Update on Surgical Management of Neuroendocrine Tumors James R. Howe, M.D. Director, Surgical Oncology and Endocrine Surgery University of Iowa College of Medicine Distribution of NETs 2000-2004 27% --- 6% 4% 13% 3% 3% 4% 17% 6% 1% 15% Yao et al. J. Clin. Oncology 26:3063, 2008 Stage at Diagnosis SEER vs. University of Iowa Localized Regional Dis tant 85% nodes 51% nodes Yao et al. J. Clin. Oncology 26:3063, 2008 77% liv er 37% liv er Median Survival by Site Months Overall Survival 5 yr. O S=79. 9% 5 yr. O S=79. 3% 10 yr. O S=57. 4% Medi an not reached SEER 88 m os. 10 yr. O S=52. 9% Medi an 126 m os. SEER 42 m os. Small Bowel Primaries (SBNETs) Most common GI site Incidence 7 per million 30% multicentric Well-differentiated Indolent but present late Yao et al. J. Clin. Oncology 26:3063, 2008 SK Sherman et al. Ann. Surg. Oncol. 21:2971, 2014 Typical SBNET Patient Resecting Mesentery www.lilienthenthalusa.com 1
Lymphadenopathy SMV SMA Benefits to Resection of Primary Prevents future metastases Cholecystectomy at Exploration Prevents obstruction Prevents bleeding Eliminates problems of biliary colic or gallstones Prevents peritoneal seeding May reduce hormone levels Prevents GB necrosis after hepatic embolization Improves Survival Exploration is Helpful in Symptomatic Patients Resection for Symptom Control SBNETs with Liver Metastases: Does Resection of the Primary Improve Symptoms? Uppsala Study 1996 u 121 pts. with midgut carcinoids u 93% with mets u 158 laparotomies in 107 pts. Makridis et al. World J. Surg. 20:900, 1996 Makridis et al. World J. Surg. 20:900, 1996 Exploration is Helpful in Symptomatic Patients Calgary Study 2008 u 66 pts. with Sx and GI NETs u 52% mesenteric masses, 77% liver u Primary and nodes removed in 45, debulked in 8 u Complete relief of obstruction, ischemia, 75% carcinoid syndrome Chambers et al. Surgery 144:645, 2008 Resection of the primary tumor improves symptoms in the majority of patients SBNETs with Liver Metastases: Does Resection of the Primary Improve Survival? 2
Difference of Removing Primary Resection of Mesenteric Nodes 314 pts. with midgut carcinoids 262 explored, 52 not explored 91% nodal, 81% liver mets Primary resected in 249 (of 262) Primary and LNs removed in 166 Hellman et al. World J. Surg. 26:991, 2002 4.0 yrs. (n=63) 7.4 yrs. (n=249) p<0.001 Hellman et al. World J. Surg. 26:991, 2002 6.2 yrs. (n=83) 68% 5 yr. 7.9 yrs. (n=166) 72% 5 yr. p<0.001 Hellman et al. World J. Surg. 26:991, 2002 Survival: Resected vs. Not Resected Survival: Explored vs. Not Explored Patients with unresectable carcinoid liver mets. 84 pts. 60 resected, 24 not Similar groups Givi et al. Surgery 140:891, 2006 159 mos. (n=60) 81% 5 yr. 47 mos. (n=24) 21% 5 yr. Givi, Pommier et al. Surgery 140:891, 2006 108 mos. (n=66) 50 mos. (n=18) Givi et al. Surgery 140:891, 2006 OHSU Conclusions Resection of primary beneficial Due to difference in PFS Not selection bias Removal of metastatic source Decrease in circulating amines Deprivation of growth factors for liver tumors 5 centers in UK/Ireland Pts with SBNETS/Liver mets 360 pts., 209 resected 12 bypassed, 17 unresectable, 80 not explored Ahmed et al. Endocrine-Related Cancer. 16:885, 2009 Multivariate Analysis Ahmed et al. Endocrine-Related Cancer. 16:885, 2009 3
Survival Analysis by Resection Pancreatic NETs 9.9 yrs. Resection of the primary tumor improves patient survival Capsule 6.7 yrs. 4.7 yrs. 5.6 yrs. Tumo r Normal islet Ahmed et al. Endocrine-Related Cancer. 16:885, 2009 Pancreatic NETs Survival in PNETs Non-functional Insulinoma Gastrinoma VIPoma Glucagonoma Somatostatinoma PPoma General Facts About PNETs Halfd an arsan, TR et al. Ann. Oncol. 19:1727, 2008 47. 6% 31. 3% Halfdanarsan, TR et al. Ann. Oncol. 19:1727, 2008 When to Resect Pancreatic Primary Functional lesions >2 cm Not < 1 cm Controversy in 1-2 cm 1-3 Not high grade, unless isolated >2 cm in MEN1 4 >3 cm in VHL 5 1. L.C. Lee et al. Surgery 152:965, 2012 2. E.J. Kuo et al. Ann. Surg. Onc. 20:2815, 2013 3. S.M. Sharpe et al. J. Gastrointest. Surg 19:117, 2015 4. F. Triponez et al. Ann. Surg. 243:265, 2006 5. S.K. Libutti et al. Surgery 124:1153, 1998 Survival Advantage in PNETs n 35 mos. median survival Resected (n=310) Recommended, not done (n=115) Not Recommended (n=302) 114 mos. Hill et al. Cancer 115:741, 2009 p<0.001 Surgical Treatment Options Enucleation Distal Pancreatectomy Pancreaticoduodenectomy Laparoscopic distal pancreatectomy 4
Enucleation CT: Pancreatic Body/Tail Mass Duodenum Uncinate Tumor SMV from Clark OH, Duh Q-Y Endocrine Surgery W.B. Saunders and Co. 1997 Pathologic Specimen PNET in Pancreatic Head Primary Node Spleen Tumor thrombus Pancreatic Margin Tumor >1 cm Cameron, JL. Atlas of Surgery BC Decker, Inc. 1990 GB Duodenum Pa n crea s Pa n crea tic sten t Cameron JL Atlas of Surgery BC Decker, Inc. 1990 Cameron JL Atlas of Surgery BC Decker, Inc. 1990 5
The Role of Laparoscopy for PNETs Especially good for small, distal lesions Can also enucleate Well-suited for distal pancreatectomy/splenectomy J. Ho we, ed. Atlas of Endocrine and Neuroendocrine Surgery, Springer-Verlag (in p ress) What to do with Liver Lesions? Options for Liver Metastases Embolization Radioembolization Peptide Receptor Radiotherapy (PRRT) Somatostatin analogues Systemic therapy Resection/Enucleation/Ablation Approach to Multiple Liver Lesions Ablation of Liver Lesions Cholecystectomy Ablation of Liver Lesions Debulking at same Procedure Reduces tumor burden Reduces hormone levels Improves targeted therapy Improves survival preop postop preop postop Survival after Hepatic Resection Overall Survival-M1 Disease Unanswered Questions in Hepatic Cytoreduction Med. Survival: 125 mos. 5 yr. Survival: 74% SEER Med. Survival: 56 mos. 5 yr. Survival: 54% Recurrence: 94% 5 yr. O S=75. 8% 5 yr. O S=71. 0% 10 yr. O S=50. 9% Medi an not reached SEER 56 m os. 10 yr. O S=45. 6% Medi an 90 m os. SEER 24 m os. Symptomatic vs. Asymptomatic? Survival Benefit? Only Attempt if Can Get >90%? Major Resections vs. Ablations? Cutoff for lesion number? Cutoff for % hepatic replacement? Mayo et al. Ann. Surg. Oncol. 17:3129, 2010 SK Sherman et al. Ann. Surg. Oncol. 21:2971, 2014 6
PFS with >70% Cytoreduction 108/142 pts. liver directed surgery 80 SBNETs, 28 PNETs Primary also resected in 84% 64% pts. had 70% cytoreduction Median 10 lesions, 10-19% replacement 76% Median 3.2 yrs. Median: 1.3 yrs. p=0.001 OS with >70% Cytoreduction Median not reached Median: 6.5 yrs. p=0.009 Answers to Questions Regarding Hepatic Cytoreduction Can be Asymptomatic Survival Benefit---Yes! >70% Cytoreduction target Parenchymal Sparing reasonable <10 lesions do better <25% replacement do better Summary: Metastatic NETs Remove the primary Resect the nodes Debulk peritoneal disease Cytoreduce liver metastases Use Somatostatin analogues Use systemic therapy* *when other options not feasible or at progression University of Iowa NeuroEndocrine Cancer Clinic Thomas O Dorisio-Endocrinology James Howe-Surgical Oncology Sue O Dorisio-Pediatric Oncology Daniel Vaena-Medical Oncology Joseph Dillon-Endocrinology Andrew Bellizzi-Pathology Yusuf Menda, Dave Bushnell-Nuc. Med. Kim Miller, Kelly Buck-Nursing 7