MCC 2011 - Slide 22

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MCC 2011 - Slide 22

  1. 1. Follow-up: Evidence and optimalisation Klaas Havenga University Medical Center Groningen The Netherlands
  2. 2. This talk: <ul><li>Rationale </li></ul><ul><li>Approaches </li></ul><ul><li>Trials </li></ul><ul><li>Framing </li></ul><ul><li>CEAwatch </li></ul><ul><li>Summary </li></ul>
  3. 3. <ul><li>Increase survival </li></ul><ul><ul><li>By early detection and treatment of recurrent disease </li></ul></ul><ul><ul><li>30 - 50% stage II - III develop recurrence </li></ul></ul><ul><li>Prevent metachronous (new) colon cancer </li></ul><ul><ul><li>By colonoscopies </li></ul></ul><ul><li>Managing patient’s problems & questions </li></ul><ul><ul><li>Maybe better done by oncology nurse </li></ul></ul><ul><li>Document results </li></ul><ul><ul><li>For auditing purposes </li></ul></ul><ul><li>Make some money </li></ul><ul><ul><li>Depending on reimbursement structure </li></ul></ul>Rationale to FU  Approaches  Trials  Framing  CEAwatch  Summary
  4. 4. Results of hepatic resection for colorectal cancer Source: Uptodate Rationale to FU  Approaches  Trials  Framing  CEAwatch  Summary Author and year Number of patients 5 yr OS, percent Hughes, KS; 1986 607 33 Scheele, J; 1995 434 33 Nordlinger, B; 1996 1568 28 Jamison, RL; 1997 280 27 Fong, Y; 1999 1001 37 Iwatsuki, S; 1999 305 32 Choti, M; 2002 133 58 Abdalla, E; 2004 190 58 Fernandez, FG; 2004 100 58 Wei, AC; 2006 423 47 Rees, M; 2008 929 36 De Jong, M; 2009 1669 47 Morris, EJ; 2010 3116 44
  5. 5. Developments in treatment of metastatic disease <ul><li>Liver metastasis surgery </li></ul><ul><ul><li>Increasingly available </li></ul></ul><ul><ul><li>Increased possibilities </li></ul></ul><ul><ul><ul><li>RFA, Microwave ablation, selective portal vein embolisation, combination of ablation and resection, stereotactic radiotherapy </li></ul></ul></ul><ul><li>Long metastasis treatment </li></ul><ul><ul><li>VATS, stereotactic radiotherapy </li></ul></ul><ul><li>Increased succes of palliative treatment </li></ul>Rationale to FU  Approaches  Trials  Framing  CEAwatch  Summary
  6. 6. <ul><li>Office visit </li></ul><ul><ul><li>History and physical examination </li></ul></ul><ul><li>Endoscopy </li></ul><ul><ul><li>Rigid proctoscopy or colonoscopy </li></ul></ul><ul><li>CEA testing </li></ul><ul><li>Imaging </li></ul><ul><ul><li>Liver ultrasound </li></ul></ul><ul><ul><li>CT scanning </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  7. 7. Office Visits <ul><li>Follow up of 530 patients (in adjuvant trial - stage II & III) </li></ul><ul><li>1993 - 1999 </li></ul><ul><li>Median FU 5.6 yrs </li></ul><ul><li>Outpatients visits: </li></ul><ul><ul><li>every 3 months in first year </li></ul></ul><ul><ul><li>Every 6 months in second year </li></ul></ul><ul><ul><li>Annually thereafter </li></ul></ul><ul><li>156 relapses </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  8. 8. . Chau I et al. JCO 2004;22:1420-1429 ©2004 by American Society of Clinical Oncology Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  9. 9. Office Visits <ul><li>Problem with symptomatic recurrence: </li></ul><ul><ul><li>Not clear if found by history or physical examination </li></ul></ul><ul><ul><li>Only 3.1% underwent curative treatment </li></ul></ul>Rationale  Approaches to FU  Trials  Guidelines  CEAwatch  Summary
  10. 10. Office Visits <ul><li>Benefit has never been demonstrated </li></ul><ul><ul><li>ASCO </li></ul></ul><ul><ul><ul><li>Maintain doctor - patient relation </li></ul></ul></ul><ul><ul><ul><li>Facilitate arranging diagnostic testing </li></ul></ul></ul><ul><ul><ul><li>Discuss test results and risk assessment </li></ul></ul></ul><ul><ul><li>Deutsche Krebsgesellschaft: </li></ul></ul><ul><ul><ul><li>No benefit in early detection </li></ul></ul></ul><ul><ul><ul><li>Still advised based on consensus </li></ul></ul></ul><ul><ul><li>Dutch guidelines: </li></ul></ul><ul><ul><ul><li>Office visit every 6 months </li></ul></ul></ul><ul><ul><ul><li>No specific evidence provided </li></ul></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  11. 11. Endoscopy: colonoscopy <ul><li>Risk of metachronous cancer or polyps: 1.5 - 3 % </li></ul><ul><li>ASCO </li></ul><ul><ul><li>Pre- or perioperative documentation of polyp free colon </li></ul></ul><ul><ul><li>At 3 years, then every 5 years </li></ul></ul><ul><li>Deutsche Krebsgesellschaft: </li></ul><ul><ul><li>Before surgery or < 6months after surgery </li></ul></ul><ul><ul><li>At 3 years, then every 5 years </li></ul></ul><ul><li>Dutch guidelines: </li></ul><ul><ul><li>Before surgery or <3 months after surgery </li></ul></ul><ul><ul><li>At 2-3 years, then after 3 or 6 years, depending on # polyps </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  12. 12. Endoscopy: sigmoidoscopy <ul><li>ASCO </li></ul><ul><ul><li>Flexible sigmoidoscopy </li></ul></ul><ul><ul><li>Rectal cancer, LAR, without radiation therapy </li></ul></ul><ul><ul><li>Every 6 months upto 5 years </li></ul></ul><ul><li>Deutsche Krebsgesellschaft: </li></ul><ul><ul><li>Rigid proctoscopy or flexible sigmoidoscopy </li></ul></ul><ul><ul><li>Rectal cancer, LAR, without radiation therapy </li></ul></ul><ul><li>Dutch guidelines: </li></ul><ul><ul><li>No advice </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  13. 13. Carcino Embryonic Antigen <ul><li>Glycoprotein involved in cell adhesion </li></ul><ul><li>Production stops before birth </li></ul><ul><li>Marker of colorectal cancer (recurrence) </li></ul><ul><li>May also be positive in: </li></ul><ul><ul><li>Gastric cancer, pancreas cancer, lung cancer, breast cancer, medullary thyroid cancer </li></ul></ul><ul><ul><li>Ulcerative colitis, Crohn’s disease, pancreatitis, cirrhosis, </li></ul></ul><ul><ul><li>smokers </li></ul></ul><ul><li>Normal value 2.0 - 2.5 ng/ml </li></ul><ul><li>Usual treshold in clinical practice: 5.0 ng/ml </li></ul><ul><li>High levels (e.g. > 15): highly suspective for recurrence </li></ul>Rationale  Approaches to FU  Trials  Guidelines  CEAwatch  Summary
  14. 14. Carcino Embryonic Antigen <ul><li>Treshold of 5.0 vs. 2.5 ng/ml </li></ul><ul><ul><li>Increase specificity </li></ul></ul><ul><ul><li>Decrease sensitivity </li></ul></ul><ul><ul><ul><li>Delay in diagnosis? </li></ul></ul></ul><ul><ul><li>Based on outdated CT techniques </li></ul></ul><ul><ul><li>Hypothesis: CEA rise is important: </li></ul></ul><ul><ul><ul><li>E.g. 20% - 25% rise in 2-3 months </li></ul></ul></ul><ul><ul><ul><li>If above 2.0 - 2.5 ng/ml </li></ul></ul></ul><ul><ul><ul><li>Consider increased frequency testing </li></ul></ul></ul><ul><ul><ul><li>CEAwatch study (later) </li></ul></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  15. 15. Grossmann et al. CEA measurement during follow-up for rectal carcinoma is useful even if normal levels exist before surgery <ul><li>CEA in follow up often omitted if preop CEA is normal </li></ul><ul><li>TME trial data (n=1861, 954 eligible for analysis) </li></ul><ul><li>Recurrent disease occured in 272 (29.5%) </li></ul><ul><li>Results: normal CEA 63% (<5.0) or 39% (<2.5) </li></ul><ul><li>Patients with normal preop CEA and recurrent disease had elevated CEA </li></ul><ul><ul><li>41% (CEA < 5.0) </li></ul></ul><ul><ul><li>50% (CEA < 2.5) </li></ul></ul><ul><li>Conclusion: </li></ul><ul><ul><li>normal CEA preop is common </li></ul></ul><ul><ul><li>CEA does rise in at least 50% of patients with normal preop CEA in the situation of a recurrence </li></ul></ul><ul><ul><li>Serial CEA testing can not be discarded based on normal preop CEA </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  16. 16. . Chau I et al. JCO 2004;22:1420-1429 ©2004 by American Society of Clinical Oncology Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  17. 17. Carcino Embryonic Antigen <ul><li>Arguments in favor of CEA testing </li></ul><ul><ul><li>CEA testing finds asymptomatic recurrence </li></ul></ul><ul><ul><li>Lead time to symptoms: probable </li></ul></ul><ul><ul><li>Lead time to other means of detection </li></ul></ul><ul><ul><ul><li>1.5 - 6 months (old CT?) </li></ul></ul></ul><ul><li>Arguments against CEA testing </li></ul><ul><ul><li>30 - 40% of recurrences do not make CEA ?? </li></ul></ul><ul><ul><li>Not cost effective ?? </li></ul></ul><ul><ul><li>Not proven to increase quality of life ?? </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  18. 18. Carcino Embryonic Antigen <ul><li>ASCO </li></ul><ul><ul><li>CEA testing every 3 months for at least 3 years </li></ul></ul><ul><li>Deutsche Krebsgesellschaft: </li></ul><ul><ul><li>CEA testing every 6 months for at least 2 years </li></ul></ul><ul><li>Dutch guidelines: </li></ul><ul><ul><li>CEA testing </li></ul></ul><ul><ul><ul><li>every 3 to 6 months in year 1-3 </li></ul></ul></ul><ul><ul><ul><li>Every 6 months in year 4-5 </li></ul></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  19. 19. Imaging <ul><li>Liver ultrasound </li></ul><ul><ul><li>Not a syllable in ASCO guideline or Uptodate </li></ul></ul><ul><ul><li>Deutsche Krebsgesellschaft: </li></ul></ul><ul><ul><ul><li>Advised because cheap and harmless </li></ul></ul></ul><ul><ul><ul><li>No frequency mentioned </li></ul></ul></ul><ul><ul><li>Dutch guidelines </li></ul></ul><ul><ul><ul><li>At six months, 12 months and yearly thereafter </li></ul></ul></ul><ul><li>Proven?: see trials </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  20. 20. Imaging <ul><li>CT scanning </li></ul><ul><ul><li>Abdomen, chest, pelvis? </li></ul></ul><ul><ul><li>Enourmous advancement in recent years </li></ul></ul><ul><ul><ul><li>64 detector multislice with contrast </li></ul></ul></ul><ul><ul><li>Therefore all old data outdated </li></ul></ul><ul><li>Arguments against: </li></ul><ul><ul><li>Cost, radiation, resources </li></ul></ul><ul><li>ASCO: </li></ul><ul><ul><li>Annual CT of abdomen and chest </li></ul></ul><ul><ul><ul><li>For ‘higher risk’ patients </li></ul></ul></ul><ul><ul><ul><li>Also pelvis in rectal cancer </li></ul></ul></ul><ul><li>Deutsche Krebsgesellschaft: </li></ul><ul><ul><li>Not routinely </li></ul></ul><ul><li>Dutch guidelines: </li></ul><ul><ul><li>Only if ultrasound is technically impossible </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  21. 21. . Chau I et al. JCO 2004;22:1420-1429 ©2004 by American Society of Clinical Oncology Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  22. 22. Not supported <ul><li>No support in literature or guidelines </li></ul><ul><ul><li>Chest X-ray </li></ul></ul><ul><ul><li>PET scanning </li></ul></ul><ul><ul><li>CA 19.9 </li></ul></ul><ul><ul><li>Fecal occult blood testing </li></ul></ul><ul><ul><li>Liver tests etc. </li></ul></ul><ul><ul><li>Barium enema </li></ul></ul><ul><ul><li>CT colonography </li></ul></ul><ul><ul><li>Molecular of cellular markers </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  23. 23. Figueredo - BioMed Central 2003 <ul><li>Systematic review </li></ul><ul><li>6 randomized trials 1997 – 2002 </li></ul><ul><li>2/6 trials demonstrate advantage intense FU </li></ul><ul><li>Pooling: improved survival intense FU: relative risk ratio 0.8 (95% CI 0.7-0.91) </li></ul><ul><ul><li>Similar rates of recurrence intense/non intense FU </li></ul></ul><ul><ul><li>More asymptomatic recurrence in intense FU group </li></ul></ul><ul><ul><li>More reoperation in intense FU group </li></ul></ul><ul><li>Intense FU includes: CEA, chest X-ray, liver imaging, colonoscopy </li></ul><ul><li>Not clear what is important from these studies. </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  24. 24. Jeffery 2007 (Cochrane) <ul><li>Meta analysis randomized controlled trials comparing different FU strategies </li></ul><ul><ul><li>More intense FU better survival: OR 0.73 (95% CI 0.59 to 0.91) </li></ul></ul><ul><ul><ul><li>absolute number of recurrences was similar </li></ul></ul></ul><ul><ul><li>more tests versus fewer tests OR was 0.64 (95% CI 0.49 to 0.85) </li></ul></ul><ul><ul><li>liver imaging versus no liver imaging OR was 0.64 (95% CI 0.49 to 0.85) </li></ul></ul><ul><li>Best combination and frequency of tests / visits is unknown </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  25. 25. <ul><li>Included trials Figueredo: </li></ul><ul><ul><li>Makela 1995 </li></ul></ul><ul><ul><li>Ohlsson 1995 </li></ul></ul><ul><ul><li>Kjeldsen 1997 </li></ul></ul><ul><ul><li>Schoemaker 1998 </li></ul></ul><ul><ul><li>Pietra 1998 </li></ul></ul><ul><ul><li>Secco 2002 </li></ul></ul>Rationale  Approaches to FU  Trials  Guidelines  CEAwatch  Summary <ul><li>Included trials Jefferey: </li></ul><ul><ul><li>Makela 1995 </li></ul></ul><ul><ul><li>Ohlsson 1995 </li></ul></ul><ul><ul><li>Kjeldsen 1997 </li></ul></ul><ul><ul><li>Schoemaker 1998 </li></ul></ul><ul><ul><li>Pietra 1998 </li></ul></ul><ul><ul><li>Secco 2002 </li></ul></ul><ul><ul><li>Rodriguez 2006 new </li></ul></ul><ul><ul><li>Wattchow 2006 new </li></ul></ul>
  26. 26. Wattchow 2006 (Australia) General practice vs surgical-based follow-up for patients with colon cancer: randomised controlled trial. <ul><li>Randomization of 203 curatively treated colon cancer patients </li></ul><ul><li>FU by general practicioner vs. surgeon </li></ul><ul><li>FU protocol identical: </li></ul><ul><ul><li>clinical review every 3 months </li></ul></ul><ul><ul><li>Annual faeces occult blood </li></ul></ul><ul><ul><li>Colonoscopy every 3 years </li></ul></ul><ul><li>Primary outcome: </li></ul><ul><ul><li>Quality of life SF-12 </li></ul></ul><ul><ul><li>Hospital anxiety and depression scale </li></ul></ul><ul><ul><li>Patient satisfaction </li></ul></ul><ul><li>Secondary outcomes at 24 months </li></ul><ul><ul><li>Investigations </li></ul></ul><ul><ul><li>Number and timing of recurrence </li></ul></ul><ul><ul><li>Death </li></ul></ul><ul><li>Results: no differences in primary or secondary outcomes </li></ul><ul><ul><li>more FOBT ordered by GP’s </li></ul></ul><ul><ul><li>More ultrasounds ordered by surgeons </li></ul></ul>Rationale  Approaches to FU  Trials  Guidelines  CEAwatch  Summary
  27. 27. Discussing Wattchow trial <ul><li>No serious systematic effort to identify early recurrence </li></ul><ul><li>Not designed to detect increased survival </li></ul>Rationale  Approaches to FU  Trials  Guidelines  CEAwatch  Summary
  28. 28. Rodriguez (2006, Barcelona) . <ul><li>Stage II or III colorectal cancer </li></ul><ul><li>Randomization 1997 2001 (n=259) </li></ul><ul><ul><li>Simple strategy: clinical evaluation and CEA monitoring, colonoscopy </li></ul></ul><ul><ul><li>Intense strategy: idem + annual chest X ray + abdominal CT (rectal cancer) or US (colon cancer) every 6 months (yr 1-2) or annualy (yr 3-5) </li></ul></ul><ul><li>Non inferiority design </li></ul><ul><li>Primary outcome survival at 5 year </li></ul><ul><li>Results after median 48 months FU </li></ul><ul><ul><li>No survival difference whole group: </li></ul></ul><ul><ul><li>Survival benefit stage II tumors: HR 0.34 95% CI 0.12 – 0.98 </li></ul></ul><ul><ul><li>Survival benefit rectal cancer: HR 0.09 95% CI 0.01 – 0.81 </li></ul></ul><ul><li>CEA positive: 25% rise and > normal limit </li></ul><ul><li>First method to detect recurrence in simple strategy: </li></ul><ul><ul><li>CEA 22/34 (65%) liver function test / anemia: 2/34 </li></ul></ul><ul><li>First method to detect recurrence in intense strategy: </li></ul><ul><ul><li>CT/US: 31%, colonoscopy 26%, lab 23% </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  29. 29. Rodriguez (2006, Barcelona) . <ul><li>No overall survival benefit </li></ul><ul><li>But: intense FU assumed better </li></ul><ul><ul><li>More resectable recurrences found </li></ul></ul><ul><ul><li>Increased survival probability in stage II or rectal tumors </li></ul></ul><ul><li>My comment: </li></ul><ul><ul><li>Complicated reasoning in paper </li></ul></ul><ul><ul><li>Small numbers </li></ul></ul><ul><ul><li>Gives no clear answer on what to do </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  30. 30. Evidence for CT? Confused? <ul><li>No direct evidence </li></ul><ul><ul><li>Meta-analysis: intense FU </li></ul></ul><ul><li>Follow-up series: CT only positive metastases </li></ul><ul><li>Consider: improvements in CT </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  31. 31. General considerations <ul><li>For patients </li></ul><ul><ul><li>every FU visit brings back memories </li></ul></ul><ul><ul><li>Causes fear for recurrence or death </li></ul></ul><ul><ul><li>Every testresult will take time </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  32. 32. General considerations <ul><li>If I suggest no FU: </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  33. 33. General considerations <ul><li>Select patients for follow up </li></ul><ul><ul><li>Finding resectable recurrence may lead to resection </li></ul></ul><ul><ul><ul><li>Co-morbidity </li></ul></ul></ul><ul><ul><ul><li>Age </li></ul></ul></ul><ul><ul><ul><li>Patient’s preference </li></ul></ul></ul><ul><ul><li>Finding irresectable recurrence will lead to chemotherapy?? </li></ul></ul><ul><ul><li>In case of co-morbidity or old age: </li></ul></ul><ul><ul><ul><li>Consider limited or no follow-up </li></ul></ul></ul><ul><li>Use informed consent </li></ul><ul><li>Follow-up of follow-up: is metastasis surgery available? </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  34. 34. CEAwatch <ul><li>Intranet based software </li></ul><ul><ul><li>Behind hospital firewall </li></ul></ul><ul><ul><li>Based on open source software </li></ul></ul><ul><ul><ul><li>MySQL databse, Java, PHP </li></ul></ul></ul><ul><ul><li>All follow-up patients in database </li></ul></ul><ul><ul><li>Every night this list is checked for new values </li></ul></ul><ul><ul><li>New values are presented on CEAwatch working page </li></ul></ul><ul><ul><li>Semi automatic reporting to patiënt </li></ul></ul><ul><li>CEA testing without outpatient clinic visits </li></ul><ul><li>One outpatient contact / year </li></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  35. 35. APR 02-07-2010 female pt 10-06-1960 T3N0 Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  36. 36. CEAwatch - study <ul><li>Aim: </li></ul><ul><ul><li>Increasing the percentage curable metastases of CRC by finding them in an earlier, treatable stage by intensifying the follow-up with a large role for CEA </li></ul></ul><ul><ul><li>Developing an evidence-based guideline for follow-up of CRC </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  37. 37. CEAwatch - study <ul><li>Study group: </li></ul><ul><ul><li>CEA every 8 weeks </li></ul></ul><ul><ul><li>Computed Tomography (CT) scan at significant rise in CEA </li></ul></ul><ul><ul><li>Rise in CEA: increase > 20% compared to last CEA, followed by increase > 20% after 4 weeks </li></ul></ul><ul><ul><li>CT scan of thorax and abdomen at year 1 and 2 after tumor resection (independent of CEA) </li></ul></ul><ul><li>Control group: </li></ul><ul><ul><li>Follow-up according to previous protocol </li></ul></ul>Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  38. 38. Stepped wedge design Patients in control group Time Patients in intervention group 1st Hospital randomization Rationale  Approaches to FU  Trials  Framing  CEAwatch  Summary
  39. 39. <ul><li>Primary medical goal is to improve survival </li></ul><ul><li>The optimal FU scheme is ‘intense’ </li></ul><ul><li>Test CEA even in case of normal preop CEA </li></ul><ul><li>Use CEA rise (e.g. 25% > 2.5) instead of static value </li></ul><ul><li>Consider CT thorax/abdomen in high risk patients </li></ul><ul><li>Select patients </li></ul><ul><li>Inform patients </li></ul><ul><li>Have patients consent to FU </li></ul>Rationale to FU  Approaches  Trials  Guidelines  CEAwatch  Summary

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