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Colorectal Cancer An oncologists perspective

Colorectal Cancer An oncologists perspective. SpR Teaching Dec 2012 Erica Beaumont. Summary. Neoadjuvant Radiotherapy for rectal cancer Neoadjuvant Chemotherapy for colon cancer Adjuvant chemotherapy Liver metastases Palliative treatments. The MDT. Neoadjuvant Radiotherapy.

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Colorectal Cancer An oncologists perspective

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  1. Colorectal CancerAn oncologists perspective SpR Teaching Dec 2012 Erica Beaumont

  2. Summary • Neoadjuvant Radiotherapy for rectal cancer • Neoadjuvant Chemotherapy for colon cancer • Adjuvant chemotherapy • Liver metastases • Palliative treatments

  3. The MDT

  4. Neoadjuvant Radiotherapy • Operable rectal cancer (SCPRT) • Inoperable / threatened CRM (CRT) • Modern Context • MRI staging • TME

  5. Gina Brown et al. Radiol 1999;211:215-222 • MERCURY study gp. Diagnostic accuracy of preop MRI in prediciting curative resection of rectal cancer: prospective observational study. BMJ 2006; 333: 779

  6. MERCURY Study 428 pts MRI mesorectal fascia involvement by tumour significantly predicted for local recurrence DFS and OS showed that avoidance of preop RT safe in patients with MRI defined good prognosis disease (3% local recurrence) Allows stratification of patients and better targeting of preoperative radiotherapy for reduced patient toxicity and morbidity Phase II/III trials to identification of key imaging predictors of patients at risk of developing metastatic disease on initial staging MERCURY staging study in rectal cancer Bmj, 2006; Salerno,Daniels et al. Dis Colon Rectum, 2009).

  7. TME Surgery • Total mesorectal excision reduces local recurrence rates • 30-40% without TME, 3.7% with TME   • TME varies between surgeons (experience, training technique ) • How can oncologists assess quality of surgery? Surgeons objectively assess Sx? Heald Lancet 1986;  1(8496):1479-82 Heald Lancet 1993;  341(8843):457-60

  8. Quality of Surgery • Quirke • Raised awareness of importance the circumferential resection margin and quality of TME specimen • Developed graded assessment of TME • Used in Dutch study & CR07

  9. Quality of TME in Dutch Study

  10. Influence of quality of TME surgery

  11. Quality of TME and outcome CR07

  12. Potential benefits of neoadjuvant RT • Improving survival • Reducing risk of local recurrence • Improving the chance of sphincter saving surgery • Increasing the chance of complete resection in advanced disease

  13. Post Op RT • Decrease rel risk LR by 30-40% • Absolute decrease 25.8% vs 16.7% (p<0.00002) • Rectal cancer † decreases by 8.6% *Lancet Meta-analysis 2001. CRC collaborative gp. >2000 pts 8 post op RCTs

  14. Pre op RT • >6000 pts 14 RCTs • Decrease relative risk LR of 50-60% • Absolute decrease 22.2% vs 12.5% (p< 0.00001) • Rectal cancer † decrease by 22% Lancet meta-analysis 2001

  15. Short Course Preoperative RTSCPRT

  16. SCPRT – Swedish studies • >1100 pts with resectable rectal Ca Sx vs RT 25/5 + Sx (1986-1990) • Not TME • 25/5#/1W • 5 yr LR 27% vs 12% • 5 yr OS 48% vs 58% • Only pre op study showing survival benefit • Benefits maintained - most recent update JCO 2005 Swedish Rectal Cancer Trial. N Engl J Med 1997; 336: 980-7

  17. SCPRT – Dutch study • Sx vs preop RT 25/5 + Sx in operable Rectal cancer • 1748 pts underwent complete resection • 2yr LR 8.2% vs 2.4% * • Longer FU relative benefit maintained • Also assessed importance of CRM and quality of surgery* * * Kapiteijn et al. Preop RT combined with TME for resectable rectal cancer. NEJM 2001; 345: 638 ** Nagtegaal et al. Dutch CCG co-operative. Macroscopic evaluation of rectal cancer specimen. 2002; 20: 1729

  18. Risk factors for LR

  19. Influence of CRM on LR & OS • A – LR with AR • B – LR with APR • C – OS with AR • D – OS with APR Grey = CRM - Black = CRM +

  20. Low rectal cancers have worse outcomes APR v AR in Dutch study • OS • 38.5% v 57.6% (p=0.008) • CRM+ • 30.4% v 10.7% (p=0.002) • Perforation rate • 13.7% v 2.5% (p<0.001)

  21. SCPRT – CR07 • SCPRT vs selective post op CRT with TME Sx • 1350 pts • 674 25/5 SCPRT • 676 Sx alone of whom 11% CRM + • 3 yr LR 4.7% v 11.1% (HR 2.47, 95% CI 1.61-3.79) • 3 yr DFS 79.5% v 74.9% (HR 1.31, 95% CI 1.02-1.67) • Benefit consistent for all levels & stages JCO 2006 ASCO Proceedings Part I. Vol 24; No. 18S: 3511

  22. Side effects of SCPRT • Minimal acute toxicity • Poor wound healing (esp perineal) • Bowel dysfunction – faecal incontinence • Less of a problem for patients post APR

  23. Who should have SCPRT? • To reduce local recurrence in: • Low rectal cancers (APR) • Bulky T3 • Node positive disease

  24. Long Course Chemoradiotherapy

  25. Polish study • 312 pts with rectal cancer palpable by DRE • Primary end point – sphincter preservation • Secondary endpoints –LR, toxicity • Operation specified by surgeon pre RT • Randomised to 25/5 vs 45/25 + 5FU wk 1&5 • Reassessed to decide on final operation post RT Bujko et al. Radioth Oncol 2004; 72: 15

  26. Polish study • No difference in sphincter-preservation rates • More acute Gd 3 & 4 toxicity with CRT • 18% v 3% (p=0.001) • More pCR, less N+ & CRM+ with CRT • 16.1% v 0.7%, 31.6% v 47.6%, 4.4%v 12.9%

  27. Polish study • No difference late toxicity • 28.3% v 27% • No difference in 4 yr LR • 15.6% v 10.6% (p=0.21)

  28. Why give CRT? • Downstage inoperable tumours (but is there a role for SCPRT?) • Downstage tumours where there is a threatened CRM (by primary or node)

  29. Practicalities of RT • Tattoos • Empty rectum, full bladder • CT scan • SCPRT: 5 daily treatments the week before surgery • CRT: 25-28 daily treatments with bd capecitabine chemotherapy

  30. Toxicities of RT • Acute: sore skin, tiredness, nausea, diarrhoea, PR bleeding, urinary • Late: bowel dysfunction, urinary, small bowel stricture, infertility, menopause, poor wound healing, vaginal stricture, impotence, pelvic bone fragility, risk of second malignancy

  31. Planning RT • CT scan • Fields vs volumes • Aristotle trial • Include – mesorectum • Extension of tumour beyond mesorectum (+margin) • Sup: sacral promontory • Inf: obturator foramen, or 2-3cm below tumour

  32. Adjuvant Radiotherapy • Post-op if positive margin (R1 resection) • Only if no pre-op RT given • Not as effective as pre-op RT • Better than nothing

  33. Neoadjuvant chemotherapy for colon cancer

  34. FOXTROT trial • Ongoing • Initial data: 150 patients • Locally advanced (T3/4) colon tumours on CT • 3 cycles (6 weeks) FOLFOX chemo and Surgery vs Surgery alone

  35. FOXTROT • No diff post-op morbidity (p=0.8) • Decreased T and N stage with neoadjuvant chemo (p=0.04) • Decreased margin involvement (p=0.002) Lancet Oncol 2012; 13:1152-60

  36. Adjuvant Chemotherapy

  37. Rectal Cancer • All data extrapolated from colon cancer • SCPRT – does not downstage cancer • CRT – downstages cancer • Treat on initial clinical staging • Chronicle trial failed to recruit • Good prognostic group: ypT0 ypN0 M0 • Distant metastases 8.9%, 5yr DFS 85%

  38. Colon cancer • Initial studies done with 5FU • Intergroup 035 (5FU vs no chemo) • 5yr OS benefit for Dukes C 13% • 5yr OS benefit for Dukes B 3-5% • X-ACT (capecitabine vs 5FU) • 4% benefit for cap • MOSAIC (5FU /oxaliplatin vs 5FU) • 3yr DFS benefit of 5%

  39. Current Practice • Node positive tumours • 5FU / Oxaliplatin • If less fit / elderly, Cap alone • High risk node negative tumours • EMVI, T4, R1, Emergency presentation, <12 nodes • Cap / 5FU alone • 5FU / Oxalipatin if lots of risk factors

  40. What does this mean for patients? • 6 months treatment (SCOT trial ongoing) • Tiredness, nausea, diarrhoea, stomatitis • Palmar plantar syndrome • Neuropathy, orolaryngeal spasm • Haematological toxicity • Cardiac toxicity • Thromboembolic disease • DPD deficiency

  41. Follow Up • Often CNS led • Risk stratified • Regular CT scans • Timing controversial • To assess for resectable liver mets

  42. Treatment of liver metastases

  43. Liver only disease • Assessment • CT, MRI Liver, PET • Resectable • Refer for surgery, ?chemo upfront • EPOC B • Unresectable • K-Ras status • Chemotherapy for 3 months and reassess • SIRT (FOXFIRE trial)

  44. Chemotherapy • FOLFOX • Every 2 weeks for 6 cycles, PICC line • If k-ras wild-type and unresectable for Cetuximab • mAb EGFR • Celim study: ph 2 (Lancet Oncol 2010) • RR: 68% with FOLFOX and Cetuximab • Resectability increased from 32% to 60%

  45. Why liver resection? • Historically 50% colorectal cancer patients develop liver mets • 30% present with liver mets • Resection can give 5yr OS rates of 21-43%

  46. After liver resection • 3 months adjuvant chemotherapy • 6 monthly CT scans • Further liver resections may be possible

  47. Presentation with liver mets • 2 problems: liver and primary • Which will kill patient first? • Risk of obstruction – surgery vs stent? • Will delaying chemo harm patient? • Risk of micrometastatic disease elsewhere • Synchronous resections? • Controversial area

  48. Lung metastases • Extrapolate from liver data • Resection of <5 lung mets • No adjuvant chemo • PULMIC study

  49. Palliative Treatments

  50. Primary in situ • Does resecting the primary give an advantage? • Assess for obstruction • Stents • May prevent use of bevacizumab (anti-angiogenesis Ab)

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