soramic newsletter no. 1 / 2015

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1 Page 1 Message from the PIs Dear colleagues and friends; esteemed members of the SORAMIC study group, This newsletter is specifically dedicated to the prevention and treatment of radioembolization induced liver disease. Since most of the patients in the palliative arm of SORAMIC do suffer from underlying liver dysfunction, preventing RILD as a result of the Y90 exposure is of great benefit to our patients. Max Seidensticker, from the Magdeburg study group, published an article describing a preventive (and possibly therapeutic) effect of a drug combination of pentoxifylline, ursodeoxycholic acid and low molecular weight heparin in a human liver radiation model, which probably can be applied to the effects of Y90-radioembolization as well. In this newsletter you will find a brief description of these findings and you will find the respective publication attached to the same as this newsletter. In case of suspected RILD/REILD, or in patients at risk (e.g. large tumor load, borderline liver function, etc.), you may want to consider the described drug combination on an individual basis. Thanks to all of you for your continuous support in SORAMIC! The 300th patient will be randomized into the palliative arm very soon which means there are less than 100 patients to go! Please do not forget about the local ablation arm either: it is mandatory for patients in this arm to answer the diagnostic question on the use of hepato-biliary MRI in comparison to Multisclice CT for HCC staging and therapeutic decisions. We remain with best wishes from Magdeburg, Jens Ricke, Peter Malfertheiner Magdeburg, (Sponsor)

2 Page 2 New data in prevention of radioembolization induced liver disease (RILD/REILD) by Max Seidensticker max.seidensticker@med.ovgu.de page 1 A key limiting factor of liver directed radiotherapy is the relatively low tolerance of the liver parenchyma to radiation leading to either subclinical focal or generalized injury of the liver parenchyma. When the intensity or the extent of radiationinduced liver injury (RILI) exceeds the functional reserve, clinical complications appear in the form of radiation (radioembolization) induced liver disease (RILD or REILD). REILD still remains a dreaded complication and a challenge in means of prediction/risk stratification, prevention, protection and treatment. According to Sangro, REILD is defined as jaundice and ascites appearing 1 to 2 months after Y90- radioembolization in the absence of tumor progression or bile duct occlusion [1]. In literature, the incidence varies with a range of 2-22% [1-4]. Following risk factors are identified with different weight of evidence: extensive chemotherapy history (specifically capecitabine), chemotherapy right after Y90-radioembolization (in pretreated patients only), treatment in a whole-liver fashion, performance status and age <55 years in patients with liver metastases and small liver volume (<1.5l), increased baseline bilirubin (>1.2mg/dl) and treatment in a selective fashion in patients with cirrhosis [1; 2]. Furthermore, a dose reduction of at least 10-20% (for whole liver treatment) and a concomitant medication with prednisolon and ursodeoxycholic acid were described to lower the incidence REILD (however, dose reduction to prevent REILD events is not validated in terms of reduced therapeutic capacity) [2]. In my own analysis, whole liver treatment in one treatment session was found to be related with more liver related toxicities and REILD as compared to a sequential lobar whole liver treatment [5]. In particular this evidence is the rationale for the mandatory sequential treatment approach in the SORAMIC trial if a whole liver treatment is necessary. Medication designed to reduce the radiation induced liver injury could improve the safety as well as enable more aggressive radiotherapy. Clinical studies suggest that veno-occlusive disease (VOD)/RILD after bone marrow transplantation (after conditioning therapy with chemotherapy and whole body irradiation) can be ameliorated by pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low molecular weight heparin (LMWH). However, these results are equivocal as evidence since most studies had quite heterogeneous study populations (including patients who have received prior chemotherapy or had underlying liver disease). Thus, a more standardized clinical model is needed to evaluate the protective effects of prophylactic regimens against VOD/ RILD. Image-guided, single-fractioned, highdose-rate catheter based radiotherapy (brachytherapy, BT) of liver malignancies is associated with a well-characterized focal radiation induced liver injury (frili), which can be visualized and quantified using functional hepatobiliary magnetic resonance imaging (MRI). Recently, we conducted a prospective study to quantify frili in patients who were randomized to BT with and without prophylactic PTX (400mg t.i.d.), UDCA (250mg t.i.d. ) and low-dose LMWH (enoxaparin, 40mg q.d.). To minimize the confounding effects of prior chemotherapy on radiation tolerability, only patients with liver metastases from colorectal cancer (mcrc) were included because these patients tend to have a more consistent pattern of prior exposition to chemotherapy. The cumulative effect of three drugs over a period of 8 weeks was assessed with patient follow-up at 6 and 12 weeks by hepatobiliary MRI. The post-therapeutic application of PTX, UDCA and

3 Page 3 New data in prevention of radioembolization induced liver disease (RILD/REILD) by Max Seidensticker max.seidensticker@med.ovgu.de page 2 low-dose LMWH significantly reduced the extent and incidence frili at 6 weeks after radiotherapy. The development of subsequent frili at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1-8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated frili [6]. Moreover, we suggest that our study results can be applied to other established radiation treatment methods of liver malignancies such as Y90-radioembolization. According to conversion calculations, the dose ranges in the liver parenchyma associated with Y90-radioembolization and BT are comparable, if re-calculated with respect to the standard fractionation. We therefore hypothesize that preventive treatment approaches against RILD/REILD should be equally effective for both Y90-radioembolization and BT. Since 2012 with more than 100 SIRT treatments per year we have not recorded symptomatic REILD events (other than in breast cancer patients who probably have a different risk profile). We attribute that to the fact that we perform whole liver treatments only in a sequential matter and apply preventive medication as described above. Further confirmatory data to support the preventive effect of the drug combination described above is not available yet. Further confirmatory data to support the preventive effect of the drug combination described above is not available yet. However, in case of suspected RILD/REILD or in patients at risk (e.g. large tumor load, borderline liver function, etc.) we suggest that the combination of pentoxifylline, ursodeoxycholic acid and low molecular weight heparin should be discussed on an individual basis to prevent liver decompensation or to overcome such events. Reference list 1 Sangro B, Gil-Alzugaray B, Rodriguez J et al (2008) Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer 112: Gil-Alzugaray B, Chopitea A, Inarrairaegui M et al (2013) Prognostic factors and prevention of radioembolization-induced liver disease. Hepatology 57: Kennedy AS, Ball D, Cohen S et al Multicenter comparison of safety and efficacy of yttrium-90 resin microsperes in elderly (>70 years) and younger patients with unresectable liverdominant metastastic colorectal cancer. Cardiovascular and Interventional Radiology Society of Europe Meeting 2013 Abstract Kennedy AS, McNeillie P, Dezarn WA et al (2009) Treatment parameters and outcome in 680 treatments of internal radiation with resin 90Y-microspheres for unresectable hepatic tumors. International journal of radiation oncology, biology, physics 74: Seidensticker R, Seidensticker M, Damm R et al (2012) Hepatic Toxicity After Radioembolization of the Liver Using Y-90-Microspheres: Sequential Lobar Versus Whole Liver Approach. Cardiovascular and Interventional Radiology 35: Seidensticker M, Seidensticker R, Damm R et al (2014) Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity. PloS one 9:e112731

4 Page 4 Recruitment Status : Total number of patients: 496 Total randomized (therapeutic Study) 363 Diagnostic Study Only: 117 Screening Phase: 16 Palliative Group: 285 Local Ablation Group: 78 First patient enrolled: 28-Dec-2010 Best recruiting center: Magdeburg University Hosp./ (PI: J. Ricke) Best recruiting country: (201 patients) Top ten recruiting SORAMIC centers Country Location Site Initiation Investigators Magdeburg University Hospital Gastro./Hepatol.: P. Malfertheiner Radiology: J. Ricke Nuclear Med.: H. Amthauer Netherlands Amsterdam AMC Oncology: H. Klumpen Hepatology: P.L.M. Jansen Radiology: O. van Delden Nuclear Med.: R. Bennink Poland MSWiA Hospital Warsaw Radiology: J. Walecki Isotop Therapy Dept.: T. Budlewski Berlin Charité University Hospital Gastro.: E. Schott Radiology: B. Gebauer Nuclear Med.: H. Bertram France Grenoble Hôpital Michallon Hepatology: V. Leroy Radiology: C. Sengel Nuclear Med.: J.-C. Bourre France Paris St. Antoine Gastro./Hepatol.: O. Rosmorduc Radiology: Y. Menu Nuclear Med.: J.-Y. Devaux LMU Munich University Hospital Hepatology: E. De Toni Radiology: M. Reiser No of Patients screened or in screening phase/ diagnostic study only/ Randomized 107/12/93 50/17/31 48/19/29 27/3/24 23/2/20 24/5/18 17/1/16 (Sponsor)

5 Page 5 Recruitment Status Austria Vienna University Hospital Gastro.: M. Peck-Radosavljevic Radiology: C. Loewe Nuclear Med.: M. Hoffmann Leipzig University Hospital Hepatology: T. Berg Radiology: M. Moche Slovenia University Medical Centre Ljubljana Radiology: P. Popovic Gastro: B. Stabuc 20/4/14 17/2/15 15/1/14 (Sponsor)