Khairuddin Memon

Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma

BACKGROUND & AIMS Chemoembolization is one of several standards of care treatment for hepatocellular carcinoma (HCC). Radioembolization with Yttrium-90 microspheres is a novel, transarterial approach to radiation therapy. We performed a comparative effectiveness analysis of these therapies in patients with HCC. METHODS We collected data from 463 patients who were treated with transarterial locoregional therapies (chemoembolization or radioembolization) over a 9-year period. We excluded patients who were not appropriate for comparison and analyzed data from 245 (122 who received chemoembolization and 123 who received radioembolization). Patients were followed for signs of toxicity; all underwent imaging analysis at baseline and follow-up time points. Overall survival was the primary outcome measure. Secondary outcomes included safety, response rate, and time-to-progression. Uni- and multivariate analyses were performed. RESULTS Abdominal pain and increased transaminase activity were more frequent following chemoembolization (P < .05). There was a trend that patients treated with radioembolization had a higher response rate than with chemoembolization (49% vs 36%, respectively, P = .104). Although time-to-progression was longer following radioembolization than chemoembolization (13.3 months vs 8.4 months, respectively, P = .046), median survival times were not statistically different (20.5 months vs 17.4 months, respectively, P = .232). Among patients with intermediate-stage disease, survival was similar between groups that received chemoembolization (17.5 months) and radioembolization (17.2 months, P = .42). CONCLUSIONS Patients with HCC treated by chemoembolization or radioembolization with Yttrium-90 microspheres had similar survival times. Radioembolization resulted in longer time-to-progression and less toxicity than chemoembolization. Post hoc analyses of sample size indicated that a randomized study with > 1000 patients would be required to establish equivalence of survival times between patients treated with these two therapies.

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).

Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic-pathologic correlation.

BACKGROUND & AIMS We sought to study receiver-operating characteristics (ROC) of the European Association for the Study of the Liver (EASL), Response Evaluation Criteria in Solid Tumors (RECIST), and World Health Organization (WHO) guidelines for assessing response following locoregional therapies individually and in various combinations. METHODS Eighty-one patients with hepatocellular carcinoma underwent liver explantation following locoregional therapies. Response was assessed using EASL, RECIST, and WHO. Kappa statistics were used to determine inter-method agreement. Uni/multivariate logistic regression analyses were performed to determine the variables predicting complete pathologic necrosis. Numerical values were assigned to the response classes: complete response=0, partial response=1, stable disease=2, and progressive disease=3. Various mathematical combinations of EASL and WHO were tested to calculate scores and their ROCs were studied using pathological examination of the explant as the gold standard. RESULTS Median times (95% CI) to the WHO, RECIST, and EASL responses were 5.3 (4-11.5), 5.6 (4-11.5), and 1.3months (1.2-1.5), respectively. Kappa coefficients for WHO/RECIST, WHO/EASL, and RECIST/EASL were 0.78, 0.28, and 0.31, respectively. EASL response demonstrated significant odds ratios for predicting complete pathologic necrosis on uni/multivariate analyses. Calculated areas under the ROC curves were: RECIST: 0.63, WHO: 0.68, EASL: 0.82, EASL+WHO: 0.82, EASL×WHO: 0.85, EASL+(2×WHO): 0.79 and (2×EASL)+WHO: 0.85. An EASL×WHO Score of ⩽1 had 90.2% sensitivity for predicting complete pathologic necrosis. CONCLUSIONS The product of WHO and EASL demonstrated better ROC than the individual guidelines for assessment of tumor response. EASL×WHO scoring system provides a simple and clinically applicable method of response assessment following locoregional therapies for hepatocellular carcinoma.

Radiographic Response to Locoregional Therapy in Hepatocellular Carcinoma Predicts Patient Survival Times

BACKGROUND & AIMS It is not clear whether survival times of patients with hepatocellular carcinoma (HCC) are associated with their response to therapy. We analyzed the association between tumor response and survival times of patients with HCC who were treated with locoregional therapies (LRTs) (chemoembolization and radioembolization). METHODS Patients received LRTs over a 9-year period (n = 463). Patients with metastases, portal venous thrombosis, or who had received transplants were excluded; 159 patients with Child-Pugh B7 or lower were analyzed. Response (based on European Association for the Study of the Liver [EASL] and World Health Organization [WHO] criteria) was associated with survival times using the landmark, risk-of-death, and Mantel-Byar methodologies. In a subanalysis, survival times of responders were compared with those of patients with stable disease and progressive disease. RESULTS Based on 6-month data, in landmark analysis, responders survived longer than nonresponders (based on EASL but not WHO criteria: P = .002 and .0694). The risk of death was also lower for responders (based on EASL but not WHO criteria: P = .0463 and .707). Landmark analysis of 12-month data showed that responders survived longer than nonresponders (P < .0001 and .004, based on EASL and WHO criteria, respectively). The risk of death was lower for responders (P = .0132 and .010, based on EASL and WHO criteria, respectively). By the Mantel-Byar method, responders had longer survival than nonresponders, based on EASL criteria (P < .0001; P = .596 with WHO criteria). In the subanalysis, responders lived longer than patients with stable disease or progressive disease. CONCLUSIONS Radiographic response to LRTs predicts survival time. EASL criteria for response more consistently predicted survival times than WHO criteria. The goal of LRT should be to achieve a radiologic response, rather than to stabilize disease.

Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes.

PURPOSE To present long-term outcomes on the safety and efficacy of Yttrium-90 radioembolization in the treatment of unresectable hepatic neuroendocrine metastases refractory to standard-of-care therapy. METHODS AND MATERIALS This study was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Forty patients with hepatic neuroendocrine metastases were treated with (90)Y radioembolization at a single center. Toxicity was assessed using National Cancer Institute Common Terminology Criteria v3.0. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS The median dose was 113 Gy (29-299 Gy). Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by 2 patients and 1 patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 (p < 0.0001), tumor burden ≤25% (p = 0.0019), albumin ≥3.5 g/dL (p = 0.017), and bilirubin ≤1.2 mg/dL (p = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin ≤1.2 mg/dL prognosticated better survival outcome on multivariate analysis (p = 0.0001 and p = 0.02). CONCLUSION Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival with low toxicity, in line with published national guidelines recommending radioembolization as a potential option for unresectable hepatic neuroendocrine metastases.

Radiation lobectomy: Time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection

BACKGROUND & AIMS Portal vein embolization (PVE) is a standard technique for patients not amenable to liver resection due to small future liver remnant ratio (FLR). Radiation lobectomy (RL) with (90)Y-loaded microspheres (Y90) is hypothesized to induce comparable volumetric changes in liver lobes, while potentially controlling the liver tumor and limiting tumor progression in the untreated lobe. We aimed at testing this concept by performing a comprehensive time-dependent analysis of liver volumes following radioembolization. METHODS 83 patients with right unilobar disease with hepatocellular carcinoma (HCC; N=67), cholangiocarcinoma (CC; N=8) or colorectal cancer (CRC; N=8) were treated by Y90 RL. The total liver volume, lobar (parenchymal) and tumor volumes, FLR and percentage of FLR hypertrophy from baseline (%FLR hypertrophy) were assessed on pre- and post-Y90 CT/MRI scans in a dynamic fashion. RESULTS Right lobe atrophy (p=0.003), left lobe hypertrophy (p<0.001), and FLR hypertrophy (p<0.001) were observed 1 month after Y90 and this was consistent at all follow-up time points. Median %FLR hypertrophy reached 45% (5-186) after 9 months (p<0.001). The median maximal %FLR hypertrophy was 26% (-14 → 86). Portal vein thrombosis was correlated to %FLR hypertrophy (p=0.02). Median Child-Pugh score worsening (6 → 7) was seen at 1 to 3 months (p=0.03) and 3 to 6 months (p=0.05) after treatment. Five patients underwent successful right lobectomy (HCC N=3, CRC N=1, CC N=1) and 6 HCCs were transplanted. CONCLUSIONS Radiation lobectomy by Y90 is a safe and effective technique to hypertrophy the FLR. Volumetric changes are comparable (albeit slightly slower) to PVE while the right lobe tumor is treated synchronously. This novel technique is of particular interest in the bridge-to-resection setting.

Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis.

PURPOSE To present data on safety, antitumoral response, and survival following yttrium-90 ((90)Y) radioembolization for patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS The present study expands on the cohort of 24 patients with ICC described in a pilot study, and includes 46 patients treated with (90)Y radioembolization at a single institution during an 8-year period. Via retrospective review of a prospectively collected database, patients were stratified by performance status, tumor distribution (solitary or multifocal), tumor morphology (infiltrative or peripheral), and presence/absence of portal vein thrombosis. Primary endpoints included biochemical and clinical toxicities, and secondary endpoints included imaging response (World Health Organization [WHO] and European Association for the Study of Liver Disease [EASL] criteria) and survival. Uni-/multivariate analyses were performed. RESULTS Ninety-two treatments were performed, with a mean of two per patient. Fatigue and transient abdominal pain occurred in 25 patients (54%) and 13 patients (28%), respectively. Treatment-related gastroduodenal ulcer developed in one patient (2%). WHO imaging findings included partial response (n = 11; 25%), stable disease (n = 33; 73%), and progressive disease (n = 1; 2%). EASL imaging findings included partial/complete response (n = 33; 73%) and stable disease (n = 12; 27%). Survival varied based on presence of multifocal (5.7 mo vs 14.6 mo), infiltrative (6.1 mo vs 15.6 mo), and bilobar disease (10.9 mo vs 11.7 mo). Disease was converted to resectable status in five patients, who successfully underwent curative (ie, R0) resection. CONCLUSIONS Radioembolization with (90)Y is safe and demonstrates antitumoral response and survival benefit in select patients with ICC. Results are most pronounced in patients with solitary tumors, for whom conversion to curative resection is possible.

Radioembolization for hepatocellular carcinoma with portal vein thrombosis: Impact of liver function on systemic treatment options at disease progression

BACKGROUND & AIMS Yttrium-90 ((90)Y) radioembolization is a microembolic procedure. Hence, it is commonly used in hepatocellular carcinoma (HCC) patients with portal venous thrombosis (PVT). We analyzed liver function, imaging findings, and treatment options (local/systemic) at disease progression following (90)Y treatment in HCC patients with PVT. METHODS We treated 291 HCC patients with (90)Y radioembolization. From this cohort, we included patients with liver-only disease, PVT and Child-Pugh (CP) score ≤ 7; this identified 63 patients with HCC and PVT (CP-A:35, CP-B7:27). Liver function, CP status, and imaging findings at progression were determined in order to assess potential candidacy for systemic treatment/clinical trials. Survival, time-to-progression (TTP), and time-to-hepatic decompensation analyses were performed using Kaplan-Meier methodology. RESULTS Of 35 CP-A and 28 CP-B7 patients, 29 and 15 progressed, respectively. Median survival and TTP were 13.8 and 5.6 months in CP-A and 6.5 and 4.9 months in CP-B7 patients, respectively. Of the 29 CP-A patients who progressed, 45% maintained their CP status at progression (55% decompensated to CP-B). Of the 15 CP-B7 patients who progressed, 20% improved to CP-A, 20% maintained their CP score and 60% decompensated. CONCLUSIONS Knowledge of liver function and CP score of HCC with PVT progressing after (90)Y is critically relevant information, as these patients may be considered for systemic therapy/clinical trials. If a strict CP-A status is mandated, our study demonstrated that 64% of cases exhibited inadequate liver function and were ineligible for systemic therapy/clinical trials. An adjuvant approach using local therapy and systemic agents prior to progression should be investigated.

Radiological-pathological analysis of WHO, RECIST, EASL, mRECIST and DWI: Imaging analysis from a prospective randomized trial of Y90 ± sorafenib

The aim of this study was to compare radiological and pathological changes and test the adjunct efficacy of Sorafenib to Y90 as a bridge to transplantation in hepatocellular carcinoma (HCC). 15 patients with 16 HCC lesions were randomized to Y90 without (Group A, n = 9) or with Sorafenib (Group B, n = 7). Size (WHO, RECIST), enhancement (EASL, mRECIST) and diffusion‐weighted imaging criteria (apparent diffusion coefficient, ADC) measurements were obtained at baseline, then at 1 and every 3 months after treatment until transplantation. Percentage necrosis in explanted tumors was correlated with imaging findings. 100%, 50%‐99% and <50% pathological necrosis was observed in 6 (67%), 1 (11%), and 2 (22%) tumors in Group A and 3 (42%), 2 (28%), and 2 (28%) in Group B, respectively (P = 0.81). While ADC (P = 0.46) did not change after treatment, WHO (P = 0.06) and RECIST (P = 0.08) response at 1 month failed to reach significance, but significant responses by EASL (P < 0.01/0.03) and mRECIST (P < 0.01/0.03) at 1 and 3 months were observed. Response was equivalent by EASL or mRECIST. No difference in response rates was observed between groups A and B at 1 and 3 months by WHO, RECIST, EASL, mRECIST or ADC measurements. Despite failing to reach significance, smaller baseline size was associated with complete pathological necrosis (CPN) (RECIST: P = 0.07; WHO: P = 0.05). However, a cut‐off size of 35 mm was predictive of CPN (P = 0.005). CPN could not be predicted by WHO (P = 0.25 and 0.62), RECIST (P = 0.35 and 0.54), EASL (P = 0.49 and 0.46), mRECIST (P = 0.49 and 0.60) or ADC (P = 0.86 and 0.93). Conclusion: The adjunct of Sorafenib did not augment radiological or pathological response to Y90 therapy for HCC. Equivalent significant reduction in enhancement at 1 and 3 months by EASL/mRECIST was noted. Neither EASL nor mRECIST could reliably predict CPN. (HEPATOLOGY 2013;58:1655–1666)

Radioembolisation for liver metastases: Results from a prospective 151 patient multi-institutional phase II study

PURPOSE To investigate the safety, response rate, progression-free and overall survival of patients with liver metastases treated with (90)Y (glass) radioembolisation in a prospective, multicenter phase II study. METHODS 151 patients with liver metastases (colorectal n=61, neuroendocrine n=43 and other tumour types n=47) refractory to standard of care therapies were enrolled in this prospective, multicenter, phase II study under an investigational device exemption. Clinical/laboratory/imaging follow-up were obtained at 30 days followed by 3-month intervals for 1 year and every 6 months thereafter. The primary end-point was progression-free survival (PFS); secondary end-points included safety, hepatic progression-free survival (HPFS), response rate and overall survival. RESULTS Median age was 66 (range 25-88). Grade 3/4 adverse events included pain (12.8%), elevated alkaline phospatase (8.1%), hyperbilirubinemia (5.3%), lymphopaenia (4.1%), ascites (3.4%) and vomiting (3.4%). Treatment parameters including dose delivery were reproducible among centers. Disease control rates were 59%, 93% and 63% for colorectal, neuroendocrine and other primaries, respectively. Median PFS was 2.9 and 2.8 months for colorectal and other primaries, respectively. PFS was not achieved in the neuroendocrine group. Median survival from (90)Y treatment was 8.8 months for colorectal and 10.4 months for other primaries. Median survival for neuroendocrine patients has not been reached. CONCLUSION Patients with liver metastases can be safely treated with (90)Y microspheres. This study is the first to demonstrate technical and dose reproducibility of (90)Y glass microspheres between centers in a prospective setting. Based on these promising data, three international, multicenter, randomised phase III studies in colorectal and hepatocellular carcinoma have been initiated.