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Learning Objectives

• After completing this activity, participants should be able to:
– Outline patient signs and symptoms that should lead to an evaluation for NETs – Describe the diagnostic work-up that can confirm a suspected diagnosis of NET – Review current treatment approaches for NETs and expected patient outcomes

NET = neuroendocrine tumor

NETs: A Not-So-Rare Disease
Epidemiology Signs and symptoms of NETs

Incidence of NETs Increasing
6.00 600

All malignant neoplasms Incidence per 100,000 - NETs
5.00 500

4.00

400

3.00

300

2.00

200

1.00

100

Neuroendocrine tumors
0.00 0 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 1975 1974 1973

Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

Incidence per 100,000 – All malignant neoplasms

312 cases (35/100. and End Results . Epidemiology. Yao JC et al. 2008.NETs Are Second Most Prevalent Gastrointestinal Tumor NET Prevalence in the US. SEER = Surveillance. 2004 1200 Cases (thousands) 1100 103.26:3063-3072.000) Median survival (1988 – 2004) • Localized 203 months • Regional 114 months • Distant 39 months 100 0 Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary 29-year limited duration prevalence analysis based on SEER. J Clin Oncol.

14:291-293.000 cases each • Islet cell3 – > 11.84:322-330. Berge T.000 cases from Hong Kong – 0. Eur J Surg Oncol.23:36-42.2% 1. 1961.1% – 0. 1997.2 – 2 studies • > 15.Autopsy Studies • Carcinoid1. 1976. Lo CY. . Lam KY. 2. Moertel CG et al. 3. Linell F. Cancer. Acta Pathol Microbiol Scand.7% to 1.

34[Suppl]:14S-27S. . Moattari AR. 1989.NETs Are Often Diagnosed Late Vague abdominal symptoms Death Diarrhea Flushing Metastases Primary tumor Time Vinik A. Dig Dis Sci.

2008.26:3063-3072. J Clin Oncol. .Missed Symptoms and Late Diagnosis Localized Distant Regional • Flushing – No sweating – First sip of alcohol • Diarrhea – Especially nocturnal 27% 50% 24% • Wheezing • Irritable bowel syndrome • Bloating Yao JC et al.

Diagnosis and Initial Work-Up Pathologic confirmation Assess disease burden Assess functional status .

. MD. CT: computed tomography.Anatomic Imaging: CT Std Arterial Venous Delayed Imaging studies property of James Yao.

MD. .Anatomic Imaging: MRI MRI = magnetic resonance imaging Imaging studies property of James Yao.

.Anatomic CT and Indium-111 Pentetreotide Scintigraphy Imaging studies property of James Yao. MD.

appendix. more variable) 5-HIAA = 5-hydroxyindoleacetic acid . cecum) – 5 HIAA (24-hr urine collection) – Serotonin (blood. proton pump inhibitors.Tumor Markers • General NET markers – Chromogranin A • Affected by somatostatin analogues. kidney function. liver function – Neuron-specific enolase • Midgut (small bowel.

Other Markers in Functional Tumors Fasting measurements when possible .

expression can change over time – Chromogranin B and C.Principles of Marker Assessment • Lots of markers. pancreatic polypeptide • Take large panel of markers at key points – Diagnosis or relapse • Follow a few elevated markers over time • Not necessary to check every marker at each visit . neurotensin. neurokinin A. pancreastatin. substance P.

Current Treatment Approaches Somatostatin analogs Chemotherapy for pancreatic NETs Regional therapy approaches .

pNET = pancreatic NET .Limited Options for Advanced NETs Functional Octreotide LAR + chemotherapy Chemotherapy Hepatic artery embolization Investigational agents Disease progression pNET Nonfunctional Carcinoid syndrome Octreotide LAR Carcinoid Midgut No syndrome Non-midgut No syndrome No standard (No approved therapies available) No standard LAR = long-acting release.

. J Clin Oncol.26:3063-3072. 2008.Need for Tumor Control Agents Remains High Survival Patients with distant NET (1988-2004) Carcinoid Pancreatic NET Limited Options • Carcinoid – No approved drugs for tumor control • pNET – Streptozocin approved but perceived to be toxic – No agreed-upon standard treatment for tumor control • Median survival – Carcinoid 43 months – pNET 27 months Yao JC et al.

Emerging Therapeutic Approaches Somatostatin receptor Peptide receptor radiotherapy Angiogenesis mTOR mTOR = mammalian target of rapamycin .

VEGF = vascular endothelial growth factor .Targeting NETs • Somatostatin receptors highly expressed by NETs – Targeting SST receptors can provide symptom and disease control • New targets could change treatment paradigm : – mTOR. VEGF inhibitors – Other antiangiogenic agents • High potential for combinations PI3K = phosphoinositide 3-kinase. SST = somatostatin. PI3K.

Potential Management of Advanced NETs Post-PROMID Functional Octreotide LAR + chemotherapy Chemotherapy pNET Nonfunctional Disease progression Investigational agents (No approved therapies available) Carcinoid syndrome Octreotide LAR Consider No Standard octreotide LAR No standard Carcinoid Midgut No syndrome Non-midgut No syndrome .

7. Ann Oncol.12:941-944.N'. 2008.10-tetraazacyclododecane-N.N''.Peptide Receptor Radiotherapy (PRRT) • Systemic radiotherapy targeting somatostatin receptors • Compounds vary by isotope and carrier molecule • 177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studies 111In pentetreotide Phe S S Thr(ol)-Cys Thr D-Trp Lys DTPA-CO-NH-D-Phe-Cys 111In 90Y DOTATOC Tyr S D-Trp Lys Thr DOTA-CO-NH-D-Phe-Cys 90Y S Thr(ol)-Cys 177Lu DOTATATE Tyr S S Thr-Cys Thr D-Trp Lys DOTA-CO-NH-D-Phe-Cys 177Lu 177Lu-DOTATATE:177Lu-1. 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide. 1.N'''-tetraacetic acid0 (DOTA).4. Kwekkeboom DJ et al.26:2124-2130. Tyr3-octreotate. . 2001. J Clin Oncol. 2. Waldherr C et al.

Bevacizumab: Randomized Phase 2 Trial Stable dose of octreotide x 2 months Protocol starts here Random assignment 18 wks Bevacizumab (+ octreotide) PEG interferon α-2b (+ octreotide) ITT by assignment Bevacizumab PEG interferon (n = 22) (n = 22) PR (confirmed) 4 17 0 16 SD PD 1 6 P = . . 2008.019 (2-sided exact) Bevacizumab + PEG interferon α-2b (+ octreotide) Additional responses: •1 pt with PD on PEG interferon had PR after addition of bevacizumab •1 pt with SD on PEG interferon had PR after addition of bevacizumab PR = partial response. SD = stable disease Yao JC et al.26:1316-1323. J Clin Oncol.

Sunitinib: Phase 2 Open-Label Study Carcinoid. . 2008. n (%) (n = 66) All pts.26:3403-3410. n (%) (N = 107) PR (confirmed) SD PD Not evaluable 1 (2) 34 (83) 1 (2) 5 (12) 11 (17) 45 (68) 5 (8) 5 (8) 12 (11) 78 (73) 6 (6) 10 (9) Kulke MH et al. n (%) (n = 41) Islet cell. J Clin Oncol.

NCCTG = North Central Cancer Treatment Group. CALGB. ECOG = Eastern Oncology Cooperative Group. CTSU = Cancer Trials Support Unit. SWOG = Southwestern Oncology Group . NCCTG Octreotide + bevacizumab CALGB = Cancer and Leukemia Group B.Carcinoid: SWOG 0518 Phase 3 Study Octreotide + interferon Poor prognosis (N = 283) R Supported by CTSU Endorsed by ECOG.

171 accrued) R Placebo Investigator-reported PFS: 11.Sunitinib Phase 3 pNET Study Stopped early at unplanned time point March 12. Abstract 127.4 mo with sunitinib vs 5. ASCO GI 2010. 2009 Sunitinib 37.5 mg continuous dosing Islet cell w/PD over prior 12 months (340 planned. .5 mo with placebo PFS = progression-free survival Raymond E et al.

J Clin Oncol. .26:4311-4318. D. 2008. Anderson Cancer Center. RR = response rate Yao JC et al.MDACC: Everolimus + Octreotide LAR Response Per protocol PR Overall N = 60 Carcinoid n = 30 Islet cell n = 30 13 (22%) 5 (17%) 8 (27%) SD PD 42 (70%) 5 (8%) 24 (80%) 1 (3%) 18 (60%) 4 (13%) PFS (median) 60 wks 63 wks 50 wks ITT RR: 20% MDACC = M.

2010. q28d) Stratum 1 n = 115 S C R E E N Everolimus Primary endpoint • RR stratum 1 Secondary endpoints Stratum 2 n = 45 Everolimus + octreotide LAR Treatment until progression.RADIANT-1: Study Design • Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapy – Stratum 1: No octreotide LAR 60d before enrollment • Received everolimus 10 mg/d – Stratum 2: Octreotide LAR ≥ 3mo before enrollment • Received everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg. J Clin Oncol. CT or MRI at baseline & q3mo PK = pharmacokinetics. RECIST = Response Evaluation Criteria In Solid Tumors Yao JC et al. • RR stratum 2 • Response duration • Safety • PFS • Survival • PK .28:69-76.

2010.7) PD Unknown Stratum 2: Everolimus + Octreotide LAR Central radiology PR SD Clinical benefit (PR + SD) (n = 45) ITT.4) 36 (80.4) 16 (13.0) 38 (84.8) 89 (77. . n (%) 11 (9.6) 78 (67.4) 0 (0.28:69-76.0) 7 (15.9) 10 (8.6) PD Unknown Yao JC et al. J Clin Oncol.RADIANT-1: Best Change from Baseline Central Radiology Review Stratum 1: Everolimus Central radiology PR SD Clinical benefit (PR + SD) (n = 115) ITT. n (%) 2 (4.

Pivotal Phase 3 Trials with Everolimus in NETs Accrual completed Advanced carcinoid with syndrome in progression (N = 429) R Octreotide LAR + Everolimus Octreotide LAR + placebo Accrual completed Advanced pNET in progression (N = 410) Best supportive care + everolimus* R Best supportive care + placebo* *Octreotide LAR included as best supportive care. .

Conclusions • NETs not that rare • Progress being made • Somatostatin analogs effective in controlling hormonal syndrome • PROMID suggests octreotide LAR controls tumor growth in midgut carcinoids • Phase 2: VEGF and mTOR inhibitors have singleagent activity in NETs • Confirmatory phase 3 studies ongoing .

HYPOGLICEMIA Agus Widiyatmoko .

postoperative . According to timing of the food ingestion a) fasting hypoglycemia (!!!) b) random hypoglycemia during the day .liver or kidney disease.reactive (functional).endogenously caused (insulinoma) 2.lack of contraregulatory hormones . According to pathogenesis a) decreased glucose production .exogenously caused (DM treatment) . alcohol b) increased glucose utilisation .CAUSE OF HYPOGLYCEMIA 1.

8-2.6 mmol/l Hormone glucagon catecholamines growth hormone cortisol neuroglycopenic symptoms neurogenic symptoms .8-3.6 mmol/l 3.1-2.7 mmol/l 2.2 mmol/l 3.5-3.Hypoglycemia and activation of contraregulatory hormones Glucose 3.

HYPOGLYCEMIC SYMPTOMS 1) neurogenic: (adrenergic) sweatting. blurred vision.headache. dysarthria. temper changes (depression. tremor 2) neuroglycopenic: a) neurologic: confusion. impaired speech and consciousness. decreased abbility to concentrate. euphory) impaired thinking . anxiety. palpitations. tachycardia. epilepsy b) psychiatric: unusual hesitation. diplopy. cramps.

INSULINOMA .

INSULINOMA • Epidemiology •Pathophysiology & Symptoms •Dignosis & Locallization •Management •Anaesthetic considerations .

Epidemiology • First described by Harris in JAMA 1924 • Commonest hormone producing Neuro Endocrine Tumors of GIT • 99% of pancreatic origin • 90% solitary. malignant in 25%) • Median age at presentation is 47yrs • F to M ratio 1. 90% < 2cm. 90% benign • 8% ass.4:1 . with Multiple Endocrine Neoplasia type I (multiple.

Pathophysiology Hypoglycemia ↑glucagon(glycemic threshold 65-70mg/dl) ↑catecholamines ↑cortisol & GH Neuroglucopenic symptoms(<50mg/dl) .

Pathophysiology • Reduced epinephrine response in response to chronic hypoglycemia (hypoglycemia unawareness) • Present with neuroglucopenic symptoms • Nonspecific & episodic in nature .

Symptoms • Neuroglucopenic symptoms – Headache – Visual disurbances – Lethargy.lassitude. coma .confusion – Difficulty in speech. thinking – Personality changes – Convulsions.

Symptoms
• Neurogenic
– Cholinergic symtoms
• Hunger • Sweating • Parasthesia

– Adrenergic symptoms
• • • • Anxiety, nervousness Tremors Tachycardia, palpitations hypertension

• Weight gain in 20-30% • Appear in early morning, after fasting • Aggravated by exercise

Diagnosis
• Whipples triad
– Hypoglycemic symptoms brought about by fasting or exercise – ↓Blood Sugar during symptoms – Relief on administration of glucose

• ↑ C peptide level • ↑ plasma insulin • Absence of sulfonylurea

Diagnostic testing
• 72 hrs fast(gold standard)
– – – – – – – – Plasma glucose ≤2.5 mmol/l Plasma insulin ≥6 μunits/ml (43 pmol/l) Plasma C-peptide ≥0.2 nmol/l Plasma proinsulin ≥0.5 nmol/l Plasma sulphonylurea Negative Plasma β-hydroxybutyrate <2.7 mmol/l Change in glucose with 1 mg glucagon ≥25 mg/dl at 30 min symptoms develop in 35 %of patients within 12 h, 75 % within 24 h, 92 % within 48 h and 99 % within 72 h

• C peptide suppression test • Stimulation tests with glucagon, Calsium, tolbutamide

Locallization • CT. Endoscopy US • Intraop US • Somatostatin receptor scintigraphy • Angiography • Selective intra-arterial Calsium injection stimulation with hepatic venous sampling . MRI • Transabdominal USG.

.

.

Octreoscan .

.

regimen (diet.pharmacological (diazoxide.by laparoscopy b) conservative . activity) .by laparotomy .TREATMENT a) surgical . octreotide) .

Nifedipine Somatostatin analogues. embolization . Verapamil. Octeotride CT.Streptozocin. Doxarubicin Hepatic art.Management • Medical – When awaiting surgery – Metastatic disease – Failed surgery • • • • • • Dietary Diazoxide (with hydrochlorthiazide) CCBs. 5FU.

Management • Surgical – Resection is the treatment of choice – Specialized units – Enecluation in most cases – Distal pacreatectomy/ whipples’s procedure in a few – Blind resection shouldn’t be performed .

Enucleation .

Resection (hemipancreatectomy) .

Surgical and histological finding a) localization (n=115) Head: 30 % Body: 28 % Tail: 42 % b) histology Benign adenoma: 103 Malign carcinoma: 4 Uncertain biological activity: 5 Multiple microadenomatosis: 3 .

Algorithm of diagnosis in organic hyperinsulinism DIAGNOSIS Clinical suspition Biochemical examination Diagnosis confirmed Topographic localisation Diagnosis unconfirmed CT Angiography Endosonography Localisation confirmed Surgery Insulinoma removed Insulinoma unremoved Conservative treatment Localisation unconfirmed TREATMENT .

In differential diagnosis: HYPOGLYCEMIA FACTITIA .

suspicion on insulinoma .HYPOGLYCEMIA FACTITIA Characteristic signs: .frequent relationship of the patient to health care providers Attention: IATROGENIC HYPOGLYCEMIA .uncertainty from clinical picture .uncertainty from laboratory findings .

Insulinoma vs hypoglycemia factitia Laboratory variable Insulinoma Hypoglycemia Hypoglycemia factitia factitia caused by insulin caused by sulphonylurea Plasma glucose ↓↓↓ ↓↓↓ ↓↓↓ Plasma insulin ↑ .↓↓ ↑↑↑ ↑ .↑↑ Serum C.↑ .↑↑ peptide Plasma ↑ .↑↑↑ ↑↑↑ ↓ .↑↑ proinsulin Sulphonylurea negative (urine) ↔ negative ↔ positive .

DIABETES HYPOGLICEMIA .

severe TREAT hypoglycemia but AVOID overtreatment AVOID hypoglycemia in the future .Hypoglycemia in Diabetes Checklist     2013 RECOGNIZE hypoglycemia and CONFIRM DIFFERENTIATE mild-moderate vs.

Definition of Hypoglycemia 1. Development of neurogenic or neuroglycopenic symptoms Neurogenic (autonomic) Trembling Neuroglycopenic Difficulty Concentrating Palpitations Sweating Anxiety Hunger Nausea Confusion Weakness Drowsiness Vision Changes Difficulty Speaking Dizziness 2. 3. Low blood glucose (<4 mmol/L if on insulin or secretagogue) Response to carbohydrate load .

Severity of Hypoglycemia • Mild – Autonomic symptoms present – Individual is able to self-treat • Moderate – Autonomic and neuroglycopenic symptoms – Individual is able to self-treat • Severe – Requires the assistance of another person – Unconsciousness may occur – Plasma glucose is typically <2.8 mmol/L .

Drug Induced Hypoglycemia • Can result in significant morbidity and mortality Serious obstacle to meet glycemic targets Counsel patients who drive on insulin or secretagogues re: self-monitoring of blood glucose and taking appropriate precautions • • .

Eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein .0 mmol/L) 3. Recognize autonomic or neuroglycopenic symptoms 2. Confirm if possible (blood glucose <4.0 mmol/L and retreat (see above) if needed 5. Retest in 15 minutes to ensure the BG >4.Steps to Address Hypoglycemia 1. Treat with “fast sugar” (simple carbohydrate) (15 g) to relieve symptoms 4.

Examples of 15 g Simple Carbohydrate • 15 g of glucose in the form of glucose tablets 15 mL (3 teaspoons) or 3 packets of sugar dissolved in water 175 mL (3/4 cup) of juice or regular soft drink 6 Lifesavers (1=2.5 g of carbohydrate) 15 mL (1 tablespoon) of honey • • • • .

Recognize Risk Factors for Severe Hypoglycemia Risk factors in Type 1 DM patients Adolescence Children unable to detect and/or treat mild hypoglycemia Risk factors in Type 2 DM patients Elderly Poor health literacy. Food insecurity A1C <6.0% Long duration of diabetes Prior episode of severe hypoglycemia Hypoglycemia unawareness Increased A1C Duration of insulin therapy Severe cognitive impairment Renal impairment Autonomic neuropathy Neuropathy .

Treatment of SEVERE Hypoglycemia in Conscious Person 1. Eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein .0 mmol/L and retreat with a further 15 g of carbohydrate if needed 3. Retest in 15 minutes to ensure the BG> 4. Treat with oral “fast sugar” (simple carbohydrate) (20 g) to relieve symptoms 2.

Call 911 3. Treat with 1 mg of glucagon subcutaneously or intramuscularly 2.Treatment of SEVERE Hypoglycemia in Unconscious Person with no IV Access 1. Discuss with diabetes healthcare team .

0 mmol/L and retreat with a further 15 g of carbohydrate if needed 3. eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein . Retest in 15 minutes to ensure the BG >4. Once conscious.Treatment of SEVERE Hypoglycemia in Unconscious Person with IV Access 1. Treat with 10-25 g (20-50 cc of D50W) of glucose intravenously over 1-3 minutes 2.

Hypoglycemia and Driving Safe blood glucose (BG) prior to driving • – – – BG ≥ 5. Begg et al . 2003. .0 mmol/L If BG <5.0 mmol/L prior to driving: Take 15 g carbohydrate Re-check in 15 minutes When BG >5 mmol/L for at least 45 minutes  safe to drive • Need to re-check BG every 4 hours of continuous driving and carry simple carbohydrate snacks Iain S. Canadian Journal of Diabetes.27(2):128-140.

Consensus] . glucose or sucrose tablets/solutions are preferable to orange juice and glucose gels [Grade B.Recommendation 1 1. Mild to moderate hypoglycemia should be treated by oral ingestion of 15 g carbohydrate. Level 2] Patients should retest blood sugar in 15 minutes and retreat with another 15 g of carbohydrates if BG remains <4.0 mmol/L [Grade D.

preferable as glucose tablets or equivalent. Blood sugar should be retested in 15 minutes. Severe hypoglycemia in a conscious person should be treated by oral ingestion of 20 g of carbohydrate. Consensus] . and then retreated with a further 15 g of glucose if BG remains <4.0 mmol/L [Grade D.Recommendation 2 2.

Caregivers or support persons should call for emergency services and the episode should be discussed with the diabetes healthcare team as soon as possible [Grade D. Consensus] – With IV access: 10-25 g (20-50 cc of D50W) of glucose should be given intravenously over 1-3 minutes [Grade D. Consensus] . Severe hypoglycemia in an unconscious individual: – No IV access: 1 mg of glucagon should be administered subcutaneously or intramuscularly.Recommendation 3 3.

Recommendation 4 4. For individuals at risk of severe hypoglycemia. support persons should be taught how to administer glucagon by injection [Grade D. Consensus] .

the person should have the usual meal or snack that is due at that time of the day to prevent repeated hypoglycemia [Grade D. a snack (including 15 g of carbohydrate and protein source) should be consumed [Grade D. Consensus]. If a meal is > 1 hour away.Recommendation 5 5. Consensus] . Once the hypoglycemia has been reversed.

Patients receiving antihyperglycemic agents that may cause hypoglycemia should be counseled about strategies for prevention.Recommendation 6 2013 6. recognition and treatment of hypoglycemia related to driving [Grade D. consensus] .

Conclusions for clinical practice Hypoglycemia is deleterious for organism and is life threatening • to analyse symptoms (history !) • to confirm hypoglycemia • to elucidate cause of hypoglycemia (confirm diagnosis) • to realize reliable treatment strategy removing hypoglycemia (related to diagnosis and clinical state of the patient) .