Toward More Aggressive Management of Neuroendocrine Tumors: Current and Future Perspectives Moderator: Ashley Grossman, MD, FRCP Professor of Neuroendocrinology William Harvey Research Institute Barts and the London School of Medicine and Dentistry St. Bartholomew's Hospital London, United Kingdom Panel: Eric Van Cutsem, MD Professor of Internal Medicine Digestive Oncology Department University Hospital Gasthuisberg Leuven, Belgium Panel (cont): Prof. Massimo Falconi, MD Department of Surgery University of Verona Verona, Italy Bertram Wiedenmann, MD, PhD Professor of Internal Medicine and Gastroenterology Chairman, Department of Hepatology, Gastroenterology, and Metabolic Diseases Charité Medical School, Campus Virchow-Klinikum Humboldt-University Berlin, Germany
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Toward More Aggressive Management of Neuroendocrine Tumors:
Current and Future Perspectives
Moderator:Ashley Grossman, MD, FRCPProfessor of NeuroendocrinologyWilliam Harvey Research InstituteBarts and the London School of Medicine and DentistrySt. Bartholomew's HospitalLondon, United Kingdom
Panel:Eric Van Cutsem, MDProfessor of Internal MedicineDigestive Oncology DepartmentUniversity Hospital GasthuisbergLeuven, Belgium
Panel (cont):Prof. Massimo Falconi, MDDepartment of SurgeryUniversity of VeronaVerona, Italy
Bertram Wiedenmann, MD, PhDProfessor of Internal Medicine and GastroenterologyChairman, Department of Hepatology,Gastroenterology, and Metabolic DiseasesCharité Medical School, Campus Virchow-KlinikumHumboldt-UniversityBerlin, Germany
• Treatment decisions require discussion by a multidisciplinary team
• Options may depend on: • Type of NET • TNM stage• Tumor grade• Extent of disease, including liver disease• Functional status of tumor• Patient: organ function, ECOG PS, comorbidity • Access to various options
ECOG: Eastern Cooperative Oncology Group; PS: performance status
or metastatic• Well differentiated• Measurable (CT/MRI)• Functioning or
nonfunctioning
Octreotide LAR 30 mg IM
every 28 days
Placebo IM every 28 days
RAN
DOM
IZAT
ION
(1:1
)
Treatment until CT/MRI
documented tumor
progression or death
CT: computed tomography; IM: intramuscular; MRI: magnetic resonance imaging; OS: overall survival; PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of
Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP: time to progression
Rinke A, et al. J Clin Oncol. 2009;27:4656-4663.
PROMID: Octreotide LAR Slows Disease Progression in Midgut NETs
Octreotide LAR vs placebo P < .001HR: 0.34 (95% CI: 0.20–0.59)
• Tumors mainly in upper GI and colon– Must be considered separately from other tumors– Treated similarly to SCLC
• Small studies (N = 18 to 41) with cisplatin + etoposide:[1,2]
– Objective response similar to that in SCLC (42% to 54%)– Median survival also low (15 to 19 mo)
[a]Moertel CG, et al. Cancer. 1991;68:227-232. [b]Mitry E, et al. Br J Cancer. 1999;81:1351-1355.
SCLC: small-cell lung cancer
Rationale for the Use of Angiogenesis Inhibitors in NETs
Dense vascularization is a
key feature of NETs
VEGF and VEGF-R are overexpressed
in NETs
Elevated circulating VEGF correlates with
tumor progression
Terris B, et al. Histopathology. 1998;32:133-138; Papouchado B, et al. Mod Pathol. 2005;18:1329-1335; Pavel M, et al. Clin Endocrinol. 2005;62:434-443; Welin S, et al. Neuroendocrinology. 2006;84:42-48; Zhang J, et al. Cancer. 2007;109:1478-1486.
VEGF: vascular endothelial growth factor
Efficacy and Tolerability of Angiogenesis Inhibition in NETsDrug(s)
1. Pavel ME, et al. J Clin Oncol. 2008;26(May 20 suppl):14684. 2. Varker KA, et al. Cancer Chemother Pharmacol. 2008;61:661-668. 3. Kulke MH, et al. Clin Oncol. 2006;24:3555-3561. 4. Hobday TJ, et al. J Clin Oncol. 2007;25(June 20 suppl):4504. 5. Raymond E, et al. Presented at 2010 ASCO GI: Abstr 127. 6. Yao JC, et al. J Clin Oncol. 2008;26:1316-1323.
*PNET; †GI NETsHTN: hypertension; MR: minor response; ND: not determined; PDGFR: platelet-derived
• Oral mTOR inhibitor with broad antitumor activity and antiangiogenic activity[a-d]
• Daily dosing with everolimus 5-10 mg resulted in continuous inhibition of mTOR activity[d,e]
[a]Beuvink I, et al. Proc Am Assoc Cancer Res. 2001;42:366. Abstract 1972; [b]O’Reilly T, et al. Proc Am Assoc Cancer Res. 2002;43:71. Abstract 359; [c]O’Donnell A, et al. J Clin Oncol. 2008;26:1588-1595; [d]Tabernero J, et al. J Clin Oncol. 2008;26:1603-1610; [e]Tanaka C, et al. J Clin Oncol. 2008;26:1596-1602.
Everolimus (RAD001): An Oral mTOR Pathway Inhibitor
mTOR: mammalian target of rapamycin
RADIANT-1: RAD001 +/- Octreotide LAR in Pancreatic NET: Open-Label Phase 2 Study
Everolimus37.2% grade 3-4 AEs
Everolimus + octreotide LAR33.0% grade 3-4 AEs
84 6
n: 115
Median PFS: 9.7 mo0
20
40
60
80
100
Prob
abili
ty (%
)
260 2 10 12 14 16 18 20 22 24
Time (mo)5481 58 0115 111 36 25 15 12 5 3 3 1
Patientsat risk
24
0Patientsat risk
84 6
n: 45
Median PFS: 16.7 mo0
20
40
60
80
100
Prob
abili
ty (%
)
0 2 10 12 14 16 18 20 22
Time (mo)
2132 2245 39 19 14 10 8 3 3 1
Yao JC, et al. J Clin Oncol. 2010;28:69-76.
PFS by Central Review
RADIANT 3: BSC + Everolimus or Placebo in Progressive Advanced pNET
• P value obtained from stratified one-sided log-rank test• HR obtained from stratified unadjusted Cox model
• Biomarkers and molecular imaging for evaluation of therapeutic response
• Personalized treatment based on molecular genetics and tumor biology
• WHO and TNM classification
• Molecularly targeted treatment will be the future:• Targeted agents• PRRT• Combinations of traditional cytotoxics with targeted agents • Combinations of targeted agents
Take-Home Messages
Role of Pathology in NET Management• Critical to appropriate management decisions in NETs• Includes staging, grading, differentiation, site of origin, Ki-67