Colorectal Cancer Therapy: What’s New?

1. Colorectal Cancer Therapy:What’s New? Robert D. Madoff, MD Professor of Surgery University of Minnesota

2. colorectal cancer treatmentwhat’s new • better screening • better surgery • less invasive surgery • shorter hospital stays • better adjuvant therapy • more options for advanced disease

3. age-adjusted cancer deathsUSA, 1930-2000 males females Jemal 2004

6. life-saving interventionscost-effectiveness interventioncost/year life saved mandatory motorcycle helmets $2000 colorectal cancer screening $25,000 breast cancer screening $35,000 dual airbags in cars $120,000 smoke detectors in homes $210,000 seat belts in school buses $2,800,000 Harvard Center for Risk Analysis Tengs 1995

7. FOBTrandomized controlled trials

9. virtual colonoscopy Macari 2005

10. virtual vs. optical colonoscopysensitivity * polyps > 10 mm Pickhardt 2003

11. preoperative care “we are creatures of habit and tradition”

12. mechanical bowel prep • time-honored! • does it do any good?

13. mechanical bowel preprandomized controlled trial 153 patients, left colon resection Bucher 2005

14. mechanical bowel preprandomized controlled trial Bucher 2005

15. mechanical bowel preparationmeta-analysis Slim 2004

16. “fast track” colon surgery • epidural analgesia • small and low incisions • avoidance of narcotics • no nasogastric tube • early feeding • early ambulation • routine laxative dose

17. “fast track” colon surgery 10 length of hospital stay (days) Kehlet 2004

18. “Let’s just start cutting and see what happens.”

20. lap vs. open colectomymorbidity

21. lap vs. open colectomyOR time

22. lap vs. open colectomyduration of ileus (days)

23. painindirect measures • COLOR- decreased opiates day 2 &3, p<0.001 • decreased use of epidurals, p<0.01 • COST - fewer days of parenteral narcotics; 3.2 vs 4.0, p<0.001 • Leung - fewer injections of analgesics; 4.5 vs 6.9, p< 0.001

24. laparoscopic colectomyadequacy of resection • results from 6 trials including 3,719 cancer patients have been reported • no difference in median number of nodes between laparoscopic and open groups • no difference in resection margins between open and laparoscopic groups for colon cancer

25. open vs. laparoscopic-assisted colectomy COST study 2004

26. colorectal cancerlaparoscopic vs. open surgery cancer-related survival Lacy 2002

27. postoperative care

28. colon canceradjuvant chemotherapy

29. colon cancer chemotherapynew agents • orally active 5-FU prodrugs • capecitabine (Xeloda) • tegafur • irinotecan • oxaliplatin

30. colon cancer chemotherapynew combinations • IFL • 5-FU (bolus), irinotecan, leucovorin • FOLFIRI • 5-FU (infusion), irinotecan, leucovorin • FOLFOX • 5-FU (infusion), oxaliplatin, leucovorin

31. 3-year DFS FOLFOX (n=1123) 77.8% LV5FU (n=1123) 72.9% Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01 adjuvant therapy Oxaliplatin/5FU: the MOSAIC trial

32. colon cancer chemotherapynew biologics • cetuximab (Erbitux) • monoclonal antibody directed against epidermal growth factor receptor • bevacizumab (Avastin) • monoclonal antibody directed against vascular endothelial growth factor • inhibits creation of new blood vessels (angiogenesis) needed for tumor growth

33. molecular markers

34. surgery for stage IV disease • curative intent • palliative intent • prevent bleeding • prevent perforation • prevent obstruction

35. is that operation necessary?

36. surgery for palliation • stage IV patients, 66 treated with surgery, 23 treated non-operatively • non-operative group • 9% of non-operative pts required surgery • no hemorrhage from primary • 91% surgery-free survival rate • operative group • 4.6% perioperative mortality • 30% perioperative morbidity Scoggins 1999

37. be conservative!

39. less is more • dramatic advances in medical therapy for advanced disease • endoscopically placed stents often an option in obstruction • may change standard of care

40. colorectal cancerisolated metastases liver lung

41. be aggressive!

42. untreated colorectal liver metastasesnatural history # of ptssurvival (m)5-ys (%) Jaffe 13 10 - Bengmark 40 6 0 Cady 269 13 - Oxley 112 - 1 Wood 113 7 1 Bengtsson 25 5 0 Wagner 252 - 2

43. resection of CR liver metastasesrecent results median 5-year n mortality morbidity survival survival (%) (%) (months) (%) Schlag 122 4 34 28 Doci 100 5 39 30 Rosen 280 4 34 25 Gajowski 204 0 33 32 Scheele 434 4 22 33 Wanebo 74 7 38 35 24 Fong 456 3 24 46 38

44. hepatic resectioncontraindications • extrahepatic disease • unable to obtain negative margin • not medically fit • co-morbid medical problems • insufficient hepatic reserve (may resect up to 6 segments in normal liver)

45. prognostic scoring systemMSKCC • LN + primary • DFI <12 months • size > 5 cm • >1 tumor • CEA > 200 % 5 yr survival score

46. synchronous liver metastasesone or two operations? advantages of 1-Stage operation • one anesthetic • shorter overall recovery • safe in selected centers disadvantages of 1-stage operation • requires preparation and expertise • ? safety outside major center

47. repeat hepatic resection n mortality (n) median survival Stone 10 0 25 months Bozzetti 10 1 23 Valliant 16 1 33 Elias 28 1 30 Que 21 1 41 Fong 25 0 30 Tuttle 23 0 40

48. increasing resectability • decrease tumor size • chemotherapy • increase hepatic reserve • preoperative embolization • staged resections • limit loss of parenchyma • ablative techniques

49. unresectable hepatic metastaseschemotherapy/salvage surgery • 1439 patients with CRC liver metastases • 335 (23%) resectable • 1104 (77%) unresectable combined chemotherapy • 138 (13% of initially unresectable group) rendered resectable • overall resection rate 23% 33% Adam 2004

50. Adam 2004