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

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

3. malesfemales Jemal 2004 age-adjusted cancer deaths USA, 1930-2000

6. life-saving interventions cost-effectiveness intervention cost/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. FOBT randomized controlled trials center# pts CRC deaths survivalstage Minnesota46,551 33%improvedshifted Nottingham150,251 15%improvedshifted Denmark61,993 18%improvedshifted

9. Macari 2005 virtual colonoscopy

10. virtual vs. optical colonoscopy sensitivity sensitivity (%) virtual92 optical88 * 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 prep randomized controlled trial 153 patients, left colon resection prep (%) no prep (%) f anastomotic leak61NS intraabdominal abscess13NS peritonitis10NS wound abscess1030.07 all infections2280.03 Bucher 2005

14. mechanical bowel prep randomized controlled trial prep (days) no prep (days) p NG2.81.90.007 1 st BM3.92.50.001 oral intake4.53.50.004 hospital stay14.99.90.02 Bucher 2005

15. mechanical bowel preparation meta-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 length of hospital stay (days) 10 Kehlet 2004

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

20. lap vs. open colectomy morbidity study lapopen COLOR21%20% CLASICC10% COST23%21% Leung20%23% Tang20%14% Braga21%38% Lacy11%26%

21. lap vs. open colectomy OR time study lapopendif COLOR14511530 CLASICC18013545 COST150 9555 Leung19014446 Tang 88 7018 Braga22217745 Lacy14211824

22. lap vs. open colectomy duration of ileus (days) study lapopenp COLOR3.64.60.0001 CLASICC56 COSTN/A Leung2.43.10.001 TangN/A Braga2.13.30.0001 Lacy1.53.00.001

23. pain indirect 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 colectomy adequacy 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. Lacy 2002 cancer-related survival colorectal cancer laparoscopic vs. open surgery

27. postoperative care

28. colon cancer adjuvant chemotherapy

29. colon cancer chemotherapy new agents orally active 5-FU prodrugs –capecitabine (Xeloda) –tegafur irinotecan oxaliplatin

30. colon cancer chemotherapy new combinations IFL –5-FU (bolus), irinotecan, leucovorin FOLFIRI –5-FU (infusion), irinotecan, leucovorin FOLFOX –5-FU (infusion), oxaliplatin, leucovorin

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

32. colon cancer chemotherapy new 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 Tumor suppressor genes and oncogenes K-ras, c-myc, p53, DCC, smad4, nm23 Apoptosis and cell suicide- related genes bcl-2, BAX DNA synthesis-related genesthymidylate synthase, thymidine phosphotase Growth factors and growth factor receptor genes TGF-ß, HER-2/neu, EGFR Mismatch repair genesMSH2, MLH1 Angiogenesis-related genesVEGF Cyclins and cyclin dependent kinase inhibitors p27, p21, p16 Adhesion molecules and glycoprotein genes cd44, E-cadherin, ICAM-1 Markers of invasionMMPs, urokinase-type plasminogen activator Proliferation indicesKi-67, Mib-1, proliferation cell nuclear antigen AntioxidantsSuperoxide dismutase, GST-pi Telomere length

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

35. is that operation necessary?

36. 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 surgery for palliation

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 cancer isolated metastases lungliver

41. be aggressive!

42. untreated colorectal liver metastases natural history # of ptssurvival (m) 5-ys (%) Jaffe 1310- Bengmark 40 60 Cady 26913- Oxley 112 -1 Wood 113 71 Bengtsson 25 50 Wagner 252 -2

43. resection of CR liver metastases recent 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 resection contraindications 1.extrahepatic disease 2.unable to obtain negative margin 3.not medically fit a.co-morbid medical problems b.insufficient hepatic reserve (may resect up to 6 segments in normal liver)

45. prognostic scoring system MSKCC 1.LN + primary 2.DFI <12 months 3.size > 5 cm 4.>1 tumor 5.CEA > 200 % 5 yr survival score

46. synchronous liver metastases one or two operations? advantages of 1-Stage operation 1.one anesthetic 2.shorter overall recovery 3.safe in selected centers disadvantages of 1-stage operation 1.requires preparation and expertise 2.? 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 metastases chemotherapy/salvage surgery Adam 2004 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%

50. Adam 2004

52. radiofrequency ablation role not well established in resectable lesions no evidence RFA is as good as formal resection in unresectable lesions no evidence RFA is better than chemotherapy

53. peritoneal carcinomatosis

54. cytoreduction and hyperthermic intraperitoneal chemotherapy vs. chemotherapy randomized controlled trial Verwaal 2004

55. extra-anatomic recurrence PET-CT

57. metastatic disease palliation goals are improved survival and quality of life –good evidence that both goals can be achieved

58. palliation of metastatic disease 12 50% per cent survival time time (mo) 0 Drugs (but well enough for a study) 1 Drug 2 Drugs 3 Drugs 14 16 18

59. treatment statusmedian survival no chemo 6 mo 5-FU 10-12 mo 5-FU + 2 nd agent 14-16 mo 5-FU + 2 nd + 3 rd agent or chemo + targeted therapy > 20 mo

60. Targeted therapies cancer type Erbituxcolon Avastinlung breast colon Gleevecstomach Herceptinbreast Tarcevalung Chemotherapies Alimtalung Camptosarcolon Gemzarlung costs of cancer therapy $9,600 8,800 7,700 4,400 3,816 3,195 2,679 $5,571 4,421 3,638