Newer Radionuclide Therapies Dr. Sandip Basu Radiation Medicine Center (BARC) Tata Memorial Centre Annexe, Parel, Mumbai NICSTAR-2018 5 th -7 th March, 2018
A. Receptor over-expression in Tumors as Target: 2 recent success stories Prostate Cancer PSMA: Prostate-specific membrane antigen Neuroendocrine Tumor Somatostatin Receptor B. Bone Targeted Therapies (Skeletal Metastasis): Chemi-adsorption of 177 Lu-EDTMP (complex of Lu & ethylenediaminetetramethylenephosphonate) on the surface of newly formed calcium hydroxyapatite crystals [Ca 10 (PO 4 ) 6 (OH) 2 ]
Radiopharmaceutical Agent Production of 177 Lu in Research Reactor Lu-176 (2.6% nat, enriched) Direct Route (n, g) σ = 2090 b & 2.8 b Lu-177 6.65 d + Lu-177m 160.5 d β- Indirect Route Yb-176 (12.7% nat, enriched) (n, g) σ = 2.85 b Yb-177 1.9 h Lutetium (Atomic number 71) is the last element in lanthanide series, and traditionally counted among the rare earths.
The structure of prostate-specific membrane antigen (PSMA), its binding sites for PSMA ligands and the most frequently used antibodies Prostate specific membrane antigen (PSMA), a type II transmembrane protein expressed in all types of prostatic tissue (but demonstrates 100-fold to 1,000-fold overexpression on the cell membrane of prostate cancer cells). PSMA expression increases progressively in higher-grade cancers, metastatic disease and castration-resistant prostate cancer (CRPC) Urea-based small-molecule PSMA inhibitors have produced most promising results. Glu- NH-CO-NH-Lys(Ahx)-HBED-CC ( 68 Ga- PSMA-HBED-CC) Maurer, T. et al. (2016) Current use of PSMA PET in prostate cancer management Nat. Rev. Urol. doi:10.1038/nrurol.2016.26 PSMA-DKFZ-617, has been used for both imaging ( 68 Ga) and molecular radiotherapy (labeled with 177 Lu).
PSMA/MR guided Prostatic Biopsy 68 Ga-PSMA PET MRI of a 50-year-old patient who had a rising serum PSA value (16 ng/ml at imaging) and two tumour-negative previous biopsy samples T2-weighted image showing a hypointense mass in the anterior fibromuscular stroma with pronounced arterial enhancement. b Typical pronounced arterial contrast enhancement compared with the surrounding tissue. c Intensity curve of the dynamic contrast enhanced sequence shows a typical fast washin followed by washout in the late phase. d Diffusionweighted imaging demonstrates markedly restricted diffusion. e PET image and f fused PET MRI showing intense prostate-specific membrane antigen (PSMA) expression in the corresponding region. Targeted PET MRI fusion biopsy revealed prostate cancer with Gleason score 7 in this region.
68 Ga-PSMA PET CT in better staging in patient of Prostate Ca 68 Ga-PSMA PET CT of a 52-year-old patient with primary prostate cancer (serum PSA value of 19 ng/ml and Gleason score 7 at biopsy) 68 Ga-PSMA PET CT of a 52-year-old patient with primary prostate cancer (serum PSA value of 19 ng/ml and Gleason score 7 at biopsy). a Contrast enhanced CT shows a small lymph node (6 mm) adjacent to the right internal iliac artery. b PET and c fused PET CT images demonstrate intense prostate-specific membrane antigen (PSMA) expression in this lymph node. Radical prostatectomy and lymphadenectomy revealed a lymph node metastasis in the corresponding template field. Maurer, T. et al. (2016) Current use of PSMA PET in prostate cancer management Nat. Rev. Urol. doi:10.1038/nrurol.2016.26
Imaging of 65-year-old patient with prostate cancer and diffuse bone metastases Imaging of 65-year-old patient with prostate cancer and diffuse bone metastases. a Bone scintigraphy demonstrates multiple bone metastases predominantly in the pelvis and ribs. b Corresponding maximum-intensity projection of 68 Ga-PSMA PET shows considerably more bone metastases than bone scintigraphy.
70-y-old patient with PSMA-avid lymph node metastases on 68Ga-PSMA PET/CT before therapy (A) and on 177Lu-PSMA scintigraphy after first PSMA RLT (B), with remarkable reduction in uptake after second PSMA RLT (C). Richard P. Baum et al. J Nucl Med 2016;57:1006-1013
68 Ga/ 177 Lu Theranostic pair of Radiopharmaceuticals for prostate cancer 68 Ga-PSMA PET/CT Scan started on a regular basis in RMC after RPC approval in April 2017 177 Lu-PSMA Therapy in Metastatic Castrate Resistant Prostate Carcinoma (mcrpc) 68 Ga-PSMA PET-CT in a patient of metastatic Prostate Carcinoma with raised serum PSA level 177 Lu-PSMA in a patient of metastatic prostate carcinoma 10
Known case of metastatic cancer of prostate with bony pain, patient received 177Lu PSMA therapy and subsequently 68Ga PSMA scan show resolution of bony lesion with significant symptomatic improvement 68 Ga PSMA scan 177 Lu PSMA Post Therapy scan 68 Ga PSMA scan August 2017 Nov 2017
SST and SSTR: Neuroendocrine Tumors Both SS 14 and SS 28 have biological activity, and they have a tissue-specific distribution with a relative dominance of SS 14 in the pancreas and stomach and of SS 28 in the intestine Five subtypes of SSTRs, 1-5, G protein-coupled receptors SSTRs, have been cloned. Of practical importance is the division of the five receptor subtypes into two groups, where SSTRs 2, 3, and 5 differ from SSTRs 1 and 4 regarding amino acid homology and pharmacological profile.
SST and Analogues
68Ga-DOTA-TOC/NOC/TATE and 177Lu- DOTATATE: Why Octreotide? The clinical use of SST is limited because it has a short half-life (about 2 minutes) in plasma. Octreotide is an octapeptide that mimics natural somatostatin (The biological activity of S-14 and S-28 resides in the cyclic region of the mature peptide. The F-W-K-T portion of the ring structure is required for receptor occupancy): absorbed quickly and completely after subcutaneous application. Maximal plasma concentration is reached after 30 minutes. The elimination half-life is 100 minutes (1.7 hours) on average when applied subcutaneously. Octreotide has its highest affinity to SSTR 2 and lower affinity to SSTRs 3 and 5, while SS 14 and SS 28 bind to all subtypes with high affinity
Science behind Radioligand Used: [177 Lu-DOTA 0,Tyr] Octreotate Octreotate: differs from octreotide only in that the C- terminal threoninol (corresponding amino alcohol) is replaced with threonine. Nine-fold increase in affinity for the SSTR 2 for [DOTA 0,Tyr 3 ]octreotate when compared with [DOTA 0,Tyr 3 ]octreotide Translates into 6-to 7-fold increase in affinity for their Radiolabeled counterparts and 4-5 times enhancement in the tumor uptake
PRRT: A somatostatin receptor based targeted radionuclide therapy The goal of targeted radionuclide therapy is to selectively deliver radiation to cancer cells and/or diseased tissue with minimal toxicity to surrounding normal tissues. The basis for successful radionuclide therapy is a theranostic approach that integrates diagnostic testing for the presence of a molecular target for which a specific treatment/drug is intended Krenning Scoring: A decision making step (Score 1-4)
The range of tumors where PRRT employed NET : Gastroenteropancreatic and Pulmonary Medullary thyroid carcinoma: Preferred compared to Vandetinib Merkel Cell carcinoma, Thymic NETs Non-iodine concentrating metastasis of DTC Pheochromocytomas, Paraganglioma, Neuroblastoma
68 Ga-DOTATATE PET/CT in Metastatic NET of Unknown Primary (CUP- NETs) 56 years old female, liver biopsy suggestive of metastatic NET of liver, Mib 1 index: <1%. The primary was undetected by conventional imaging. 68-Ga-DOTATATE PET/CT scan showing multiple metastatic liver lesions and a focal tracer concentration in the pelvic ileum. Final diagnosis: Ileal NET with bilobar hepatic metastases.
SPECT and PET-CT agents Somatostatin Receptor Based Imaging: Significant Advances towards Management of NET Glucose Metabolism Based FDG-PET/CT Gamma Camera Based Planar and SPECT imaging PET-CT Based Imaging 111 In- Pentetreotide 99m Tc- HYNIC-TOC 68Ga-DOTA- TOC/NOC/TATE Decision Making Scan Options for 177Lu-DOTATATE PRRT/Chemotherapy
68 Ga DOTATATE PET 99m Tc HYNIC- TOC SPECT 177 Lu DOTATATE post therapy SPECT Gratifying Experience with BARC produced Indigenous 99m Tc- HYNIC-TOC
Gratifying PRRT Results over last 7 years 70 year old male, NET of body and tail of pancreas with hepatic metastasis, HPR 10-12%, no surgical intervention Baseline After 3 cycles 68 Ga-DOTATATE PET-CT FDG PET-CT
53/F, diagnosed as a case of atypical carcinoid of lung (MiB1 index of 6-10%.), MiB 1 index of 6-10%. Multiple SSTR positive lesions in liver, both lungs, multiple rib & right sided pelvis. received 3 cycles of chemotherapy with cisplatin and etoposide Reported a dramatic decrease in symptoms which includes decrease in abdominal pain and frequency of diarrhea. Also patient reports weight gain and overall improvement in general condition. Received 2 # of PRRT and being worked up for the 3 rd. Before 1 st PRRT Before 3 rd PRRT Timing of Test Ser CgA (ng/ml) Before 1 st PRRT 496.7 After 1 st PRRT and before 2 nd PRRT 243.1
Well-differentiated and moderately differentiated neuroendocrine carcinomas defined as NET grade 1 or 2 according to the WHO 2010 classification (i.e. upto 20%) Eur J Nucl Med Mol Imaging. 2013 May;40(5):800-16.
Pre-1 st cycle PRRT Pre-2 nd cycle PRRT 26 /M, Bleeding PR, anorectal polyp excision in March 2013: HPR : High grade rectal NET with MiB 1 index of 22%. Took 5 inj of Long acting Octreotide injections. After the 5th injection started complaining of abdominal pain and flushing. 68-Ga DOTATOC scan showed multiple SSTR positive lesions in liver and pre sacral nodes. Seg III, Seg IV B (SUVmax : 39.7), Seg VI and Seg VIII (SUVmax : 26.3). Presacral node at S1 (SUVmax : 45.6), 2 presacral node at 4 (SUVmax : 48.9 larger and smaller is 22.5). Patient was treated with 166 mci of 177-Lu based PRRT. Follow up 68-Ga DOTATOC scan shows complete resolution of lesions in Seg III and VI (no documented lesion on CT). Other SSTR positive lesions in liver and in pre sacral area have decreased in metabolic intensity. Seg IV B (SUVmax : 24.9), Seg VIII (SUVmax : 25), Presacral node at S1 (SUVmax : 32.9), 2 presacral node at 4 (SUVmax : 5.9 larger and smaller is 16.8) Patient has overall reported a dramatic response with total resolution of the abdominal pain and episodes of flushing. Subsequently patient again received 2 more cycles of PRRT with the scan findings being now almost same with progressive decrease in the serum chromogranin A
ESMO Clinical Practice Guidelines for GEP-NETs Treatment algorithm. Öberg K et al. Ann Oncol
61/M, Post Whipple s (Primary- Head and Proximal Body of Pancreas); Biopsy- Poorly diff NE Ca; MiB1---20%; FDG-PET/CT: Total Discordance; CgA: 125.01 93.47; with excellent symptomatic response Somatostatin Receptor Imaging 18F-FDG PET CT Following 60 months after the 1 st therapy the patient is alive, progression free and asymptomatic. Sunil Walke
PRRT Beyond Neuroendocrine Tumors: Recurrent Skull-Base Phosphaturic Mesenchymal Tumor Causing Osteomalacia 53/F, vitamin D resistant hypophosphataemic osteomalacia: bilateral groin pain and difficulty in walking. Low serum phosphorus level & High serum fibroblast growth factor 23 (FGF23) [(725 RU/ml; reference range: < or =180 RU/mL)] 177Lu-DOTATATE
Selective Internal Radiation Therapy with Transarterial Radioembolization for Advanced Liver Cancer Patients with unresectable intermediate stage Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC). Special emphasis in patients with portal vein thrombosis (PVT), a relative contraindication to TACE. Other Indications: Cholangiocarcinoma and some metastases (colorectal cancers, NET, breast, lung, etc.) Radiopharmaceuticals: 90 Y products are commercially available: TheraSphere glass microspheres (BTG, London, United Kingdom) and (Sirtex Medical, North Sydney, Australia) SIR-Spheres resin microspheres 131 I/ 188 Re-LIPIODOL: Both are important cost-effective alternative important in Indian settings
Radioembolization for the treatment of hepatocellular carcinoma: example of efficacy CT scan shows 13cm sized well-demarcated hypervascular tumor (arrows) in liver S4/8. (B) MR image 1 month after two sessions of TARE shows no enhancement of tumor (arrows). Note shrinkage of tumor to 7cm
177 Lu/ 153 Sm-EDTMP in Metastatic Bone Pain Palliation Suitable decay characteristics of 177 Lu compared to 153 Sm: [T(1/2) = 6.73 d, E((max)) = 497 kev, E(γ) = 113 kev (6.4%), 208 kev (11%)] In patients with breast cancer and hormone refractory prostate cancer with skeletal metastases
Tc-99m MDP Bone Scan and Post Therapy 177 Lu-EDTMP Scan Tc-99m MDP Bone Scan (Left panel) and Post Therapy 177 Lu-EDTMP Scan (right panel) of a 69 yr old male, known case of adenocarcinoma of prostate (Gleason s score 9) (operated primary) presented with multiple painful skeletal metastases. Patient was on oral NSAIDS thrice a day (analgesic score 3) and had already received RT to pelvis 6 months back. Pre-therapy parameters were: VAS- 9, BAP- 109.6, EORTC- 68, Karnofsky- 80 and ECOG- 2. Corresponding post 177 Lu-EDTMP therapy value were: VAS- 4, BAP- 87, EORTC- 40, Karnofsky- 80 and ECOG- 1. Post therapy analgesic score was zero.
9 8 7 6 5 4 Lu177-EDTMP Sm153-EDTMP 3 2 1 0 Pretherapy Week 4 Week 8 Week 12 Mean VAS pain score in responders treated with 153 Sm-EDTMP and 177 Lu-EDTMP
Graph demonstrating bone alkaline phosphatase (BAP) parameters in responders 60 50 40 30 20 Lu177-EDTMP Sm153-EDTMP 10 0 Pretherapy Posttherapy
Acknowledgement to the Radiopharmaceutical Scientists, Technologists & Physicians