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ECR 2018

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Interactive Workshop: Staging Rectal Cancer

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ECR 2018

  1. 1. THE ROYAL MARSDEN Rectal Cancer Gina Brown The Royal Marsden Hospital and Imperial College, London Gina.Brown@rmh.nhs.uk @prof_gina_brown Slides on www.profginabrown.com
  2. 2. THE ROYAL MARSDEN UNITED STATES of AMERICA CANADA ALASKA (USA) MEXICO COLOMBIA VENEZUELA BRAZIL PERU BOLIVIA HONDURAS NICARAGUA ECUADOR GUYANA SURINAME FRENCH GUIANA COSTA RICA PANAMA GUATEMALA CUBA PARAGUAY ARGENTINA URUGUAY CHILE GREENLAND ICELAND UNITED KINGDOM REPULIC OF IRELAND NORWAY SWEDEN FINLAND DENMARK ESTONIA LATVIA LITHUANIA POLAND BELARUS GERMANY CZECH REPUBLIC NETHERLANDS BELGIUM FRANCE SPAIN PORTUGAL SWITZ. AUSTRIA SLOVAKIA HUNGARY ROMANIA BULGARIA ITALY UKRAINE TURKEY GREECE SYRIA IRAQ SAUDI ARABIA YEMEN OMAN UAE EGYPTLIBYA ALGERIA MOROCCO TUNISIA WESTERN SAHARA MAURITANIA MALI NIGER CHAD SUDAN ETHIOPIA SOMALIAUGANDA SENEGAL GUINEA LIBERIA COTE D’IVOIRE BURKINA GHANA NIGERIA CAMEROON CENTRAL AFRICAN REPUBLIC GABONCONGO DEMOCRATIC REPUBLIC OF CONGO KENYA TANZANIA ANGOLA ZAMBIA NAMIBIA BOTSWANA ZIMBABWE REPUBLIC OF SOUTH AFRICA MADAGASCAR RUSSIAN FEDERATION KAZAKHSTAN GEORGIA IRAN UZBEKISTAN TURKMENISTAN AFGHANISTAN KYRGYZSTAN TAHKISTAN PAKISTAN INDIA CHINA NEPAL MYANMAR THAILAND SRI LANKA MONGOLIA NORTH KOREA SOUTH KOREA JAPAN TAIWAN CAMBODIA LAOS VIETNAM PHILIPPINES MALAYSIA INDONESIA PAPUA NEW GUINEA AUSTRALIA NEW ZEALAND www.profginabrown.com Rectal Cancer Workshops
  3. 3. THE ROYAL MARSDEN Using the Proforma
  4. 4. THE ROYAL MARSDEN
  5. 5. THE ROYAL MARSDEN
  6. 6. THE ROYAL MARSDEN Pelvic phased array: Coil Position incorrect correct
  7. 7. THE ROYAL MARSDEN
  8. 8. THE ROYAL MARSDEN Should we be using i.v. contrast to stage rectal cancers?
  9. 9. THE ROYAL MARSDEN Poor Quality little useful information! • T1 tumor and vessels are not distinguished leads to overstaging • Fat saturation – lost anatomy –fascial layers lost • Benign and malignant nodes enhance equally
  10. 10. MERCURY Standardised Technique • Slice thickness 3mm • 16cm FOV • 4-6 NSA • Min 256x256 matrix • TR >3,000, TE 80-100, ETL 16 • In plane resolution 0.6mm x 0.6mm • 6-7mins to obtain images To download protocol/ reporting templates www.profginabrown.com
  11. 11. THE ROYAL MARSDEN Is the puborectalis invaded? 1. Yes 2. No
  12. 12. THE ROYAL MARSDEN Check with the localiser
  13. 13. THE ROYAL MARSDEN What do we mean by accuracy? • Diagnostic Accuracy – STARD definitions – MERCURY
  14. 14. THE ROYAL MARSDEN STARD report by the MERCURY Study Group BMJ 2006;333:779 ©2006 by British Medical Journal Publishing Group
  15. 15. THE ROYAL MARSDEN Status by histopathology Clear Involved Total Primary surgery/short course radiotherapy‡: Clear 269 21 290 Involved 6 15 21 Total 275 36 311 After chemoradiotherapy§: Clear 58 1 59 Involved 21 17 38 Total 79 18 97 Accuracy=359/408 (88%, 95%CI 85% - 91%); NPV=327/349 (94%, 91% to 96%) PPV=32/59 (54%, 42% to 67%)…. So MRI is not accurate enough
  16. 16. THE ROYAL MARSDEN Survival outcomes according to magnetic resonance imaging– predicted circumferential resection margin (mrCRM) Fiona G.M. Taylor; Philip Quirke; Richard J. Heald; Brendan J. Moran; Lennart Blomqvist; Ian R. Swift; David Sebag-Montefiore; Paris Tekkis; Gina Brown; JCO 2014, 32, 34-43. DOI: 10.1200/JCO.2012.45.3258 Overall survival Disease-free survival Local Recurrence Prognostic accuracy of MRI is better than Diagnostic Accuracy
  17. 17. THE ROYAL MARSDEN mrCRM involvement defined as tumour spread (continuous or discontinuous) within 1mm of the TME plane (bounded by mesorectal fascia and intersphincteric plane). MRI CRM status independent risk factor for local recurrence (Hazard Ratio 3.5) mrCRM clear local recurrence 7% versus 20% if mrCRM involved pCRM clear local recurrence 6.5% versus 26% if pCRM involved
  18. 18. THE ROYAL MARSDEN mrCRM status as a prognostic and predictive biomarker
  19. 19. THE ROYAL MARSDEN 1. The anterior quadrant 2. The left lateral quadrant 3. The posterior quadrant 4. The right lateral quadrant 5. More than 1 quadrant Q1:Where is the closest circumferential margin? 1 2 3 4
  20. 20. THE ROYAL MARSDEN 1 2 3 4 Q1:Answer 1. The anterior quadrant 2. The left lateral quadrant 3. The posterior quadrant 4. The right lateral quadrant 5. More than 1 quadrant
  21. 21. THE ROYAL MARSDEN Raised Rolled Edges non-invasive versus Central Invasive Crater
  22. 22. THE ROYAL MARSDEN T staging • Location of tumour – anterior, posterior, r or l lateral • Morphology: annular, semi annular, polypoidal, ulcerating, mucinous, villous • For annular/ulcerating – location of central invasive portion vs raised edges are non invasive • For polypoidal/villous lesions – site of stalk • Invasive margin: nodular infiltrating, broad based pushing margin
  23. 23. THE ROYAL MARSDEN 1 2 3 4 1. The anterior quadrant 2. The left lateral quadrant 3. The posterior quadrant 4. The right lateral quadrant 5. More than 1 quadrant Q2: Where is the closest circumferential margin?
  24. 24. THE ROYAL MARSDEN 1 2 3 4 1. The anterior quadrant 2. The left lateral quadrant 3. The posterior quadrant 4. The right lateral quadrant 5. More than 1 quadrant Q2 Answer
  25. 25. THE ROYAL MARSDEN
  26. 26. THE ROYAL MARSDEN Morphological spectrum of tumours Semi-annular or annular Annular ulcerating Polypoida l Mucinous Annular ulcerating Annular pushing
  27. 27. THE ROYAL MARSDEN Q3: How will you report this lymph node? 1. >5mm high probability of being malignant 2. If it restricts on DWI then it is highly likely to be malignant 3. Cannot exclude that it is malignant – therefore describe it 4. Benign based on morphology 5. It makes no difference
  28. 28. THE ROYAL MARSDEN Q3 Answer 1. >5mm high probability of being malignant 2. If it restricts on DWI then it is highly likely to be malignant 3. Cannot exclude that it is malignant – therefore describe it 4. Benign based on morphology 5. It makes no difference
  29. 29. THE ROYAL MARSDEN Overstaging of nodes Size cannot be used to diagnose malignant nodes
  30. 30. THE ROYAL MARSDEN Size and number of enlarged nodes is a good prognostic factor!
  31. 31. THE ROYAL MARSDEN
  32. 32. THE ROYAL MARSDEN Are lymph nodes still a biomarker for local recurrence? The TME era 2000 - present The Dukes era 1932 - 1990s
  33. 33. THE ROYAL MARSDEN Randomised trial evidence unimportance of nodal status on local recurrence if a proper TME is performed • For a good quality total mesorectal excision that is circumferential resection margin negative – there is no difference – CR07 5-6% LR (Quirke et al Lancet Oncology) rates irrespective of node status, Lancet 2009 • OCUM trial (Germany) and Quicksilver trial (Canada) LR and stage III disease, is linked to poor quality surgery Where surgical quality is good and CRM is clear, lymph nodes are not associated with LR Lymph Nodes are not the cause of CRM involvement
  34. 34. THE ROYAL MARSDEN Limitations of the TNM – T3 category forms 80% of rectal cancers • Jass (St Marks, UK) : – independent prognostic significance • Harrison (Tennessee, USA): prognostic score depth of spread in mm • Cawthorne (Guildford, UK): depth of spread significance • Merkel and Hermanek (Erlangen, Germany) : – T3 subclassification • T3a <1mm • T3b>1-5mm, • T3c>5-15mm • T3d>15mm (TNM staging system 1993 supplement) Erlangen: >800 patients pT3<5mm N any same survival as T2 85% pT3>5mm N any, 54% survival T3<5mm T3>5mm
  35. 35. THE ROYAL MARSDEN “measuring extramural depth is the least subjective and most reliable of all the observations by radiologists” 295/311 (95 %) patients who underwent primary surgery. The mean difference between MRI and histopathology assessment of tumor EMD was -0.046 mm, SD = 3.85 mm, the 95 % CI was -0.487 to 0.395 mm. MRI and histopathology assessment of tumor spread are considered equivalent to within 0.5 mm (R). Radiology 2007
  36. 36. THE ROYAL MARSDEN MERCURY trial • 2002-2003 • 11 international centres (30 radiologists) • 295 patients undergoing primary surgery • Policy to avoid pre and post operative radiotherapy for mrCRM clear, mrEMVI negative, T3b or less rectal cancers, regardless of N stage
  37. 37. THE ROYAL MARSDEN Outcomes for MRI good prognosis rectal cancers: regardless of N stage Taylor et al, MERCURY Annals of Surgery 2011
  38. 38. THE ROYAL MARSDEN Q4:How would you report this? 1. A malignant lymph node 2. Focus of EMVI 3. An extranodal tumour deposit N1c 4. Not sure/ not important 5. Further investigations are needed: eg DWI or PET
  39. 39. THE ROYAL MARSDEN Q4: Answer 1. A malignant lymph node 2. Focus of EMVI 3. An extranodal tumour deposit N1c 4. Not sure/ not important 5. Further investigations are needed: eg DWI or PET
  40. 40. THE ROYAL MARSDEN How are TD Seen on MRI?We classify TD as discrete nodules within the mesenteric fat interrupting the course of veins and closely related to EMVI
  41. 41. THE ROYAL MARSDEN
  42. 42. THE ROYAL MARSDEN
  43. 43. THE ROYAL MARSDEN The clones in lymph nodes and in distant metastases are not the same
  44. 44. THE ROYAL MARSDEN Pathways of spread in colorectal cancer
  45. 45. THE ROYAL MARSDEN How do patients get recurrence from rectal cancer? to the lateral compartment To the liver to the lateral compartment
  46. 46. THE ROYAL MARSDEN Tumour deposits are seen in the Superior Rectal Vein and in branches of the middle rectal vein – therefore EMVI positive and N1c
  47. 47. THE ROYAL MARSDEN Tumour deposit in superior rectal vein– it is seen as a nodule in vein surrounded by fat therefore N1c and EMVI positive
  48. 48. THE ROYAL MARSDEN
  49. 49. THE ROYAL MARSDEN Tumour deposits in small vein branches – N1c
  50. 50. THE ROYAL MARSDEN Tumour deposit on left is in a small vein branch – N1c
  51. 51. THE ROYAL MARSDEN Contiguous EMVI in branches of middle rectal vein
  52. 52. THE ROYAL MARSDEN
  53. 53. THE ROYAL MARSDEN
  54. 54. THE ROYAL MARSDEN COMET TRIAL • Opened to recruitment 2017 MRI and Pathology study
  55. 55. THE ROYAL MARSDEN TD and EMVI Iris D. Nagtegaal; Nikki Knijn; Niek Hugen; Helen C. Marshall; Kenichi Sugihara; Tibor Tot; Hideki Ueno; Philip Quirke; JCO 2017, 35, 1119-1127. DOI: 10.1200/JCO.2016.68.9091
  56. 56. THE ROYAL MARSDEN The link between tumour deposits and EMVI A.C. Lord et al. European Journal of Cancer 82 (2017) 92-102
  57. 57. THE ROYAL MARSDEN TDs associated with worse DFS
  58. 58. THE ROYAL MARSDEN MRI-EMVI score & Outcome 0 20 40 60 80 100 0 1 2 3 4 5 6 Time since operation (Years) %Relapse-free MRI-EMVI score= 0-2 MRI-EMVI score= 3-4 p = 0·0015 71% 32% n=135. Median follow-up=3·12 (0·9-5·7) years. Smith et al. “Prognostic significance of MRI-detected Extramural Vascular Invasion." BJS. 2008
  59. 59. THE ROYAL MARSDEN Radiological predictors of Liver mets in the first 12 months (Slesser et al, in press)
  60. 60. THE ROYAL MARSDEN Variables Group Patient numbers Univariate analysis Multivariate analysis HR 95% CI P HR 95% CI P Patient characteristics Sex Female Male 67 121 Ref 1.093 0.625-1.912 0.756 Ref 0.93 0.53-1.68 0.832 Height Upper/mid Low 119 69 Ref 1.369 0.815-2.298 0.235 Ref 1.46 0.80-2.68 0.223 Baseline MR staging mrT stage Good Poor 51 137 Ref 1.187 0.638-2.206 0.588 Ref 1.12 0.51-2.43 0.782 mrN stage Negative Positive 65 123 Ref 1.196 0.691-2.071 0.523 Ref 1.72 0.90-3.28 0.199 mrEMVI Negative Positive 0 188 Ref 0.902 0.527-1.544 0.706 Ref 0.89 0.42-1.89 0.078 mrCRM Negative Positive 107 81 Ref 0.846 0.497-1.441 0.539 Ref 0.85 0.44-1.62 0.617 Post-CRT preoperative MR staging ymrT stage Good Poor 116 72 Ref 1.218 0.723-2.052 0.459 Ref 1.01 0.54-1.89 0.984 ymrN stage Negative Positive 104 84 Ref 1.179 0.701-1.982 0.534 Ref 0.431 0.21-0.91 0.206 ymrEMVI Negative Positive 89 99 Ref 1.987 1.237-4.323 0.004 Ref 1.97 1.01-3.90 0.044 ymrCRM Clear Involved/threatened 148 40 Ref 1.26 0.674-2.354 0.469 Ref 1.16 0.50-2.67 0.729 Final pathology staging ypT Good Poor 64 124 Ref 1.125 0.695-1.279 0.534 Ref 0.99 0.11-8.62 0.994 ypN Negative Positive 118 70 Ref 2.912 1.724-4.878 <0.001 Ref 3.41 0.91-12.82 0.069 ypEMVI Negative Positive 142 46 Ref 3.889 2.088-6.281 <0.001 Ref 2.39 1.11-5.14 0.026 ypCRM Negative Positive 178 10 Ref 3.352 1.421-7.907 0.006 Ref 1.32 1.24-2.38 0.032 Chand M, et al. Ann Surg 2015;261:473–479 UNIVARIATE AND MULTIVARIATE ANALYSIS By clinical, preoperative MRI and postoperative histopathology characteristics (Cox Proportional Hazards for DFS)
  61. 61. THE ROYAL MARSDEN 3-year DFS between ymrEMVI negative and ymrEMVI positive patients versus 3-year DFS between ypEMVI negative and ypEMVI positive patients Chand M, et al. Ann Surg 2015;261:473–479 0.00 1.0 0.8 0.6 0.4 0.2 0.0 Cumulativesurvival 10.00 20.00 30.00 40.00 Months ymrEMVI positive DFS 42.7% (95% CI 16.8-68.6%) ymrEMVI negative DFS 79.2% (95% CI 70.0-88.4%) ymrEMVI – 23/89 25.8% ymrEMVI+ 40/99 40.4% Recurrences 0.00 1.0 0.8 0.6 0.4 0.2 0.0 Cumulativesurvival 10.00 20.00 30.00 40.00 Months post CRT pathology EMVI positive DFS 36.9% (95% CI 15.7-48.1%) ypEMVI negative DFS 65.9% (95% CI 56.1-75.7%) ypEMVI – 34/142 23.9% ypEMVI+ 20/46 43.5% Recurrences
  62. 62. THE ROYAL MARSDEN POST CRT EFFECT ON MRI DETECTED EMVI – 3-YEAR DFS mrVein invasion neg mrVein converted pos to neg mrVein remains pos after Rx Chand M, et al. Ann Surg 2015;261:473–479
  63. 63. THE ROYAL MARSDEN What we know so far… • MRI staged T1/T2 EMVI negative mrN negative: 90% prediction of node negative status. Even if nodes positive …evidence suggests that they will never metastasise or be responsible for recurrence: Preserve and Tesar trials • MR staged T3a/b EMVI negative N any: primary surgery, neoadjuvant therapy and adjuvant chemo – no beneficial effect. • MR staged T any, EMVI positive – have Tumour deposits, spread to pelvic sidewall, high rate of CRM involvement, poorer DFS – preop CRT changes prognosis
  64. 64. THE ROYAL MARSDEN Lymph nodes versus extranodal deposits
  65. 65. THE ROYAL MARSDEN Early Rectal Cancer Staging
  66. 66. THE ROYAL MARSDEN Staging of ERC used to be suboptimal • Overstaging of lymph nodes • Underestimation of tumour • Underestimation of discontinuous EMVI • “Free-style”TEM – destruction of TME plane/ intersphincteric plane • Many missed pT1/earlyT2N0 undergoing radical surgery • Many patients undergoing completion TME/proctectomy with pT0N0 in final specimen
  67. 67. THE ROYAL MARSDEN Overstaging of nodes Size cannot be used to diagnose malignant nodes
  68. 68. THE ROYAL MARSDEN Underestimation of tumour
  69. 69. THE ROYAL MARSDEN
  70. 70. THE ROYAL MARSDEN
  71. 71. THE ROYAL MARSDEN Current problem • Almost 1/3 of screen detected rectal cancers are limited to the bowel wall without nodal spread but 90% undergo major anterior resection or abdominoperineal surgery with a high associated rate of co-morbidity and economic cost. • This is because previous attempts at offering less radical surgery have failed due to poor identification of patients suitable for the procedure.
  72. 72. THE ROYAL MARSDEN Hypotheses • Precision MRI staging of ERC significantly reduces the need for radical surgery compared with current national rates by instead offering a local endoluminal excision. • Using MRI to stage these will lead to a significant improvement in quality of life in patients diagnosed with early rectal cancer.
  73. 73. THE ROYAL MARSDEN Just look for the black stripe
  74. 74. THE ROYAL MARSDEN Recommended reporting structure for staging early rectal cancer using MRI • State morphology – flat, polypoidal, mucin containing • Measure diameter and thickness of lesion • If polypoidal –state site and diameter of fibromuscular stalk • If flat – quadrant or clockface location of central depression versus raised rolled edges • Measure extent/diameter of invasive border • Assess degree of preservation of the mucosa, submucosa, muscularis propria layers at the stalk • Assess lymph nodes for malignant characteristics based on nodal capsule breach or heterogeneity of signal • Assess height of lesion in relation to anal verge and puborectalis sling • Evaluate extramural veins for discontinuous spread
  75. 75. THE ROYAL MARSDEN Q5: How would you report this? 1. T1sm3/early T2 muscularis is visible – may be suitable for TEM 2. T2 – for primary surgery 3. T2/T3 4. T4 tumour
  76. 76. THE ROYAL MARSDEN Q5: Answer 1. T1sm3/early T2 muscularis is visible – may be suitable for TEM 2. T2 – for primary surgery 3. T2/T3 4. T4 tumour
  77. 77. THE ROYAL MARSDEN Full thickness TEM Morphology – flat semi-annular Diameter 16mm Thickness of lesion : 7mm Clockface location of central depression =4 oclock Invasive edge = 5mm diameter Muscularis fully preserved Submucosa/muscle interface lost over 3mm distance on single slice at 4 o’clock Lymph nodes show smooth nodal capsule and no heterogeneity - benign Assess height of 6.5 cm above anal verge and 12mm above puborectalis sling No extramural venous invasion T1sm3/ with potential focal early T2 invasion on a single slice section
  78. 78. THE ROYAL MARSDEN Full thickness TEM Morphology – flat semi-annular Diameter 16mm Thickness of lesion : 7mm Clockface location of central depressio =4 oclock Invasive edge = 5mm diameter Muscularis fully preserved Submucosa/muscle interface lost over 3mm distance on single slice at 4 o’cloc Lymph nodes show smooth nodal capsule and no heterogeneity - benign Assess height of 6.5 cm above anal ver and 12mm above puborectalis sling No extramural venous invasion T1sm3/ with potential focal early T2 invasion on a single slice section
  79. 79. THE ROYAL MARSDEN Local excision scar
  80. 80. THE ROYAL MARSDEN T1sm2 – pre-treatment Scar post TEM - no recurrence
  81. 81. THE ROYAL MARSDEN Balyasnikova S, Read J, Tait D, Wotherspoon A, Swift I, Cunningham D, Tekkis P, Brown G. Colorectal disease. 2016. 22/24 patients with low tumours and high risk features which would have required APER have so far avoided radical surgery and remain disease free at a median follow up 3.2 years.
  82. 82. MRI-PRESERVE 82 65 patients undergoing primary surgery/local excision for mrT3b or less tumours MRI accuracy for <T1sm2 =89%(95%Cl:63-87%) PPV 77%, NPV 92% MRI accuracy <T2 89% (95%Cl:79%-95%), PPV 93%, NPV 81% Kappa score 0.7 for radiologists (GB and SB) 21/65(32%) patients underwent local excision or TEM 20/21 were staged as MR<T2 and confirmed as such by pathology. On follow up, none had relapse. 65 patients undergoing primary surgery/local excision for mrT3b or less tumours MRI accuracy for <T1sm2 =89%(95%Cl:63-87%) PPV 77%, NPV 92% MRI accuracy <T2 89% (95%Cl:79%-95%), PPV 93%, NPV 81% Kappa score 0.7 for radiologists (GB and SB) 21/65(32%) patients underwent local excision or TEM 20/21 were staged as MR<T2 and confirmed as such by pathology. On follow up, none had relapse.
  83. 83. THE ROYAL MARSDEN MRI staged patients <T2 undergoing radical surgery • 22/44 were <mrT2. MRI accuracy in predicting lymph node status was 84%(95%Cl:70%-92%), PPV 71% and NPV 90% • If the decision had been made to offer local excision on MRI TN staging rather than clinical assessment a significant increase in organ preservation surgery from 32% to 60% would have been observed (difference 23%, 95%Cl:9%-35%) MRI-PRESERVE 83
  84. 84. THE ROYAL MARSDEN The PRESERVE trial • Non randomised control trial comparing MRI pathway with matched controls: non recruiting sites using Public Health England registry data for pT1 and pT2 rectal cancer patients Primary Endpoint: • To compare proportion of patients with pT1/pT2 cancers avoiding radical surgery in control versus interventional arm Secondary • Report Quality of life and survival outcomes at 3 and 5 years • Measure the cost savings to the NHS compared to the current standard of major surgery for ERC (hospital stay, perioperative mortality, complications and permanent colostomy)
  85. 85. THE ROYAL MARSDEN What has changed for early rectal cancer? • Better techniques and access • Improved pathology • Improved selection of patients with ERC • Better surveillance after TEM www.profginabrown.com
  86. 86. THE ROYAL MARSDEN Can we further stratify after initial treatment? • Reduce cumulative toxicity from over treatment of good responders • Intensify therapy in patients that remain at risk of relapse • Obtain tissue/blood markers of radioresistance – opportunity to develop new therapeutic agents
  87. 87. THE ROYAL MARSDEN WHAT SHOULD WE CONSIDER AS A GOOD RESPONSE? PCR? Infrequent finding for “clinically staged” T3 tumours Metaanalysis had shown that pCR was more likely achieved in clinical T1 and T2 tumours - ? Was there a survival advantage to achieving pCR for T1 and T2 tumours? Influence of timing of surgery on pCR Is pCR realistic goal for treatment of advanced rectal cancer? Maas M, et al. Lancet Oncol 2010;11:835–44. Reprinted from Lancet Oncology, Copyright 2010, with permission from Elsevier.
  88. 88. TIMING AFTER CRT? WHEN IS MAXIMUM RESPONSE REACHED? 6 weeks ymrT3b 12 weeks ymrT2 Baseline mrT4 invading Bladder and peritoneum Final Pathology: ypT2N0 Patients undergoing surgery with a delay of at least 8 weeks after completion of radiotherapy are 3 times more likely to undergo T downstaging (OR, 3.79; CI: 1.10 –12.99; P<0.03) than patients undergoing surgery at less than 8 weeks. A greater delay to surgery following the completion of pre-operative therapy is associated with an increased likelihood of achieving a pathological complete response. This is being prospectively tested in a randomised trial evaluating the timing of response assessment and surgery (the 6 vs. 12 trial) Dis Colon Rectum 2011;54:1251–9
  89. 89. THE ROYAL MARSDEN MR TRG  Assessment of tumour response using the mrTRG scale  Base line scans shows an annular tumour infiltrating the mesorectal margin between the 10 and 12 o'clock position. Post treatment, the intermediate (grey) signal of tumour has been replaced by fibrotic (black) signal with fibrosis involving the rectal wall and normal fat signal at the mesorectal margins. As no intermediate signal intensity remains within the dark fibrosis – this is classified as dense fibrosis only mrTRG2 with either no tumour cells or microscopic residual tumour cells of questionable long term viabilityPatel UB, et al. Am J Roentgenology 2012;199:W486–W95.
  90. 90. THE ROYAL MARSDEN 0 10 20 30 40 50 60 70 2006 2007 2008 2009 2010 2011 2012 2013 2014 PATIENT ACCRUAL FICARE 2007 Trial Protocol Proforma reporting mrTRG driven Clinical trial : Avoiding Surgery in Rectal Cancer After Pre-Operative Therapy, ClinicalTrials.gov Identifier: NCT01047969
  91. 91. THE ROYAL MARSDEN TRG 2 Good response : dense fibrosis; no obvious residual tumour, signifying microscopic residual disease only and on continued surveillance may become TRG1 no viable tumour Courtesy of The Royal Marsden Hospital
  92. 92. THE ROYAL MARSDEN Magnetic tumor regression grade identified 10 times more patients with a pathological complete response (diagnostic OR = 10.2 (95% CI, 1.30– 73.73) compared with clinical assessment with RMA. 17 detected using mrTRG 1-3 Further 30-40% patients with mrTRG 1-3 than pCR – what would have happened if we had deferred surgery for those….?
  93. 93. THE ROYAL MARSDEN Ruled out for deferral rate of regrowth for the eligible Clinical assessment (DRE, colonoscopy) 55/69 27% mr RECIST Reduction of cranio-caudal length > 50% 43/69 30% mr Volumetric analysis Volume reduction > 80% 40/69 30% DWI Hypointense signal (no tumour) 44/69 27% Clinical and T2+DWI Meet all of the above criteria 63/69 23% mrTRG TRG1 0/69 26%TRG2 TRG3 • mrTRG up to 10 times more likely to find patients suitable for deferral in advanced rectal cancer • The other evaluated methods reduce number of patients who could potentially avoid surgical treatment - with no improvement in specificity. MRI TRG performance of predicting lack of regrowth at 1 year
  94. 94. THE ROYAL MARSDEN mrTRG 1= Complete fibrosis Pretreatment. Post treatment. MRI Tumour Regression Grade (Grade 1-5) Good Response = 1&2. Poor Response = 3-5
  95. 95. THE ROYAL MARSDEN Pretreatment. Post treatment. mrTRG 5= no change from baseline MRI Tumour Regression Grade (Grade 1-5) Good Response = 1&2. Poor Response = 3-5
  96. 96. THE ROYAL MARSDEN mrTRG 1 -2 and pathology status when surgery is performed 6-8 weeks after CRT
  97. 97. THE ROYAL MARSDEN mrTRG vs DFS ypT vs DFS mrTRG as a predictor for DFS MRI Tumour Regression Grade (Grade 1-5) Good Response = 1&2. Poor Response = 3-5
  98. 98. THE ROYAL MARSDEN Overall Survival by TRG (1-2 v 3 v 4-5) after Chemo- Radiotherapy in EXPERT-C trial (both arms) mrTRG1-2 89.8% 65.9% 67.5% mrTRG1-2, 39.8% mrTRG3 , 29% mrTRG4-5, 31%
  99. 99. THE ROYAL MARSDEN TRIGGER: 30 Units recruiting/in set-up. You can join this trial! Contact: Michelle.Frost@rmh.nhs.uk @battersbynick International Set-up • Australia - Rodney Lynch • Brazil - Rodrigo Perez /Angelita Habr-Gama • Cyprus - Vasilis Vasiliou • Italy - Antonella Petrillo • Portugual - Tania Rodrigues • Slovenia - Veneja Velenik • South Korea - Kil Lee • Sri Lanka - Bawantha Gamage • Thailand - Art Hiryankas
  100. 100. THE ROYAL MARSDEN TRIGGER: More Units Welcome! Contact: Michelle.Frost@rmh.nhs.uk @battersbynick @prof_gina_brown Early Indications: • Radiologists can be reliably trained to perform mrTRG • Feasible to Recruit and Randomise • No severe adverse events in intervention arm to date
  101. 101. THE ROYAL MARSDEN Results: Recruitment (Sept 2017)
  102. 102. THE ROYAL MARSDEN Training and support of radiologists for mrTRG assessment in the TRIGGER trial
  103. 103. THE ROYAL MARSDEN A case to finish • Hx change in bowel habit 2 months • colonoscopy • 12/5/2017 • 2.5 cm rectal malignant looking lesion at 7 cms from anal verge - histology confirms adenocarcinoma Relevant Medical History and Comorbidities PMH • Hypothyroidism- thyroxine • BPH • Appendicectomy • Performance Status (WHO) 0
  104. 104. THE ROYAL MARSDEN
  105. 105. THE ROYAL MARSDEN
  106. 106. THE ROYAL MARSDEN
  107. 107. THE ROYAL MARSDEN Is the CRM at risk? 1. Yes 2. No
  108. 108. THE ROYAL MARSDEN Q6 : Answer No
  109. 109. THE ROYAL MARSDEN MRI detected Lymph Nodes close to the mesorectal fascia are not associated with pCRM involvement (Shihab et al, BJS 2010) • Involvement of CRM by lymph node metastases alone is uncommon (1.3% of all patients in MERCURY series). • Caution when recommending neoadjuvant therapy based solely on an MRI-detected lymph node close to the mesorectal fascia.
  110. 110. THE ROYAL MARSDEN The peritoneum is not a CRM
  111. 111. THE ROYAL MARSDEN Expectations from Preoperative Staging of Rectal Cancer • mrT and mrN stage is not enough to base treatment decisions: patients/colorectal MDTs need more information • mrT3<5mm MRI negative EMVI and clear CRM has a good prognosis irrespective of N status
  112. 112. THE ROYAL MARSDEN Validated prognostic biomarkers in Rectal Cancer • mrEMVI positvity: prevalence 40% at baseline • Post CRT EMVI status is also prognostic • MRI Tumour extramural spread >5mm is superior to T2 versus T3 category • MRI CRM unsafe risk factor for local recurrence • Patients with multiple enlarged nodes who are mrEMVI negative: prognostically good • Patients with lymph nodes close to CRM no additional risk of recurrence • mrTRG status as a means of determining next steps – being tested in phase III trial
  113. 113. THE ROYAL MARSDEN Further Resources : www.profginabrown.com Gina.Brown@rmh.nhs.uk @prof_gina_brown

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