Minimal invasive surgery for pancreatic insulinoma: Current evidence Dr. HO Man-fung Prince of Wales Hospital

CURRENT TREATMENT

Medical therapy Dietary modification Diazoxide Somatostatin analogue Minimal effect on disease progression (especially for non-responder) Pre-operative symptoms control 60% response rate only…

Surgery Surgery is the Mainstay of treatment for insulinoma Curative (local disease / limited liver metastasis) Symptomatic control in metastastic disease Enucleation Distal pancreatectomy +/- splenectomy Pancreaticoduodenectomy Central / total pancreatectomy Resection of liver metastasis

Special concerns of insulinoma Small size < 2cm in ~ 80% Difficulty in localization 90% benign and solitary Resection strategy Room for minimal invasive surgery Overt symptoms, poorly controlled by drugs Pre-operative control of symptoms Even palliative resection in metastatic disease wound be beneficial

Surgical approach Pre-operative localization IOUS Enucleation or Pancreatectomy ? Blind distal pancreatectomy

Lo et al. Surgical Endoscopy (2004) 18: 297-302 60% with CT, 80% with EUS, 100% with THPVS K. Ravi et al. Ann R Coll Surg Engl 2007; 89: 212-217. 67% (incl. USG, CT, MRI, THPVS) Mehrdad Nikfarjam et al. Annals of Surgery • Volume 247, Number 1, January 2008 29-80% with non invasive investigation, 85-100% with invasive investigations

Surgical approach Pre-operative localization IOUS Enucleation or Pancreatectomy ? Blind distal pancreatectomy

IOUS being the most sensitive test among all investigations of choice Ref: A Fuller Understanding of Pancreatic Neuroendocrine Tumours Combined with Aggressive Management Improves Outcome. S.L.Ong et al. Pancreatology 2009;9:583–600

Amelia C. Grover et al. A prospective evaluation of laparoscopic exploration with intraoperative ultrasound as a technique for localizing sporadic insulinomas. Surgery 2005; 138:1003-8

See the difficulties? Ref: The American association of endocrine surgeons.Pancreatic neuroendocrine tumors: insulinoma

Surgical approach Pre-operative localization IOUS Enucleation or Pancreatectomy ? Blind distal pancreatectomy

Enucleation Pancreatectomy Solitary lesion Size < 2cm Away from major vessels / pancreatic ducts Pancreatectomy Multifocal lesions Size > 2cm Close to major vessels / pancreatic ducts MEN 1

Ref: L. Fernandez-Cruz et al Ref: L.Fernandez-Cruz et al. Is laparoscopic ressection adequate in patients with neuroendocrine pancreatic tumour. World Journal of Surgery (2008) 32: 904-917.

Surgical approach Pre-operative localization IOUS Enucleation or Pancreatectomy ? Blind distal pancreatectomy

? Blind resection 4/61 persistent symptoms despite resection Further resection jeopadized parachymal preservation (90% benign) Importance of pre-operative localization Portal venous sampling (~100% localization) Ref: Improved Contemporary Surgical Management of Insulinomas. A 25-year Experience at the Massachusetts General Hospital. Mehrdad Nikfarjam et al. Annals of Surgery • Volume 247, Number 1, January 2008

K. Ravi et al. Ann R Coll Surg Engl 2007; 89: 212-217.

Management of liver metastasis Resection Transarterial chemoembolization Ablation Systemic chemotherapy Targeted therapy(e.g. Sunitinib, everolimus) Liver transplantation

MINIMAL INVASIVE SURGERY Inapproapiate large wound for small benign tumours Going through evidence of lapasroscopic treatment. Lack of RCT due to scarcity of case MINIMAL INVASIVE SURGERY

Lapasroscpic pancreatic resection 1st laparoscopic pancreatic resection -1992 Gagner M et al (1996). J Gastrointest Surg 1: 20-26 Cushieri A. et al (1996). Ann Surg 223:280-285 1st laparoscopic resection of insulinoma – 1992 Low incidence and difficult anatomical location, laparoscopic experience published relatively late compared to other laparoscopic surgery

2 enucleations and 2 distal pancreatectomies done laparoscopically 100% pre-operative localization Only for lesions over body and tail 1 patient with post operative pancreatic leakage Pancreatic head tumour were traeted with open surgeries. 2004

1st comparative study of laparoscopic vs open approach (12 vs 9) Comparison with historical cohort No significant difference in morbidty, mortality, intraoperative variables Only 1 patient used intra-operative USG Denied use of intra-operative USG to be necessary 2007

Laparoscopic USG Only way to replace palpation in laparoscopic surgery Localization of lesion(s) Sensitivity 83-98%a Comparable to THPVS b Define anatomical relationship with major vessels, main pancreatic duct a) Mehrdad Nikfarjam et al . Improved Contemporary Surgical Management of Insulinomas. A 25-year Experience at the Massachusetts General Hospital.. Annals of Surgery • Volume 247, Number 1, January 2008 Amelia C. Grover et al. A prospective evaluation of laparoscopic exploration with intraoperative ultrasound as a technique for localizing sporadic insulinomas. Surgery 2005; 138:1003-8

pNETs with pancreatic resection, 20 patients with insulinoma Pre-op localization 100% 1/20 conversion to open Mean follow up of 36 months, no recurrence Significant less blood loss and operative time for laparoscopic enucleation Published in 2008: from 1998 -2007 Concerning the result of insulinoma only Converted to open due to failure to identify the lesion

Pre-operative localization - unknown 1/21 converted open 21 patients Pre-operative localization - unknown 1/21 converted open IOUS: localization, intraoperative decision, marking of transection line 3 patients with pancreatic fistula All except 1 discharged in 1 week No recurrence Convert due to previous pancreatitis resulted un dense adhesion 1 grade B fistula stayed 60 days

89 patients (Lap vs open : 43 vs 46) 100% pre-operative localization 2000-2009

No recurrence in 6 months Only the 4 patients with tumour cannot located intra-operatively remain symptomatic (tumour not resected)

Distal pancreatectomy Enucleation Number of patients 85 496 101 Whipple’s operation Distal pancreatectomy Enucleation Number of patients 85 496 101 Mortality (%) 3.5 0.4 Mobidity (%) 30.7 34.1 47 Mean blood lost (ml) 126 311 - Conversion rate (%) 8.75 12.1 23.3 Mean operation time (min) 371 229 132 Mean hospital stay 13.6 7.5 7.8 Pancreatic fistula / intra-abdominal collection and respiratory complications are most common cause of morbidity Results for laparoscopic distal pancreatectomy is more favourable compared with open Lack of survival analysis

Represent early experience Highly selected cases Indicating minimal invasive surgery is feasible Pancreatic fistula is still the most prevalent complication Lacking of long term results, e.g. survival, recurrence Heterogeneous disease

Laparoscopic arm (LDP): 773 (43%) Open arm : 1041 (57%) Total n= 1814 (18 studies) Laparoscopic arm (LDP): 773 (43%) Open arm : 1041 (57%) Conversion rate : 0 – 30% (not reported in 4 studies) Among all pancreatic surgery, laparoscopic distal pancreatectomy seen getting more attention than others

Operative parameters: Blood loss

Post operative recovery: Length of stay

Post operative complications: pancreatic fistula

Laparoscopic distal pancreatectomy has the advantage of: Lower blood loss Faster recovery Comparable complication profile with open approach This technique is a reasonable approach in selected cancer patients Also commented on oncological clearance with only positivity of resection margin (4 studies only) 4.5% vs 8.8%– Not adequate to draw conclusion 10 of 18 studies excluded cases of malignant lesion / invasive ductal carcinoma Results maybe applicable to patients with insulinoma, that laparoscopic surgery could have benefits

Most extensive experience in published literature are from USA, Italy and South Korea Focused on distal pancreatectomy What about robots?

1st 30 cases in University of Pittsburgh Compared with 94 patient with laparoscopic distal pancreatectomy 0% conversion rate 100% R0 resection Median LN harvest (Lap vs Robot = 9 vs 19) Similar tumour size

Notice a high rate of planned splenic resection on this initial cohort

v Better visualization, freedom of movement, stability Preservation of spleen and splenic vessels 21/22 patient with successful splenic preservation 17 patient with splenic vessels preserved 1 patient developed post op splenic infarct Further expand the advantage minimal invasive surgery by improving rate of spleen preservation DP with splenic preservation has been documented to increase hospital stay – mainly due to splenic complications Splenic infarct in 1 paitent with splenic vessles sacrifies. Managed conservatively Robot confers additional advantage for splenic preservation

Open vs Laparoscopic / robotic Whipple’s operation Open vs Laparoscopic / robotic distal pancreatectomy Longer operative time Decreased blood lost Shorter hospital stay Similar complication profile Improved rate of R0 resection Inlcuded few series up to 40 patients comparing… with results of …

Robotic pancreatic surgery Literature in its infancy Small cohort available even for high volume centres Case selection bias Learning curve Long term results ?

Local ablative therapy Percutaneous RFA ablation Stephan Limer et al. European Journal of Gastroenterology and Hepatology 2009, 21:1097-1101 EUS Guided ablation of insulinoma: a new treatment option Michael J. Levy et al. gastrointestinal Endoscopy, Vol 75, No.1;200-206

Conclusion Insulinoma is benign most of the time, but causing significant biochemical disturbance that require surgical treatment Localization is of utmost importance in surgical success Laparoscopic surgery offers treatment with less trauma and similar safety profile Novel treatment for surgically unfit individuals

Conclusion Insulinoma is an ideal entity for minimal invasive pancreatic surgery Lesion are small and benign most of the time no concern for involved margin, lymphatic dissection Laparoscopic and robotic pancreatic surgery is feasible for management of pancreatic insulinoma

INSULINOMA

Insulinoma Subgroup of pancreatic neuroendocrine tumours (pNETs) Commonest functional pNETs (25%) Incidence : 4 in 1,000,000 Unsuppressed production of endogenous insulin As part of genetic syndromes (5-8%) MEN I, VHL, NF I, TS

Presentation Whipple’s triad: Weight gain Other related syndromes Fasting hypoglycaemia (< 2.2 mmol/L) Symptomatic hypoglycaemia (autonomic and neuroglycaemic symptoms) Relieve of symptoms after administration of glucose Weight gain Other related syndromes

Biochemical diagnosis Ref: A Fuller Understanding of Pancreatic Neuroendocrine Tumours Combined with Aggressive Management Improves Outcome. S.L.Ong et al. Pancreatology 2009;9:583–600 To rule out other causes of hypoglycaemia

Localization Non-invasive Ultrasounography Computed tomography Magnetic resonance imaging Somatostatin receptor scintigraphy

Localization Invasive Endoscopic ultrasound +/- FNAC Selective arteriography Transhepatic portal venous sampling +/- calcium stimulation Surgical exploration + intra-operative US (IOUS) Endoscopic ultrasound +/- FNAC

Ref: A Fuller Understanding of Pancreatic Neuroendocrine Tumours Combined with Aggressive Management Improves Outcome. S.L.Ong et al. Pancreatology 2009;9:583–600

WHO classification Ref: A Fuller Understanding of Pancreatic Neuroendocrine Tumours Combined with Aggressive Management Improves Outcome. S.L.Ong et al. Pancreatology 2009;9:583–600

Ref: L. Fernandez-Cruz et al Ref: L.Fernandez-Cruz et al. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumour. World Journal of Surgery (2008) 32: 904-917.