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Update in the Management of Neuroendocrine Tumours

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1 Update in the Management of Neuroendocrine Tumours
Please see Brief Summary and accompanying full Prescribing Information on slides Indications may vary between countries. This piece is for promotional use with healthcare professionals upon local regulatory approval in your particular country. Each CPO is responsible for ensuring that this material is reviewed and approved in accordance with the local NP4 approval process.

2 Neuroendocrine Tumour (NET) Overview
This section provides an overview of neuroendocrine tumours (NETs), including incidence, prevalence, survival rates, and dynamics of progressive disease.

3 Neuroendocrine Tumours (NETs)
Site of Primary Tumour2 (Incidence per 100,000)* Lung (1.35) Thymus (0.02) Other/Unknown (0.74) GI SYSTEM (2.89) Pancreas (0.32) Liver (0.04) Stomach (0.30) Duodenum (0.19) Jejunum/ileum (0.67) Cecum (0.16) Appendix (0.15) Colon (0.20) Rectum (0.86) Arise from cells of the neuroendocrine system1 Most common type are gastroenteropancreatic NETs (GEP-NETs) of the gastrointestinal (GI) system2 Generally small (< 1 cm in diameter) and slow-growing3 Have metastatic potential3 Neuroendocrine tumours (NETs) arise from the hormone-secreting cells of the neuroendocrine system.1 Traditional NET classification system is derived from the embryonic tissue or origin:2,3 Foregut – Respiratory tract, thymus, stomach Midgut – Small intestine, appendix, proximal colon Hindgut – Distal colon, rectum, genitourinary tract Gastro-entero-pancreatic NETs (GEP-NETs) of the GI system are most common.4 NETs are generally small and slow-growing, but have metastatic potential.5 REFERENCES Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54:iv1-iv16. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology ;128: Pinchot SN, Holen K, Sippel RS, Chen H. Carcinoid tumors. Oncologist. 2008;13:1255–1269. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26: Kufe DW, Pollock RE, Weichselbaum RR, et al. eds. Holland-Frei Cancer Medicine, 6th ed. Hamilton (ON): BC Decker; 2003. *Age-adjusted annual incidence per 100,000 in the 2000 US population; from the SEER 17 registry Ramage JK, Davies AH, Ardill J, et al. Gut. 2005;54:iv1-iv16. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26: Kufe DW, Pollock RE, Weichselbaum RR, et al. eds. Holland-Frei Cancer Medicine, 6th ed. Hamilton (ON): BC Decker; 2003.

4 NETs are More Prevalent Than Many Tumours of the GI System
Because NETs are slow-growing tumours,1 patients may survive for many months after diagnosis.2 Therefore, although NET incidence is relatively low, prevalence is quite high.2 In the US, NETs are more prevalent than tumours of the:3 Stomach Pancreas (> 2x as prevalent) Oesophagus and liver (> 3x as prevalent) REFERENCES Kufe DW, Pollock RE, Weichselbaum RR, et al. eds. Holland-Frei Cancer Medicine, 6th ed. Hamilton (ON): BC Decker; 2003. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26: National Cancer Institute. SEER Cancer Statistics Review Complete and Limited-Duration Cancer Prevalence Estimates. Accessed 28 March 2011. National Cancer Institute. SEER Cancer Statistics Review Complete and Limited-Duration Cancer Prevalence Estimates. Accessed 28 March 2011. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:

5 A Lack of Distinct Symptoms May Delay NET Diagnosis
NETs are typically present for 5–7 years prior to diagnosis1 ASYMPTOMATIC NETs Also called nonfunctioning NETs More common than symptomatic NETs1 Do not cause clinical syndromes2 Usually present due to mass effects and/or metastatic disease1,2 SYMPTOMATIC NETs Also called functioning NETs Release bioactive substances to the bloodstream2 May cause paraneoplastic disease2 Symptoms may mimic other conditions1 (e.g. symptomatic GEP-NETs typically produce flushing and diarrhoea)3 One key property of NETs is that they have the potential to become symptomatic (or “functioning”) tumours and secrete bioactive substances that can cause characteristic paraneoplastic disease.1 However, even when symptoms exist, they often mimic other, more common conditions2 —for example, GEP-NETs typically cause flushing and diarrhoea3 —and so may be overlooked. More commonly, NETs are asymptomatic (or “nonfunctioning”)1 and do not cause clinical symptoms.2 Asymptomatic NETs may be detected on routine screening for other conditions.3 They may also present with mass effects or metastatic disease following extended tumour growth.1,2 Typically, there is a delay of 5–7 years between tumour initiation and diagnosis.2 REFERENCES Kaltsas G, Androulakis II, de Herder WW, Grossman AB. Paraneoplastic syndromes secondary to neuroendocrine tumours. Endocr Relat Cancer. 2010;17:R173–R193. Modlin IM, Öberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61–72. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology ;128:1717–1751. Modlin IM, Öberg K, Chung DC, et al. Lancet Oncol. 2008;9:61–72. Kaltsas G, Androulakis II, de Herder WW, Grossman AB. Endocr Relat Cancer. 2010;17:R173–R193. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128:1717–1751.

6 Nearly Half of all NETs are Advanced at Diagnosis
Because NETs symptoms may be absent or nonspecific, nearly half of all NETs are advanced at diagnosis, presenting with regional spread and/or distant metastases. REFERENCE Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26: *Includes the 78.4% of NET patients in the SEER 17 registry with staging information available at diagnosis. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:

7 Advanced Disease is Associated With Poorer 5-Year Survival
Advanced disease is associated with poorer median 5-year survival rates, demonstrating a need for tumour control soon after diagnosis. REFERENCE Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26: Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:

8 WITHOUT TREATMENT, THE MAJORITY OF PATIENTS WITH ADVANCED MIDGUT NETs WILL PROGRESS WITHIN 1 YEAR
In a randomised, controlled, phase III clinical trial (PROMID): More than half of the advanced midgut NET patients with in the placebo arm (51%) had progressed at 6 months. Nearly 4 in 5 placebo advanced midgut NET patients (79%) had progressed at 1 year. N = 43 Median time since diagnosis (at baseline): 3.3 months (range: 0.8–109.4 months) REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

9 Somatostatin Signalling
This section introduces somatostatin signalling and the rationale for the use of somatostatin analogues in the treatment of NETs and NET-related disease.

10 POTENTIAL THERAPEUTIC TARGET: SOMATOSTATIN SIGNALLING IN NETs
Decreases hormone secretion and controls symptoms Promotes cell death (apoptosis) Inhibits cell growth The majority of NETs express somatostatin receptors (SSTRs)2 Approximately 80% of GEP-NETs express the SSTR2 subtype3 Binding of somatostatin or somatostatin analogues to somatostatin receptors (SSTRs) leads to:1 Decreased hormone secretion Inhibition of cell growth Promotion of apoptosis The majority of NETs express SSTRs.2 There are five SSTR subtypes: SSTR1–5.3 Approximately 80% of GEP-NETs express SSTR2.3 Somatostatin signalling has proven to be an excellent target for GEP-NET symptom control, and clinical evidence (from PROMID) indicates that it is a strong target for tumour control as well.1 REFERENCES Öberg KE, Reubi J-C, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010;139: Hicks RJ. Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy. Cancer Imaging ;10:S83-S91. Kulaksiz H, Eissele R, Rössler D, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies Gut. 2002;50:52-60. Öberg KE, Reubi J-C, Kwekkeboom DJ, Krenning EP. Gastroenterology. 2010;139: Hicks RJ. Cancer Imaging. 2010;10:S83-S91. Kulaksiz H, Eissele R, Rössler D, et al. Gut. 2002;50:52-60.

11 Direct and Indirect Antiproliferative Effects of Somatostatin Signalling
Somatostatin receptor activation Binding of somatostatin receptors on tumour cells Systemic effect Direct antiproliferative effect Indirect antiproliferative effect Inhibition of cell cycle Inhibition of growth factor effects Pro-apoptotic effect Inhibition of growth factor and trophic hormones Inhibition of angiogenesis Immune system modulation Somatostatin receptor activation may have both direct and indirect antiproliferative effects on NETs.1 Direct effects – Binding of somatostatin receptors on the tumours themselves causes:1 Inhibition of the cell cycle and tumour cell division Inhibition of growth factor effects, diminishing tumour response to those factors Pro-apoptotic effects, inducing tumour cell death Indirect effects – Somatostatin receptor activation indirectly affects NET growth through:1 Inhibition of growth factor and trophic hormones that can promote tumour cell growth Inhibition of angiogenesis, limiting tumour blood supply Immune system modulation, potentially inducing immune-mediated tumour control Note that the information provided in this slide is intended to describe the general effects of somatostatin receptor activation, and does not reflect data obtained through the PROMID clinical trial.2 Several small, uncontrolled, clinical studies indicated that somatostatin analogues could stabilize tumour growth in NET patients.2 REFERENCES Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 2006;17: Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Susini C, Buscail L. Ann Oncol. 2006;17:

12 DELAYING THE PROGRESSION OF NEUROENDOCRINE TUMOURS
This section describes the PROMID trial: a randomised, double-blind, placebo-controlled study assessing the use of Sandostatin LAR 30 mg to control NET growth and disease progression.

13 PROMID: Pivotal Phase III Trial Demonstrating Tumour Control by Sandostatin LAR
PROMID: Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine MIDgut Tumors Phase III, randomised, double-blind, placebo-controlled trial Designed to evaluate the antiproliferative effects of the somatostatin analogue Sandostatin® (octreotide) LAR® 30 mg Conducted at 18 centres in Germany (2001–2008) PROMID was the pivotal phase III trial demonstrating tumour control by the somatostatin analogue Sandostatin (octreotide) LAR 30mg. PROMID: Placebo-Controlled, Double Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine MIDgut Tumors Phase III, randomised, double-blind, placebo-controlled trial Conducted at 18 centres in Germany (2001–2008) REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

14 PROMID Design and Endpoints
Randomised Patients (N = 85) Treatment naïve Karnofsky status > 60% Tumour criteria Midgut origin Well-differentiated histology Locally inoperable or metastatic Measurable (CT/MRI) Symptomatic or asymptomatic Randomisation (1:1) Sandostatin LAR 30 mg (N = 42) IM every 28 days Placebo (N = 43) IM every 28 days Treatment until tumour progression or death Primary Endpoint TTP (defined as time to tumour progression or time to tumour-related death) Secondary Endpoints Survival time Quality of life Clinical and biochemical response (in patients with symptomatic disease) Safety Inclusion criteria Treatment-naïve: Patients were excluded if they had received pretreatment with somatostatin analogs for four weeks or previous treatment with interferon alfa, chemotherapy, or chemoembolisation. Resection of the primary tumour was not cause for exclusion. Karnofsky status > 60% Tumour of midgut origin with well-differentiated histology: Limiting enrolment to patients with well-differentiated midgut NETs avoided the potential for confounding factors due to differences in tumour origin or biological behaviour. Locally inoperable or metastatic tumour Measurable disease by CT or MRI Either symptomatic or asymptomatic disease– Symptomatic tumours were defined by the presence of carcinoid syndrome and elevated 5-hydroxyindole acetic acid (5-HIAA) levels. After 1:1 randomisation, patients received either Sandostatin LAR 30 mg or placebo intramuscularly every 28 days. Treatment continued until tumour progression or death. Primary endpoint: TTP (defined as time to tumour progression or time to tumour-related death) Secondary endpoints Overall survival: Calculated from the date of randomisation to the date of tumour-related death. Quality of life: Assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 at randomisation and at 3-month intervals. Clinical and biochemical response in patients with symptomatic disease: Clinical response was defined as a reduction to less than one flush per week, fewer than four stools per day, and absence of abdominal pain. Biochemical response was defined as a decrease in tumour markers to normal levels. Safety: Adverse events were documented according to the National Cancer Institute Common Toxicity Criteria (version 2.0) or to the WHO criteria. REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

15 PROMID Patient Characteristics at Baseline
Sandostatin LAR 30 mg (N = 42) Placebo (N = 43) Total (N = 85) Median age, years (range) 63.5 (38–79) 61 (39–82) 62 (38–82) Male (%) 20 (47.6) 23 (53.5) 43 (50.6) Months since diagnosis (range) 7.5 (0.8–271.7) 3.3 (0.8–109.4) 4.3 (0.8–271.7) Karnofsky performance status > 80% (%) 35 (83.3) 38 (88.4) 73 (85.9) Symptomatic disease (%) 17 (40.5) 16 (37.2) 33 (38.8) Resection of primary tumour (%) 29 (69.1) 27 (62.8) 56 (65.9) Ki-67 up to 2% (%) 41 (97.6) 40 (93.0) 81 (95.3) Octreoscan Positive (%) Negative (%) 32 (76.2) 4 (9.5) 31 (72.1) 6 (14.0) 63 (74.1) 10 (11.8) Liver involvement ≤ 10% (%) > 10% (%) 10 (23.8) 32 (74.4) 11 (25.6) 64 (75.3) 21 (24.7) Chromogranin A Elevated (%) Not elevated (%) 26 (61.9) 15 (35.7) 30 (69.8) 12 (27.9) 27 (31.8) Baseline characteristics of the patients were well balanced between treatment arms. The median time between diagnosis and randomization for the whole group was 4.3 months. The discrepancy in median time between the two groups (7.5 months for Sandostatin LAR 30mg; 3.3 months for placebo) was due largely to skewing introduced by the inclusion of two patients in the Sandostatin LAR 30 mg group with a much longer time since diagnosis than patients in the placebo arm. About 40% of all patients had symptomatic disease (carcinoid syndrome). REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

16 Sandostatin LAR 30 mg Significantly Prolongs TTP* Over Placebo
Results seen in the Sandostatin LAR 30 mg group, compared with placebo More than double the median TTP (14.3 months with Sandostatin LAR 30 mg vs 6.0 months with placebo; P = ) 66% reduction in the risk of disease progression (HR = 0.34) The key finding from PROMID is that Sandostatin LAR 30 mg significantly extended TTP (defined as time to tumour progression or time to tumour-related death) over placebo (P = ), based on conservative intent to treat analysis. The median TTP of the Sandostatin LAR 30 mg group (14.3 months) was more than double that of the placebo group (6.0 months). Sandostatin LAR 30 mg provided a 66% reduction in the risk of tumour progression (HR = 0.34). Some patients in the Sandostatin LAR 30 mg group had still not progressed by the end of the study (78 months), while all placebo patients had progressed by 36 months. These results are from a pre-planned interim analysis, carried out after 67 progressions or tumour-related deaths. The median survival time in the Sandostatin LAR 30 mg group was not reached at the time of the interim analysis (> 77.4 months). The median survival time in the placebo group was 73.7 months. REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. *TTP: Time to tumour progression or tumour-related death Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

17 The Majority of Patients in the PROMID Trial Were Asymptomatic
Sandostatin LAR 30 mg prolonged TTP over placebo, regardless of symptomatic or asymptomatic disease Symptomatic: HR = (95% CI: 0.09–0.57) Asymptomatic: HR = (95% CI: 0.10–0.59) Symptomatic disease was defined by the presence of carcinoid syndrome and elevated 5-hydroxyindole acetic acid (5-HIAA) levels. The majority of patients in the PROMID trial were asymptomatic (N = 52 versus N = 33). Sandostatin LAR improved TTP, regardless of whether patients had symptomatic or asymptomatic disease. REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

18 Majority of Patients Who Received Sandostatin LAR 30 mg Achieved Stable Disease at 6 Months*
67% of patients in the Sandostatin LAR group achieved stable disease at 6 months(according to WHO criteria), compared with 37% of patients in the placebo group. REFERENCE Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. *As defined by WHO criteria Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

19 Sandostatin LAR is Generally Well Tolerated1
Observed safety findings in the PROMID trial were consistent with those seen in previous studies of Sandostatin LAR in patients with nets1-3 Adverse events in PROMID3 Sandostatin LAR 30 mg (N = 42) Placebo (N = 43) Serious adverse event 11 10 Most frequent serious adverse events Gastrointestinal tract 6 8 Haematopoietic system 5 1 General health status (fatigue, fever) 2 Adverse event causing discontinuation Similar to other studies, Sandostatin LAR 30 mg was well-tolerated in PROMID.1-3 Serious adverse events were found at similar rates in the Sandostatin LAR and placebo groups.3 Five patients in the Sandostatin LAR group and no patients in the placebo group experienced an adverse event leading to discontinuation.3 There were no treatment-related deaths.3 Please consult the Prescribing Information for a full description of the safety profile. REFERENCES Sandostatin LAR Basic Prescribing Information. Novartis Pharma AG. 20 May 2010. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17: Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Sandostatin LAR Basic Prescribing Information. Novartis Pharma AG. 20 May 2010. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol. 1999;17: Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

20 Guidelines CPO: Please provide your local guidelines here
Placeholder for local guidelines.

21 MANAGEMENT OF SYMPTOMATIC GEP-NETs
This section describes the use of Sandostatin LAR in the control of GEP-NET symptoms.

22 GEP-NET Symptoms Can Have Immediate and Long-Term Consequences
Common GEP-NET Symptoms1 Diarrhoea and flushing are the two most common GEP-NET symptoms.1 Patients may have up to 30 stools per day, accompanied by pain.2 Flushing is an outwardly visible sign of the disease.2 Potentially life-threatening dehydration, hypotension, arrhythmias, and unconsciousness can develop from early symptoms, like diarrhoea and flushing.3 Diarrhoea and flushing are the two most common GEP-NET symptoms.1 Patients may have up to 30 stools per day, accompanied by pain.2 Flushing is an outwardly visible sign of the disease.2 Potentially life-threatening dehydration, hypotension, arrhythmias, and unconsciousness can develop from early symptoms, like diarrhoea and flushing.3 REFERENCES Creutzfeldt W. Carcinoid tumors: Development of our knowledge. World J Surg. 1996;20: McCormick D. Carcinoid tumors and syndrome. Gastroenterol Nurs. 2002;25: Zuetenhorst JM, Taal BG. Metastatic carcinoid tumors: A clinical review. Oncologist. 2005;10: Creutzfeldt W. World J Surg. 1996;20: McCormick D. Gastroenterol Nurs. 2002;25: Zuetenhorst JM, Taal BG. Oncologist. 2005;10:

23 REDUCTION IN THE FREQUENCY OF DIARRHOEA WITH SANDOSTATIN LAR 20 MG
In Functional Carcinoid Patients: After 24 weeks, patients taking Sandostatin LAR 20 mg experienced a 48% reduction from baseline in the median number of diarrhoea episodes per day.1 These data are from a 6-month clinical trial of malignant carcinoid syndrome.2 93 patients who were previously shown to be responsive to Sandostatin Injection (Sandostatin SC). 67 patients randomized at baseline to receive, double-blind doses of 10 mg, 20 mg or 30 mg Sandostatin LAR Depot every 28 days. 26 patients continued, unblinded, on the previous Sandostatin Injection regimen (100–300 mcg three times daily). REFERENCES Data on file. Novartis Pharma AG. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17: Data on file. Novartis Pharma AG.

24 In Functional Carcinoid Patients:
REDUCTION IN THE FREQUENCY OF FLUSHING EPISODES WITH SANDOSTATIN LAR 20 MG In Functional Carcinoid Patients: After 24 weeks, patients taking Sandostatin LAR 20 mg experienced a 90% reduction from baseline in the median number of flushing episodes per day.1 These data are from a 6-month clinical trial of malignant carcinoid syndrome.2 93 patients who were previously shown to be responsive to Sandostatin Injection (Sandostatin SC). 67 patients randomized at baseline to receive, double-blind doses of 10 mg, 20 mg or 30 mg Sandostatin LAR Depot every 28 days. 26 patients continued, unblinded, on the previous Sandostatin Injection regimen (100–300 mcg three times daily). REFERENCES Data on file. Novartis Pharma AG. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol ;17: Data on file. Novartis Pharma AG.

25 SUPPRESSION OF 5-HIAA* LEVELS WITH SANDOSTATIN LAR 20 MG
In Functional Carcinoid Patients: After 20–24 weeks, patients taking Sandostatin LAR 20 mg experienced a 54% reduction from baseline in 5- HIAA levels.1 5-HIAA levels may be used to monitor tumour activity and recurrence, and decreasing 5-HIAA levels may indicate effective management of carcinoid tumours.2 Abnormally high 5-HIAA levels have been associated with poorer patient prognosis.3 These data are from a 6-month clinical trial of malignant carcinoid syndrome.1 93 patients who were previously shown to be responsive to Sandostatin Injection (Sandostatin SC).1 67 patients randomized at baseline to receive, double-blind doses of 10 mg, 20 mg or 30 mg Sandostatin LAR Depot every 28 days.1 26 patients continued, unblinded, on the previous Sandostatin Injection regimen.1 REFERENCES Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17: NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine Tumors. V Kocha W, Maroun J, Kennecke H, et al. Consensus recommendations for the diagnosis and management of well-differentiated gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National Expert Group. Curr Oncol Jun;17(3):49-64. *5-hydroxyindoleacetic acid: serotonin metabolite used to assess tumour hormone secretion ** 20 and/or 24 weeks Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol. 1999;17:

26 Sandostatin LAR Dosing
Sandostatin is available in a subcutaneous (SC) formulation for breakthrough symptoms TUMOUR CONTROL Sandostatin LAR 30 mg IM every 4 weeks Continue treatment in the absence of tumour progression SYMPTOM CONTROL IN PATIENTS WITH ADEQUATE SYMPTOM CONTROL WITH SANDOSTATIN SC Initiate Sandostatin LAR 20 mg every 4 weeks Continue Sandostatin SC for 2 weeks after initiating Sandostatin LAR After 3 months, assess need for dose adjustments based on symptomatic response Sandostatin LAR is available in 3 doses (10 mg, 20 mg, and 30 mg) for IM delivery. Sandostatin is available in an SC formulation for breakthrough symptoms Sandostatin LAR Basic Prescribing Information. Novartis Pharma AG. 20 May 2010.

27 Summary NETs are more prevalent than many other tumours of the GI system.1,2 Although most NETs are small tumours, they can progress to metastatic disease, which has implications for survival.2,3 Nearly half of all NET patients are diagnosed with advanced disease.2 The randomised, placebo-controlled phase III PROMID trial demonstrated that: Sandostatin LAR 30 mg is the only somatostatin analogue to significantly prolong TTP in patients with advanced midgut NETs.4,5 Significantly more patients achieved stable disease with Sandostatin LAR than with placebo.4 Sandostatin LAR is the first and only somatostatin analogue proven to have an antiproliferative effect on advanced midgut NETs.5 Updated treatment guidelines now recommend Sandostatin LAR for early tumour control in patients with advanced midgut NETs or unknown primary tumour location.6 National Cancer Institute. SEER Cancer Statistics Review Complete and Limited-Duration Cancer Prevalence Estimates. Accessed 28 March 2011. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26: Kufe DW, Pollock RE, Weichselbaum RR, et al. eds. Holland-Frei Cancer Medicine, 6th ed. Hamilton (ON): BC Decker; 2003. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663. Öberg KE. J Clin Oncol. 2009;27: NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine Tumors. V

28 Summary (continued) The most common symptoms are diarrhoea and flushing.1 Potentially life-threatening dehydration, hypotension, arrhythmias, and unconsciousness can develop from early symptoms, like diarrhoea and flushing.2 In functional carcinoid patients, Sandostatin LAR has been proven to reduce: The frequency of diarrhoea and flushing episodes.3,4 5-HIAA levels.4 Sandostatin is available in a subcutaneous (SC) formulation for breakthrough symptoms. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128:1717–1751. Zuetenhorst JM, Taal BG. Oncologist. 2005;10: Data on file. Novartis Pharma AG. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol. 1999;17:

29 Full Prescribing Information
CPO: Please provide your local full Prescribing Information

30 Brief Summary Important note: Before prescribing, consult full prescribing information. Presentation: Octreotide acetate. Vials containing 10 mg, 20 mg or 30 mg octreotide free peptide supplied as powder (microspheres) for suspension for injection together with a prefilled syringe (solvent for parenteral use), containing: sodium carboxymethylcellulose 12.5 mg, mannitol 15 mg; water for injection qs ad 2.5 mL; two needles [40 mm (1.5 inch), 19 gauge]. Sandostatin® LAR® suspension contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially ‘sodium-free’. Indication: Acromegaly: in patients who are adequately controlled on SC treatment with Sandostatin; in patients in whom surgery or radiotherapy is inappropriate or ineffective; in the interim period until radiotherapy becomes fully effective. Relief of symptoms associated with functional gastro-entero-pancreatic endocrine tumours: carcinoid tumours with features of the carcinoid syndrome, VIPomas, glucagonomas, gastrinomas/Zollinger-Ellison syndrome, insulinomas, GRFomas. Treatment of patients with advanced neuroendocrine tumours of the midgut or unknown primary tumour location. Dosage: 10 to 30 mg every 4 weeks, administered as a deep intragluteal injection.

31 Brief Summary (continued)
Contraindications: Known hypersensitivity to octreotide or to any of the excipients. Warnings/Precautions: Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary; caution in patients with insulinomas; diabetes mellitus thyroid function should be monitored in patients receiving prolonged treatment with octreotide. Periodic examination of gallbladder; monitoring of vitamin B12 levels in patients who have a history of vitamin B12 deprivation; caution in patients with pregnancy, patients should be advised to use adequate contraception if necessary. Patients should not breast-feed during Sandostatin LAR treatment. Interactions: Impaired intestinal absorption of ciclosporin, cimetidine; increased bioavailability of bromocriptine. Caution with concomitant use of drugs mainly metabolised by CYP3A4 and which have a low therapeutic index.

32 Brief Summary (continued)
Adverse reactions: Very common (≥1/10) adverse drug reactions are: diarrhoea, abdominal pain, nausea, constipation, flatulence, headache, cholelithiasis, hyperglycaemia, and injection-site localised pain. Common (≥1/100, <1/10) adverse drug reactions are: dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces, dizziness, hypothyroidism, thyroid dysfunction (e.g. decreased thyroid stimulating hormone [TSH], decreased Total T4, and decreased Free T4), cholecystitis, biliary sludge, hyperbilirubinaemia, hypoglycaemia, impairment of glucose tolerance, anorexia, elevated transaminase levels, pruritus, rash, alopecia, dyspnoea, and bradycardia. Uncommon (≥1/1000, <1/100) adverse drug reactions are: dehydration, and tachycardia. Post-marketing the following adverse reactions have been reported: anaphylaxis, allergy/hypersensitivity reactions, urticaria, acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, arrhythmia, increased alkaline phosphatase levels, and increased gamma glutamyl transferase levels. Packs and prices: Country specific. Legal classification: Country specific.


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