Multidisciplinary Management of Hepatic Metastases

1. Multidisciplinary Management of Hepatic Metastases Michael J. Kraut, M.D. Medical Director Providence Cancer Institute November 2, 2013

2. Outline • Definitions • Resectable Liver Mets • Multidisciplinary Management • Modalities • Clinical Trial Data

3. Resectable Liver Metastases Approximately 50% of colorectal cancer pts will develop liver metastases at some point during the course of their disease About 20% of pts will have synchronous liver metastases Only about 15% of patients with liver metastases from colorectal cancer will have resectable disease

4. Resectable Liver Metastases • There will be approx 145,000 new cases of colon cancer in the US in 2012 • About 72,000 will develop liver mets • About 10000 patients will have resectable disease • Approx 1.5% of the US population lives in SE Michigan = 1500 cases/year

5. Resectable Liver Metastases • Patients with successful resection of liver metastases have 5-year survivals of 25-58% (with a solitary met can be as high as 70%) • This is better than what can be achieved with chemotherapy alone

6. Multidisciplinary Approach • Colorectal Surgeon • Hepatobiliary Surgeon • Medical Oncologist • Radiation Oncologist • Interventional Radiologist All may play important roles at different points in the successful management of these patients

7. Multidisciplinary Approach • Implies a meaningful interaction among the involved physicians • Dedicated conference • Mutual respect for the expertise of the members Results in Better Outcomes for our Patients (which is, after all, why we are here)

8. Modalities • Surgical Resection • Hepatic lobectomy and segmentectomy • Wedge resections of superficial lesions • Requires expertise in the vascular anatomy of the liver • May require embolization of the involved regions to stimulate hypertrophy in the remnant liver, increasing the probability of good post-op liver function

9. Modalities • Ablation • RFA (radiofrequency ablation) • Microwave ablation (actually a specific type of RFA) • Cryotherapy Each modality has strengths and weakness All suffer from “heat sink” phenomenon when performed near larger vessels

10. Modalities • Stereotactic radiotherapy • Limited to lesions up to 4 cm in diameter • Can sterilize the area of cancer cells, but will cause significant scarring • Not affected by “heat sink’ issues, but have to be cognizant of damage to vessels

11. Modalities • Radiolabeled microspheres • microspheres labeled with 90Yttyruim are marketed under the trade name Theraspheres • While more commonly used in HCC and cholangiocarcinoma, can have a role in the palliation of colorectal liver metastases

12. Modalities • Chemotherapy • There are several active drugs in colorectal cancer • Modified FOLFOX6 is most commonly employed • Oxaliplatin • 5FU bolus + leucovorin, followed by • 48 hr high dose 5FU infusion • Capecitabine can be substituted for 5FU • CapOx • Irinotecan regimens • Increased GI toxicity without added effectiveness

13. Modalities • Chemotherapy • Bevacizumab is problematic in the setting of potential resection, as there is a 4-6 week washout period required both before and after surgery • Antiangiogenesis effect can result in bleeding and delayed wound healing

14. Resectable Liver Metastases • Definition of “resectable” has expanded over time • Recognition that multiple lesions can be resected and can still obtain a good outcome • Better surgical techniques • Reduced operative mortality • Portal vein reconstruction • Preop embolization • Better post operative supportive care

15. Resectable Liver Metastases • Combining liver resection with ablation (RFA, microwave, and cryoablation) • Expands population of patients eligible for “complete resection” • Allows preservation of liver parenchyma when hepatic lobectomy is not feasible • Bilateral disease • Relatively central disease

16. Resectable Liver Metastases • For lesions that are “too central”, i.e. situated near large vessels, surgery may entail an extensive resection, and RFA or cryotherapy may not be feasible due to the “heat sink” phenomenon • In those circumstances, stereotactic radiotherapy may be the preferred choice

17. Resectable Liver Metastases • Chemotherapy for colorectal cancer has improved with the addition of new agents, particularly • oxaliplatin • cetuximab

18. Resectable Liver Metastases The timing and sequencing of surgery and chemotherapy is a topic of ongoing investigation Surgery in synchronous mets can be performed simultaneously with removal of primary Later Immediately, while leaving primary in place (“liver-first”)

19. Chemotherapy in Resectable Liver Metastases • Chemotherapy can be delivered • Before surgery (“neoadjuvant”) • After surgery (“adjuvant”) • Both (sometimes referred to as “perioperative”)

20. Chemotherapy in Resectable Liver Metastases • There have been relatively few prospective trials, especially with newer agents • HAI (hepatic artery infusion) trials dominate earlier literature • 5FU/Leucovorin based trials show marginal benefit • Trials with newer combinations are in progress

21. Neoadjuvant Trials • Multiple phase II trials completed or underway showing feasibility • Only one randomized trial - EORTC Intergroup trial 40983 • Compared FOLFOX4 pre- and post-op with liver resection alone • Chemo arm pts received 6 14-day cycles pre- and post-op • Median FU – 3.9 years

22. EORTC 40983

23. Issues with Neoadjuvant Chemotherapy • How to manage “disappearing” mets • Stop before they are completely gone? • Continue, and then wait for relapse? • How to manage progression • Operate immediately? • Forego surgery? • Chemotherapy-induced hepatotoxicity • Steatosis/steatohepatitis from irinotecan • Sinusoidal dilitation from oxaliplatin • Irinotecan may be bigger culprit

24. Neoadjuvant Trials • Several Phase III trials are currently accruing • MIROX compares post op alternating FOLFOX and FOLFIRI - France • XELOX +/- bevacizumab – Netherlands • FOLFOX +/- bev or panitumumab –EORTC • Phase II • Cetuximab +HAI • Neoadj FOLFOX +bev followed by adj 90Y theraspheres

25. Adjuvant Therapy • Limited randomized data • European trial, ENG trial • Metaanalysis • Trial of 5FU/LV vs. FOLFIRI showed no difference between 2 arms • Hepatic Artery Infusion (HAI) trials • Primarily at MSKCC

26. Adjuvant Therapy • FFCD trial (French) • 173 pts with R0 resections • Regimen: • Modified Mayo clinic regimen of 5FU/LV x6 Vs. • Observation

27. FFCD trial

28. Pooled Analysis FFCD and ENG trials had difficulty accruing and were underpowered Pooled analysis done – regimens were very similar

29. HAI • Trials done primarily at MSKCC (N Kemeny) • FUDR via implanted pump • Requires expertise • Liver toxicity requires dose reductions • Toxicity requires biliary stent in 5% of pts • Dexamethasone added to HAI to reduce toxicity in more recent trials

30. HAI – 5FU/LV +/- FUDR Kemeny et al. NEJM 341:2039, 1999 • 156 pts randomized after resection of liver mets • Regimen: HAI of FUDR+dexamethasone plus IV 5FU/LV Vs. 5FU/LV alone • Med Survival: 72.2 mo vs 59.3 mo • 2yr PFS: 57% vs 42%, p=0.07

31. HAI A subsequent ph II trial of HAI + FOLFOX +/- bevacizumab showed no improvement with bevacizumab and increased hepatic toxicity on bevacizumab arm Bevacizumab arm actually did a little worse, but not statistically significantly so

32. Targeted Agents • Cetuximab and panitumumab • Phase II data suggest that the addition of these agents in patients with KRAS wild type tumors may be beneficial • Await phase III data

33. Potentially Resectable Liver Metastases Several studies have examined the role of chemotherapy in making unresectable liver metastases resectable In a large retrospective study, 12.5% of patients converted to resectable Recurrence rate was 80% Survival of these patients was 33% and 23% at 5 and 10 yrs, respectively

34. Potentially Resectable Liver Metastases Mayo Clinic trial gave 42 consecutive unresectable patients FOLFOX4 15 patients became resectable 73% recurred within 3 years Median survival = 26 mo Denominator is nebulous – not clear how “unresectable” one was allowed to be to get on trial

35. Potentially Resectable Liver Metastases • Chinese trial published June 2013 • 138 patients deemed “unresectable” by panel of > surgeons and 1 radiologist • Liver only mets, resected primary, no prior therapy • KRAS wild type ONLY

36. Shanghai Trial • Randomized mFOLFOX6 OR FOLFIRI Plus cetuximab vs. mFOLFOX6 OR FOLFIRI alone • Treated until deemed resectable or to progression or intolerance

37. Shanghai Trial All significant at p < 0.05 Le-chi et al, JCO 31:1931-38, 2013

38. Shanghai Trial R0 resection rate Patients on CT + cetux arm who had an R0 resection had a MS of 46.4 months ( n=18)

39. Conclusions • Achieving R0 status is important and improves the chance of long term survival • Combining several approaches may be necessary to achieve the R0 state • Adjuvant or Perioperative chemotherapy employing an oxaliplatin containing regimen likely improves survival • Cetuximab may be effective in improving survival in KRAS wt patients

40. Caveats • Patients with disease outside the liver are not good candidates for aggressive management • Too much preoperative chemotherapy can be harmful, especially if irinotecan is used