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

NETs Are Second Most Prevalent Gastrointestinal Tumor

NET Prevalence in the US, 2004
1200

Cases (thousands)

1100

103,312 cases (35/100,000)

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. Yao JC et al. J Clin Oncol. 2008;26:3063-3072. SEER = Surveillance, Epidemiology, and End Results

Autopsy Studies
Carcinoid1,2
2 studies
> 15,000 cases each

Islet cell3
> 11,000 cases from Hong Kong 0.1%

0.7% to 1.2%

1. Berge T, Linell F. Acta Pathol Microbiol Scand. 1976;84:322-330. 2. Moertel CG et al. Cancer. 1961;14:291-293. 3. Lam KY, Lo CY. Eur J Surg Oncol. 1997;23:36-42.

NETs Are Often Diagnosed Late

Vague abdominal symptoms
Death Diarrhea Flushing

Metastases
Primary tumor Time
Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

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. J Clin Oncol. 2008;26:3063-3072.

Diagnosis and Initial Work-Up

Pathologic confirmation Assess disease burden Assess functional status

Anatomic Imaging: CT

Std

Arterial

Venous

Delayed

Imaging studies property of James Yao, MD.

CT: computed tomography.

Anatomic Imaging: MRI

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

Anatomic CT and Indium-111 Pentetreotide Scintigraphy

Imaging studies property of James Yao, MD.

Tumor Markers
General NET markers
Chromogranin A
Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function

Neuron-specific enolase

Midgut (small bowel, appendix, cecum)

5 HIAA (24-hr urine collection) Serotonin (blood, more variable)

5-HIAA = 5-hydroxyindoleacetic acid

Other Markers in Functional Tumors

Fasting measurements when possible

Principles of Marker Assessment

Lots of markers; expression can change over time
Chromogranin B and C, pancreastatin, substance P, neurotensin, neurokinin A, 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

Current Treatment Approaches

Somatostatin analogs Chemotherapy for pancreatic NETs Regional therapy approaches

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; pNET = pancreatic NET

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. J Clin Oncol. 2008;26:3063-3072.

Emerging Therapeutic Approaches

Somatostatin receptor Peptide receptor radiotherapy Angiogenesis mTOR

mTOR = mammalian target of rapamycin

Targeting NETs
Somatostatin receptors highly expressed by NETs
Targeting SST receptors can provide symptom and disease control

New targets could change treatment paradigm :

mTOR, PI3K, VEGF inhibitors Other antiangiogenic agents

High potential for combinations

PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

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

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-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0

(DOTA), Tyr3-octreotate; 90Y

DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide. 1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130. 2. Waldherr C et al. Ann Oncol. 2001;12:941-944.

Bevacizumab: Randomized Phase 2 Trial

Stable dose of octreotide x 2 months Protocol starts here Random assignment 18 wks Bevacizumab (+ octreotide) PEG interferon -2b (+ octreotide)

ITT by assignment
Bevacizumab PEG interferon
(n = 22) (n = 22)

PR
(confirmed)

4 17

0 16

SD

PD

P = .019 (2-sided exact)

Bevacizumab + PEG interferon -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. J Clin Oncol. 2008;26:1316-1323.

Sunitinib: Phase 2 Open-Label Study

Carcinoid, n
(%) (n = 41)

Islet cell, n
(%) (n = 66)

All pts, 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. J Clin Oncol. 2008;26:3403-3410.

Carcinoid: SWOG 0518 Phase 3 Study

Octreotide + interferon
Poor prognosis (N = 283)

Supported by CTSU Endorsed by ECOG, CALGB, NCCTG

Octreotide + bevacizumab
CALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology Cooperative Group; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group

Sunitinib Phase 3 pNET Study

Stopped early at unplanned time point March 12, 2009
Sunitinib 37.5 mg continuous dosing
Islet cell w/PD over prior 12 months (340 planned, 171 accrued)

R
Placebo

Investigator-reported PFS: 11.4 mo with sunitinib vs 5.5 mo with placebo

PFS = progression-free survival Raymond E et al. ASCO GI 2010; Abstract 127.

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. D. Anderson Cancer Center; RR = response rate Yao JC et al. J Clin Oncol. 2008;26:4311-4318.

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, 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; CT or MRI at baseline & q3mo

PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid Tumors Yao JC et al. J Clin Oncol. 2010;28:69-76.

RR stratum 2 Response duration Safety PFS Survival PK

RADIANT-1: Best Change from Baseline

Central Radiology Review
Stratum 1: Everolimus
Central radiology
PR SD Clinical benefit
(PR + SD)

(n = 115)

ITT, n (%)
11 (9.6) 78 (67.8) 89 (77.4) 16 (13.9) 10 (8.7)

PD Unknown

Stratum 2: Everolimus + Octreotide LAR

Central radiology
PR SD Clinical benefit
(PR + SD)

(n = 45)

ITT, n (%)
2 (4.4) 36 (80.0) 38 (84.4) 0 (0.0) 7 (15.6)

PD Unknown Yao JC et al. J Clin Oncol. 2010;28:69-76.

Pivotal Phase 3 Trials with Everolimus in NETs

Accrual completed

Advanced carcinoid with syndrome in progression

(N = 429)

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

CAUSE OF HYPOGLYCEMIA
1. According to pathogenesis a) decreased glucose production
- lack of contraregulatory hormones - liver or kidney disease, alcohol

b) increased glucose utilisation

- exogenously caused (DM treatment) - endogenously caused (insulinoma)

2. According to timing of the food ingestion a) fasting hypoglycemia (!!!) b) random hypoglycemia during the day
- reactive (functional), postoperative

Hypoglycemia and activation of contraregulatory hormones

Glucose 3,8-3,6 mmol/l 3,5-3,2 mmol/l 3,1-2,7 mmol/l 2,8-2,6 mmol/l Hormone glucagon catecholamines growth hormone cortisol
neuroglycopenic symptoms

neurogenic symptoms

HYPOGLYCEMIC SYMPTOMS
1) neurogenic: (adrenergic) sweatting, palpitations, tachycardia, anxiety, tremor

2) neuroglycopenic: a) neurologic: confusion,headache, blurred vision, diplopy, dysarthria, decreased abbility to concentrate, impaired speech and consciousness, cramps, epilepsy b) psychiatric: unusual hesitation, temper changes (depression, euphory) impaired thinking

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, 90% < 2cm, 90% benign 8% ass. with Multiple Endocrine Neoplasia type I (multiple, malignant in 25%) Median age at presentation is 47yrs F to M ratio 1.4:1

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,confusion Difficulty in speech, thinking Personality changes Convulsions, coma

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 units/ml (43 pmol/l) Plasma C-peptide 0.2 nmol/l Plasma proinsulin 0.5 nmol/l Plasma sulphonylurea Negative Plasma -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, MRI Transabdominal USG, Endoscopy US Intraop US Somatostatin receptor scintigraphy Angiography Selective intra-arterial Calsium injection stimulation with hepatic venous sampling

Octreoscan

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

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

Management
Surgical
Resection is the treatment of choice Specialized units Enecluation in most cases Distal pacreatectomy/ whippless procedure in a few Blind resection shouldnt 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

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

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

Hypoglycemia in Diabetes Checklist

2013

RECOGNIZE hypoglycemia and CONFIRM DIFFERENTIATE mild-moderate vs. severe

TREAT hypoglycemia but AVOID overtreatment

AVOID hypoglycemia in the future

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

Steps to Address Hypoglycemia

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

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. Treat with oral fast sugar (simple carbohydrate) (20 g) to relieve symptoms
2. Retest in 15 minutes to ensure the BG> 4.0 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

Treatment of SEVERE Hypoglycemia in Unconscious Person with no IV Access

1. Treat with 1 mg of glucagon subcutaneously or intramuscularly

2. Call 911

3. Discuss with diabetes healthcare team

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. Retest in 15 minutes to ensure the BG >4.0 mmol/L and retreat with a further 15 g of carbohydrate if needed 3. Once conscious, eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein

Hypoglycemia and Driving

Safe blood glucose (BG) prior to driving

BG 5.0 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. Begg et al . Canadian Journal of Diabetes. 2003;27(2):128-140.

Recommendation 1
1. Mild to moderate hypoglycemia should be treated by oral ingestion of 15 g carbohydrate; glucose or sucrose tablets/solutions are preferable to orange juice and glucose gels [Grade B, 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, Consensus]

Recommendation 2
2. Severe hypoglycemia in a conscious person should be treated by oral ingestion of 20 g of carbohydrate, preferable as glucose tablets or equivalent.

Blood sugar should be retested in 15 minutes, and then retreated with a further 15 g of glucose if BG remains <4.0 mmol/L [Grade D, Consensus]

Recommendation 3
3. Severe hypoglycemia in an unconscious individual: No IV access: 1 mg of glucagon should be administered subcutaneously or intramuscularly. 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]

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

Recommendation 5
5. Once the hypoglycemia has been reversed, the person should have the usual meal or snack that is due at that time of the day to prevent repeated hypoglycemia [Grade D, Consensus].

If a meal is > 1 hour away, a snack (including 15 g of carbohydrate and protein source) should be consumed
[Grade D, Consensus]

Recommendation 6

2013

6. Patients receiving antihyperglycemic agents that may cause hypoglycemia should be counseled about strategies for prevention, 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)