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

OBJECTIVES

• Review Treatment for Gastrointestinal Neuroendocrine Tumors (GI-NETs)

• Introduction to Peptide Receptor Radionuclide Therapy (PRRT)• Mechanism of Action• Clinical Data• Patient Experience

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)

INCIDENCE OF METASTASES AT TIME OF DIAGNOSIS

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

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

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

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

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)

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

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

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

INITIAL DATA

• Prospective report of 504 patients with GEPNET treated with Lu-DOTATATE• 46% response rate• Survival related to response to therapy

TOXICITY PROFILE

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

NETTER- 1 TRIAL

NETTER- 1 TRIAL

• PFS at 20 months: 65.2% vs. 10.8% (p<0.001)• Interim OS significant• Response rate: 18% vs. 3%

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

CANCER CARE ONTARIO TRIAL: OZM-067

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

CCO STUDY SCHEMA

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

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

CCO STUDY WORKFLOW- INDIVIDUALIZED DOSIMETRY

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

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

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

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

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

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

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

THE SUSAN LESLIE CLINIC FOR NEUROENDOCRINE TUMORS

http://sunnybrook.ca/NETS