BALKAN MCO 2011 - D. Sebag-Montefiore - Imaging and local therapy of rectal cancer

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BALKAN MCO 2011 - D. Sebag-Montefiore - Imaging and local therapy of rectal cancer

  1. 1. Rectal cancer David Sebag-Montefiore Professor of Clinical Oncology St James’s Institute of Oncology, Leeds,UK
  2. 2. The rectum Dutch UK 0-5cm >5-10cm >10-15cm German 0-6cm >6-12cm >12-18cm
  3. 3. The Holy Plane – Mesorectal Excision Mesorectal fat Mesorectal fascia
  4. 4. MRI – mesorectal fascia
  5. 5. Histopathology +ve CRM = microscopic tumour <=1mm from the painted margin
  6. 6. Role of circumferential margin involvement in the local recurrence of rectal cancer Adam et al Lancet 1994;344;707-711 <ul><li>All patients n=190 LR 29% </li></ul><ul><li>“ Curative resections” n=141 LR 23% </li></ul><ul><ul><li>CRM+ve (25%) n=35 LR 66% </li></ul></ul><ul><ul><li>CRM -ve (75%) n=106 LR 8% </li></ul></ul><ul><ul><li> </li></ul></ul><ul><li>Now confirmed in:- </li></ul><ul><ul><li>Local studies (Many UK inc Leeds) </li></ul></ul><ul><ul><li>National UK audit data </li></ul></ul><ul><ul><li>Norwegian audit </li></ul></ul><ul><ul><li>Within context of phase III trials (UK studies x2, Dutch x1) </li></ul></ul><ul><ul><li> </li></ul></ul>
  7. 7. How good is your surgeon? Quirke et al Lancet 2009 373:821-8
  8. 8. Grade of surgical excision specimen <ul><li>Mesorectal plane </li></ul><ul><ul><li>Intact mesorectum with only minor irregularities..smooth mesorectal surface..no defect greater than 5mm..smooth CRM on slicing </li></ul></ul><ul><li>Intra-mesorectal plane </li></ul><ul><ul><li>Moderate bulk to mesorectum with irregularities of the mesorectal surface..muscularis not visible with the exception of levator insertion.. Moderate irregularity of the CRM </li></ul></ul><ul><li>Muscularis propria plane </li></ul><ul><ul><li>Little bulk to mesorectum with defects down onto muscularis propria; very irregular CRM or both </li></ul></ul>
  9. 9. Mesorectal Intra-mesorectal Muscularis propria n=596 53% n=382 34% n=141 13% CR07 – Plane of surgical specimen Quirke et al Lancet 2009
  10. 10. Local recurrence Muscularis Propria Plane Intra Mesorectal Plane Mesorectal Plane HR 95% CI Surgery with selective post CRT 16% 10% 7% 0.48 (0.23-1.00) Pre-op RT 10% 4% 1% 0.09 (0.02-0.49)
  11. 11. RCP Minimum Colorectal Dataset http://www.rcpath.org/resources/pdf/G049-ColorectalDataset-Sep07.pdf
  12. 12. Pelvic MRI
  13. 13. MERCURY study Radiology 2007 243: 132-139; BMJ 2006 333:779-783 <ul><li>679 consecutive rectal cancer patients </li></ul><ul><li>Multicentre prospective observational study </li></ul><ul><li>27 colorectal surgeons, 18 radiologists </li></ul><ul><li>Standardised MRI protocol </li></ul><ul><li>Aim – to compare the findings on pre-op MRI with the histopathological specimen </li></ul>
  14. 14. Primary end point The MRI and histopathological measurements were considered equivalent when the 95% CI of the difference between them was +/- 0.5mm Observed mean extramural depth 2.80mm 2.81mm Extent of extramural spread on MRI Extent of extramural spread on histopathology =
  15. 15. MRI – Selection for pre-op (C)RT Margin at risk = Pre-op CRT <ul><li>Options </li></ul><ul><li>Surgery alone </li></ul><ul><li>Surgery then post-op CRT </li></ul><ul><li>Pre-op SCPRT then surgery </li></ul>
  16. 16. Rectal cancer – role of radiotherapy <ul><li>Reduce local recurrence </li></ul><ul><ul><li>Convincing and large evidence base </li></ul></ul><ul><ul><li>Regimens differ internationally </li></ul></ul><ul><li>Shrink locally advanced tumours </li></ul><ul><ul><li>Chemoradiation is the standard approach </li></ul></ul><ul><ul><li>Facilitate “curative resection” with clear margins </li></ul></ul><ul><li>Increase the chance of sphincter preservation </li></ul><ul><ul><li>Very controversial </li></ul></ul><ul><ul><li>Not evidence based </li></ul></ul><ul><li>Definitive treatment /Organ preservation </li></ul><ul><ul><li>In patients not fit for surgical resection </li></ul></ul>
  17. 17. Early stage disease – TREC study CRUK/Birmingham CTU – Simon Bach T2 or less node -ve - biopsy proven adeno suitable for TEM MRI and TRUS – no mets Anterior resection or APER RADICAL TME Resection DEFINITE DEFINITE UNCERTAIN
  18. 18. Systematic Overview n=8507 Lancet 2001;358:1291-304 5 years Pre-operative trials S RT+S Post-operative trials S RT+S Isolated LR 23% 15% 22% 12% P<0.00001 P=0.0002 Cancer specific mortality 12% proportional reduction (absolute=4%) p=0.0003 22% reduction (BED >30Gy) p=0.00002 9% reduction p=NS Overall survival 5.6% reduction SE 3.3 p=NS 4.6% reduction SE 5.9 p=NS
  19. 19. Causes of death Lancet 2001 358:1291-304
  20. 20. Radiotherapy regimens <ul><li>Short course pre-operative RT </li></ul><ul><ul><li>Developed in Sweden </li></ul></ul><ul><ul><li>25Gy in 5 fractions </li></ul></ul><ul><ul><li>Surgery within one week </li></ul></ul><ul><li>Long course chemoradiation (CRT) </li></ul><ul><ul><li>Radiation dose 45-54Gy </li></ul></ul><ul><ul><li>Concurrent fluoropyrimidine now standard </li></ul></ul><ul><ul><li>Benefit of additional drugs uncertain </li></ul></ul>
  21. 21. Dutch TME and MRC CR07 trial design n = 1350 Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases Adjuvant chemotherapy given as per local policy – CR07 PRE SEL POST Pre-operative RT 25Gy / 5F Surgery Pathology Surgery Pathology CRM-ve CRM+ve Post-op (C)RT Dutch RT CR07 CRT No CRT
  22. 22. Key conclusions from Dutch and CR07 <ul><li>Efficacy </li></ul><ul><ul><li>Reduced LR </li></ul></ul><ul><ul><li>No impact on OS so far </li></ul></ul><ul><li>Acute Toxicity </li></ul><ul><ul><li>No impact on anastomotic leak </li></ul></ul><ul><ul><li>Minimal impact on histopathological stage </li></ul></ul><ul><ul><li>Delay in perineal wound healing </li></ul></ul><ul><li>Late Toxicity </li></ul><ul><ul><li>Increase in sexual dysfunction </li></ul></ul><ul><ul><li>Bowel dysfunction inclusing incontinence (ant resection) </li></ul></ul><ul><ul><li>(Loss fertility, premature menopause, second malignancy) </li></ul></ul>
  23. 23. Local recurrence (ITT) – med FU 4 yrs Sebag-Montefiore et al 2009 0.0 0.2 0.4 0.6 0.8 1.0 Local Recurrence 0 1 2 3 4 5 Time (Years) PRE 674 27 4.4% SEL POST 676 72 10.6% 674 676 462 334 216 120 SEL POST 674 676 PRE Total Events 3 yr LR HR(95% CI) =0.39 (0.27-0.58) p=0.000004 587 477 342 242 137 594
  24. 24. Disease free survival (ITT) med FU 4 yrs Sebag-Montefiore et al 2009 674 676 462 334 216 120 SEL POST 674 676 PRE 587 477 342 242 137 594 0.0 0.2 0.4 0.6 0.8 1.0 Disease Free Survival 0 1 2 3 4 5 Time (Years) PRE 674 147 77.5% SEL POST 676 189 71.5% Total Events 3 yr DFS HR(95% CI) =0.76 (0.62-0.94) p=0.013
  25. 25. 3 year LR for T3a/b and T3c/d tumours Events N 3yr LR SEL POST Number at risk PRE 0.0 0.2 0.4 0.6 0.8 1.0 Local Recurrence 237 213 162 115 72 47 203 193 155 111 77 51 0 1 2 3 4 5 Years T3a/3b PRE 5 203 2.1% SEL POST 25 237 7.7% HR (95%CI) =0.27 (0.13-0.56), p<0.001 0.0 0.2 0.4 0.6 0.8 1.0 77 68 50 36 25 9 52 46 38 25 18 9 0 1 2 3 4 5 Years T3c/3d Events N 3yr LR PRE 2 52 4.3% SEL POST 14 77 13.5% HR (95%CI) =0.30 (0.11-0.82), p=0.192
  26. 26. Dutch trial 10 year data Marijnen et al ASTRO 2010 <ul><li>Local recurrence </li></ul><ul><ul><li>6.4% RT+TME vs 13.3% TME p<0.001 </li></ul></ul><ul><li>Overall recurrence </li></ul><ul><ul><li>28.8% RT + TME vs 33.6% TME p<0.042 </li></ul></ul><ul><li>Overall survival </li></ul><ul><ul><li>No difference </li></ul></ul><ul><li>In a subgroup with lymph node positive patients with a negative CRM, preoperative radiotherapy improves 10 year survival from 41% to 51%, p = 0.02 </li></ul>
  27. 27. Combined result from the trials <ul><li>Concurrent CRT became standard treatment </li></ul><ul><ul><li>FFCD and EORTC used 5FU/LV </li></ul></ul><ul><ul><li>German trial used 5FU </li></ul></ul><ul><ul><li>Recent change to oral fluoropyrimidine </li></ul></ul><ul><li>Change from post-op CRT to pre-op CRT </li></ul><ul><ul><li>Lower rate of LR </li></ul></ul><ul><ul><li>Less acute and late toxicity </li></ul></ul><ul><ul><li>Important to select correct patients </li></ul></ul>
  28. 28. FFCD 9203 trial n= 733 Gerard et al JCO 2006;24:4620-6 Primary end point – Overall survival improvement 10% RT 45Gy / 25 , RT 45Gy / 25 + concurrent 5FU/LV Post-op 5FU/LV Post-op 5FU/LV S S
  29. 29. FFCD 9203 trial – Outcome measures Gerard et al JCO 2006;24:4620-6 RT alone CRT p value Local recurrence 17% 8% P=0.004 PFS 55.5% 59.4% HR 0.96 (0.77-1.20) OS 67.9% 67.4% HR 0.96 (0.73-1.27)
  30. 30. EORTC 22921 trial n=1011 Bosset et al NEJM 2006;355:1114-23 n= 253 RT 45Gy / 25 . RT long course + concurrent 5FU/LV S S Post-op 5FU/LV Post-op 5FU/LV No chemo No chemo n= 252 n= 253 n= 253 n= 505 n= 506
  31. 31. EORTC 22921 trial – Local recurrence Bosset et al NEJM 2006;355:1114-23 Evidence of an interaction between pre-op and post-op chemotherapy p=0.09 RT n=252 17% (95% CI 12.3-21.9) RT + post C n=253 9.6% (95% CI 5.7-13.5) CRT n=253 8.7% (95% CI 4.9-12.6) CRT + post C n=253 7.6% (95% CI 4.2-11)
  32. 32. EORTC 22921 – Progression free survival Bosset et al NEJM 2006;355:1114-23 27% of patients randomised to post-op chemotherapy did not start treatment RT RT + post C 54.4% p=0.52 56.1% Pre CRT Pre CRT + post C 52.2% 58.2% p=0.13
  33. 33. German Rectal Cancer Study Group n=823 Sauer et al 2004; 351:1731-40 RT 45Gy / 25 + concurrent 5FU/LV RT 45Gy / 25 + concurrent 5FU/LV S S Post-op 5FU/LV Post-op 5FU/LV
  34. 34. German RCSG - Outcome Sauer et al 2004; 351:1731-40 Pre-op CRT Post-op CRT p value Primary end point Overall survival 10% improvement LR 6% 13% P=0.006 PFS 68% 65% P=0.32 OS 76% 74% P=0.80
  35. 35. German RCSG – Toxicity Sauer et al 2004; 351:1731-40 Pre-op CRT Post-op CRT p value Acute G3/4 27% 40% P=0.001 Late G3/4 14% 24% P=0.01
  36. 36. Summary of RT/CRT studies <ul><li>Lowers local recurrence </li></ul><ul><ul><li>Should therefore by risk adapted </li></ul></ul><ul><li>No difference in survival </li></ul><ul><li>Increased long term sides effects </li></ul><ul><li>No evidence re sphincter preservation </li></ul><ul><li>BALANCE between risk and benefit </li></ul>
  37. 37. TROG AGIT LSSANZ RACS trial Ngan et al ASCO 2010 CRT – 5FU 225mg/m2 50.4Gy CRT Short course Pre op (25Gy in 5F) N=326 S 5FU/LV x4 S 5FU/LV x 6 Resectable T3 on TRUS or MRI and >90% 10cm or less from anal verge
  38. 38. TROG AGIT LSSANZ RACS trial Ngan et al ASCO 2010 CRT n=163 SCRT n=163 3 year local recurrence 4% 7% P=0.27 5 yr FFS 67% 71% P=0.46 5 yr OS 74% 70% P=0.56 RTOG Grade 3/4 late toxicity 8% 9% P=0.84 Quality of life No significant difference ASCO 2008
  39. 39. TROG AGIT LSSANZ RACS trial Ngan et al ASCO 2010
  40. 40. SCPRT and delay to surgery <ul><li>Radu et al 2007 </li></ul><ul><ul><li>pCR 2/24 (8%) in patients without mets and unfit for SCPRT </li></ul></ul><ul><li>Hatfield et al </li></ul><ul><ul><li>Median age 82 </li></ul></ul><ul><ul><li>pCR 2/24 (8%) </li></ul></ul><ul><li>Stockholm III trial (Petterson et al) </li></ul><ul><ul><li>SCPRT imm vs SCRT delay vs 50Gy in 25F </li></ul></ul><ul><ul><li>pCR 15/120 (12.5%) </li></ul></ul>
  41. 41. <ul><li>Good </li></ul><ul><ul><li>Avoid Radiotherapy </li></ul></ul><ul><li>Bad </li></ul><ul><ul><li>SCPRT/CRT </li></ul></ul><ul><li>Ugly </li></ul><ul><ul><li>CRT </li></ul></ul>Tailored treatment
  42. 42. International differences <ul><li>Multidisciplinary team meetings (MDT) </li></ul><ul><li>Use of short course radiotherapy </li></ul><ul><li>Selection criteria for chemoradiation </li></ul><ul><li>Surgical specialisation and quality </li></ul><ul><li>Rates of sphincter preserving surgery </li></ul>
  43. 43. Intensification of pre-op CRT Second drug Molecular targeted therapy Integration systemic chemotherapy
  44. 44. Phase III trials – Evaluating +/-Oxaliplatin Eligibility Platform NSABP R04 N=1500 <12cm; resectable stage II, III TRUS or MRI – CT if T4/ N1-2 PVI 5FU Capecitabine FFCD N=598 Palpable; resectable; T3/4 N0-2; T2 distal anterior Capecitabine STAR – 01 N=747 Resectable stage II, III <12cm from anal verge PVI 5FU PETTAC 6 N=1090 Stage II or III resectable or expected to become resectable <12cm from anal verge Capecitabine
  45. 45. NSABP R04 – Factorial 2x2 Primary end point- Locoregional relapse Oxaliplatin 50mg/m2 x 5 Capecitabine 825mg/m2 bd 5 days / week PVI 5FU 225mg/m2 Capecitabine 825mg/m2 bd 5 days / week Oxaliplatin 50mg/m2 x 5 PVI 5FU 225mg/m2
  46. 46. STAR-01 trial Aschele et al ASCO 2009 Oxaliaplatin 50mg/m2 x 6 PVI 5FU 225mg/m2 50.4Gy CRT PVI 5FU 225mg/m2 50.4Gy CRT N=747 S 5FU (PVI or with LV S 5FU (PVI or with LV
  47. 47. CRT acute toxicity 5FU CRT Ox 5FU CRT p value Any G3/4 8% 24% p=0.001 Gd 3/4 diarrhoea 4% 15% p=0.001 Grade II neuro/sens 1% 36% P=0.001 RT compliance 97% 90% NS Treatment related death 0.3% 0.6% NS
  48. 48. Histopathology 5FU CRT Ox 5FU CRT pCR (ypT0ypN0) 16% 16% ypT0 17% 18% ypT1-2 35% 35% ypT3-4 44% 42% ypN0 70% 68% pM1 3% 0.5% CRM +ve 6 4
  49. 49. Prodige/ACCORD 12/0450 trial Gerard et al ASCO 2009 Oxaliaplatin 50mg/m2 x 5 Capecitabine 800mg/m2 * 50.4Gy CRT Capecitabine 800mg/m2 45 Gy CRT N=598 S Centre policy S Centre policy
  50. 50. CRT acute toxicity 5FU CRT Ox 5FU CRT p value Any Grade 3/4 11% 25% p=0.001 Grade 3/4 diarrhoea 3% 13% p=0.001 Haematological Gd 3/4 4% 5% P=NS Grade II neuro sensory 0.4% 5% P=0.02
  51. 51. Histopathology 5FU CRT Ox 5FU CRT P value pCR 14% 19% 0.11 No tumour + microfoci 30% 41% P=0.008 ypT0 14% 19% P=0.11 ypN0 70% 68% NS CRM +ve 12% 7% P=0.21
  52. 52. Oxaliaplatin Capectabine Cetuximab CRT ph II Rodel et al JCO 2007;IJROBP 2008 Ox Cap Cetxumib CRT Historical data Ox Cap RT Number 48 /60 ph II doses 110 Oxaliplatin Capectabine 50mg/m2 x 4 825mg/m2 4 weeks (13 at 500/650 ph I) 50mg/m2 x 4 825mg/m2 4 weeks RT dose 50.4Gy 50.4Gy Gd 3/4 diarrhoea 19% 12% pCR (Gd 4 TRG) 9% 19% TRG 3+4 (pCR + >50% regression) 47% 74%
  53. 53. Irinotecan Capetabine Cetuximab CRT Willeke et al BJC 2007; Horisberger IJROBP 2009 Ir Cap Cetxumib CRT Historical data Ir Cap RT Number 50 36 Irinotecan Capectabine 40mg/m2 x 5 500mg/m2 bd 4 cont 50mg/m2 x 5 500mg/m2 bd cont RT dose 50.4Gy 50.4Gy Gd 3/4 diarrhoea 30% 4% pCR 8% 15% pCR + microfoci NS 41%
  54. 54. ARISTOTLE – Phase III trial testing standard CRT (one drug) versus combination CRT (two drugs) NCRI rectal cancer group Funded by Cancer Research UK / UCL CTU
  55. 55. ARISTOTLE – NCRI phase III CTAAC Funded MRI defined locally advanced rectal cancer No metastases Capectabine CRT (Cape 900mg/m2 5 days/week) Declare proposed post-op chemotherapy policy Irinotecan Capecitabine CRT (Capecitabine 650mg/m2 5d/wk Irinotecan 60mg/m2 wk 1-4) Proposed post-op policy Proposed post-op policy SURGERY (8-10 weeks) SURGERY (8-10 weeks) N=920 Primary end point – Disease Free survival n=920
  56. 56. MRI defined eligibility Levator Puborectalis External sphincter Internal sphincter Diagram adapted from Shihab et al Lancet Oncology 2009
  57. 57. 0-5cm >5-10-5cm >10cm Local recurrence pattern Dutch trial Nijkamp et al IJROBP 2010 online doi:10.1016
  58. 58. Superior and Inferior Limits to the Clinical Target Volume
  59. 59. Clinical Target Volume
  60. 60. Conclusions <ul><li>Simple pathological assessment extremely useful and predicts outcome </li></ul><ul><li>Adjuvant radiotherapy </li></ul><ul><ul><li>Selection using imaging </li></ul></ul><ul><ul><li>Strong evidence supporting SPCRT and CRT </li></ul></ul><ul><li>Intensification of CRT experimental </li></ul><ul><li>Radiotherapy QA – hitting the target whilst reducing the toxicity </li></ul>

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