal cancer • Reduces local recurrence • Allows for sphincter preservation • In terms of local recurrence, we have reached a point where we can consider de- intensification for selected patient (less surgery or less RT) • Trimodality treatment still needed for high-risk patients. • Can biomarkers or functional imaging help in patient selection? • Distant mets continues to pose a problem – more effective systemic therapy/biologics or TNT may reduce the rate of DM, and perhaps improve OS
- 51. Thank you foryour attention! Bala_vellayappan@nuhs.edu.sg