Joseph P. Erinjeri

Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma A Randomized Clinical Trial

IMPORTANCE Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01143402.

Cryoablation: Mechanism of Action and Devices

Cryoablation refers to all methods of destroying tissue by freezing. Cryoablation causes cellular damage, death, and necrosis of tissues by direct mechanisms, which cause cold-induced injury to cells, and indirect mechanisms, which cause changes to the cellular microenvironment and impair tissue viability. Cellular injury, both indirect and direct, can be influenced by four factors: cooling rate, target temperature, time at target temperature, and thawing rate. In this review, the authors describe the mechanisms of cellular injury that occur with cryoablation, the major advantages and disadvantages of cryoablation compared with other thermal ablation techniques, and the current commercially available cryoablation ablation systems.

Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone

PURPOSE Transarterial chemoembolization is accepted therapy for hepatocellular carcinoma (HCC). No randomized trial has demonstrated superiority of chemoembolization compared with embolization, and the role of chemotherapy remains unclear. This randomized trial compares the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres. MATERIALS AND METHODS At a single tertiary referral center, patients with HCC were randomly assigned to embolization with microspheres alone (Bead Block [BB]) or loaded with doxorubicin 150 mg (LC Bead [LCB]). Random assignment was stratified by number of embolizations to complete treatment, and assignments were generated by permuted blocks in the institutional database. The primary end point was response according to RECIST 1.0 (Response Evaluation Criteria in Solid Tumors) using multiphase computed tomography 2 to 3 weeks post-treatment and then at quarterly intervals, with the reviewer blinded to treatment allocation. Secondary objectives included safety and tolerability, time to progression, progression-free survival, and overall survival. This trial is currently closed to accrual. RESULTS Between December 2007 and April 2012, 101 patients were randomly assigned: 51 to BB and 50 to LCB. Demographics were comparable: median age, 67 years; 77% male; and 22% Barcelona Clinic Liver Cancer stage A and 78% stage B or C. Adverse events occurred with similar frequency in both groups: BB, 19 of 51 patients (38%); LCB, 20 of 50 patients (40%; P = .48), with no difference in RECIST response: BB, 5.9% versus LCB, 6.0% (difference, -0.1%; 95% CI, -9% to 9%). Median PFS was 6.2 versus 2.8 months (hazard ratio, 1.36; 95% CI, 0.91 to 2.05; P = .11), and overall survival, 19.6 versus 20.8 months (hazard ratio, 1.11; 95% CI, 0.71 to 1.76; P = .64) for BB and LCB, respectively. CONCLUSION There was no apparent difference between the treatment arms. These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.

Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes—A 10-year Experience at a Single Center

PURPOSE To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score (CRS) adapted for ablation as a patient stratification and prognostic tool. MATERIALS AND METHODS This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of data in 162 patients with 233 CLMs treated with percutaneous RFA between December 2002 and December 2012. Contrast material-enhanced CT was used to assess technique effectiveness 4-8 weeks after RFA. Patients were followed up with contrast-enhanced CT every 2-4 months. Overall survival (OS) and local tumor progression-free survival (LTPFS) were calculated from the time of RFA by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariate and multivariate analysis to identify predictors of outcomes. RESULTS Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS. CONCLUSION Tumor size of less than 3 cm and ablation margins greater than 5 mm are essential for satisfactory local tumor control. Tumor size of more than 3 cm and the presence of more than one site of EHD are associated with shorter OS.

Acute and Subacute Effects of Irreversible Electroporation on Nerves: Experimental Study in a Pig Model

PURPOSE To evaluate whether irreversible electroporation (IRE) has the potential to damage nerves in a porcine model and to compare histopathologic findings after IRE with histopathologic findings after radiofrequency ablation (RFA). MATERIALS AND METHODS This study was approved by the institutional animal care and use committee. Computed tomography (CT)-guided IRE of 11 porcine sciatic nerves was performed in nine pigs, and histopathologic analysis was performed on the day of ablation or 3, 6, or 14 days after ablation. In addition, acute RFA of six porcine sciatic nerves was performed in six pigs that were harvested on the day of ablation. All nerves and associated muscles and tissues were assessed for histopathologic findings consistent with athermal or thermal injury, respectively, such as axonal swelling, axonal fragmentation and loss, Wallerian degeneration, inflammatory infiltrates, Schwann cell proliferation, and coagulative necrosis. The percentage of fascicles affected was recorded. RESULTS All nerves had an axonal injury. The percentage of affected nerve fascicles after IRE was 50%-100%. Axonal swelling and perineural inflammatory infiltrates were detectable at every time point after ablation. Axonal fragmentation and loss, macrophage infiltration, and Schwann cell proliferation were found 6 and 14 days after ablation. Distal Wallerian axonal degeneration was observed 14 days after ablation. The endoneurium and perineurium architecture remained intact in all cases. RFA specimens at the day of ablation revealed acute coagulative necrosis associated with intense basophilic staining of extracellular matrix, including collagen of the perineurium and epineurium consistent with thermal injury. CONCLUSION IRE has the potential to damage nerves and may result in axonal swelling, fragmentation, and distal Wallerian degeneration. However, preservation of endoneurium architecture and proliferation of Schwann cells may suggest the potential for axonal regeneration. In contrast, RFA leads to thermal nerve damage, causing protein denaturation, and suggests a much lower potential for regeneration.

Split-Dose Technique for FDG PET/CT–guided Percutaneous Ablation: A Method to Facilitate Lesion Targeting and to Provide Immediate Assessment of Treatment Effectiveness

PURPOSE To describe a split-dose technique for fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-guided ablation that permits both target localization and evaluation of treatment effectiveness. MATERIALS AND METHODS Institutional review board approved the study with a waiver of consent. From July to December 2011, 23 patients (13 women, 10 men; mean age, 59 years; range, 35-87 years) with 29 FDG-avid tumors (median size, 1.4 cm; range, 0.6-4.4 cm) were targeted for ablation. The location of the lesion was the liver (n = 23), lung (n = 4), adrenal gland (n = 1), and thigh (n = 1). Radiofrequency ablation was performed in 17 lesions; microwave ablation, in six; irreversible electroporation, in five; and cryoablation, in one. The pathologic condition of the tumor was metastatic colorectal adenocarcinoma in 18 lesions, primary hepatocellular carcinoma in one lesion, and a variety of metastatic tumors in the remaining 10 lesions. A total of 4 mCi (148 MBq) of FDG was administered before the procedure for localization and imaging guidance. At completion of the ablation, an additional 8 mCi (296 MBq) of FDG was administered to assess ablation adequacy. Results of subsequent imaging follow-up were used to determine if postablation imaging after the second dose of FDG reliably helped predict complete tumor ablation. Descriptive statistics were used to summarize the results. RESULTS Twenty-eight of 29 (97%) ablated lesions showed no residual FDG activity after the second intraprocedural FDG dose. One patient with residual activity underwent immediate biopsy that revealed residual viable tumor and was immediately re-treated. Follow-up imaging at a median of 155 days (range, 92-257 days) after ablation showed local recurrences in two (7%) lesions that were originally negative at postablation PET. CONCLUSION Split-dose FDG PET/CT may be a useful tool to provide both guidance and endpoint evaluation, allowing an opportunity for repeat intervention if necessary. Further work is necessary to validate these concepts.

Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement

The authors investigated how the timing of administration of bevacizumab, a targeted vascular endothelial growth factor‐inhibiting chemotherapeutic agent, affected the risk of wound healing in patients undergoing chest wall port placement.

Image-guided Thermal Ablation of Tumors Increases the Plasma Level of Interleukin-6 and Interleukin-10

PURPOSE To identify changes in plasma cytokine levels after image-guided thermal ablation of human tumors and to identify the factors that independently predict changes in plasma cytokine levels. MATERIALS AND METHODS Whole-blood samples were collected from 36 patients at three time points: before ablation, after ablation (within 48 hours), and at follow-up (1-5 weeks after ablation). Plasma levels of interleukin (IL)-1α, IL-2, IL-6, IL-10, and tumor necrosis factor (TNF)-α were measured using a multiplex immunoassay. Univariate and multivariate analyses were performed using cytokine level as the dependent variable and sample collection, time, age, sex, primary diagnosis, metastatic status, ablation site, and ablation type as the independent variables. RESULTS There was a significant increase in the plasma level of IL-6 after ablation compared with before ablation (9.6-fold ± 31-fold, P<.002). IL-10 also showed a significant increase after ablation (1.9-fold ± 2.8-fold, P<.02). Plasma levels of IL-1α, IL-2, and TNF-α were not significantly changed after ablation. Cryoablation resulted in the largest change in IL-6 level (>54-fold), whereas radiofrequency ablation and microwave ablation showed 3.6-fold and 3.4-fold changes, respectively. Ablation of melanomas showed the largest change in IL-6 48 hours after ablation (92×), followed by ablation of kidney (26×), liver (8×), and lung (6×) cancers. Multivariate analysis revealed that ablation type (P<.0003) and primary diagnosis (P<.03) were independent predictors of changes to IL-6 after ablation. Age was the only independent predictor of IL-10 levels after ablation (P< .019). CONCLUSIONS Image-guided thermal ablation of tumors increases plasma levels of IL-6 and IL-10, without increasing plasma levels of IL-1α, IL-2, or TNF-α.

Arterial Patency after Repeated Hepatic Artery Bland Particle Embolization

PURPOSE To evaluate hepatic arterial patency after serial bland particle embolization procedures in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS All patients with HCC who underwent five or more hepatic artery bland embolization procedures with permanent particulate and spherical embolic agents between September 1996 and December 2007 were retrospectively reviewed. Data analyzed included patient demographics, vessels embolized, embolic agent used, and duration of arterial patency. RESULTS Forty-three patients were identified who underwent five or more bland embolization procedures in the same arterial distribution. Of the 43 patients examined, 83% (n = 36) showed no change in the hepatic arterial tree after repeated bland embolization (mean treatment period of 48 months +/- 23). Six patients (13%) exhibited occlusion of a fifth-order or more distal vessel after an average of 5 embolizations +/- 2 over a period of 34 months +/- 27. A single case of vascular occlusion of a fourth-order vessel was observed after five embolizations over a period of 52 months. CONCLUSIONS Repeated bland embolization of the hepatic arteries in HCC preserves patency of the hepatic arterial vasculature despite the fact that embolization is carried out to complete stasis.

AKT Inhibition in Solid Tumors With AKT1 Mutations

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.