1. Endocrinology Unit Pathophysiology Department Laikon General Hospital Case Presentation: Dr. Chatzellis Eleftherios MD Intern in Endocrinology

2.  58 year old male patient  2001: abdominal pain  CT scan:5cm tumor pancreatic tail Multiple focal lesions in the liver  FNAB (liver lesion)  Well Differentiated NEN grade 2 (ki67 = 4%)  CgA = 5,2 nmol/l (<4), other markers negative  No secretory symptoms (non-functioning pNEN)  SRS (Octreoscan): avid uptake (Krenning score = 3) in both primary pNEN and liver metastases

3. Chromogranin A ki67 H&E stain

4.  Sweden (Uppsala)  Suggested surgery to reduce tumor burden and local complications  Patient refused  Chemotherapy (Streptozotocin + 5-FU) + Somatostatin analogues (SSA’s)  1 year later (2002): DISEASE PROGRESSION (PD)  Addition of pegylated INF-a  Chemotherapy was discontinued after 2,5 years (mild renal impairment)  2002-2005 : STABLE DISEASE (SD)  CgA = 10,5 nmol/l (<4)

5.  2006: Hypercalcemia occurred for the first time Ca = 11,8 mg/dl (8,5 - 10,1) Ca = 11,8 mg/dl (8,5 - 10,1) P = 1,98 mg/dl (2,5 - 4,5) P = 1,98 mg/dl (2,5 - 4,5) PTH = 2,54 pg/ml (10 - 65) PTH = 2,54 pg/ml (10 - 65) PTHrP = 84 pmol/l (<2) PTHrP = 84 pmol/l (<2) CgA = 45 nmol/l (<4) CgA = 45 nmol/l (<4)  Imaging: DISEASE PROGRESSION (PD)  Increased SSA’s dosage [+peg-INFa]  Normalization Ca  2006-2008: STABLE DISEASE (SD) - Biochemical control Humoral Malignancy-associated Hypercalcemia (PTHrP- related)

6.  2008: peg-INFa discontinued (depression)  2008: Hypercalcemia (12,9 mg/dl) + DISEASE PROGRESSION (PD)  2008-2009: 177 Lu-DOTATATE x5 cycles (25.6 GBq)  Increased SSA’s dosage  Addition of pasireotide 1200μg bid   Ca = 10,7 mg/dl, CgA=115 nmol/l, PTHrP=140 pmol/l  2009: DISEASE PROGRESSION (PD) + biochemical relapse (Ca = 11,8 mg/dl)

7.  + Temozolomide + Capecitabine (CAP-TEM)  2009-2010: STABLE DISEASE (SD)  Biochemical control of Ca required additional treatment: SOM230 and SSA’s SOM230 and SSA’s Forced Diuresis Forced Diuresis Prednisolone 40mg/d Prednisolone 40mg/d Biphosphonates (i.v. zolendronate 4mg monthly) Biphosphonates (i.v. zolendronate 4mg monthly) Cinacalcet 90mg/d] Cinacalcet 90mg/d]  SIDE-EFFECTS: Proximal myopathy - muscle atrophy, patient immobilization (wheel chair), severe Diabetes Mellitus (~100 IU insulin/d)

8.  Tumor burden reduction (cytoreduction) necessary Biochemical control (Ca) Biochemical control (Ca) Reduce treatment side-effects Reduce treatment side-effects  OPTIONS: SurgeryPatient still denied SurgeryPatient still denied PRRTAlready performed (GFR, marrow toxicity) PRRTAlready performed (GFR, marrow toxicity) RF AblationNot applicable due to large liver lesions RF AblationNot applicable due to large liver lesions Embolization (TAE/TACE) Embolization (TAE/TACE)  Pre-embolization evaluation : Portal vein thrombosis  Selective approach (embolization of small branches of hepatic artery)

9. Pre-embolizationPost-embolization

10. Post-embolization status  TMZ + Capecitabine  SSA’s  Pasireotide 1200mcg/d  Prednisolone 40 mg/d  Zolendronate 4mg/m  Insulin treatment Ca = 10,2 mg/dl CgA = 50 nmol/l PTHrP = 38 pmol/l  TMZ + Capecitabine  SSA’s at ½ dosage  X  Prednisolone 8 mg/d  X

11.  6 months after TAE  Ca = 13,2 mg/dl  DISEASE PROGRESSION (PD)  Painful lump on left thigh T1 T2

12. Bone scintigraphy Tc 99m

13.  BONE METASTASES vs BENIGN LESION  Bone Biopsy  Brown tumor (in the context of prolonged PTHrP action on bone)  New liver lesion biopsy  ki67 = 4%, IHC (+) for PTHrP PTHrP ImmunohistochemistryH&E stain Bone biopsy Liver metastases biopsy

14.  Temozolomide (200mg/m 2 Days 1-5 q4w) + Bevacizumab (10 mg/kg q2w) + Everolimus (10mg/d)  [+SSA’s]  Ca = 8,8 mg/dl  Temozolomide and Bevacizumab D/C after 6 months due to thrombocytopenia  2010-2012: STABLE DISEASE (SD)

15.  2012: DISEASE PROGRESSION (PD)  Ca=9,34 mg/dl, PTHrP = 50 pmol/l  Sunitinib 37,5 mg/d [+SSA’s]  6 months later: Ca = 6,5 mg/dl !!!  2012-2014: STABLE DISEASE (SD) April 2014: Patient deceased † (hepatic encephalopathy - malnutrition)

16. 200520012006 20082009 2010 2012 2014 SSA’s STZ+5FU Pegylated INFa PRRT Pasireotide EverolimusSunitinib Embolization PD PDPDPD CAP-TEM PDPD BEV-TEM PTHrP Ca CgA †

17.  WD pNEN grade 2 Stage IV (liver metastases)  Change of functional status during disease course  Rare PTHrP secretion (paraneoplastic syndrome)  Even more rare: brown tumor due to PTHrP  Employment of several treatment agents/modalities to achieve both tumoral and biochemical control  Importance of cytoreductive interventions and novel molecular targeted therapies in controlling secretory symptoms/syndrome  Long survival despite metastatic disease at presentation (application of different therapeutic modalities)

18. James Yao, ENETS 2014