A presentation on Selective Internal Radiation therapy for liver cancer

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

34. Rhenium-188/lipiodol SIRT agents…
34

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