Rare Solid Cancers: An Introduction - Slide 14 - E. Baudin - Neuroendocrine tumors
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Rare Solid Cancers: An Introduction - Slide 14 - E. Baudin - Neuroendocrine tumors
- 1. Neuroendocrine tumors : introduction E.Baudin Endocrine oncology - Reference center Institut Gustave Roussy Villejuif France
- 2. US and European Incidence of NETs 2000–2004 1983–1998 1989–1996 1993–2004 1974–1997 1985–1991 Study Period: 1. Yao JC, Hassan M, Phan A, et al. J Clin Oncol . 2008;26:3063-3072. 2. Taal BG, Visser O. Neuroendocrinology . 2004;80(suppl 1):3-7. 3. Hauso O, Gustafsson BI, Kidd M, et al. Cancer. 2008;113:2655-2664. Incidence Rates Per 100,000 0.0 2.0 4.0 6.0 8.0 US 1 (SEER) Netherlands 2 Sweden 2 Men Women Italy 2 (Tuscany) Switzerland 2 (Vaud) Norway 3 Country: SEER = Surveillance, Epidemiology, and End Results (for malignant NETs)
- 4. NET : various terminologies but a simple definition Endocrine Tumors Others : gastrinomas, insulinomas ….. Endocrine morphology Positive Chromogranine A / Synaptophysine / CD 56 … staining
- 5. Yao J et al. JCOC 2008, Hauso O et al. Cancer 2008 : SEER (US, 17312 pts) and NRC (Norway, 2030 pts) from 1993 to 2004 NET : a network of tumors
- 8. Functioning NET are characterized by hormone-related symptoms at diagnosis : dedicated management required O’Toole et al. Neuroendocrinology 2009 : measure Chromogranine A in all cases, and additional markers or tests depending on patients’ history (insulinomas, gastrinomas, Cushing Syndrome) 5-HIAA Glucagon ACTH, UFC
- 10. WHO 2000/10 of NET WHO Lung 2000 Digestive 2010 Well differentiated 1.Typical carcinoid 2.Atypical carcinoid 1. Neoplasm, Grade1 2. Neoplasm, Grade2 Poorly Differentiated 3.Large cell 4.Small cell 3.Carcinoma, large or small cell, Grade 3
- 11. Travis et al. Am J Surg Pathol 1998 : analysis of 200 bronchial ET WHO classification of lung NET is prognostic Typical carcinoid < 2 mitoses/10 GC no necrosis Atypical Carcinoid >= 2-10 mitoses/ 10 GC no,punctiform necrosis 87% 35% Poorly different. EC cell size : large/small >10 mitoses/ 10 GC large necrosis 9% Well differentiated Poorly differentiated
- 12. Digestive NET : tumour Grade and Survival 1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch . 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265. 0 50 100 150 200 250 Survival Time (mo) 0.0 0.2 0.4 0.6 0.8 1.0 Cumulative Survival G1 G2 G3 G1 vs G2 G1 vs G3 G2 vs G3 P =0.040 P <0.001 P <0.001 *ENETS and AJCC grading system N=193 Grade* Mitotic count (10 HPF) Ki67 index (%) G1 <2 ≤ 2 G2 2-20 3-20 G3 >20 >20
- 13. pTNM staging for lung cancer T based on : Size Nodules same lobe (T3) or side (T4) Invasion (T3) / Extension (T4) N1 : peribronchial/hilar N2 : mediastinum N3 : supraclavicular/controlateral M1 includes controlateral nodules Travis WD et al. JTO 2008 Stage T N M IA IB T1 T2a N0 N0 M0 M0 IIA IIB T1-2a T2b-3 N1 N0 M0 M0 IIIA IIIB T1-2 T3- 4 N2 N3 M0 M0 IV _ _ M1
- 14. NET : pTNM – ENET classification T: size, local spread N : N1/N analyzed (>12) Stade T N-regional M I T1 N0 M0 II T2-3 N0 M0 III T4 - N0 N1 M0 M0 IV - - M1(N1 distal)
- 15. NET : pTNM – ENET classification T: size, local spread N : N1/N analyzed (>12) NEW UICC TNM CLASSIFICATION 2010 = ENET 2010 but pancreas, appendix Stade T N-regional M I T1 N0 M0 II T2-3 N0 M0 III T4 - N0 N1 M0 M0 IV - - M1(N1 distal)
- 18. NET therapy Poorly differentiated NEC WHO classification
- 20. NET therapy Poorly differentiated NEC WHO classification Hormone-related symptoms Well differentiated NEC
- 21. Control of Hormone-related symptoms Treat before and or during surgery : Akerström G et al Neuroendocrinology 2009 >7O% of NET express somatostatin receptors, most patients are responders Hormone-related syndromes First line Additional therapies for Gastrinoma Proton Pump Inhibitors - Insulinoma Diazoxid Glucose Glucagonoma SMS analogs Nutritional status, diabetes, thrombosis VIPoma SMS analogs Hydratation ,HypoK Cushing Various Diabetes, HTA, HypoK,decreased BMD Carcinoid SMS analogs Right-sided heart dysfct, Diarrhea, nutritional status Acromegalic SMS analogs Diabetes
- 22. NET therapy Poorly differentiated NEC WHO classification Hormone-related symptoms Well differentiated NET
- 23. NET therapy Poorly differentiated NEC WHO classification Hormone-related symptoms Well differentiated NET Localized Stage I-III
- 24. NET staging by imaging combined CT/MRI and scintigraphy Dromain C et al JCO 2005 PET/SPECT somatostatin receptor scintigraphy or PET FDG
- 26. NET therapy Poorly differentiated NEC WHO classification Hormone-related symptoms Well differentiated NET Localized Stage I-III Diffuse Stage III-IV Surgery / Survey No adjuvant therapy
- 30. Octreotide LAR improves time to progression (PROMID study) in good prognostic metastatic well differentiated digestive NET TTP SDSLAR Placebo OR 1 1 S 28 16 P 10 23 SSP 6m 66% 37% Ongoing-phase III : Lanreotide versus Placebo Rinke A et al. JCO 2009 : 40% functioning, 95% Ki67<2%, 75% liver involvement < 10% / centralized imaging and WHO criteria Octreotide LAR vs placebo HR=0.34 P =0.000072 [95% CI: 0.20–0.59] Octreotide LAR (42) : Median 14.3 months Placebo (43) : Median 6.0 months Time (months) Proportion without progression 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78
- 31. Comparable antitumor effect of somatostatin analogs and or interferon Randomized studies in patients with progressive tumors J Clin Oncol 2003 (1) ; Clin Gastroenterol Hepato 2005 (2) n Duration PR and SD FAISS S Progressive over 3 months LAN 1 mg x 3/d SC 25 1 yr 32% NS IFN 5 mUx3/sem SC 27 30% LAN+IFN 28 25% ARNOLD R Progressive WHO OCT 200µg x 3/j SC 51 1 yr , till progression 17% OCT+IFN 4.5 millionU x 3/sem sc 54 24% NS
- 33. Chemotherapy in unresectable Islet Cell Carcinoma : DXR-STZ a standard that remains to be validated TTP OS Moertel et al NEJM 1992 : old WHO criteria, unknown progressive status 17% OR as second line DXR-STZ 5Fu-STZ CZT OR 69% 45% 39% PFS m 18 14 17 OS yr 2.2 1.5 1.4
- 34. Chemotherapy in unresectable Islet Cell Carcinoma : DXR-STZ a standard that remains to be validated TTP OS Moertel et al NEJM 1992 : old WHO criteria, unknown progressive status 17% OR as second line STZ-DXR regimen for pancreatic WD NEC : objective response rate between 6-36% with a duration of 9-19 months in the litterature DXR-STZ 5Fu-STZ CZT OR 69% 45% 39% PFS m 18 14 17 OS yr 2.2 1.5 1.4
- 35. Before treatment After treatment ENET recommendations : DXR or 5Fu- STZ for metastatic Well diff pancreatic NET Dacarbazine as second line Chemotherapy not recommend for other primaries Eriksson b et al Neuroendocrinology 2009 Pancreatic NET is relatively chemosensitive
- 36. Pancreas well differentiated metastatic neoplasms : other or new polychemotherapy WHO or RECIST except * STUDY N OR DURATION MEDIANE Eriksson 1990* 5Fu-STZ / 3 wks Retrospective study 19/ 1st line 31% - Bukowski 1992 * 5Fu-CTZ / 6 wks P II 44 32% 11 Beretta 2006 XELOX , P II progressive 11 27 % - Isacoff ASCO 2006 CAPE-TMZ Retrospective study 33 ? 67% 18 ? Strosberg ASCO 2009 CAPE-TMZ Retrospective study Prog ? 17/ 1st line 71% 12 + Cassier 2009 GEMOX/ Retrospective study/ progressive >2 nd line 5 40% -
- 37. Peptide receptor radionucleide therapy (PRRT) : limited availability, used in positive SRS tumors Kaltsas GA et al. Endoc Relat Cancer 2005 SRS : somatostatin receptor scintigraphy SRS posterior view sst 2 sst 1 sst 3 sst 4 sst 5
- 38. Peptide receptor radionucleide therapy : academic research studies in positive SRS patients Kwekkeboom D et al. ENET consensus 2009 Study PRRT agent n OR-CR PFS Months Waldher 2001 [90Y-DOTA, Tyr3] –Octreotide 41 24% >26 Kwekkeboom 2008 [ 177 Lu-DOTA,Tyr 3 ] –Octreotate 310 30% 40
- 39. PRRT with Octreotate – 177 Lu is able to provide partial response Avant +2 OCLU + 4 OCLU SRS IRM-T2 préparé par C.-T. Pham
- 40. mTOR Pathway in Sporadic pNETs Missiaglia E, Dalai I, Barbi S, et al. J Clin Oncol. 2010;28:245-255. TSC2 Expression PTEN Expression 0 5 10 15 20 High-level TSC2 Low-level TSC2 Overall Survival Time (yr) 1.0 0.5 0 5 10 15 20 High-level TSC2 Low-level TSC2 Progression-free Survival Time (yr) 1.0 0.5 Time (yr) 0 High-level PTEN Low-level PTEN Progression-free Survival 1.0 0.5 5 10 15 20
- 41. mTOR inhibitors in NET : phases II rational increased IGF1-VEGF, downregulation of PTEN-TSC2 in NET Traitement Population RECIST PFS Duran B 2006 N=32 Temsirolimus 25 mg IV/sem Multiple primaries Progressive disease First line or not OR 5% S 58% 6 months Yao J 2008 N=60 Everolimus 5-10 mg po/j Octreotide Multiple primaries Progressive or not First line or not OR 22% S 70% 15 months Yao j 2009 N=146 Everolimus 10 mg po/j +/- SDS LAR* (stratification) Pancreas Progressive Post first line OR 4-9*% S 67-80*% 9-16* months
- 45. Takahashi Y et al. Clin Cancer Res 2007;13:187-196 Angiogenesis inhibitors in GEP NET: rationale High micro vascular density is associated with a favourable outcome High proliferative index in Endothelial cell is associated with a poor outcome
- 46. Antiangiogenic therapy in non-pancreatic NET SDS LAR + BEVA 0R + IFN : a randomized phase II study Yao J et al JCO 2008 : non pancreatic metastatic well differentiated NEC Phase III ongong Treatment (n) SDS +BEVA (22) SDS+IFN * (22) OR at 18 sem 4(18%) 0 PFS at 18 sem 95% 68%
- 47. Sunitinib –phase 2 multicentric : 50 mg/j 4/6 w, 6 cycles VEGFR2(4nM), FLT-3(8-14nM), PDGFRb(39nM), FGFR-1(880nM), cKIT(1-10nM), CSF-1R(50-100nM), RET 100nM Well differentiated ,progressive or not, RECIST, 2nd ligne (50% pts) Safety profile Grade 3-4 toxicity : 10-29% Kulke MH et al. JCO 2008 : 117 patients Primitif (n) A.Digestive (41) B.Pancreas (66) RO 1(2%) 11 (16%) TTP months Range 10.2 (2-19) 7.7 (2-15)
- 48. Sunitinib vs Placebo: Phase III, a randomized study in progressive well differentiated pancreatic NEC RANDOM I ZAT I ON 340 patients First line or not Fonctioning or not Sunitinib 37.5 mg/jour Arm A Placebo Arm B Objectif principal : Survie sans progression 1:1 E Raymond et al : 169 patients : positive interim analysis, median survival 5 (IC 95, 3.5-7.4) vs 11 (IC 95, 7.4-NR) months HR 0.397 ( p < 0.001)
- 50. Progression-free Survival* Kaplan-Meier median PFS Sunitinib : 11.4 mo Placebo: 5.5 mo HR = 0.42 (95% CI, 0.26–0.66) P <0.001 Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. * Local review 0.8 0.6 0.4 0.2 0 1.0 Proportion of Patients 5 10 15 20 25 0 Sunitinib 39 19 4 0 0 86 Sunitinib 28 7 2 1 0 85 Placebo Number at risk Time (mo) Placebo
- 52. Metastatic NET : locoregional therapy Steinmüller T et aL ENET guideline Neuroendocrinology 2008 : in case of extra-hepatic spread = non surgical treatment in most cases unless palliation needed (RF, TACE…) HEPATIC MET UNILOBAR / LIMITED BILOBAR LIVER SURGERY Surg contra-indicated ABLATION TACE SURGERY TACE ou TAE DIFFUSE MEDICAL THERAPY Transplantation Selected cases
- 53. NET options Pancreas Non-pancreas Biotherapies SMS analogs IFN SMS analogs IFN Chimiothérapies STZ-DXR/Fu DTIC+/-Fu Oxaliplatine+Fu ? PRRT Yes Yes TKI Everolimus Sunitinib Everolimus LRT Yes Yes
- 56. NET specialist Pathologist Biomarkers Imaging Molecular Imaging Genetics Surgeon Embolisation, RFA Organ-specialist Supportive care Endoscopic investigation Chemotherapy Radiotherapy WORK WITHIN MULTIDISCPLINARY TEAMS and NETWORKS, THANK YOU
Notes de l'éditeur
- Epidemiologic studies from 1974 to1998 from 5 European countries and the United States showed the levels of incidence as lowest in the Tuscany region of Italy with the highest incidence in the United States (5.35 per 100,000 in US men and 4.76 per 100,000 in US women). The data collection in Europe is mainly from population-based studies, whereas the US SEER data comprise a random sampling representative of the entire country. Yao JC, Hassan M, Phan A, et al. J Clin Oncol . 2008;26:3063-3072. Taal BG, Visser O. Neuroendocrinology . 2004;80(suppl 1):3-7. Hauso O, Gustafsson BI, Kidd M, et al. Cancer. 2008;113:2655-2664. US Department of Health and Human Services, National Institutes of Health, SEER Brochure.
- Retrospective data from 158 patients with histopathologic confirmed diagnosis of gastric, duodenal, or pNET underwent survival analysis according to the ENET/AJCC grading system. The analysis indicated that survival was significantly poorer for patients who had grade 3 tumours compared with patients who had grade 1 and grade 2 tumours and for patients who had grade 2 tumours compared with patients who had grade 1 tumours. A key concept that needs to be emphasized is that poorly differentiated tumours are always grade 3. However, grade 3 tumours are not always poorly differentiated. Rindi G, Klöppel G, Alman H, et al. Virchows Arch. 2006;449:395-401. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265.
- PROMID was a placebo-controlled, double-blind, phase IIIB study in patients with well-differentiated advanced (metastatic and locally inoperable) small intestine (midgut) NETs. The hypothesis was that octreotide LAR prolongs time to tumour progression. After randomization, patients received octreotide LAR 30 mg or placebo every 28 days until tumour progression, documented by CT or MRI, or death. Octreotide LAR 30 mg or placebo were administered by a study nurse or physician not involved in further patient care. Patients were blinded and all clinical assessments were performed without knowledge of the assigned treatment. During the study, additional antiproliferative therapy was not allowed. Poststudy treatment in patients with tumour progression was at the discretion of the investigator. All patients will be followed-up until death. Tumour progression was evaluated using the WHO criteria. Importantly, CT and/or MRI scans were evaluated by a blinded central reader. In the event of progression, patients were unblinded to the investigator, who could then decide further treatment options for the patient. Once the study was finished, the investigator was unblinded with regard to the treatment. In patients who progressed while receiving placebo, octreotide LAR or a different treatment could be administered. Patients enrolled in the PROMID study were treatment-naïve with locally inoperable or metastatic well-differentiated NET with a small intestinal primary tumour without curative therapeutic options. Patients could have either a functioning or nonfunctioning tumour. Patients with a tumour of unknown origin were believed to have a small intestinal tumour if a primary within the pancreas, chest, and elsewhere was excluded by multiphasic CT and/or MRI. Progressive metastatic disease was not required for enrollment; however, all patients were required to demonstrate metastatic or inoperable disease measurable by CT or MRI. Patients with symptoms of carcinoid syndrome and increased urinary 5-hydroxyindole acetic acid (5-HIAA) were classified as having a functioning tumour. Only those patients with carcinoid syndrome who tolerated flushing without intervention or responded to treatment with loperamide and/or cholestyramine in case of diarrhea were included. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol . 2009;27:4656-4663.
- A better control in terms of stable didease
- Downregulation of TSC2 and PTEN expression in primary tumours were significantly associated with shorter disease-free survival and OS. 1. Missiaglia E, Dalai I, Barbi S, et al. J Clin Oncol. 2010;28:245-255.
- RADIANT-3, was the largest phase III trial ever conducted in advanced pancreatic NET (pNET). This prospective, double-blind, randomized, placebo-controlled, phase III trial, assessed the efficacy and safety of everolimus + best supportive care vs placebo + best supportive care in patients with advanced pNET. It accrued more rapidly than anticipated, meeting full enrollment in <2 years—410 patients. The study was designed to detect an HR of 0.67 with 282 events needed to achieve 92% power. The primary endpoint of this trial was PFS per investigator assessment. Secondary endpoints include safety and OS. Patients with advanced pNET and radiologic progression within the preceding 12 months were randomized 1:1 to everolimus + best supportive care vs placebo + best supportive care. Best supportive care may include the use of somatostatin analogues. There are 2 stratification factors: Prior cytotoxic chemotherapy WHO PS at baseline (0 vs 1-2) Multiphasic CTs and/or MRIs were performed every 12 weeks for response evaluation. Treatment continued until progression, unacceptable toxicity, or withdrawal. The patient may have discontinued participation in the study for any of the following: Disease progression Subject withdrew consent AEs Lost to follow-up Abnormal laboratory value(s) Administrative problems Abnormal test procedure result(s) New cancer therapy Protocol deviation Death At progression, patients were unblinded and if on placebo allowed to crossover to open label everolimus. 91% of eligible patients who had progressed (148 of 163) on the placebo arm received open-label everolimus at the time of progression. 1. Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
- Results of the PFS analysis as per central review were consistent with and support those generated from the local investigator assessment. Central review results: HR=0.34 (95% CI:0.26–0.44); P <0.001, reflecting a 66% PFS risk reduction. Median PFS values were also consistent with those reported for the local investigator assessment. The median PFS was 11.4 months with everolimus and 5.4 months with placebo. The prolongation in median PFS was 6.0 months 1. Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
- RADIANT-2 is a randomized, double-blind, placebo-controlled, phase III study with the primary endpoint of PFS comparing everolimus 10 mg/day + octreotide LAR 30 mg/28 days to octreotide LAR 30 mg/28 days + placebo. RADIANT-2 was the largest phase III trial ever conducted in patients with advanced NET Patients with advanced NETs who have had a history of symptoms attributed to carcinoid syndrome (eg, flushing or diarrhea) were included in the study. Patients need not have flushing or diarrhea at the time of entry. Secondary endpoints included comparing OS between the treatment arms and determining the safety and tolerability of everolimus + octreotide LAR. Patients were allowed to cross over from the control arm to receive everolimus + octreotide LAR at the time disease progression was documented by the investigator. The study was blinded until there was documented disease progression, at which point the patient could be unblinded and, if on the control arm, allowed to cross over to receive open-label everolimus 10 mg/day + octreotide LAR 30 mg/28 days The study was designed for well- or moderately differentiated NETs (low- or intermediate-grade); poorly differentiated tumours were excluded. 1. Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
- A, C, and D, relationship between vascular index and WHO classification. B, E, and F, Kaplan-Meier survival curves of 37 patients with PETs. A, S-MVD significantly decreased according to progression of PETs in terms of the WHO classification (Kruskal-Wallis test, P = 0.003). B, patients were divided into two groups by median S-MVD. The high S-MVD group showed significantly longer survival than the low S-MVD group (log-rank test, P = 0.002). C, EPC significantly increased according to progression of PETs in terms of the WHO classification (Kruskal-Wallis test, P = 0.019). D, EPI significantly increased according to progression of PETs in terms of the WHO classification (Kruskal-Wallis test, P = 0.001). E, patients were divided into two groups by median EPI. The high EPI group showed significantly shorter survival than the low EPI group (log-rank test, P = 0.005). F, patients were divided into two groups by the quartile value of CXCL-12 expressed in the tumor cells. Patients with PETs showing high expression of CXCL-12 in the tumor cells had significantly shorter than those whose tumors showed low expression (log-rank test, P = 0.018).
- This multinational (42 centers in 11 countries) , randomized, double-blind, placebo-controlled, phase III trial was conducted to assess the efficacy and safety of continuous daily administration of sunitinib 37.5 mg in patients with advanced pNETs. Eligible patients had pathologically confirmed, well-differentiated pNETs (advanced, metastatic, or both) and were not eligible for surgery, ECOG PS 0 or 1, documented disease progression within the previous 12 months (defined by RECIST criteria), and adequate hematologic, hepatic, and renal function. Patients with poorly differentiated pNETs; previous tyrosine kinase or VEGF inhibitor treatment, cardiac events, or pulmonary embolism in the previous 12 months; ongoing cardiac dysrhythmias or a prolonged QT interval corrected for heart rate (QTc); symptomatic brain metastases; or a left ventricular ejection fraction of ≤50% were excluded. Treatment: once-daily oral sunitinib 37.5 mg or matching placebo was given until RECIST-defined disease progression was documented, unacceptable AEs occurred, or the patient died. Dose reduction to 25 mg daily and treatment interruption were permitted to manage AEs, with a subsequent increase in dose if grade ≥2 toxicity did not recur. Dose escalation to 50 mg daily was permitted for patients without an objective tumour response who had grade ≤1 nonhematologic or grade ≤2 hematologic treatment-related AEs during first 8 weeks. Endpoints: The primary endpoint was PFS, defined as the time from randomization to the first evidence of progression or death from any cause. For patients with inadequate baseline assessments, data on PFS time were censored on the date of randomization, with a 1-day duration. Secondary efficacy endpoints were OS, objective response rate (ORR), time to tumour response (TTR), duration of response, safety, and patient-reported outcomes. Tumour response was assessed by investigators (RECIST version 1.1). Confirmed responses were those that persisted on repeat imaging ≥4 weeks after initial documentation. Safety assessments included documentation of AEs (NCI CTC version 3.0), hematologic and biochemical laboratory tests, physical examination, and vital-sign measurements. The self-administered European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ-C30, version 3.0) was used to measure patient-reported outcomes. 1. Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513 .
- Disease progression or death was reported for 81 patients (local review). Median PFS was 11.4 months in the sunitinib group and 5.5 months in the placebo group; HR=0.42 (95% CI: 0.26–0.66; P <0.001). The probability of PFS at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group. 1. Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.