SBRT and hypofractionated RT for HCC patients with varying degrees of hepatic impairment

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1 SBRT and hypofractionated RT for HCC patients with varying degrees of hepatic impairment Nima Nabavizadeh, MD Assistant Professor Division Leader Hematologic Malignancies Co-division Leader Gastrointestinal Malignancies Department of Radiation Medicine Oregon Health & Science University

2 Disclosures Disclosure I have a financial arrangement with RadOnc Questions, LLC Section editor for lymphoma and skin malignancies for online question bank RadOnc Questions

3 Cooperation between multiple specialties Livers tumors represent an ultimate paradigm of multidisclipinary care Internists/Hepatologists Medical oncologists Surgical oncologists Transplant surgeons Diagnostic and interventional radiology Radiation oncology Optimal plan requires a common language between specialities

4 Liver (dys)function scoring ALBI= (log(bilirubin)*0.66)+(albumin*-0.085) Johnson, JCO, 2014.

5 BCLC staging

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8 Liver directed therapies Surgical resection (most not candidates) Anatomic resection Wedge Liver transplant Radiation therapy SBRT Particle radiotherapy Whole liver radiation (palliative) Interventional radiology Intra-arterial therapies IA chemo TACE Radio-embolization (Y90) Thermal Ablation Radiofrequency ablation (RFA) Microwave ablation

9 Ablative Treatments When tumors are localized, focal highly ablative treatments are preferred as they minimize risk of collateral damage in an already diseased liver Radiofrequency ablation (RFA) Stereotactic body radiation therapy (SBRT) No randomized evidence comparing these two modalities

10 Historical RT techniques Limited role of radiation therapy for hepatic malignancies historically Large treatment fields (frequently whole liver) to account for early limitations in imaging and tx delivery Classic radiation-induced liver disease Triad of anicteric hepatomegaly, ascites and elevated alk phos out of proportion to transaminitis and bilirubinemia which occurs 2 weeks to 4 months post RT Pathologically: veno-occlusive injury with fibrin deposition in central veins Incidence up to 44% among patients treated with doses greater than 35 Gy Abandonment of RT on the basis of early studies deeming whole liver RT unsafe at low doses Ingold, ATRNM, 1965.

11 Stereotactic body radiation therapy (SBRT) Delivers high-doses of RT in a small number of treatments with high precision Several technological advances were necessary before SBRT could be applied safely Accounting of liver motion (4DCT, abdominal compression, ABC) Pre-treatment imageguidance to ensure lesion stability and avoidance of critical structures Delivery of highly conformal radiation (3D-CRT, IMRT and VMAT, particle therapy)

12 Tanguturi, Oncologist, 2014.

13 TACE prior to SBRT (or RFA) Commonplace at OHSU since 2007 Benefits Ability to perform angiogram prior to ablative therapies to rule out hepatomas not evident on volumetric imaging Lipiodol (iodized poppyseed oil) is retained within hepatomas lacking phagocytic Kuppfer cells tumor is stained allowing daily image guidance Possible synergy with combination approach Most TACE failures are at periphery where ischemic effects are attenuated by collataterals RT most effective at welloxygenated periphery

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17 OHSU HCC radiotherapy experience The safety of RT for patients with the greatest degree of hepatic dysfunction (CP-B8+) is largely unreported with only a handful of patients distributed among multiple publications Report of toxicities and outcomes for 146 patients with CP A/B/C cirrhosis treated with definitive or bridge-to-transplant intent at OHSU between SBRT: 50 Gy in 5 fractions QOD (n=110) or AHRT: 45 Gy in 18 fractions daily (n=41) AHRT provided independent of baseline liver functionality and typically for lesions > 6 cm or lesions in close proximity to bowel Median followup of 23 months (1-59 mo) Primary toxicity endpoint of increase of CP > 2 WITHIN 6 months following RT Of note, extremely difficult to discern treatment related toxicities from natural progression of HCC or cirrhosis Placebo arm of SHARP trial (sorafenib RCT) had 52% rate of serious AEs Patients were divided into clinically better compensated (CP-A/B7) and decompensated (CP-B8+) groups a priori Nabavizadeh, IJROBP, 2017, in press.

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19 RT treatment characteristics

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21 ALBI change after RT

22 Predictors of toxicity Nabavizadeh, conditionally accepted to IJROBP.

23 HCC meta-analysis 2014 AAPM meta-analysis presented at ASTRO 2014, results unpublished 13 papers that met inclusion criteria, 771 lesions treated with SBRT (394 HCC, 37 CCA, 290 metastases) Doses ranged from Gy in 1-5 fractions Median BED of 88 Gy 10, IQR: Gy local failures SBRT for primary liver tumors provides high rates of durable local control, with no evidence of dose-response relationship Ohri, ASTRO, 2014.

24 Local control and BED

25 OHSU fractionation scheme SBRT: 50 Gy in 5 fractions: BED of 100 Gy 10 AHRT: 45 Gy in 18 fractions: BED of Gy 10 At OHSU, AHRT Rxed for lesions > 5-6 cm, or lesions in near proximity to endoluminal organs Excluding lesions > 5.5 cm in AHRT group SBRT vs. AHRT 1 yr LC: 95% vs. 71% Nabavizadeh, conditionally accepted to IJROBP.

26 OHSU Liver SBRT experience Tolerability of RT as measured by CP score decline of 2 or more within 6 months was similar across all baseline liver functionality groups Careful not to over-generalize as our cohort of selected patients had small PTV sizes, minimal portal vein invasion and low mean liver doses (albeit heavily pre-treated with TACE) One and two year LC rates excellent for SBRT (95%), AHRT associated with inferior control OHSU practice paradigm has changed to now offer dosereduced SBRT (~30 Gy in 5 fx) rather than hypofractionated RT for lesions in close proximity to bowel

27 If ablative options are being considered No randomized evidence for RFA vs. SBRT, go to tumor board and have a VOICE!!! At OHSU in 2017, SBRT is favored over RFA when: Lesion at the liver dome or near a major vessel When general anesthesia is too high risk Bleeding risk due to thrombocytopenia from liver disease As a bridge to transplant for those whose liver functionality preclude trans-arterial or percutaneous approaches (T bili ~3) More prospective data needed regarding safety and efficacy of SBRT for patients with low volume HCC and advanced background liver dysfunction

28 Charles Thomas Martin Fuss Joseph Waller Arthur Hung David Elliott Robbie Fain Yiyi Chen Catherine Degnin James Tanyi Brandon Mullins Ishan Patel Brandon Dyer Acknowledgements