Department of Surgery, University Medical Center Groningen Multidisciplinary treatment of locally advanced rectal cancer T...
Multidisciplinary treatment of locally advanced rectal cancer  T3 + T2
Rectal cancer subgroups:     “the good”:     no radiotherapy   “the bad”:     short course 5x5 Gray   “the ugly”:     long...
This lecture <ul><li>Definition </li></ul><ul><li>10 FAQ </li></ul><ul><li>Take home messages </li></ul>Multidisciplinary ...
Definition <ul><li>Any primary rectal tumor with a chance after a Total Mesorectal Excision  </li></ul><ul><li>of a R1 res...
Definition ( = outcome) <ul><li>Any primary rectal tumor with a chance after a Total Mesorectal Excision  </li></ul><ul><l...
Definition (=input) <ul><li>Fixed or tethered tumors  </li></ul><ul><li>Any T4, any T3 with  a predicted margin of less th...
Goals (neo) adjuvant treatment =strategy <ul><li>Decrease of local recurrences (if the expected rate is over 5%)  </li></u...
10 FAQ’s <ul><li>How to stage locally advanced tumors? </li></ul><ul><li>Are lymph nodes important ? </li></ul><ul><li>Wha...
<ul><li>MRI ! </li></ul>Multidisciplinary treatment of locally advanced rectal cancer How to stage locally advanced tumors ?
Are lymph nodes important ?  Pathological lymph nodes outside the endopelvic fascia Multidisciplinary treatment of locally...
What is the optimal radiation dose?   <ul><li>Total dose: 45 - 50 Gy </li></ul><ul><li>Schedules: conventional fractionate...
Postoperative radiotherapy  after R1 resection Marijnen et al  In J Rad Oncol 2003 Multidisciplinary treatment of locally ...
Radiotherapy Schedules  HART <ul><li>Phase II, 250 patients, preoperative hyperfractionated accelerated radiotherapy, 250 ...
Radiotherapy Extra <ul><li>Hyperthermia: </li></ul><ul><ul><li>Phase II 37 patients 45 Gy +5-FU  hyperthermia each week pr...
Is there a standard chemotherapy regime ?  Yes chemoradiation <ul><li>EORTC 22921  2x2 factorial designed 1011 patients  L...
Preoperative chemoradiotherapy (CRT)  with Capecitabine and Oxaliplatin,  in advanced rectal cancer.  A phase I-II multi-c...
Improvement of chemoradiation not likely <ul><li>Intensifying chemotherapy: </li></ul><ul><ul><li>More toxicity without cl...
What is the optimal time interval ?  <ul><li>Phase III, 5x5 Gy with direct surgery versus 50.4 Gy chemoradiation with surg...
Optimal time interval <ul><li>107 patients with different time intervals between chemoradiation and surgery </li></ul><ul>...
Which kind of surgery is necessary?  Does chemoradiation and long interval improve sphincter preserving rates? <ul><li>Bal...
Which kind of surgery is necessary?  Multidisciplinary treatment of locally advanced rectal cancer <ul><li>Stick to your o...
<ul><li>Total Mesorectal Excision </li></ul><ul><li>Total Mesorectal Excision  “en bloc” with  adjacent organs   </li></ul...
Technical aspects  <ul><li>Primary goal is a  R0  resection (both circumferential and distal) </li></ul><ul><li>Sharp  dis...
Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><ul><...
Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><ul><...
Vaginal reconstruction Multidisciplinary treatment of locally advanced rectal cancer
Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><li>P...
Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><ul><...
“ Filling the gap” Multidisciplinary treatment of locally advanced rectal cancer
What to do with synchronous metastases ? <ul><li>Prognosis depends on the distant metastases </li></ul><ul><li>The respons...
Synchronous metastases M1 study <ul><li>Phase II study short course radiation therapy, neoadjuvant bevacizumab, capecitabi...
Adjuvant chemotherapy Multidisciplinary treatment of locally advanced rectal cancer ?
Rutten et al 2003 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 1  2  3  4  5  6  7   years Locally  advanced  rectal cancer Overall surv...
Take home <ul><li>How to stage locally advanced tumors? </li></ul><ul><li>MRI </li></ul><ul><li>Are lymph nodes important ...
Take home <ul><li>What is the optimal time interval ? </li></ul><ul><li>Unclear but 6-8 weeks should be enough </li></ul><...
Next step: <ul><li>RAPIDO </li></ul>Multidisciplinary treatment of locally advanced rectal cancer  R ectal cancer  A nd  P...
Next step: <ul><li>RAPIDO </li></ul>Multidisciplinary treatment of locally advanced rectal cancer  Locally advanced tumour...
I like movies Multidisciplinary treatment of locally advanced rectal cancer  Thank you for your attention Happy to answer ...
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MCC 2011 - Slide 26

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  1. 1. Department of Surgery, University Medical Center Groningen Multidisciplinary treatment of locally advanced rectal cancer Theo Wiggers Cascais, Portugal February 16 th , 2011
  2. 2. Multidisciplinary treatment of locally advanced rectal cancer T3 + T2
  3. 3. Rectal cancer subgroups: “the good”: no radiotherapy “the bad”: short course 5x5 Gray “the ugly”: long course chemoradiation Multidisciplinary treatment of locally advanced rectal cancer ?
  4. 4. This lecture <ul><li>Definition </li></ul><ul><li>10 FAQ </li></ul><ul><li>Take home messages </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  5. 5. Definition <ul><li>Any primary rectal tumor with a chance after a Total Mesorectal Excision </li></ul><ul><li>of a R1 resection of ? percent and a subsequent local recurrence rate of ? percent </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  6. 6. Definition ( = outcome) <ul><li>Any primary rectal tumor with a chance after a Total Mesorectal Excision </li></ul><ul><li>of a R1 resection of 10 percent and a subsequent local recurrence rate of 5 percent </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  7. 7. Definition (=input) <ul><li>Fixed or tethered tumors </li></ul><ul><li>Any T4, any T3 with a predicted margin of less than 1 millimeter to the endopelvic fascia : most distal tumors are advanced </li></ul><ul><li>Any lymph node outside the TME field </li></ul><ul><li>Any presence of distant metastases </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  8. 8. Goals (neo) adjuvant treatment =strategy <ul><li>Decrease of local recurrences (if the expected rate is over 5%) </li></ul><ul><li>Facilitate resection! </li></ul><ul><li>Improve sphincter preserving rates ? </li></ul><ul><li>Increase in overall survival ? </li></ul><ul><li>To allow more local excisions (TEM) ? </li></ul><ul><li>To allow wait full watching? </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  9. 9. 10 FAQ’s <ul><li>How to stage locally advanced tumors? </li></ul><ul><li>Are lymph nodes important ? </li></ul><ul><li>What is the optimal radiation dose ? </li></ul><ul><li>Is there a standard chemotherapy regime ? </li></ul><ul><li>How do we predict and evaluate response ? </li></ul><ul><li>What is the optimal time interval ? </li></ul><ul><li>Which kind of surgery is necessary? </li></ul><ul><li>What to do with synchronous metastases ? </li></ul><ul><li>Is adjuvant chemotherapy necessary ? </li></ul><ul><li>How is the prognosis after treatment ? </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  10. 10. <ul><li>MRI ! </li></ul>Multidisciplinary treatment of locally advanced rectal cancer How to stage locally advanced tumors ?
  11. 11. Are lymph nodes important ? Pathological lymph nodes outside the endopelvic fascia Multidisciplinary treatment of locally advanced rectal cancer Clinical relevance yes! Inclusion in the radiation field Removal if still present on MRI after chemoradiation
  12. 12. What is the optimal radiation dose? <ul><li>Total dose: 45 - 50 Gy </li></ul><ul><li>Schedules: conventional fractionated, 5x5 Gy, hyperfractionated accelerated radiotherapy (HART) </li></ul><ul><li>Extra: hyperthermia, IORT </li></ul><ul><li>Conformation of fields </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  13. 13. Postoperative radiotherapy after R1 resection Marijnen et al In J Rad Oncol 2003 Multidisciplinary treatment of locally advanced rectal cancer
  14. 14. Radiotherapy Schedules HART <ul><li>Phase II, 250 patients, preoperative hyperfractionated accelerated radiotherapy, 250 patients T3,T4,N+ </li></ul><ul><li>41.6 Gy (1.6 Gy per fraction twice daily) total treatment time 17 days, interval to surgery one week </li></ul><ul><li>Local recurrence rate 8.3% at 5-years </li></ul><ul><li>Overall survival 59.6% </li></ul><ul><li>No downstaging </li></ul>Multidisciplinary treatment of locally advanced rectal cancer Coucke, Radiotherapy and Oncology 79,2006
  15. 15. Radiotherapy Extra <ul><li>Hyperthermia: </li></ul><ul><ul><li>Phase II 37 patients 45 Gy +5-FU hyperthermia each week prior to radiotherapy 84% R0 feasible good local control </li></ul></ul><ul><li>Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases </li></ul>Multidisciplinary treatment of locally advanced rectal cancer Rau Strahlenther Onkol 1998 Kusters et al Annals of Oncology 21: 1279–1284, 2010 Unfortunately, it is difficult to study the quantitative effect of IORT. But fact is that the 5-year LR rate of 12.0% is very low in this high-risk group of patients. Further, 55% of the patients with positive surgical margins did not develop LR, suggesting that these residual tumor cells were sterilized
  16. 16. Is there a standard chemotherapy regime ? Yes chemoradiation <ul><li>EORTC 22921 2x2 factorial designed 1011 patients LR 17% XRT, 9% CRT OS ns </li></ul><ul><li>Bosset, NEJM 2006 </li></ul><ul><li>FFCD 9203 733 patients LR 16,5% XRT , 8% CRT OS ns </li></ul>Multidisciplinary treatment of locally advanced rectal cancer Gerard, NEJM 2006
  17. 17. Preoperative chemoradiotherapy (CRT) with Capecitabine and Oxaliplatin, in advanced rectal cancer. A phase I-II multi-centre study of the Dutch Colorectal Cancer Group <ul><li>Oxaliplatin 85 mg/m 2 , Capecitabine 1000mg/m2 bid </li></ul><ul><li>21 patients </li></ul><ul><li>pCR 10%, R0 81% </li></ul><ul><li>Local recurrence 1 (follow-up 2 years) </li></ul>Hospers et al Eur J Cancer 2007 Multidisciplinary treatment of locally advanced rectal cancer
  18. 18. Improvement of chemoradiation not likely <ul><li>Intensifying chemotherapy: </li></ul><ul><ul><li>More toxicity without clear increase in R0 resections and overall survival </li></ul></ul><ul><ul><li>pCR is not a good marker (small series, different pathology) </li></ul></ul><ul><ul><li>R0 resection rate is a good surrogate marker </li></ul></ul><ul><li>Use of biological modifiers: bevacizumab: </li></ul><ul><ul><li>Probably more morbidity no better effect </li></ul></ul>Multidisciplinary treatment of locally advanced rectal cancer
  19. 19. What is the optimal time interval ? <ul><li>Phase III, 5x5 Gy with direct surgery versus 50.4 Gy chemoradiation with surgery after 4-6 weeks , toxicity more in chemoradiation, effect the same </li></ul><ul><li>Retrospective comparison two regimens after long course chemoradiation: two versus six weeks: less downstaging no effect local recurrence rate </li></ul>Multidisciplinary treatment of locally advanced rectal cancer Bujko, BJS 2006 Veenhof, Int J Colorectal Dis. 2007
  20. 20. Optimal time interval <ul><li>107 patients with different time intervals between chemoradiation and surgery </li></ul><ul><li>A longer time interval between chemo/RT and surgery was associated with tumour downstaging </li></ul><ul><li>A longer time interval was not associated </li></ul><ul><ul><li>nodal downstaging </li></ul></ul><ul><ul><li>pathologic complete response (PCR) </li></ul></ul><ul><ul><li>likelihood of performing an LAR </li></ul></ul><ul><ul><li>improved disease free survival (DFS), local control or distant control </li></ul></ul>Multidisciplinary treatment of locally advanced rectal cancer J Surg Oncol. 2007
  21. 21. Which kind of surgery is necessary? Does chemoradiation and long interval improve sphincter preserving rates? <ul><li>Balance between sphincter preservation and incontinence </li></ul><ul><li>Recent review phase III studies : no difference </li></ul>Department of Surgery, University Medical Center Groningen Multidisciplinary treatment of locally advanced rectal cancer
  22. 22. Which kind of surgery is necessary? Multidisciplinary treatment of locally advanced rectal cancer <ul><li>Stick to your original plan </li></ul><ul><li>Exception: </li></ul><ul><ul><li>Large bulky tumors, </li></ul></ul><ul><ul><li>Presence of extra nodal disease </li></ul></ul>
  23. 23. <ul><li>Total Mesorectal Excision </li></ul><ul><li>Total Mesorectal Excision “en bloc” with adjacent organs </li></ul><ul><li>uterus </li></ul><ul><li>vagina </li></ul><ul><li>bladder </li></ul><ul><li>vesicles </li></ul><ul><li>prostate </li></ul><ul><li>sacrum </li></ul><ul><li>Total Mesorectal Excision with lateral extension or inguinal resection </li></ul>Surgical options in locally advanced rectal cancer Multidisciplinary treatment of locally advanced rectal cancer
  24. 24. Technical aspects <ul><li>Primary goal is a R0 resection (both circumferential and distal) </li></ul><ul><li>Sharp dissection under direct vision many times not in anatomical planes , based on pathophysiology and extension on imaging </li></ul><ul><li>Conservation of nerves and sphincter complex in most cases not possible </li></ul><ul><li>Reconstruction of bladder, pelvic floor and/or vagina </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  25. 25. Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><ul><li>lateral </li></ul></ul>Multidisciplinary treatment of locally advanced rectal cancer Stripping of the fascia of the sacrum, Resection of the sacrum (below S3) or os coccyx
  26. 26. Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><ul><li>lateral </li></ul></ul>Multidisciplinary treatment of locally advanced rectal cancer Resection outside the TME field (sometimes with resection of the vessels)
  27. 27. Vaginal reconstruction Multidisciplinary treatment of locally advanced rectal cancer
  28. 28. Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><li>Perineal (knee elbow position) </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  29. 29. Technique <ul><li>Abdominal </li></ul><ul><ul><li>retrorectal </li></ul></ul><ul><ul><li>anterior </li></ul></ul><ul><ul><li>lateral </li></ul></ul><ul><li>Perineal (knee elbow position) </li></ul>Exposure to the operative field is better Hydrostatic venous pressure is lower, reducing bleeding Assistance and tutoring is feasible Gravity will pull the perineum downwards, flattening the pelvic floor Multidisciplinary treatment of locally advanced rectal cancer
  30. 30. “ Filling the gap” Multidisciplinary treatment of locally advanced rectal cancer
  31. 31. What to do with synchronous metastases ? <ul><li>Prognosis depends on the distant metastases </li></ul><ul><li>The response on induction chemotherapy predicts outcome </li></ul><ul><li>Many tumors are locally advanced </li></ul><ul><li>A rectum resection is a big operation </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  32. 32. Synchronous metastases M1 study <ul><li>Phase II study short course radiation therapy, neoadjuvant bevacizumab, capecitabine and oxaliplatin, radical resection of primary tumor and metastases in primary stage IV rectal cancer </li></ul><ul><li>Primary endpoint: % R0 resection of all tumour sites. Secondary endpoints: t wo-year survival, two-year recurrence rate, treatment associated toxicity </li></ul><ul><li>Start 5x5 Gy followed by two cycles of chemotherapy, evaluation if progress consider resection otherwise two more cycles followed by surgery (primary tumor and liver) </li></ul><ul><li>High response rate: 72 % R0 resection </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  33. 33. Adjuvant chemotherapy Multidisciplinary treatment of locally advanced rectal cancer ?
  34. 34. Rutten et al 2003 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 1 2 3 4 5 6 7 years Locally advanced rectal cancer Overall survival; radiation vs chemoradiation CRT RT p=0.017 start 3 5 rs CRT 100% 67% 57% RT 100% 50% 43% T3 Dutch TME study
  35. 35. Take home <ul><li>How to stage locally advanced tumors? </li></ul><ul><li>MRI </li></ul><ul><li>Are lymph nodes important ? </li></ul><ul><li>Yes clinical relevant especially outside the TME field </li></ul><ul><li>What is the optimal radiation dose? </li></ul><ul><li>Between 45-50 Gray either 5x5 or conventional fractionated </li></ul><ul><li>Is there a standard chemotherapy regime </li></ul><ul><li>capcetabine </li></ul><ul><li>How do we evaluate response </li></ul><ul><li>Sometimes MRI if extension due to tumor bulk was difficult to access and lymph nodes outside TME field were present </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  36. 36. Take home <ul><li>What is the optimal time interval ? </li></ul><ul><li>Unclear but 6-8 weeks should be enough </li></ul><ul><li>Which kind of surgery is necessary? </li></ul><ul><li>Total Mesorectal Excision in T3+ </li></ul><ul><li>TME with adjacent structures in T4 </li></ul><ul><li>What to do with synchronous metastases? </li></ul><ul><li>Induction chemotherapy (with radiotherapy) </li></ul><ul><li>Is adjuvant chemotherapy necessary ? </li></ul><ul><li>Not outside trials </li></ul><ul><li>How is the prognosis after treatment ? </li></ul><ul><li>Similar to limited T3 cases </li></ul>Multidisciplinary treatment of locally advanced rectal cancer
  37. 37. Next step: <ul><li>RAPIDO </li></ul>Multidisciplinary treatment of locally advanced rectal cancer R ectal cancer A nd P re-operative I nduction therapy followed by D edicated O peration experimental group : 5 x 5 Gy radiation followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin) and surgery control group : with long course chemoradiotherapy followed by surgery
  38. 38. Next step: <ul><li>RAPIDO </li></ul>Multidisciplinary treatment of locally advanced rectal cancer Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to TNM version 5), cT4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient. Positive MRF (previously named CRM), i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes, > 1 cm (lat LN+).
  39. 39. I like movies Multidisciplinary treatment of locally advanced rectal cancer Thank you for your attention Happy to answer questions

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