neuroendocrine tumors and peptide receptor … · neuroendocrine tumors and peptide receptor...
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NEUROENDOCRINE TUMORS AND PEPTIDE RECEPTOR RADIONUCLIDE
THERAPY (PRRT)
STEN MYREHAUG, MD, FRCPC
ASSISTANT PROFESSOR, DEPARTMENT OF RADIATION ONCOLOGY, UNIVERSITY OF TORONTO
RADIATION ONCOLOGIST, ODETTE CANCER CENTRE, SUNNYBROOK HEALTH SCIENCES CENTRE
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OBJECTIVES
• Review Treatment for Gastrointestinal Neuroendocrine Tumors (GI-NETs)
• Introduction to Peptide Receptor Radionuclide Therapy (PRRT)• Mechanism of Action• Clinical Data• Patient Experience
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INTRODUCTION TO GASTROINTESTINAL NEUROENDOCRINE TUMORS (GI-NETS): BACKGROUND
• Heterogeneous tumors arising from neuroendocrine cells found along the GI tract (stomach, pancreas, intestine, rectum).
• Clinically significant division: secretory vs. non-secretory• Carcinoid syndrome (elevated levels of serotonin): flushing, diarrhea,
dyspnea, cardiac disease• Gastrinomas, VIPoma, insulinoma, glucagonoma
• Clinical incidence rising (improved detection, improved classification, but also increasing numbers)
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INCIDENCE OF METASTASES AT TIME OF DIAGNOSIS
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INTRODUCTION: WORKUP• Pathology
• Identify primary source of disease
• Identify morphology (well vs. poorly differentiated)
• Identify proliferative status (Ki67)
• Biochemical status• Urinary 5HIAA, other markers based on syndromic status (glucagon, insulin,
metanephrines, etc)
• Liver function (hepatic masses common)
• Staging/Imaging• Endoscopy
• CT Chest/Abdomen; CT enterogram
• Triphasic Liver CT/MRI
• Functional imaging (octreotide scan, Ga-68 PET)
Grade Differentiation Ki67 Mitotic Count
G1 Well <3% <2/10HPFG2 Well 3-20% 2-20/HPFG3 Well >20 >20/HPFG3- NEC Poorly >20 >20/HPF
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INTRODUCTION TO GI-NETS: TREATMENT
GI-NET
Functional
SSA
Localized
Surgical Resection
Metastatic
Surgical Resection
Ablative Therapies
Systemic Therapies
Non-Functional
Localized
Surgical Resection
Metastatic
Surgical Resection SSA Ablative
TherapiesSystemic Therapies
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TREATMENT FOR GI-NETS: SURGICAL RESECTION
• Surgery with curative intent should always be performed if feasible• Minimally invasive approach if possible for gastric, rectal NET
• Goal for remaining GI NET: complete resection of primary tumor and associated lymphatic drainage
• For patients with metastatic disease, surgery is to be considered for:• Solitary/isolated liver metastases; functional metastases
• Removal of primary/mesenteric disease to prevent bowel obstruction
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TREATMENT: ABLATIVE THERAPIES
• Ablative approaches to primary or metastatic disease with aim of providing local tumor control and/or reducing functional secretory syndromes
• Radiofrequency Ablation (RFA) for small number, low volume disease
• Transarterial embolization (TAE) for multifocal/diffuse liver disease
• Symptomatic response rates ~60-95%• Biochemical response rate ~50-90%
• Median Response duration 18-24 months
• Radiation
• Typically felt to be a radioresistant disease due to slow disease kinetics
• Stereotactic Body Radiotherapy (SBRT) now being used as a local ablative modality
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SYSTEMIC TREATMENT FOR GI-NETS
• Somatostatin analogues• Octreotide-LAR• Lanreotide
• Targeted Agents• Everolimus• Sutent
• Chemotherapy• Capecitabine/Temozolomide• Cisplatin based (used only in High Grade Neuroendocrine ca)
• Peptide Receptor Radionuclide Therapy (PRRT)
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SYSTEMIC TREATMENT FOR GI-NET: PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT)
• Concept has been studied since the 1990’s
• Based on the unique biologic feature of NET: overexpression of peptide hormone receptors
• Somatostatin receptors are found in small bowel NET, pancreatic NET as well as other non-GI sites
• 5 somatostatin receptor subtypes, with sst2 being most common.
• PRRT delivers a radioactive isotope via a chelated somatostatin analogue
• Yttrium-90 and Lutetium-177 are commonly used isotopes
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PHYSICAL PROPERTIES OF LU-177 AND Y-90
Lutetium-177• Half-life: 6.71 days
• Decay particles
• Beta (average energy 0.497MeV)
• Gamma (0.208 MeV and 0.113 MeV)
• Average penetration in tissue: 2mm
Yttrium-90• Half-life: 2.7 days
• Decay Particles
• Beta (average energy 2.28MeV)
• Average penetration in Tissue: 12 mm
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TYPICAL ADMINISTRATION OF RADIONUCLIDE
Lutetium-177• Administered activity: 150-200 mCi• Number of treatments: 3-5• Interval between cycles: 6-12 weeks
Yttrium-90• Administered activity: 100 mCi/m2
• Number of treatments: 2• Interval between cycles: 6-12 weeks
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INITIAL DATA
• Prospective report of 504 patients with GEPNET treated with Lu-DOTATATE• 46% response rate• Survival related to response to therapy
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TOXICITY PROFILE
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NETTER-1 TRIAL
• Randomization: 177Lu-DOTATATE + Octreotide LAR 30 mg vs. Octreotide LAR 60 mg (n=229, 1:1)• Stratified based on Krenning score, and duration of SSA use prior to
enrollment• Inclusion criteria: Metastatic or Inoperable Grade I-II locally advanced midgut NET • Must have had progression on SSA therapy
• Exclusion criteria: Creatinine >150 or CrCl <50, WBC <2, HgB <80, Plt <75, Bili >3xULN, chemo/surgery/liver directed therapy within 12 weeks of treatment
• Primary endpoint: Progression Free Survival• Secondary endpoints: objective response rate, overall survival, toxicity, QoL
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NETTER- 1 TRIAL
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NETTER- 1 TRIAL
• PFS at 20 months: 65.2% vs. 10.8% (p<0.001)• Interim OS significant• Response rate: 18% vs. 3%
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NETTER- 1 TRIAL
• Grade III/IV Adverse Events: 41% vs. 33% • Tumor related events > in LAR only arm• In PRRT arm: mostly related to
nausea/vomiting and lymphopenia (transient)
• Long term Adverse events• 2-4% reported risk of MDS or leukemia• 1 patient in PRRT arm with prior MGUS
developed MDS• No long term renal toxicity noted
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CANCER CARE ONTARIO TRIAL: OZM-067
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CCO STUDY
• Planned patient accrual: 195 patients over 4 years. • Planned patient follow-up: 5 years• Primary endpoint: PFS• Secondary endpoints: overall response rate, biochemical response
rate, acute/late side effects, QoL, OS• Tertiary endpoints: determine proportion of serotonin receptor
positive patients using Ga-PET, role of Ga-PET for response prediction
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CCO STUDY SCHEMA
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PRRT: PATIENT SELECTION ABSOLUTE/RELATIVE (CONTRA)INDICATIONS
Eligibility Criteria
• Diagnosis of NET
• Well differentiated
• Grade I-2 (allow Ki67 up to 30%)
• Progression on SSA therapy
• Demonstration of presence of somatostatin
receptor (Octreotide scan or Gallium PET)
• Require Krenning Score >2.
Exclusion Criteria
• Pregnancy, severe acute concurrent illness
• Cardiac Insufficiency
• Poorly differentiated tumors
• Compromised renal function
• GFR should be at least 60% of age-adjusted value
• Severe renal outflow obstruction
• Compromised bone marrow
• Prior myeloablative chemo/radiation
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PATIENT PREPARATION: RENAL PROTECTION AND SSA
• Isotope can accumulate in the kidney interstitium via proximal tubule reabsorption
• Current accepted dose to kidney should be <27Gy
• Concurrent infusion of charged amino acids (Lysine/Arginine) inhibits the reabsorption of the isotope
• Reduces renal absorption in range of 10-50%
• Highly Nauseating (requires pre-medication with antiemetic and corticosteroid)
• Given with IV fluid administration
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CCO STUDY WORKFLOW- INDIVIDUALIZED DOSIMETRY
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MORE ON RENAL PROTECTION- INDIVIDUALIZED DOSIMETRY• Dutch group looked at long term results of 323
patients treated with Lu-177
• Found no significant long term impact on renal
function in patients treated with standard
doses.
• Controversy over individualized dosimetry from a
renal perspective
Bergsma et al. Eur J Nucl Med Mol
Imaging, online
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TRIAL PROCESS- OCC
• Patient deemed clinically appropriate for enrollment in trial• Provincial MCC discussion • Appointment to review trial, establish informed consent, enroll on
study• Ga-68 PET scan to establish presence of SSR• Review with radiation safety officer• Book Lu-177 infusion date
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SYSTEM PREPARATION: DAY OF TREATMENT AT OCC• Lutetium received by nuclear medicine
• AA received by chemotherapy pharmacy
• Patient brought to isolation room• Anti-emetics/steroids , IV fluids and amino acid infusion started
• 30-60 min following, infusion of lutetium (comes pre-prepared in normal saline) over 30-60 min
• Continue on amino acids for total of 4 hours
• Patient sent for whole body planar and SPECT images• Individualized dosimetry for subsequent treatments
• Patient scanned for radioactivity level• If below standard value, discharge home with safety instructions OR
• Preplanned admission to C2 shielded room for radiation protection
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POTENTIAL ACUTE COMPLICATIONS OF THERAPY
• NAUSEA!!!• PRRT may exacerbate any hormonal syndrome due to mass release
of hormones• Carcinoid crisis, glucagon, insulin, metanephrines• Must be prepared to manage these syndromes
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PATIENT DISCHARGE INSTRUCTIONS• Not allowed to be passenger in car for >3 hours• Limits outpatient option for those outside of study centres
• High levels of isotope excretion in urine for first 2 days• Dedicated bathroom• Double flush• Men should sit down
• Wash clothes separately• Women should practice contraception for at least 6 months following
treatment
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WHY PRRT OVER OTHER TREATMENTS
Pros
• “Systemic” radiation• Effective therapy• Modest side effect profile• Controlled dosing
Cons
• Radiation safety• Difficult for out of town patients• Hospital resources• Cost
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INTRODUCTION TO GI-NET: TREATMENT
GI-NET
Functional
SSA
Localized
Surgical Resection
Metastatic
Surgical Resection
Ablative Therapies
Systemic Therapies
Non-Functional
Localized
Surgical Resection
Metastatic
Surgical Resection SSA Ablative
TherapiesSystemic Therapies
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THE SUSAN LESLIE CLINIC FOR NEUROENDOCRINE TUMORS
http://sunnybrook.ca/NETS