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Brief history and current status of sirt agents
- 1. Dr. Madhava B Mallia Radiopharmaceuticals Division, Radiochemistry and Isotope Group Bhabha Atomic Research Centre, Trombay, Mumbai - 400 085, INDIA A Brief History And Current Status Of Selective Internal Radiotherapy (SIRT) Agents
- 2. Scope of this lecture • Introducing various SIRT agents developed during the last seven decades • ―touch upon‖ studies that led to significant improvements in SIRT or the patient selection criteria • Minimum discussion on clinical studies 2
- 3. Some statistics on HCC… • Most common primary liver cancer and second most common cause of death • Fifth most common cancer among men • Ninth most common cancer among women • From 2006 to 2010, rate of liver cancer increased by 3.7% per year in men and 2.9% per year in women • Incident rates are highest in Eastern and South-Eastern Asia 3 Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386) Cancer Facts & Figures 2014. American Cancer Society. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/. Accessed December 13, 201
- 4. Selective Internal Radiation Therapy (SIRT) SIRT is a form of radiation therapy used in interventional radiology to treat cancer. It is generally for those patients with surgically un-resectable cancers, especially hepatic cell carcinoma (HCC) or metastasis to the liver from other cancers. 4
- 5. Why internal radiation therapy and not external... • External radiation therapy – Dose delivered to the tumor is limited by dose received by normal liver – Therefore, therapy ineffective • Internal radiation therapy • High dose of radiation can be selectively delivered to tumor without effecting normal liver tissue 5
- 6. That something which permits SIRT of liver cancer… 6 Tumor Tumor Tumor Feeds blood to tumor lesions • Bierman et al…1951 • Angiographically demonstrated liver tumors received their blood supply through hepatic artery and not portal vein..Origin of the tumor is immaterial…
- 7. 7 Embolization + Delivery of therapeutic radiation dose to liver tumor SIRT Trans Arterial Radioembolization (TARE)
- 8. 8 Hepatic artery Embolized liver tumor
- 9. 9 Radioembolization Microspheres Lipiodol (Poppy seed oil) Poppy seeds
- 10. 10 Image courtesy: google images Radiolabeled microspheres Radiolabeled lipiodol (In-situ formation of Microdroplets) Image courtesy: Yì-Xiáng J. Wáng et al., Chinese Journal of Cancer Research, Vol 27, No 2, 2015. Microdroplets How do they do it: Embolization... Wang EA, Stein JP, Bellavia RJ, Broadwell SR. Treatment options for unresectable HCC with a focus on SIRT with Yttrium-90 resin microspheres. Int J Clin Pract. 2017 Nov;71(11). Typical diameter of end capillary – 8 to 10 um
- 11. Radioisotope of choice… 11 Radioisotop e Half-life Beta energy (Max.) MeV Gamma photon Yttrium-90 64.1 hours 2.28 Nil Rhenium-188 17 hours 2.12 155 keV Holmium-166 26.8 hours 1.77, 1.85 81 keV Iodine-131 8.02 days 0.606 364 keV
- 12. Microsphere based SIRT agents… 12
- 13. The Birth... • Year 1960… • Nolan and Grady… • 76 patients… • 90Y2O3 encapsulated in 50-100 micron metallic particles… • Favorable tumor response: Reduction in size of palpable liver masses… • Leaching of 90Y from the site of injection Myelosupression… 13 (Nolan TR, Grady ED. Intravascular particulate radioisotope therapy; clinical observations of 76 patients with advanced cancer treated with 90-yttrium particles. Am Surg 1969;35: 181–188)
- 14. • Year 1982… • Mantravadi et al… • 15 patients with primary and metastatic liver cancer… • 90Y-microspheres… FINDINGS… • Non-responders Avascular metastatic tumors originating from lungs.. • Responders Hypervascular primary and metastatic tumors… 14
- 15. Important patient selection criteria Hypervasculatiry of tumor 15 (Mantravadi RVP. Intraarterial yttrium 90 in the treatment of hepatic malignancy. Radiology 1982;142:783–786)
- 16. Dawn of 90Y-glass microspheres... • Wollner et al.....1987-88 • Animal studies using 90Y-glass microspheres 16 89Y 89Y89Y 89Y 89Y 89Y 89Y 89Y 90Y 90Y90Y 90Y 90Y 90Y 90Y 90Y (n, )
- 17. • No leaching of 90Y no myelosupression • Dose escalation study in dogs Human dose 100-500 Gy 17 Wollner I, Knutsen C, Smith P, et al. Effects of hepatic arterial yttrium 90 glass microspheres in dogs. Cancer 1988;61:1336–1344. Wollner I, Knutsen C, Ullrich KA, et al. Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs. Cancer Res 1987;47:3285–3290.
- 18. First human studies with 90Y-glass microspheres... • Shepherd et al...1992 • 10 patients with primary HCC 50 Gy – 4 patients; 75 Gy – 2 patients; 100 Gy – 3 patients • No leaching No myelosupression 18 Shepherd FA, Rotstein LE, Houle S, et al. A phase I dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma. Cancer 1992;70:2250– 2254
- 19. • Significance of this study: – Refined the technique of SIRT – provided critical patient selection criteria • excluding patients at risk for extrahepatic shunting • suggested the importance of assessing peritumoral hepatic vasculature. 19
- 20. 90Y-Resin microspheres: SIR-spheres… • Gray BN et al…1989 • 10 patient with metastatic colorectal cancer (mCRC) • Disease stabilization • No leaching No myelosupression 20 Gray BN, Burton MA, Kelleher DK, Anderson J, Klemp P. Selective internal radiation (SIR) therapy for treatment of liver metastases: measurement of response rate. J Surg Oncol. 1989 Nov;42(3):192-196. Several clinical studies available in the literature
- 21. 166Ho-Poly(L-lactic acid)[PLA] microspheres… • Mumper RJ et al…1991 • Biodegradable poly (L-lactic acid) microspheres containing Ho- 165 • 165Ho-microspheres neutron activated in nuclear reactor to obtain 166Ho-microspheres (Emax = 1.84 MeV, half-life = 26.9 hr) 21 Mumper RJ, Ryo UY, Jay M. Neutron-activated holmium-166-poly (L-lactic acid) microspheres: a potential agent for the internal radiation therapy of hepatic tumors. J Nucl Med. 1991 Nov;32(11):2139-43. 165Ho (n, ) 165Ho 165Ho 165Ho 165Ho 165Ho 166Ho 166Ho 166Ho 166Ho 166Ho 166Ho
- 22. • PLA spheres administered via the portal vein in rabbits showed 94.5% retention of the original 166Ho activity in the liver after 6 days. • Recent clinical studies 22 Hepar 1: 15 patient study 166Ho radioembolization is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Main Findings HEPAR 1 study: • 166Ho radioembolization is considered feasible and safe. • Toxicity after 166Ho-radioembolization was mainly confined to fatigue, nausea, vomiting, abdominal pain, fever, and anorexia. •The Maximum Tolerated Radiation Dose was 60 Gy. •The distribution of 166Ho microspheres can be visualized in vivo by both single-photon-emission CT (SPECT) and MRI.
- 23. Hepar 2: 38 patient study Main Findings HEPAR 2 study: • Radioembolization with 166Ho microspheres was efficacious; in 73% of the patients the target lesions showed disease control after 3 months. • Most common adverse events were transient abdominal pain and nausea (18% and 8%). • 166Ho microspheres could be quantified with high accuracy and precision using SPECT 23 …Its different. http://www.terumo-europe.com/en-emea/interventional-oncology/radioembolization/ quiremspheres%C2%AE-microspheres
- 24. 188Re-HSA microspheres... • Wunderlich G et al…2000 • Biodegradable 188Re-HSA microspheres • Size ~25 um • RCP > 90% • Preparation time ~1h • ―preclinical studies in rat showed sufficient in vivo stability‖ • However, no further study reported... 24 Wunderlich G, Pinkert J, Andreeff M, Stintz M, Knapp FF Jr, Kropp J, Franke WG. Preparation and biodistribution of rhenium-188 labeled albumin microspheres B 20: a promising new agent for radiotherapy. Appl Radiat Isot. 2000 Jan;52(1):63-8.
- 25. At present… 25 90Y-Glass microspheres Therasphere® 90Y-resin microspheres SIR-spheres® 166Ho-PLA microspheres QuiremSpheres® Images not to scale…
- 26. A comparison of the three commercial microspheres for SIRT… 26 TheraSphere® SIR-spheres® QuiremSpheres® Microsphere made of Glass; non-biodegradable Resin; non-biodegradable Poly (L-lactic acid); biodegradable Radioisotope 90Y 90Y 166Ho Half-life 64.1 h 64.1 h 26.8 Beta Max. (MeV) 2.28 2.28 1.77 MeV (48.7%) 1.86 MeV (50.0%) Max. range in tissue (mm) 11 11 8.6 Avg. Particle size (um) 22 ± 10 um 32 ± 10 um 30 ± 10 um Mean number of microsphere 1.2 million/3GBq 60 million/3GBq -- FDA approval? Humanitarian device exemption (HDE) Premarket approval (PMA) -- Manufacturer MDS Nordion (Canada) Inc (for BTG International Canada Inc.) Sirtex Medical Limited, Australia Quirem Medical BV (sales by Terumo corporation, Japan) Approximate cost - - --
- 27. HDE Vs PMA... • Humanitarian device exemption (HDE) A product may be designated a humanitarian use device (HUD) eligible for HDE approval if it is intended to benefit patients in the treatment or diagnosis of ―a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.‖ An HDE approval is based on a reasonable assurance of safety and probable benefit — rather than the safety and effectiveness standard for PMA approval 27
- 28. 90Y-SIRT Vs TACE for intermediate stage disease... • Median survival rates similar • Post-embolization syndrome significantly severe with TACE • Considering post-embolization complications and resulting hospitalization, 90Y-SIRT is cost-effective compared to TACE • 90Y-SIRT outperforms TACE with regard to down-staging and quality of life measures 28
- 29. Radiolabeled lipiodol based SIRT agents… 29
- 30. LIPIOCIS® - commercial product by Cisbio International Discontinued? 131I-Lipiodol… 30 First article on 131I-lipiodol (Pub med) Bonadonna G, Chiappa S, Musumeci R, Uslenghi C. Endolymphatic radiotherapy in malignant lymphomas. A clinical evaluation of 285 patients. Cancer. 1968 Oct;22(4):885-98. Effect of intrahepatic arterial infusion of 131I-labelled lipiodol on hepatocellular carcinoma in rat Tsai C, Kusumoto Y, Harada R, Shima M, Nakata K, Kono K, Sato A, Ishii N, Koji T, Nagataki S. Ann Acad Med Singapore. 1986 Oct;15(4):521-4.
- 31. 131I-Lipiodol: Preparation… 31 Lipiodol Contrast agent ~37% Iodine content, w/w 131I-Lipiodol Lo JG, Wang AY, Wei YY, Lui WY, Chi CW, Chan WK. Preparation of [131I]lipiodol as a hepatoma therapeutic agent. Int J Rad Appl Instrum A. 1992 Dec;43(12):1431-5. Brief procedure: Na131I in ethanol heated with 2-5 mL of lipiodol at 80ºC for 20 min followed by heating at 100ºC for another 30 min. RCP - >95% Labeling efficiency – 80 to 97% QC – ITLC/SG using 85% methanol
- 32. Semi-automated module for 131I-Lipiodol preparation… Mukherjee A et al…2017 32 Mukherjee A, Subramanian S, Ambade R, Avhad B, Dash A, Korde A. Development of Semiautomated Module for Preparation of (131)I Labeled Lipiodol for Liver Cancer Therapy. Cancer Biother Radiopharm. 2017 Feb;32(1):33-37. Dose: 2.76 GBq (75 mCi) on reference date Cost per injection: Rs. 40,000/- ($588) Shelf-life: 7 days from date of production
- 33. Issues with 131I-radioisotope… • Long half-life (8 days) • Medium beta energy (0.606 MeV) • High gamma energy (364 keV) Need for isolation of the patient • Commercial availability • Need for a delay tank!! 33
- 35. Available options… 35 • Lee YS, Jeong JM, et al. Nucl Med Commun. 2002; 23(3):237-42. • Paeng JC, Jeong JM, et al. J Nucl Med. 2003 Dec;44(12):2033-8. 188Re-HDD/Lipiodol 188Re-SSS/Lipiodol •Nicolas Lepareur et al., Nuclear Medicine Communications 2004, 25:1007–1013 188ReN-DEDC/Lipiodol •Boschi A, Uccelli L et al. Nucl Med Commun. 2004;25(7):691-9.
- 36. Lee Y S et al…2002 36 188Re-HDD/Lipiodol… AHDD kit 188Re-HDD/Lipiodol Lee YS, Jeong JM, Kim YJ, Chung JW, Park JH, Suh YG, Lee DS, Chung JK, Lee MC. Synthesis of 188 Re-labelled long chain alkyl diaminedithiol for therapy of liver cancer. Nucl Med Commun. 2002 Mar;23(3):237-42.
- 37. • Nicolas Lipareur et al…2004 37 188Re-SSS/Lipiodol... Kit 1 Kit 2 188Re-SSS/Lipiodol Nicolas Lepareur et al., Nuclear Medicine Communications 2004, 25:1007–1013 Labeling efficiency Final Yield 188Re-SSS/Lipiodol 97.3 ±2.1%. 87% ± 9.1
- 38. Automated module for 188Re-SSS/Lipiodol... 38 Lepareur N, Ardisson V, Noiret N, Boucher E, Raoul JL, Clément B, Garin E. Automation of labelling of Lipiodol with high-activity generator-produced 188Re. Appl Radiat Isot. 2011 Feb;69(2):426-30. TADDEO module (Comecer) The flip side.... Overall yield (Manual preparation) - 87% ± 9.1 Overall yield (Automated module) - 52.6% ± 9.6
- 39. 188ReN-DEDC/Lipiodol... Boschi A et al…2004 39 188ReN-DEDC complex Kit 1 Kit 2 188ReN-DEDC/Lipiodol Boschi A, Uccelli L, Duatti A, Colamussi P, Cittanti C, Filice A, Rose AH, Martindale AA, Claringbold PG, Kearney D, Galeotti R, Turner JH, Giganti M. A kit formulation for the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma. Nucl Med Commun. 2004 Jul;25(7):691-9. Erratum in: Nucl Med Commun. 2004 Sep;25(9):983. Labeling efficiency Final Yield 188ReN-DEDC/Lipiodol 97% ± 2 96% ± 3
- 40. The flip side.... Overall yield (Manual preparation) - 96% ± 3 Overall yield (Automated module) - 58% ± 3.6 40 Automated module for 188ReN-DEDC/Lipiodol…
- 41. 188Re-EDTB-Lipiodol... • EDTB - N,N,N',N'-tetrakis(2-benzymidazoylmethyl)- 1,2- ethanediamine • EDTB can complex with rhenium-188 41 Ligand synthesis difficult; radiolabeling complicated... Wang SJ, Lin WY, Chen MN, Hsieh BT, Shen LH, Tsai ZT, Ting G, Knapp FF Jr. Radiolabelling of Lipiodol with generator-produced 188Re for hepatic tumor therapy. Appl Radiat Isot. 1996 Mar;47(3):267-71.
- 42. All options: Quick glance… 42 90Y-Glass microspheres Therasphere® 90Y-resin microspheres SIR-spheres® 166Ho-PLA microspheres QuiremSpheres® Images not to scale… 188ReN-DEDC/Lipiodol188Re-SSS/Lipiodol188Re-HDD/Lipiodol 131I-Lipiodol
- 43. THANK YOU... 43