MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours

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  • Master Class 2011
  • Master Class 2011
  • Master Class 2011
  • Master Class 2011
  • Survival in 324 patients with pancreatic endocrine tumours according to WHO classification The median overall survival was 99 months (95% confidence interval, 81-117). Five- and 10-year survival rates were 64% and 44%, respectively. In univariate analysis, TNM stage, radical surgery, WHO classification, nonfunctioning tumor, Ki67 > or = 2%, chromogranin A > or = 3 times the upper normal limit, BMI < 20 kg/m2, sporadic tumor, tumor size, and referral from our primary uptake area had a significant prognostic effect. In multivariate analysis, TNM stage, WHO classification, radical surgery, and Ki67 > or = 2% retained their significance. Having a nonfunctioning tumor was not an independent marker of poor prognosis and neither was heredity.
  • Please enter the initial presenting situation here. It should be typical for the case. If possible, please do not include terms of the final diagnosis.
  • Please enter the initial presenting situation here. It should be typical for the case. If possible, please do not include terms of the final diagnosis.
  • Master Class 2011
  • Master Class 2011
  • Master Class 2011
  • Other secreted products have been proposed as diagnostic markers but few have achieved widespread acceptance. Reference: Vinik A, Silva M, Woltering G et al. Pancreas . 2009;38: 876-889  
  • The three "classic" granins are chromogranin A, which was first isolated from chromaffin cells of the adrenal medulla 5 , 6 ; chromogranin B, initially characterized in a rat pheochromocytoma cell line 7 ; and secretogranin II (sometimes called chromogranin C), which was originally described in the anterior pituitary. 8 , 9 Four other acidic secretory proteins were later proposed for membership in the granin family 10 : secretogranin III (or 1B1075), 11 secretogranin IV (or HISL-19), 12 secretogranin V (or 7B2), 13 and secretogranin VI (or NESP55). 14
  • The three "classic" granins are chromogranin A, which was first isolated from chromaffin cells of the adrenal medulla 5 , 6 ; chromogranin B, initially characterized in a rat pheochromocytoma cell line 7 ; and secretogranin II (sometimes called chromogranin C), which was originally described in the anterior pituitary. 8 , 9 Four other acidic secretory proteins were later proposed for membership in the granin family 10 : secretogranin III (or 1B1075), 11 secretogranin IV (or HISL-19), 12 secretogranin V (or 7B2), 13 and secretogranin VI (or NESP55). 14
  • Master Class 2011
  • World Tour 2009
  • Stenungsund Aug 2010
  • Stenungsund Aug 2010
  • Arlanda-Biological treatment jan-2009
  • Results from this interim analysis demonstrate that octreotide LAR inhibits the progression of tumour growth in patients with malignant midgut NETs. The primary efficacy analysis shows there were 26 patients with tumour progressions or tumour-related deaths in the octreotide LAR group, compared with 40 events in the placebo group. Octreotide LAR more than doubled the time without tumour growth compared with placebo. The median TTP was 14.3 months with octreotide LAR and 6.0 months with placebo. The P value for this result was 0.000072, indicating a very high statistical significance. The hazard ratio for TTP with octreotide LAR versus placebo was 0.34, which means there is a 66% reduction in the risk of disease progression with octreotide LAR versus placebo. Median survival has not been reached at this time. Additional notes The median survival time in the octreotide LAR group has not yet been reached (>77.4 months). The median survival time in the placebo group was 73.7 months. Overall survival was included as a secondary endpoint. Overall survival was a secondary endpoint because in the case of octreotide LAR significantly extending TTP, the trial would be halted and patients on placebo would be informed of the superior result of octreotide LAR. Furthermore, treatment of patients after tumour progression was at the discretion of the individual study centre, which means that placebo recipients were allowed to crossover to octreotide LAR or receive another therapy once they had a documented tumour progression. Likewise, octreotide LAR recipients were allowed to receive additional or alternative treatment once they had experienced disease progression. After progressing, 33/43 placebo recipients (77%) received octreotide LAR, and 25/42 octreotide LAR recipients (60%) continued to receive octreotide LAR. Other post-study treatments in the placebo and octreotide LAR groups were hepatic chemoembolization (9 versus 4 patients), peptide receptor radionuclide therapy (6 versus 4 patients) and chemotherapy (3 versus 3 patients). The influence of these treatments on survival cannot be ruled out. TTP was the primary endpoint of this trial and an acceptable surrogate for overall survival.
  • The molecular basis of octreotide’s mechanism of action is conceptually straightforward - binding to somatostatin receptors and thereby shutting down hormone secretion from cells of the diffuse neuroendocrine system. As demonstrated, effects of octreotide treatment can include cell cycle arrest, amplification of proapopotic effects, inhibition of angiogenesis and modulation of the immune system. In order to achieve these multiple effects the pathways activated following octreotide binding to somatostatin receptors are many and complex.
  • Helsinki jun 2008 This is what someone will call a pretty busy slide. However, it demonstrates the number of studies, the number of patients, the doses used, the study periods,, clinicla response in regard to symptoms of the carcinoid syndrome, biochemical response which in most cases represenst changes in U-5HIAA. In addition a number of studies has provided data on chnages in NET as determined by CT or US. To sumarise these 27 studies with a total of 679 patients. The average weekly doses used were 16 MU, most often 3-5 MU 3 times per week. Study period varies considerably from 2 til 170 with a mean of approximately 40 weeks. Symptomatic repsonse rate was 62% with a range of 30-100%, biochemical response slightly lower of 50%, range 9 to 100%. For imaging studies tumor regression was obser ved in only 10% range 0-25%, tumor stabilisation in 65% (40-95%) and progression in about a quarter (6-50%).
  • The main player n tumor biology is unknowm. There are several GF receptors and their ligands expressed in NET cells. As kn own from other tumors the expression… D2-like receptor signaling is mediated by the heterotrimeric G proteins Galphai and Galphao. These pertussis toxin-sensitive G proteins regulate some effectors, such as adenylate cyclase, via their Galpha subunits, but regulate many more effectors such as ion channels, phospholipases, protein kinases, and receptor tyrosine kinases as a result of the receptor-induced liberation of Gbetagamma subunits. In addition to interactions between dopamine receptors and G proteins, other protein:protein interactions such as receptor oligomerization or receptor interactions with scaffolding and signal-switching proteins are critical for regulation of dopamine receptor signaling.
  • A phase III , randomised, double-blind study of Sutent ® vs. placebo investigated the safety and efficacy of Sutent ® in patients with well-differentiated malignant pancreatic NETs. Sutent ® 37.5 mg/day or placebo was administered by continuous daily dosing. This study was terminated early due to differences in efficacy between the groups, as recommended by the Independent Data Monitoring Committee. Between June 2007 and April 2009, a total of 171 patients were recruited; 86 and 85 patients were randomised to the Sutent ® and placebo groups, respectively. Median age was 56 years. 52% of participants were female. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rate, time to response, duration of response, safety and patient-reported outcomes. Cohorts were balanced by region, such that there was a similar proportion of patients from Europe, Asia, and the Americas/Australia in each treatment group. Reference Raymond E, Raoul J-P, Niccoli-Sire P et al . Phase III, randomized, double-blind trial of sunitinib versus placebo in patients with progressive, well-differentiated, malignant pancreatic islet cell tumors. Poster presented at the 2010 ASCO Gastrointestinal Cancers Symposium; Orlando, USA, 22–24 January 2010.
  • Median progression-free survival was more than doubled in patients receiving Sutent ® compared to those receiving placebo (HR=0.418, 95% CI 0.263–0.662 ; P =0.0001). The Kaplan-Meier estimate of median progression-free survival was 11.4 months (95% CI 7.4–19.8) in the group receiving Sutent ® , compared to 5.5 months (95% CI 3.6–7.4) in the placebo cohort. This study was terminated early due to differences in efficacy between the groups, as recommended by the Independent Data Monitoring Committee. Reference Raymond E, Raoul J-P, Niccoli-Sire P et al . Phase III, randomized, double-blind trial of sunitinib versus placebo in patients with progressive, well-differentiated, malignant pancreatic islet cell tumors. Poster presented at the 2010 ASCO Gastrointestinal Cancers Symposium; Orlando, USA, 22–24 January 2010.
  • The slide highlights the importance of IGF-1 signaling and the PI3-K/Akt/mTOR pathway in NET and the reason why mTOR inhibition is a rational approach to treating these tumors. mTOR also responds to changes in oxygen, energy levels, and nutrients through their effects on the activity of the tuberous sclerosis complex (TSC1/2) In addition, stimulation of PI3-K by the ER, Abl kinase, or Ras/Raf signaling can activate mTOR References Van Gompel JJ, Chen H. Insulin-like growth factor I signaling in human gastrointestinal carcinoid tumor cells. Surgery . 2004;136:1297-1302. Von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res . 2000;60:4573-4581. Verhoef S, van Diemen-Steenvoorde R, Akkersdijk WL, et al. Malignant pancreatic tumour within the spectrum of tuberous sclerous complex in childhood. Eur J Pediatr . 1999;158:284-287. Francalanci P, Diomedi-Camassei F, Purificato C, et al. Malignant pancreatic endocrine tumor in a child with tuberous sclerosis. Am J Surg Pathol . 2003;27:1386-1389. Charland S, Boucher M-J, Houde M, et al. Somatostatin inhibits AKT phosphorylation and cell cycle entry, but not p42-p44 mitogen-activated (MAP) kinase activation in normal and tumoral pancreatic acinar cells. Endocrinology . 2001;142:121-128.
  • Helsinki jun 2008 The importance of mTOR in regulating normal cell growth, cell division and angiogenesis is highlighted by the number of proteins involved in its activation or inhibition mTOR is deregulated in cancer by increased upstream signaling, loss-of-function mutations in upstream inhibitors, and activating mutations in mTOR activators Increased mTOR activity results in the increased protein synthesis of more than 100 genes and proteins involved in cellular responses. Many of the proteins that are regulated by mTOR support the growth, metabolic requirements, and survival of cancer cells. Deregulation of the mTOR-linked pathways increase the risk of developing cancer or have been identified in many cancers (details on specific mutation rates in cancer are listed on page 11). References Averous and Proud. Oncogene . 2006 Oct 16;25(48):6423-6435. Mamane et al. Oncogene . 2006;25(48):6416-6422. Ellisen. Cell Cycle . 2005;4(11):1500-1502. Kaper et al. Cancer Res . 2006;66(3):1561-1569.
  • An ongoing, randomized, double-blind, placebo-controlled, phase III study (RADIANT-2) is assessing the clinical activity of octreotide LAR with and without everolimus in patients with low- to intermediate-grade, metastatic/unresectable NETs (excluding pNETs) Patients have secretory symptoms and have experienced disease progression Patients are assigned to treatment with everolimus 10 mg/day plus octreotide LAR 30 mg/month or placebo plus octreotide LAR 30 mg/month. The primary endpoint of the study is progression-free survival (PFS) per central review Secondary endpoints include objective response rate, overall survival, safety, changes in the biomarkers 5-HIAA and CgA, and pharmacokinetics for the combined active agents
  • Såstaholm-2-jan 2011
  • MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours

    1. 1. Master Class 2011 Neuroendocrine Tumors – Current Diagnosis and Therapeutic Strategies by Kjell Öberg, M.D., Ph.D. Professor Endocrine Oncology Dept. of Endocrine Oncology, University Hospital, Uppsala, Sweden
    2. 2. Incidence of neuroendocrine tumors in the western world 2.5-5.0/100000 inhabitants GEP-NET ~ 75% Lung Small intestine Rectum Surveillance, Epidemiology and End Results (SEER), US population 1974-2005 Modlin et al., Lancet Oncol. 2008
    3. 3. Neuroendocrine Tumors <ul><li>Outline of the presentation: </li></ul><ul><li>Tumor types and classification </li></ul><ul><li>Biomarkers </li></ul><ul><li>Imaging </li></ul><ul><li>Treatment options </li></ul>
    4. 4. <ul><li>Generally characterized by their ability to produce peptides that may lead to associated syndromes (functional vs non-functional) 1,2 </li></ul><ul><li>Historically classified based on embryonic origin 3 </li></ul><ul><ul><li>Foregut tumours </li></ul></ul><ul><ul><li>Midgut tumours </li></ul></ul><ul><ul><li>Hindgut tumours </li></ul></ul><ul><li>Today, primary tumor location </li></ul><ul><li>is recommended for NET classification </li></ul>NET Vary by Primary Tumor Site 1. Modlin IM, Oberg K, Chung DC, et al. Lancet . 2008;9:61-72. 2. Modlin IM, Kidd M, Latich I, et al. Gastroenterology . 2005;128:1717-1751. 3. NCCN. Neuroendocrine tumors, carcinoid tumors: management of recurrent or unresected disease. In: Practice Guidelines in Oncology . V.1. 2008. February, 2008. Foregut • Thymus • Esophagus • Lung • Stomach • Pa ncreas • Duodenum Midgut • Appendix • Ileum • Cecum • Ascending colon Hindgut • Distal large bowel • Rectum
    5. 5. Distribution of GE-NETs by primary tumour site Maggard MA, et al. Ann Surg 2004;240:117–22
    6. 6. Hallmarks of GEP-NETs <ul><li>Initially diffuse symptoms (Doctors and patient delay of 3-4 years!) </li></ul><ul><li>More than 60% present metastatic disease at diagnosis </li></ul><ul><li>Variable growth rate </li></ul><ul><li>Expression of specific receptors (SSTR, DA, GF) </li></ul><ul><li>Highly vascular </li></ul>
    7. 7. Staging and Grading of NETs <ul><li>WHO classificqation </li></ul><ul><li>TNM staging (ENETS) </li></ul><ul><li>Grading (ENETS) </li></ul>
    8. 8. General Neuroendocrine Neoplasms Categories WHO 2010
    9. 9. Correlation of WHO Classification and Ki67 with Survival Ekeblad et al Clin Cancer Res . 2008 Dec 1;14(23):7798-803. P < 0.001 N=324 0.0 150 0.2 0.4 0.6 0.8 1.0 Proportion alive WHO I WHO II WHO III 100 50 0 250 200 350 300 months P < 0.001 N=324 0.0 150 0.2 0.4 0.6 0.8 1.0 Proportion alive 100 50 0 250 200 months Ki67 ≥ 2 Ki67 < 2
    10. 10. 155 cases: WDET/C 149, PDEC 6 All cases, events-free survival curve La Rosa et al. Human Pathol 2009, 40:30 44 34 33 44 P < 0.001 ENETS TNM Staging PANCREAS
    11. 11. GUT ENDOCRINE TUMORS TUMOR GRADING AND CLASSIFICATION ENETS GRADING PROPOSAL 10 HPF: High Power Field = 2mm2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic density MIB1 antibody; percentage of 2,000 tumor cells in areas of highest nuclear labelling Virchows Arch (2006) 449:395-401 Virchows Arch (2007) 451:757-762 a b Grading proposal for foregut (neuro)endocrine tumors Grade Mitotic count (10 HPF) a Ki67 index (%) b G1 <2 ≤ 2 G2 2-20 3-20 G3 >20 >20
    12. 12. 202 cases: gastric (48), duodenal (23), pancreatic (131) FOREGUT ENDOCRINE TUMORS TUMOR GRADING AND CLASSIFICATION ENETS GRADING PROPOSAL Pape et al. Cancer 2008, 113:256 Cumulative survival according to grading
    13. 13. <ul><li>Biomarkers </li></ul><ul><ul><li>Histopathology, tumor biology </li></ul></ul><ul><ul><li>Circulating markers </li></ul></ul><ul><ul><li>Response evaluation </li></ul></ul><ul><ul><li>Circulating tumor cells </li></ul></ul><ul><li>Molecular Imaging </li></ul>
    14. 14. Immunohistochemical NE markers Pan-neuroendocrine markers Cytosolic NSE , PGP 9.5 Related to secretory granules Chromogranins Related to synaptic vesicles Synaptophysin , VMAT Intermediate filaments NF, CK HMW Adhesion molecules N-CAM
    15. 16. Survival in 324 patients with pancreatic endocrine tumors Ekeblad et al P < 0.001
    16. 17. WHO group II: well differentiated endocrine carcinoma, WDEC intense CgA reactivity faint synaptophysin low Ki-67 (<1%) WHO group III: poorly differentiated endocrine carcinoma, PDEC faint CgA reactivity intense synaptophysin high Ki-67 (~30%)
    17. 18. Biomarkers in NET <ul><li>CgA is the best available biomarker for diagnosis of NET </li></ul><ul><ul><li>Elevated CgA may correlate with tumour progression </li></ul></ul><ul><ul><li>CgA is elevated 80-100% of the time in NET </li></ul></ul><ul><li>NSE is also expressed in NET </li></ul><ul><ul><li>Not as commonly used as CgA </li></ul></ul><ul><ul><li>Often elevated in poorly differentiated tumours </li></ul></ul><ul><li>Other biomarkers are available, however few have achieved widespread acceptance </li></ul><ul><li>New biomarkers in NET are needed to provide better diagnostic and prognostic information </li></ul>NSE Adrenomedullin Alkaline phosphatase Bradykinin Catecholamines GHRH hCG α / β Natriuretic peptide: ANP/BNP Neurokinin A Neuropeptide K/L PYY 5-HIAA = 5-hydroxy-3-indoleacetic acid 5-HT = serotonin GHRH= gonadotropin hormone release hormone hCG = human chorionic gonadotropin ANP/BNP = atrial natriuretic peptide and brain/ventricular natriuretic peptide NSE = neuron-specific enolase PYY = peptide YY Vinik A, Silva M, Woltering G et al. Pancreas. 2009;38: 876-889 CgA Somatostatin Histamine Substance P Glucagon 5-HIAA 5-HT Gastrin Insulin
    18. 19. Biomarkers in NET Vinik AI el a., Pancreas 2009;38: 876Y889 Tumour marker GI-NET pNET Plasma markers Chromogranin A (CgA) X X Chromogranin B (CgB) X X Neuron-specific enolase (NSE) X X Pancreatic polypeptide X X α subunit of glycoprotein hormones X X HCG-beta X X Gastrin X Glucagon X Insulin X Proinsulin X Somatostatin X Ghrelin X Substance P X X Neuropeptide K (NPK) X Vasoactive intestinal polypeptide (VIP) X Calcitonin X Urinary markers 5-hydroxyindolacetic acid (5-HIAA) X Tele-methylimidazoleacetic acid (MelmII) X
    19. 20. Focus on Chromogranin A <ul><li>The Chromogranin Family </li></ul><ul><li>Chromogranin A (CgA) </li></ul><ul><li>Chromogranin B (CgB) </li></ul><ul><li>Secretogranin II (CgC) </li></ul><ul><li>Secretogranin III (1B1075) </li></ul><ul><li>Secretogranin IV (HISL-19) </li></ul><ul><li>Secretogranin V (7B2) </li></ul><ul><li>Secretogranin VI (NESP55) </li></ul>Taupenot L et al. N Engl J Med . 2003;348(12):1134-49 Chromogranin A Related Peptides A1-15 77 S 114 208 Chromostatin Chromasin I Chromasin II WE14 248 322 338 Catestatin GE25 Parstatin Pancreastatins Vasostatins 378 400 409 437 10 1 100 1000 10,000 Carcinoid EPT MEN1 PHEO Normal log CgA (nmol/I) p-CgA 1 0.1 Carcinoid EPT MEN1 PHEO Normal log CgB (nmol/I) p-CgB 10 100 Chromogranin A and B Levels in NET Patients
    20. 21. Overview of Chromogranin A <ul><li>The Chromogranin Family 1 </li></ul><ul><li>Chromogranin A (CgA) </li></ul><ul><li>Chromogranin B (CgB) </li></ul><ul><li>Secretogranin II (CgC) </li></ul><ul><li>Secretogranin III (1B1075) </li></ul><ul><li>Secretogranin IV (HISL-19) </li></ul><ul><li>Secretogranin V (7B2) </li></ul><ul><li>Secretogranin VI (NESP55) </li></ul><ul><li>Taupenot L et al. N Engl J Med . 2003;348(12):1134-49 </li></ul><ul><li>Oberg K and Stridsberg M . Adv Exp Med Biol . 2000.482:329-37 </li></ul><ul><li>Janson ET et al. Annals of Oncology . 1997.8:685-690 </li></ul>Chromogranin A Related Peptides 1 Serum CgA as Indication of Tumour Presence 2,3 <ul><li>Non-tumour associated increases of CgA </li></ul><ul><li>Decreased renal function </li></ul><ul><li>Type A gastritis </li></ul><ul><li>Drugs </li></ul><ul><li>Deteriorated liver function </li></ul><ul><li>Inflammatory bowel disease </li></ul><ul><li>Stimulation of the sympathetic nervous system? </li></ul>A1-15 77 S 114 208 Chromostatin Chromasin I Chromasin II WE14 248 322 338 Catestatin GE25 Parstatin Pancreastatins Vasostatins 378 400 409 437 > 5 liver met 5 < liver met Lymph node met 100 1,000 10,000 100,000 CgA ( μ g/L)
    21. 23. Non-tumor associated increases of Chromogranin A <ul><li>Decreased renal function </li></ul><ul><li>Type A gastritis </li></ul><ul><li>Drugs </li></ul><ul><li>Deteriorated liver function </li></ul><ul><li>Stimulation of the sympathetic nervous system? </li></ul><ul><li>Inflammatory bowel disease </li></ul>
    22. 24. macrometastasis 10 3 Detection of Tumor Lesions in Relation to Size and Cellular Number Tumor diameter (mm) tumor cell number positive genetic markers 10 6 10 9 micrometastasis (0,3 mm) (3 mm) (30 mm) 1cm
    23. 25. Neuroendocrine tumors Modlin 2008 PET (FDG)
    24. 26. Molecular Imaging Functional techniques <ul><li>Octreoscan  (somatostatin receptor scintigraphy) </li></ul><ul><li>MIBG-scintigraphy (metaiodobenzylguanidine) </li></ul><ul><li>PET (positron emission tomography) ( 11 C-5-HTP, 18 F-DOPA, 68 Ga-Dota-octreotide 99 Tc EDDA-HYNIC-TOC) </li></ul>
    25. 27. <ul><li>Specific isotopes for NETs </li></ul><ul><li>11 C-5HTP (hydroxytryptophan) </li></ul><ul><li>11 C-Dopamine </li></ul><ul><li>18 F-Dopamine </li></ul><ul><li>68 Ga-Dota Octreotide </li></ul><ul><li>99 Tc EDDA-HYNIC-octreotide </li></ul><ul><li>[Lys40(Ahx-DTPA- 111 In)NH2]-Exendin-4 (GLP-1) </li></ul>
    26. 28. Results <ul><li>Tumors were imaged by </li></ul><ul><li> PET in 95% (36/38) </li></ul><ul><li> SRS in 84% (32/38) </li></ul><ul><li> CT in 79% (30/38) </li></ul><ul><li>More lesions were detected with PET than with SRS and CT in 58% and equal number in 34% </li></ul>Orlefors et al. JCEM
    27. 29. PET/CT with 11 C-5-HTP
    28. 30. Koopmans, K. P. et al. J Clin Oncol; 26:1489-1495 2008 Fig 3. (A) Computed tomography (CT) scan, (B) somatostatin receptor scintigraphy (SRS), (C) 18F-dihydroxy-phenyl-alanine (18F-DOPA) positron emission tomography (PET), and (D) 11C-5-hydroxy-tryptophan (11C-5-HTP) PET of a 54-year-old male patient with metastatic islet cell tumor
    29. 31. PET/CT with 68 Ga-DOTA-octreotide
    30. 32. PET with 68 Ga-DOTA-octreotide <ul><li>Advantages: </li></ul><ul><li>no cyclotron required </li></ul><ul><li>more sensitive than Octreoscan </li></ul><ul><li>possible to use for radioactive or tumor-targeted treatment </li></ul><ul><li>may be possible to quantify somatostatin receptors - tumor-targeted therapy </li></ul><ul><li>“ one-stop” procedure </li></ul>
    31. 33. Therapeutic Options NETs <ul><li>Surgery </li></ul><ul><ul><li>Curative (rarely), Ablative (very often) </li></ul></ul><ul><li>Debulking </li></ul><ul><ul><li>Radiofrequency ablation (RFA) </li></ul></ul><ul><ul><li>Embolization/chemoembolization/radioembolization (Spherex®) </li></ul></ul><ul><li>Irradiation </li></ul><ul><ul><li>External (bone, brain-mets) </li></ul></ul><ul><ul><li>Tumor targeted, radioactive therapy (MIBG, Y 90 -DOTATOC, Lu 177 -DOTATATE) </li></ul></ul><ul><li>Medical therapy </li></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Biological treatment: </li></ul></ul><ul><ul><ul><li>Somatostatin analogs </li></ul></ul></ul><ul><ul><ul><li>α -interferon </li></ul></ul></ul><ul><ul><ul><li>m-TOR inhibitors </li></ul></ul></ul><ul><ul><ul><li>VEGF R inhibitors </li></ul></ul></ul><ul><ul><ul><li>Other TKI’s </li></ul></ul></ul>
    32. 34. Factors Influencing the Therapeutic Decision <ul><li>Type of NET-tumor </li></ul><ul><li>TNM stage and grade </li></ul><ul><li>Extent of liver involvement </li></ul><ul><li>Functioning vs. non-functioning tumor </li></ul><ul><li>Patients performance status </li></ul><ul><li>Availability of different therapeutic modalities </li></ul><ul><li>NB! The treatment of most patients is a combination of surgery, PRRT and medical treatment </li></ul>
    33. 35. Targeted irradiation therapy <ul><li>111 In-DTPA 0 -octreotide </li></ul><ul><li>90 Y-DOTA 0 ,Tyr 3 -octreotide </li></ul><ul><li>177 Lu-DOTA 0 ,Tyr 3 -octreotate </li></ul><ul><li>131 I-MIBG </li></ul>
    34. 36. 177 Lu-DOTA-octreotate therapy The Uppsala experience <ul><li>229 patients (96 midgut, 13 lung, 17 rectal, 44 non-functioning EPT, 9 gastrinoma, 6 glucagonoma, 7 paraganglioma/pheochromocytoma) </li></ul><ul><li>842 treatments </li></ul><ul><li>Follow-up (n=185): Mean 13 months (2–57) </li></ul>32 patients with response or SD have later progressed Results: CR 1 (1%) PR 57 (31%) 42% MR 20 (11%) SD 99 (54%) PD 8 (4%)
    35. 37. Medical treatment <ul><li>Chemotherapy: </li></ul><ul><ul><li>Local (chemoembolization) </li></ul></ul><ul><ul><li>Systemic </li></ul></ul><ul><li>Biotherapy: </li></ul><ul><ul><li>Somatostatin analogs </li></ul></ul><ul><ul><li>α -IFN </li></ul></ul><ul><ul><li>m-TOR inhibition </li></ul></ul><ul><ul><li>VEGF-inhibitors: bevacizumab, sunitinib </li></ul></ul>
    36. 38. Chemotherapy
    37. 39. Temozolomide, alkylates DNA-bases (guanin) discovered in 1981 <ul><li>oral imidazotetrazine with activity in advanced melanoma and primary brain tumors </li></ul><ul><li>temozolomide and dacarbazine share the active intermediary MTIC </li></ul><ul><li>has a high oral bioavailability (100%) and extensive tissue distribution, and rapid penetration through blood-brain barrier, 10-30%, (shown by PET) </li></ul>
    38. 40. Chemotherapy: Temozolomide <ul><li>Ekeblad; Clin Cancer Res 2007 </li></ul><ul><ul><li>36 patients (35 foregut, 12 EPT, 12 bronchial, 7 thymus) </li></ul></ul><ul><ul><li>median 2.4 prior anti-tumor medical regimen </li></ul></ul><ul><ul><li>RR 14% (40% in low O 6 MGMT), TTP 7 m </li></ul></ul><ul><li>Isacoff; ASCO 2006 Abs #14023 </li></ul><ul><ul><li>+ capecitabine </li></ul></ul><ul><ul><li>17 patients, failed prior chemotherapy, histology? </li></ul></ul><ul><ul><li>1 CR, 9 PR (59%), duration 9 months </li></ul></ul><ul><li>Kulke; ASCO 2006 Abs # 4044 </li></ul><ul><ul><li>+ bevacizumab </li></ul></ul><ul><ul><li>34 patients, 18 EPT, 16 carcinoids </li></ul></ul><ul><ul><li>12 prior chemotherapy </li></ul></ul><ul><ul><li>EPT; RR 24%. Carcinoids RR 0% </li></ul></ul><ul><ul><li>PFS 8.6 m </li></ul></ul>
    39. 41. O 6 -methylguanine DNA methyltransferase (MGMT*) expression # may predict response to temozolomide in GEP NETs Ekeblad, et al, Clin Cancer Res, 2007; 13: 2986-2991. N Response Response Median Median (RECIST) (CgA) PFS OS (mo) (mo) MGMT 16 0/16 0/10 9.25 14 positive MGMT 5 4/5** 4/5 19 NR Negative ** p<0.05 # MGMT expression studied by IHC NR = not reached * MGMT is a DNA repair enzyme believed to induce cancer cell resistance to O 6 -alkylating agents like temozolomide
    40. 42. Capecitabin plus Temozolomide in Pancreatic Endocrine Tumors N=33 Capecitabin 750 mg/m 2 x 2 Daily 1-14 Temozolomide 200 mg/m 2 x 1 10-14 PR 70% (RECIST) PFS 18 mo Adverse events (Grade 3/4) 12% Strosberg et al. Cancer. 2010 Sep.
    41. 43. ala gly lys cys asn phe thr s l s Somatostatin Octreotide acetate D- phe cys tyr val Thr -NH 2 Lanreotide Biotherapy: Somatostatin Analogues phe phe trp lys phe thr ser cys D- phe cys phe lys thr cys D- trp thr -ol lys cys D- trp
    42. 44. Novel somatostatin analogue - SOM230 Novel cyclohexapeptide
    43. 45. Binding affinity of different somatostatin analogs to the five somatostatin receptors Data are mean IC 50 ±SEM values (nmol/l) Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 2002; 146: 707–716. Compound sst 1 sst 2 sst 3 sst 4 sst 5 Somatostatin 0.93 ±0.12 0.15 ±0.02 0.56 ±0.17 1.35 ±0.4 0.29 ±0.04 Octreotide 280 ±80 0.38 ±0.08 7.10 ±1.4 >1000 6.3 ±1 Lanreotide 180 ±20 0.54 ±0.08 140 ±9 230 ±40 17 ±5 SOM230 9.3 ±0.1 1.0±0.1 1.5±0.3 >100 0.16 ±0.01
    44. 46. Somatostatin Receptor Expression in Endocrine Pancreatic Tumors Fjällskog et al Med Oncol. 2003;20(1):59-67 Kulaksiz et al Gut. 2002 Jan;50(1):52-60 Papotti Virchows Arch. 2002 May;440(5):461-75 Sst1 Sst2 Sst3 Sst4 Sst5 Fjällskog et al 19/28 24/28 13/28 26/28 16/28 Kulaksiz et al 21/69 54/69 54/69 ND 53/69 Papotti et al 30/33 37/48 30/48 8/33 29/48 Technique PCR PCR
    45. 47. Response: Standard dose High dose Slow release (100-1500 µg/d) (>3000 µg/d) (20-30 mg/d/2-4w) Symptomatic n (%) 146/228 (64%) 11/26 (42%) 76/119 (63%) Biochemical n (%) CR 6/54 (11) 1/33 (3) 3/119 (3) PR 116/211 (55) 24/83 (72) 76/119 (64) SD 72/211 (34) 7/33 (21) 21/119 (18) PD 11/211 (11) 1/33 (3) 19/119 (15) Tumor n (%) CR - 1/53 (2) - PR 7/131 (5) 6/53 (11) 4/119 (3) SD 50/131 (38%) 25/53 (47%) 94/119 (79%) PD 74/131 (56) 21/51 (39) 21/119 (18) Neuroendocrine tumors: Somatostatin analogue therapy, Summary of several trials
    46. 48. PROMID Study Design Month -1 0 3 6 9 12 15 18 Screening Informed consent Randomization 1:1 Continuation of treatment if no progression Octreotide LAR 30 mg i.m. every 4 weeks Placebo i.m. every 4 weeks Primary endpoint: time to tumor progression <ul><li>Treatment was continued until CT or MRI documented tumor progression (WHO) </li></ul><ul><li>Follow-up until death </li></ul><ul><li>CT and/or MRI were evaluated by a blinded central reader </li></ul>
    47. 49. Octreotide LAR 30mg Significantly Increases Time to Tumor Progression (TTP) Octreotide LAR vs placebo P =0.000017 HR= 0.33 [95% CI: 0.19 – 0.55] Based on Intention to treat analysis Proportion without progression Time (months) Octreotide LAR : 42 patients / 27 events Median 15.6 months [95% CI: 11.0–29.4] Placebo : 43 patients / 41 events Median 5.9 months [95% CI: 5.5–9.1] 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
    48. 50. Prognostic factors for TTP <ul><li>Most favorable treatment outcome in patients with </li></ul><ul><ul><li>Hepatic tumor load <10% ( P <0.0009) </li></ul></ul><ul><ul><li>Resected primary ( P <0.0104) </li></ul></ul><ul><li>Benefit of octreotide LAR versus placebo seen irrespective of </li></ul><ul><ul><li>Functioning or nonfunctioning NETs </li></ul></ul><ul><ul><li>Elevated or non-elevated CgA </li></ul></ul>
    49. 51. DIRECT ANTIPROLIFERATIVE EFFECT INDIRECT ANTIPROLIFERATIVE EFFECT Inhibition of cell cycle Inhibition of growth factor effects Pro-apoptotic effect Inhibition of the release of growth factor and trophic hormones Inhibition of cell angiogenesis Modulation of immune system Multiple Cellular Effects Mediated by Octreotide LAR Systemic activity Adapted from Susini & Buscail Ann. Oncol. 2006 Binding of the somatostatin receptor on tumor cells Antiproliferative Effect of Somatostatin Analogs
    50. 53. Interferon NET studies <ul><li>27 studies, 679 patients </li></ul><ul><li>Interferon doses: 16 ± 11 MU/w (3-5 MU 3x/week) </li></ul><ul><li>Study period 39 ± 35 weeks (2-170 weeks) </li></ul><ul><li>Symptomatic response 62% (29-100%) </li></ul><ul><li>Biochemical response 50% (9-100% ) </li></ul><ul><li>Tumor response </li></ul><ul><ul><li>Regression 10% (0-25%) </li></ul></ul><ul><ul><li>Stabilization 65% (38-94%) </li></ul></ul><ul><ul><li>Progression 23% (6-50%) </li></ul></ul>
    51. 54. Multiple Cellular Effects of α -IFN Binding of the interferon receptor <ul><li>Direct effects </li></ul><ul><li>Cellcycle inhibition G1/S </li></ul><ul><li>Induction of bcl-2 </li></ul><ul><li>Inhibition of growth factor/receptor expression </li></ul><ul><li>Upregulation of SSTR-2 </li></ul><ul><li>Indirect effects </li></ul><ul><li>Stimulation of the immune system </li></ul><ul><ul><li>Cytotoxic T-cells </li></ul></ul><ul><ul><li>NK-cells </li></ul></ul><ul><ul><li>Monocytes/Macrophages </li></ul></ul><ul><li>Stimulation of other cytokines </li></ul><ul><li>Anti-angiogenesis </li></ul>
    52. 55. GTP GDP  c-kit TGFß-R GPCR Menin Smad4 Ca ++ channel VEGF VEGF p16 RET VMAT PDGF-R IGF-R IGF-1 IGF-1 CgA VEGF-R TGFß Molecular Targets in Neuroendocrine Tumors IFN-R EGF-R SSTR-2 SSTR-3 SSTR-5 Inhibitors of Angiogenesis Molecular-targeted therapies SSTR-1 Novel somatostatin analogs Courtesy by M. Pavel mTOR
    53. 56. Angiogenesis inhibitors Adapted from Phan and Yao, Oncology 2008 Agent (s) Target (s) N Tumour ORR Outcomes Comments Bevacizumab + octreotide VEGF 22 Carcinoid 18% 16.5 mo (PFS) - Sunitinib VEGFR, PDGFR, RET, FLT3 41 66 Carcinoid PNETs 2% 17% 10.5 mo (TTP) 7.7 mo (TTP) - Sorafenib VEGFR, PDGF, Raf 51 42 Carcinoid PNETs 7% 17% 7.8 mo (PFS) 11.9 mo (PFS) - Vatalanib VEGFR, PDGFR 11 GEPNET 0% NR Ongoing Pazopanib VEGFR, PDGFR, 30 30 Carcinoid PNET - - - - Ongoing Motesanib VEGFR, PDGFR, RET 44 LGNET - - Ongoing Atiprimod Unclear 25 LGNET 0% 76% at 6 mo (TTP) Ongoing Bevacizumab + 2-methoxyestradiol VEGF 31 Carcinoid 0 Median PFS not reached at 8.9 mo Ongoing
    54. 57. Phase III Study Design Raymond E et al . Phase III, randomized, double-blind trial of sunitinib versus placebo in patients with progressive, well-differentiated, malignant pancreatic islet cell tumors. Poster presented at the 2010 ASCO Gastrointestinal Cancers Symposium; Orlando, USA, 22–24 January 2010. *With best supportive care <ul><li>Primary endpoint </li></ul><ul><li>Progression-free survival </li></ul><ul><li>Other endpoints </li></ul><ul><li>Overall survival </li></ul><ul><li>Objective response rate </li></ul><ul><li>Time to response </li></ul><ul><li>Duration of response </li></ul><ul><li>Safety </li></ul><ul><li>Patient-reported outcomes </li></ul>Sutent ® 37.5 mg/day continuous daily dosing* Placebo* Patients with well-differentiated malignant pancreatic NETs who had experienced disease progression in the past 12 months and were not candidates for curative surgery (n=340)
    55. 58. Phase III Primary Endpoint: Progression-Free Survival (contd.) <ul><li>Study stopped early </li></ul><ul><li>Many events censored </li></ul><ul><li>Number at risk low from month 15 </li></ul>Proportion of patients 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 Time (months) Median PFS –– Sutent ® 11.4 months (95% CI 7.4–19.8) –– Placebo 5.5 months (95% CI 3.6–7.4) HR: 0.418 (95% CI 0.263–0.662) P =0.0001 Raymond E et al . Phase III, randomized, double-blind trial of sunitinib versus placebo in patients with progressive, well-differentiated, malignant pancreatic islet cell tumors. Poster presented at the 2010 ASCO Gastrointestinal Cancers Symposium; Orlando, USA, 22–24 January 2010. Number at risk Sutent ® Placebo 86 85 39 28 4 2 0 1 0 0 19 7
    56. 59. Rationale for Combining Everolimus with Octreotide LAR <ul><li>The PI3-K/Akt/mTOR pathway is activated by IGF-1 in NET 1,2 </li></ul><ul><li>mTOR regulates signaling downstream of IGF-1R 1 </li></ul><ul><li>Everolimus and Octreotide LAR may act synergistically </li></ul>+ <ul><li>Octreotide LAR can decrease </li></ul><ul><li>the production of IGF-1 </li></ul><ul><li>IGF-1 is an autocrine stimulator </li></ul><ul><li>of CgA secretion and tumor </li></ul><ul><li>growth in human NET cells </li></ul>Oxygen, energy and nutrients 1. Von Wichert et al. Cancer Res . 2000;60:4573-4581, 2. Van Gompel et al. Surgery. 2004;136:1297-1302, 3. Francalanci et al. Am J Surg Pathol. 2003;27:1386-1389, 4. Verhoef et al. Eur J Pediatr. 2003;27:1386, 5. Charland et al. Endocrinology. 2001;142:121-128 Apoptosis Octreotide LAR
    57. 60. mTOR Pathway is Deregulated by Mutations in Cancer <ul><li>Normal cell growth, proliferation, and metabolism are maintained by a number of mTOR regulators </li></ul><ul><li>Regulators of mTOR activity </li></ul><ul><ul><li>mTOR activating </li></ul></ul><ul><ul><li>mTOR deactivating </li></ul></ul><ul><li>Deregulation of mTOR can result in loss of growth control and metabolism (TSC1/2, IGF/-R, VHL) </li></ul><ul><li>Mutations in the mTOR pathway have been linked to specific cancers </li></ul>mTOR Protein Synthesis Akt PI3K ER Abl Ras Ras EGF IGF Nutrients VEGF Growth Signaling Cancer Cell Angiogenesis Bioenergetics Cell Growth & Proliferation PTEN TSC2 TSC1 Everolimus Octreotide LAR
    58. 61. RADIANT-1: Response Assessment Intent-to-Treat; Central Radiology Review * Response documented according to RECIST criteria * Yao J et al. JCO:2008:28;4311 Everolimus Everolimus + Octreotide LAR N = 115 n (%) N = 45 n (%) ORR (PR) 9 (7.8) 2 (4.4) Stable disease (SD) 9 (68.7) 35 (77.8) Clinical benefit (PR + SD) 88 (76.5) 37 (82.2) Progressive disease 16 (13.9) 1 (2.2) Unknown 11 (9.6) 7 (15.6) Response duration (median) 10.6 mo NA
    59. 63. RADIANT-3 Study Design: Phase III Trial in Advanced Pancreatic Tumors <ul><li>Progressive disease </li></ul><ul><li>Previous chemotherapy permitted </li></ul>Everolimus 10 mg/d + best supportive care Placebo + best supportive care Multi-phasic CT or MRI performed at baseline and every 3 months <ul><li>Primary Endpoint </li></ul><ul><li>PFS (Results expected in 2010) </li></ul><ul><li>Secondary Endpoints </li></ul><ul><li>Objective response rate, response duration, overall survival </li></ul>Treatment continued until tumor progression Enrollment completed Randomize Patients with advanced P-NETs n=410 www.clinicaltrials.gov NCT00510068
    60. 64. Primary Endpoint: PFS by Treatment <ul><li>p -value obtained from stratified one-sided log-rank test </li></ul><ul><li>Hazard ratio is obtained from stratified unadjusted Cox model </li></ul>Time (months) No. of patients still at risk Censoring Times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) Everolimus Placebo 207 203 189 177 153 98 126 59 114 52 80 24 49 16 36 7 28 4 21 3 10 2 6 1 2 1 0 1 Kaplan Meier median PFS Everolimus: 11.04 months Placebo : 4.60 months HR: 0.35 (95% CI [0.27,0.45]) p -value: <0.0001 0 1 0 0 100 80 60 40 20 0 Percentage of event-free 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Yao et al Ann Oncol (2010) 21(suppl 6): NP doi:10.1093/annonc/mdq340
    61. 67. Metastatic NET Surgery (resection, debulking RF, embolization) Low prolif. Ki-67 <3% Median prolif. Ki-67 3-20% High prolif. Ki-67 >20% <ul><li>Biotherapy Chemotherapy Chemotherapy: </li></ul><ul><li>-Somatostatin analogue (SMS) - STZ+5FU/Dox Cispl + Etoposide </li></ul><ul><li>α-IFN - STZ + Everolimus Temozolomide </li></ul><ul><li>Sunitinib - Temozolomide + + capecitabine </li></ul><ul><li>Combinations capecitabine + bevacizumab </li></ul><ul><li>SMS + α-IFN - Sunitinib SMS for symptom control </li></ul><ul><li>SMS + Everolimus - SMS + Sunitinib </li></ul><ul><li>SMS + bevacizumab - SMS for symptom control </li></ul><ul><li>SMS + Sunitinib </li></ul>Targeted Radiotherapy Lu 177 DOTA-octreotate, Y 90 DOTATOC Experimental Protocols Treatment Algorithm
    62. 68. NET-development during the last four decades A clinicians view 1988-99 n=892 SEER data base. Median survival 37 mo 1973-87 n=787 SEER data base. Median survival 17 mo Midgut carcinoid, n=284 Uppsala. Median survival 148 mo (5yr survival 77%) 1990-2008 1974-2004 SEER. Median survival 33 mo
    63. 69. NET Multidisciplinary Teams Patient Endo-crinologist Oncologist Surgeon Nuclear Medicine Pathologist Tumor Board Patient support group Gastro- enterologist
    64. 70. Future Therapy <ul><li>Explore the WHO- and TNM-classification system for improved therapy </li></ul><ul><li>Personalized treatment based on tumor biology and molecular genetics </li></ul><ul><li>Completely new therapeutic modalities (vaccines, oncolytic viruses, nanoparticles) </li></ul>
    65. 71. Thank you! Centre of Excellence Endocrine Tumors, Uppsala University http://www.endocrinetumors.org/ endocrinetumors.org Endocrine Tumors C e n t r e o f E x c e l l e n c e

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