Carlo Spreafico

Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.

Yttrium‐90 radioembolization (Y90RE) is a novel approach to radiation therapy for hepatocellular carcinoma (HCC), never tested in phase 2 studies. Fifty‐two patients with intermediate (n.17) to advanced (n.35) HCC were prospectively recruited to assess, as the primary endpoint, efficacy of Y90RE on time‐to‐progression (TTP). Secondary endpoints were tumor response, safety, and overall survival (OS). All patients were Eastern Cooperative Oncology Group (ECOG) score 0‐1, Child‐Pugh class A‐B7. Y90RE treatments aimed at a lobar delivery of 120 Gy. Retrospective dosimetric correlations were conducted and related to response. Fifty‐eight treatments were performed on 52 patients. The median follow‐up was 36 months. The median TTP was 11 months with no significant difference between portal vein thrombosis (PVT) versus no PVT (7 versus 13 months). The median OS was 15 months (95% confidence interval [CI], 12‐18 months) with a nonsignificant trend in favor of non‐PVT versus PVT patients (18 versus 13 months). Five complete responses occurred (9.6%), and the 2 year‐progression rate was 62%. Objective response was 40.4%, whereas the disease control rate (78.8%) significantly affected survival (responders versus nonresponders: 18.4% versus 9.1%; P = 0.009). Tumor response significantly correlated with absorbed dose in target lesions (r = 0.60, 95% CI, 0.41‐0.74, P < 0.001) and a threshold of 500 Gy predicted response (area under the curve, 0.78). Mortality at 30‐90 days was 0%‐3.8%. Various grades of reduction in liver function occurred within 6 months in 36.5% of patients, with no differences among stages. On multivariate analysis, tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child‐Pugh class). Conclusion: Y90RE is an effective treatment in intermediate to advanced HCC, particularly in the case of PVT. Further prospective evaluations comparing Y90RE with conventional treatments are warranted. (HEPATOLOGY 2013)

Research Reporting Standards for Radioembolization of Hepatic Malignancies

Primary Liver Tumors Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver; its incidence is increasing worldwide. It ranks as the sixth most common tumor and third most common cause of cancer-related mortality (1,2). Primary liver tumors include HCC and intrahepatic cholangiocarcinoma. Surgical resection is preferred over transplantation and is considered potentially curative in patients with resectable HCC and normal liver function (3). Transplantation is considered the gold standard for patients with unresectable HCC and whose disease is within the Milan criteria (4). Resection and transplantation have limited roles, given advanced disease (chronic liver disease and/or tumor extent) at presentation and limited organ availability (5–7). Chemoembolization and radiofrequency ablation represent standard therapies in treating patients and serve as a bridge to transplantation in selected patients (8,9). Radioembolization has an emerging role in “bridging” patients within criteria by delaying tumor progression. It has also been shown to downstage disease beyond the Milan, to within, transplant criteria (10–12). A recent study has demonstrated that radioembolization leads to longer time-to-progression and better toxicity profile when compared with chemoembolization (13). Patients with macrovascular tumor involvement have also exhibited evidence of clinical benefit after radioembolization (14).

Standards of Practice in Transarterial Radioembolization

Complications (minor/major) A minor complication is a treatment-related adverse event requiring no or minimal therapy with or without overnight hospitalization for observation. A major complication is a treatment-related adverse event requiring further therapy, increased level of care, or prolonged hospitalization [11]. Lung Shunting Fraction (LSF) LSF is the percentage shunt fraction of radioactive-labeled microspheres from liver to lung. Postradioemblization Syndrome (PRS) PRS is any constellation of symptoms, including fatigue, low-grade fever, nausea and vomiting, abdominal discomfort, and malaise occurring shortly after RE. Radiation-Induced Liver Disease (RILD) RILD comprises mostly anicteric, nonmalignant ascites and elevation of alkaline phosphatase level of at least twice the upper normal level within 4 months after treatment. Technical Success Technical success is the ability to access the appropriate segments of the liver and to perform the treatment according to protocol.

Use of a Retrievable Vena Cava Filter with Low-intensity Anticoagulation for Prevention of Pulmonary Embolism in Patients with Cancer: An Observational Study in 106 Cases

PURPOSE To evaluate a retrievable inferior vena cava (IVC) filter in combination with low-intensity oral anticoagulation for prevention of pulmonary embolism (PE) in patients with malignancy complicated by thromboembolic disease. MATERIALS AND METHODS From October 2005 to December 2009, 107 Bard G2 filters were placed in 106 patients. Forty-eight patients had deep vein thrombosis (DVT) alone, 53 had PE with DVT, and five had PE with no evidence of DVT. After an initial period of anticoagulation with heparin, low-intensity oral anticoagulant therapy to achieve a target International Normalized Ratio of 1.5-2.0 was instituted. Follow-up computed tomography to evaluate the pulmonary circulation, IVC, and lower limbs was performed at 3 and 6 months. RESULTS PE recurred in three of 58 patients (5.2%). None of the 48 patients with DVT alone developed PE, nor was there any recurrence of DVT. The filter was removed in 14 patients (13.2%). No complications occurred during the retrieval procedure. A total of 16 complications occurred in seven patients: one migration (0.9%); four cases of vena cava thrombosis (3.7%), three of which were associated with recurrent PE (2.8%); one filter fracture (0.9%); and one IVC penetration (0.9%). Filter tilting greater than 15° occurred in six patients (5.7%) and was associated with other complications in five (4.7%). CONCLUSIONS In patients with malignancies complicated by venous thromboembolic disease, an IVC filter together with low-intensity anticoagulation may be a possible treatment strategy for PE prophylaxis. Controlled studies are warranted.

The dosimetric importance of the number of 90Y microspheres in liver transarterial radioembolization (TARE)

Transarterial radioembolization (TARE) with Y microspheres is a very promising treatment modality in inoperable primary liver malignancies (mainly hepatocellular carcinoma, HCC), as well as in secondary liver lesions (mainly colorectal metastases), with some interesting results in other less diffused malignancies such as intrahepatic cholangiocarcinoma and neuroendocrine metastases. However, TARE is not yet included in liver management guidelines, since it has been introduced into clinical practice only recently, randomized studies demonstrating better outcomes with respect to consolidated standard of care have not yet been performed. Two kinds of Y-loaded microspheres are available, as we discuss in detail in the following sections. The guidelines published by the European Association for the Study of the Liver (EASL) [1] recommend the use of transarterial chemoembolization (TACE) in patients with intermediate stage HCC (multinodular, stage B according to the Barcelona Clinic Liver Cancer, BCLC, classification system) [2], while the administration of a biological pharmaceutical (sorafenib, a multikinase inhibitor) is recommended in patients with advanced stage disease (BCLC stage C; that is, patients with symptomatic tumours and/or an invasive tumoral pattern, i.e. vascular invasion/extrahepatic spread) [3, 4]. Many studies below the highest level of evidence in which patients with intermediate and advanced HCC were treated with Y microspheres have already suggested the outcomes following TARE compare favourably with those following conventional treatments [5–10]. Several phase III randomized trials studies are recruiting or have just been activated to provide the highest level of evidence of the outcome improvement after TARE in these two class of patients [11]. Two worldwide trials are planned with Y glass microspheres. STOP-HCC (http://clinicaltrials.gov/ct2/show/ NCT01556490?term=NCT01556490&rank=1) will compare the safety and effectiveness of microspheres in patients with advanced unresectable hepatocellular carcinoma in whom treatment with standard-of-care is planned. All patients will receive the standard-of-care sorafenib with or without the addition of microspheres. Patients with portal vein thrombosis are excluded from this study, since they will be specifically under study in the YES-P trial (http://clinicaltrials.gov/show/ NCT01887717), in which the outcomes after treatment with sorafenib alone and with microspheres alone will be compared. Y resin microspheres in HCC are also under investigation. The study SIRVENIB has as its primary objective to compare overall survival between TARE and sorafenib. Patients with intermediate stage (BCLC stage B) or advanced stage (BCLC stage C) without extrahepatic disease (only with branch portal vein thrombosis) can be enrolled in this study (http://clinicaltrials.gov/ct2/show/NCT01135056?term= SIRspheres&rank=16). The SARAH study is enrolling only patients with advanced HCC (BCLC stage C) with or without portal vein thrombosis. The comparison will be between sorafenib alone and TARE alone (http://clinicaltrials. gov/ct2/show/NCT01482442?term=SIRspheres&rank= 18). The SORAMIC study (http://www.clinicaltrials.gov/ ct2/show/NCT01126645?term=soramic&rank=1) will compare the TARE + sorafenib and sorafenib alone in the palliative treatment group. Regarding metastases, because of C. Spreafico (*) Radiology 2, Foundation IRCCS National Tumor Institute, Via G. Venezian 1, 20133 Milan, Italy e-mail: carlo.spreafico@istitutotumori.mi.it

Transarterial chemoembolization using 40 µm drug eluting beads for hepatocellular carcinoma

AIM To assess the safety and efficacy of transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) using a new generation of 40 μm drug eluting beads in patients not eligible for curative treatment. METHODS Drug eluting bead TACE (DEB-TACE) using a new generation of microspheres (embozene tandem, 40 μm) preloaded with 100 mg of doxorubicin was performed on 48 early or intermediate HCC patients with compensated cirrhosis. Response to therapy was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) guidelines applied to computed tomography or magnetic resonance imaging. Eleven out of the 48 treated patients treated progressed on to receive liver orthotopic transplantation (OLT). This allowed for histological analysis on the treated explanted nodules. RESULTS DEB-TACE with 40 μm showed a good safety profile without major complications or 30-d mortality. The objective response rate of treated tumors was 72.6% and 26.7% according to mRECIST and RECIST respectively. Histological examination in 11 patients assigned to OLT showed a necrosis degree > 90% in 78.6% of cases. The overall time to progression was 13 mo (11-21). CONCLUSION DEB-TACE with 40 μm particles is an effective treatment for the treatment of HCC in early-intermediate patients (Barcelona Clinic Liver Cancer stage A/B) with a good safety profile and good results in term of objective response rate and necrosis.

Intrahepatic Flow Redistribution in Patients Treated with Radioembolization

IntroductionIn planning Yttrium-90 (90Y)-radioembolizations, strategy problems arise in tumours with multiple arterial supplies. We aim to demonstrate that tumours can be treated via one main feeding artery achieving flow redistribution by embolizing accessory vessels.MethodsOne hundred 90Y-radioembolizations were performed on 90 patients using glass microspheres. In 19 lesions/17 patients, accessory branches were found feeding a minor tumour portion and embolized. In all 17 patients, the assessment of the complete perfusion was obtained by angiography and single photon emission computerized tomography–computerized tomography (SPECT–CT). Dosimetry, toxicity, and tumor response rate of the patients treated after flow redistribution were compared with the 83 standard-treated patients. Seventeen lesions in 15 patients with flow redistribution were chosen as target lesions and evaluated according to mRECIST criteria.ResultsIn all patients, the complete tumor perfusion was assessed immediately before radioembolization by angiography in all patients and after the 90Y-infusion by SPECT–CT in 15 of 17 patients. In the 15 assessable patients, the response rate in their 17 lesions was 3 CR, 8 PR, and 6 SD. Dosimetric and toxicity data, as well tumour response rate, were comparable with the 83 patients with regular vasculature.ConclusionsAll embolization procedures were performed successfully with no complications, and the flow redistribution was obtained in all cases. Results in term of toxicity, median dose administered, and radiological response were comparable with standard radioembolizations. Our findings confirmed the intratumoral flow redistribution after embolizing the accessory arteries, which makes it possible to treat the tumour through its single main feeding artery.

Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion

BACKGROUND & AIMS Yttrium-90 transarterial radioembolization (TARE) has shown promising efficacy in the treatment of patients with hepatocellular carcinoma (HCC), associated with portal vein tumor thrombus (PVTT). The aim of this study is to identify prognostic factors for survival in patients with HCC and PVTT undergoing TARE, and build a prognostic classification for these patients. METHODS This is a single center retrospective study conducted over six years (2010-2015), on consecutive patients undergoing TARE. Patients were included if they met the following criteria: presence of at least one measurable HCC, presence of PVTT not occluding the main portal trunk, absence of extrahepatic metastases, Child-Pugh score within B7, Eastern Cooperative Oncology Group performance status 0-1. Uni- and multivariable analysis was used to explore the variables that showed an independent relationship with survival. A prognostic score was then derived, and three prognostic categories were identified. RESULTS A total of 120 patients were included in the study. Median overall survival (OS) was 14.1 months (95% CI 10.7-17.5) and median progression-free survival (PFS) was 6.5 months (95% CI 3.8-9.2). The only variables independently correlated with OS were bilirubin, extension of PVTT and tumor burden. Three prognostic categories were identified: favourable prognosis (0 points), intermediate prognosis (2-3 points) and dismal prognosis (>3 points). Median OS in the three categories was 32.2 months, 14.9 months and 7.8 months respectively (p <0.0001). PFS (p = 0.045) and the risk of liver decompensation (p <0.0001) also significantly differed along the same prognostic categories. CONCLUSIONS Radioembolization with Yttrium-90 is an effective therapy for patients with HCC and PVTT. The proposed prognostic stratification may help to better identify good candidates for the treatment, and those for whom TARE may be futile. LAY SUMMARY Yttrium-90 transarterial radioembolization (TARE) is a microembolic procedure that minimizes alterations to hepatic arterial flow, and thus can be safely performed in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). In this study, we retrospectively evaluated the independent predictors of long-term outcomes in patients with HCC and PVTT treated with TARE. Bilirubin level, extension of PVTT and tumor burden were independently related to post-treatment survival: the combination of these factors allowed us to build a prognostic stratification that may help to better identify good candidates for the treatment, and those for whom TARE may be futile.

External validation of an individual prognostic calculator after transarterial chemoembolization for hepatocellular carcinoma

To the Editor: We read with great interest the study by Cappelli et al. (1) published in Liver International. The authors found number of tumours, serum albumin, serum total bilirubin, alpha-foetoprotein (AFP) and maximum tumour size as independent predictors of mortality following transarterial chemoembolization (TACE) for patients with unresectable hepatocellular carcinoma (HCC). They then developed an individual prognostic calculator, available online for quick consultation at http://www.livercancer.eu/mhap3.html. Their model showed a significantly higher accuracy than that of previously published pretreatment prognostic models [hepatoma arterial embolization Prognostic (HAP) (2) and the modified HAP-II score (mHAP-II) (3)]. However, the study adopted a 10-fold cross-validation approach and it is possible that a quote of increased accuracy could derive from this approach of internal validation. Therefore, an external validation from a completely different cohort is needed to promote the value of the model. Between Jan 2007 and Dec 2013, 298 patients with unresectable HCC underwent TACE at our centre. Indications and exclusion criteria for TACE in our context have been previously published (4). Among the 298 patients, 168 (56.4%) were at intermediate stage according to the Barcelona Clinic Liver Cancer (BCLC) classification, median number of nodules was 3 (1–12), Child-Pugh class was A in 269 patients (90.3%) and median AFP was 15.2 ng/ml (0–27 486). Overall, patients underwent a median number of two TACE sessions (1–6) until the last follow-up; the median overall survival of the entire series was 32.7 months. The model fit was verified in our series by means of Cox regression on the prognostic index and Wilcoxon’s test on the difference between theoretical b coefficients and data-driven b coefficients. Accuracy of the model was then tested: the model showed a Harrell’s c-statistics of 0.627 (95% CI: 0.580–0.673), significantly higher than that of the HAP score (0.579; 95% CI: 0.533–0.626; P = 0.043) and of the mHAP-II score (0.574; 95% CI: 0.531–0.617; P = 0.01), confirming the better discriminatory power of the model also in our series. A time-dependent area under the curve showed that the model had the best prognostic performance around 18 months, significantly higher than that of HAP (P = 0.005) and mHAP-II (P = 0.002). Thus, our data provide an external validation to the proposed model for individual prognostication after TACE (1), confirming that it may provide better prediction of survival with respect to other available scores. Availability of a web-based calculator increases the use of the model in daily practice, helps physicians decisionmaking and provides more accurate patients’ information, based on easily available pre-TACE parameters.

Focal therapy in urology: kidney cancer

Focal therapy has gained attention in the treatment of small renal masses (SRM). However, its use is limited due to scarce data on long-term outcomes. The availability of such data is significantly lower as compared to the relevant data on surgery outcomes. At the same time, minimally invasive surgery has seen the development of laparoscopic nephron-sparing surgery and, recently, robot-assisted surgery. Our purpose is to review the possibilities of treatment for SMR with particular attention on focal therapy. Clinical series and comprehensive reviews support safety and mid/long-term efficacy of renal cryoablation or radiofrequency ablation. Comparative studies and meta-analysis outlined oncological inferiority against partial nephrectomy in local tumor control. For smaller and more peripheral lesions, radiofrequency ablation showed best indications than cryoablation. There are significant demographic and tumor differences between patients treated by one or another approach. The correct indication for each treatment seems to be of key importance to achieve the best oncological and functional outcome. Open partial nephrectomy remains the gold standard treatment for PMR, but laparoscopic approaches have been showing similar results.