Michael A. Choti, MD Department of Surgery UT Southwestern Medical Center

1. Great Debates & Updates in GI Malignancies March 28-29, 2014 DEBATE: What is the Optimal Strategy for Liver Only Metastatic Colon Cancer? Chemotherapy Followed By Surgical Resection Michael A. Choti, MD Department of Surgery UT Southwestern Medical Center

2. Disclosures Bayer Healthcare: consultant Bristol Mayer Squibb: research, consultant

3. Trends in Long-Term Outcome of Liver Resection for Metastatic Colorectal Cancer Overall Survival Recurrence-Free Survival (2001-2005) (1995 -2000) (1985 -1994) Vigano et al. Ann SurgOnc (Jan 2012)

4. Integrating Chemotherapy and Liver Surgery for Metastatic Colorectal Cancer LIVER METASTASES RESECTABLE~25% NON RESECTABLE~75% “Conversion” “Neoadjuvant” SURVIVAL BENEFIT ~ 60% OS AT 5 YEARS 15% DFS AT 10 YEARS “Adjuvant” Integration of chemotherapy

5. Categories of Resectability • Initially resectable disease by standard approach • Initially surgical but requires extended approach • staged resections • preoperative portal vein embolization • resection plus RFA • Initially unresectable but likely convertible with response • Initially unresectable and unlikely convertible BORDERLINE

6. Liver Metastases in Colorectal Cancer: Outcomes LIVER METASTASES location NON RESECTABLE~75% number RESECTABLE~25% size Downsizing ? SURVIVAL BENEFIT ~ 60% OS AT 5 YEARS 15% DFS AT 10 YEARS RESECTABLE10-20%

7. Improving Systemic Chemotherapy for Advanced CRC BSC 0 7 5FU/ LV1 21 13 Irinotecan1 18 12 IFL1 39 15 FOLFOX2 or FOLFIRI2 54 – 56 20 - 22 With bevacizumab3 ~70 >24 or cetuximab4 Response % Median Surv (mo) 1 Saltz LB. NEJM 2000 2 Tournigand C. J ClinOncol2004 3 Hoff, PM. GI ASCO, 2006 4 Diaz Rubio E. ASCO, 2005 IFL = bolus 5FU, folinic acid, and irinotecan FOLFOX = infusion 5FU, folinic acid, and oxaliplatin FOLFIRI = infusion 5FU, folinic acid, and irinotecan

8. Initially resectable? • Initially unresectable but potentially convertible? • Initially unresectable and unlikely convertible?

9. Initially resectable? • Initially unresectable but potentially convertible? • Initially unresectable and unlikely convertible?

10. What is the Role of Preoperative Bevacizumab in the Unresectable But Potentially Convertible Patient? Morphologic but not RESCIST response Chun et al. JAMA (Dec 2009)

11. Chemotherapy Plus Biological Agents For Initially Unresectable Liver Metastases Which is the best biological agent to use to increase response rate? 1. Saltz, L.B., et alJournal of Clinical Oncology, 2008. 26(12): p. 2013-2019. 2. Hurwitz, H., et al., New England Journal of Medicine, 2004. 350(23): p. 2335-2342. 3. Giantonio, B.J., et al.,. Journal of Clinical Oncology, 2007. 25(12): p. 1539-1544. 4. Van Cutsem, E., et al . New England Journal of Medicine, 2009. 360(14): p. 1408-1417. 5. Bokemeyer, C., et al.,. Journal of Clinical Oncology, 2009. 27(5): p. 663-671. 6. Maughan, T.S., et al.,. The Lancet. 377(9783): p. 2103-2114. 7. Douillard JY, et al J ClinOncol, 2011. 29(Suppl)(:3510).

12. Downsizing the Unresectable Patient: Are They All the Same?

13. QUESTION How should patients be managed when alloriginal sites could not be resected? • Should the surgeon operate and resect residual macroscopic sites? • Should resection be undertaken only after a waiting period to determine durability of the CR? • What is the role of “adjuvant” HAI therapy in such situations of originally liver-only disease? • What is the role of a chemotherapy break as a provocative test to determine a durable CR?

14. Disappearing Colorectal Liver Metastases After Preoperative Chemotherapy Now What? Preoperative chemotherapy

15. Disappearing Colorectal Liver Metastases After Preoperative Chemotherapy • Disappearing metastases occurred in 24% of patients treated with preoperative chemotherapy. • Disappearance was associated with high tumor number, longer duration of chemotherapy, and small lesion size. • 53% of DLM were found during surgery. • When metastases were not found at the time of surgery, only 24% were resected. • Local recurrence occurred in 70% when DLM were left untreated. • Survival was not significantly impacted if DLM were left untreated. Van Vledder et al. J GastrointestSurg(Nov 2010)

16. Disappearing Liver Metastases: Predictors of Complete Pathologic Response Auer et al. Cancer. 2010 Mar 15;116(6):1502-9.

17. Disappearing Liver Metastases Left In Situ: Time to Lesion Recurrence Auer et al. Cancer. 2010 Mar 15;116(6):1502-9.

18. What is the role of adjuvant therapy or neoadjuvant therapy in initially resectable patients undergoing hepatic resection?

19. Combining Chemotherapy with Liver Resection in the Initially Resectable Patient • Chemotherapy is generally recommended, at least in the chemo-naive patient (based on extrapolation of stage III studies). • Little evidence to guide recommendations in previously treated patients. • No RCT has demonstrated efficacy of peri- or postop chemotherapy in resectable stage IV pts. • Questionable role for biologics in resectable patients, either pre- or postoperatively.

20. EORTC 40983 Progression-Free Survival: Eligible Patients HR= 0.77; CI:0.60-1.00, p=0.041 100 90 +8.1%At 3 years Periop CT 80 70 60 50 36.2% 40 30 Surgery only 28.1% 20 10 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5

21. EORTC 40983: Long Term Follow Up Nordlinger et al. Lancet Oncol(2013)

22. Combining Chemotherapy with Liver Resection in the Initially Resectable Patient CHEMOTHERAPY DURATION Responses occur early… …Toxicity occurs later Kishi et al. Ann SurgOncol(Jun 2010)

23. No Clear Role of Biologics Combined with Liver Resection in the Initially Resectable Patient Primrose et al (ASCO 2013, abstr 3504) New EPOC” 272 pts with resectable CRLM, kraswt Randomized to FOLFOX cetuximab Findings: cetuximab group did worse (PFS 14.8 vs 24.2 mo) de Gramont et al (Lancet Oncol Dec 2012) AVANT Trial stage 3 CRC, FOLFOX bev Findings: detrimental effect of bevacizumab

24. What is the Optimal Strategy for Liver Only Metastatic Colon Cancer? The Unresectable Patient • Determine if “borderline” vs “definitely unresectable” • Preoperative “conversion” chemotherapy with regimen with high radiologic response (e.g. chemo+cetuximab, FOLFOXIRI) • Role of preopbevacizumab is more questionable • Monitor every 2 months to evaluate for resectability • Limit duration to minimize disappearing lesions and hepatotoxicity • Can potentially convertible patient be identified initially or should all fit patients with liver-limited disease be offered aggressive first line therapy?

25. What is the Optimal Strategy for Liver Only Metastatic Colon Cancer? The Resectable Patient • Role of any chemotherapy in the low risk patient is controversial (e.g. solitary, long DFI) • Consider chemotherapy in the high-risk patient (e.g. synchronous, multiple, short DFI) • Optimal sequencing, peri- or postoperative, is dealer’s choice • Limited evidence for the use of any biologics, either perioperatively or postoperatively • Limit the duration or preoperative chemotherapy to avoid DLM or toxicity (4-6 cycles)