MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours
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Similaire à MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours
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MCO 2011 - Slide 30 - K. Öberg - Spotlight session - Neuroendocrine tumours
- 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. 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
- 5. Distribution of GE-NETs by primary tumour site Maggard MA, et al. Ann Surg 2004;240:117–22
- 8. General Neuroendocrine Neoplasms Categories WHO 2010
- 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. 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. 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. 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
- 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
- 16. Survival in 324 patients with pancreatic endocrine tumors Ekeblad et al P < 0.001
- 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%)
- 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
- 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
- 25. Neuroendocrine tumors Modlin 2008 PET (FDG)
- 29. PET/CT with 11 C-5-HTP
- 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
- 31. PET/CT with 68 Ga-DOTA-octreotide
- 38. Chemotherapy
- 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
- 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.
- 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
- 44. Novel somatostatin analogue - SOM230 Novel cyclohexapeptide
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 69. NET Multidisciplinary Teams Patient Endo-crinologist Oncologist Surgeon Nuclear Medicine Pathologist Tumor Board Patient support group Gastro- enterologist
- 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
Notes de l'éditeur
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- 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.
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- 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 &quot;classic&quot; 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 &quot;classic&quot; 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
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- 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
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