Microsphere cold kit for Selective Intra-arterial Radionuclide Therapy (SIRT) Dr. Jaya Shukla Additional Professor, PGIMER, Chandigarh The product is for the treatment of large/ unresectable liver cancer And is ready to commercialize

Provide cost effective treatment of liver cancer Vision Current issue More than 8.4 lakh new cases of liver cancer in 2018 across the world*, more than 50,000 new cases diagnosed in India Due to lack of symptoms, patients often present with advanced stage Surgery are not possible due to size, location and spread of tumor Available options are expensive Proposed solution Provide cost effective treatment of liver cancer *Source: American Institute for Cancer Research

Proposed solution: Value Proposition Y-90 Sirtex/Therespheres Commercially available, ready to use Y-90 is for therapy only Dose estimation not possible. Separate procedure is required Particulate Two day procedure Large sized particles (20-30 µm) may cause delivery reflux Stable Product cost: Highly expensive (lakhs) Re-188 lipiodol Re-188 Microspheres Non-radioactive microsphere kit Can determine dosage quantity to minimize peripheral organ damage Labelling yield is ≥90% Small size particles (~5 µm) – easy to deliver, no reflux Single day procedure Very stable Product cost: 1% of Y-90 Spheres Commercially available nonparticulate non-radioactive kit Labelling yield is 50-60 % Non-particulate Not very stable, i.e. may leave from liver, excretes with urine Product cost: Relatively less expensive) Ref: RSNA 2005; 25:41-55 Ref: J Nucl Med 2005; 46:1326-1332 Ref: Clin Nucl Med. 2019;44: e93–5

Product features Market ready Patent pending Easy to prepare – mix & use Freeze dried Shelf life more than 1 year Easy to administer due to smaller size Product features

Appendix

Therapy Liver has dual blood supply Hepatic artery and portal vein Normal liver gets 80% of blood supply from portal vein and 20% from hepatic artery However, Liver cancer gets 80% blood supply from hepatic artery and 20% by portal vein Dual blood supply property is exploited to deliver radioactive compounds through hepatic artery Trans-arterial delivery of treatment Tumor also form collaterals and communicates with adjacent organs For radiation delivery, pretherapy assessment is important and done using γ emission Radioactive microspheres delivered to tumor results in effective tumor damage, while limiting the radiation injury to the normal liver

Radio isotopes Rhenium-188 (Re-188) Yttrium-90 (Y-90) Obtained from transportable W-188/Re-188 generator Produced from decay of the reactor-produced W-188 parent (T1/2-69 days) Re-188 is a high energy beta-emitting radioisotope Βmax: 2.12 MeV, γ: 155 keV T1/2: 16.9 hrs Decays to Os-188 Shelf-life: 6 months Cost effective Yttrium-90 (Y-90) Cyclotron produced Y-90 is a pure β emitter Pretherapy assessment not possible βmax-2.2Mev, T1/2-64 h, No gamma (γ) photons for imaging costly

Mix & use non-radioactive kit A lyophilized kit has been developed Kits are stable up to one year Tc-99m or Re-188 is incorporated into the reconstituted microspheres by heating at 100 °C for 30 min Free Re-188 is separated by 5 min centrifugation post labeling Radiolabeling yield is above 90% Radiochemical purity is above 99% Stability after radiolabellig is studied up to 96 h

Patients Study Protocol A informed written consent from patient and attendant Trans-arterial catheter is placed by interventional radiologist Scout dose (111-185 MBq) 188Re-Microspheres (Pellet) + Req. vol. of contrast Lipiodol may be added to visualize delivery of microspheres Image at 140 keV/155 keV photo peak (±20% window) Anterior and posterior whole body/3-min static chest , SPECT/CT Chest (optional) Geometric means of counts in the liver, Lung, spleen & tumor Calculation of lung shunt Administer dose; WB Image at 24 and 48 hr and SPECT/CT Chest at 24 hr/48 hr Just before therapy: 55Y/F, HCV related cirrhosis, HCC BCLC-C Left lobe-13.8x9.8x8.4 cm, left branch PVT 3.5 mCi Re-188 microspheres were administered for lung shunt study Geometric means (GM) of Lung, liver +spleen counts are calculated lung shunt = GM lungs GM lung + liver + spleen x 100 = 16%

Distribution of microspheres To observe gastro-dudonal reflex Abdomen SPECT/CT To observe Lung shunt Lung SPECT/CT Note: good localization in tumor is abserved. No gastro-dudonal reflex and no lung activity is noted

Re-188 microsphere SIRT (D) (E) (F) (G) (A) (C) (B) Patient underwent selective internal radiation therapy (SIRT) using indigenously prepared Re-188-microspheres (80 mCi), (A) shunt calculation-Tc-99m-microsphere (1.5%); (B) whole body image 24hr post SIRT; (C) SPECT/CT at 24 h post SIRT; (D) and (E) Ga-68-DOTATATE pre therapy PET/CT and CT; (F) and (G) PET/CT and CT; after 6 months of SIRT treatment showing complete disappearance of the liver lesion. Patient is surviving after more than 1.5 year post SIRT

Publications Shukla J, Kalra N, Kumar R, Bhusari P, Chhabra A, Parmar M, Vatsa R, Singh H, Duseja a, mittal BR. Two cases of Rhenium-188 microspheres for inoperable hepatocellular carcinoma. Clin Nucl Med, 2019;44: e93–5. DOI-10.1097/RLU.0000000000002373 (IF-6.309). .Vadi SK, Mittal BR, Kumar R, Parihar AS, Shukla J, Kalra N. Demonstration of treatment response to trans-arterial radio-embolization (TARE) on 68Ga-DOTANOC PET/CT in a patient with metastatic neuroendocrine tumor. Clinical Nuclear Medicine 43 (9), e312-e313. doi: 10.1097/RLU.0000000000002177 (IF-6.309). Shukla J, Kalra N,  Bhusari P,  Vatsa R, Duseja A, Dhiman R, Mittal BR, Agrawal K. 188Re-microspheres for selective intra-arterial radionuclide therapy (SIRT) in patients with HCC: Feasibility study. J Nucl Med 2015 56:1242. Patents: Indian: 201811015874 Published International: PCT/IN2019/050304