1. Hepatic Ablation Therapies Before Systemic Therapy Jordan D. Berlin, M.D. Ingram Professor of Cancer Research Co-director, GI Oncology Director, Phase I Research Vanderbilt-Ingram Cancer Center

2. Disclosures Advisory Boards here and there in last year –Genentech/Roche –Karyopharm –Amgen –Astra Zeneca –BMS –Lilly/Imclone –Symphogen –Celgene –Vertex –Ipsen Current Research Support –Amgen, Lilly/Imclone, Pfizer, Novartis, Abbvie, Immunomedics, Otsuka, Merrimack, Oncomed, Genentech/Roche, Taiho

3. Presumption by me Liver dominant or liver only disease with no symptoms from extrahepatic disease

4. First, a thank you to the organizers Thanks for recognizing the importance of NE tumors Thanks also for finding the debate topic with absolutely no supporting data on either side –This is the most un-winnable and un-losable debate I have gotten so far

5. What are the ablative options? Surgery Radiofrequency ablation Cryoablation Chemoembolization Bland Embolization Radioembolization Stereotactic radiation –(usually comes with foreign names like cyberknife or gamma knife, terms that loosely translated mean, “we bought these really expensive machines so we’re gonna use ‘em, data or no data”)

6. Reasons to perform locoregional treatment of liver metastases Improve OS (only for complete removal) Symptom reduction/QOL Because we can—please don’t use this one

7. Surgery Limited to patients with a limited number of metastases, or anatmoically resectable disease –Some people perform pluckitouttame removals of some of the disease I can’t give you data supporting this and I can’t recommend it Surgical resection should be limited to those with “curative intent” although morbidity and mortality are very low for these procedures now Data for surgery is retrospective only

8. Surgery AuthorReferenceTotal N (N who had resection) 5yr OS Resection vs not 10 year OS Chen, et al J Amer Coll Surg 187: 88-92, 1998 38 (15)73% vs 29% Chamberlain, et al J Amer Coll Surg 190: 432-5, 2000 85 (28)82% vs Sarmiento, et al J Amer Coll Surg 197: 29-37, 2003 (170)61%35% Mayo, et al Ann Surg Oncol 17: 3129-36, 2010 (339)74%51% >90% with symptoms have improvement Recurrences at 5 years reported to be 67-76%

9. Radiofrequency Ablation One whole decent retrospective study –89 patients, 39 were symptomatic –Median OS was 6 years Women lived 2x longer than men (125 vs 51 months) p, 0.03 –Of 39 symptomatic patients 97% had symptom improvement or relief Symptom benefits lasted median of 14 months –Median DFS was 15 months –Majority add intrahepatic progression, but I could not figure out if anybody remained disease free Akyidiz, et al Surgery 148: 1288-93, 2010

10. Embolization Several modalities, in many ways, but I will separate it into: –Trans-arterial chemoembolization Theoretically delivers 10-20 fold concentrations of drug to the tumor Traditionally favored in PNET –Bland embolization Favored in carcinoid (non-PNET)

11. Embolization Despite traditions (PNET vs carcinoid), we have little data to tell us which is better –TACE provides symptom relief in 53-95% of patients –Bland embolization provides symptom relief in 65-93% of patients –Caveat: most studies include both diseases and carcinoid is more likely to be symptomatic hormonally One study looked at 100 patients treated with either of the two methods –37% of TACE had PNET –45% of bland had PNET

12. Embolization TACE vs TAE –Symptom relief in 86% vs 83% for TACE vs bland –OS from diagnosis was 50.1 vs 39.1 months (p, NS) for TACE vs bland –OS from 1 st embolization was 25.5 vs 25.7 months –5 year survival from 1 st embolization was 19% vs 13% –Not sure we have proven our belief systems but it is clear both modalities improve symptoms

13. Radioembolization Blood supply is not blocked Much more expensive Than embolization Appears there are differences: –Slower onset to effect for radioembo –Fewer immediate morbidities for radioembo –Not as clear about symptom relief

14. Radioembolization Largest study was 148 patients –Median survival not reported, but curve looks like ~ 70 months Caveat is that like most of the reports, there is unclear duration of follow-up and most of the patients are censored (listed as censured) early –Long-term toxicity is not reported in most of the studies –Efficacy is mostly reported with RECIST response 50-70%

15. So, what are the systemic agents PNET: –Chemo: cape, temozolamide, combination and the oft maligned (and deservedly so) strepozocin and doxorubicin –Everolimus –Sunitinib –Octreotide LAR Carcinoid –Octreotide LAR –Interferon

16. Why do hepatic therapies first? If surgery is an option, it looks like a small percentage, but a real one, remains disease-free at 5 years, so this is an obvious choice –Especially with carcinoid we don’t produce shrinkages to make tumors more resectable If not, the number one reason would be symptom control –We can’t say we make them live longer than systemic therapy alone if we can’t remove disease –However, survival may be better, but I can’t prove it.

17. Why do hepatic therapy first? In PNET, systemic therapies have side effects –They prolong PFS, but no data for OS –Not clear they improve symptoms In carcinoid, octreotide LAR has limited side effects –But once on octreotide we rarely stop this agent –It is costly and requires regular visits –Local therapy can provide relief, reduce patients’ health care burdens (ie they don’t actually enjoy seeing us that much)

18. Other reasons Angiogenesis –Sunitinib in PNET and potentially bevacizumab in carcinoid –After blocking blood supply or reduction of tumor burden, evaluating these inhibitors to prevent re- growth/delay progression would be reasonable Everolimus –Similarly, can delay growth, but does that provide a survival advantage

19. Conclusions In a disease largely treated based on anecdote and retrospective series, –You can pretty much do what you please –However, you need to do what will affect the patient in a positive way –Symptom relief appears to prolong survival in NE tumors, so hepatic therapies which are short term and can reduce symptoms for prolonged periods are a nice way to treat them