Elena N. Petre

Potent Induction of Tumor Immunity by Combining Tumor Cryoablation with Anti–CTLA-4 Therapy

Thermal ablation to destroy tumor tissue may help activate tumor-specific T cells by elevating the presentation of tumor antigens to the immune system. However, the antitumor activity of these T cells may be restrained by their expression of the inhibitory T-cell coreceptor CTLA-4, the target of the recently U.S. Food and Drug Administration-approved antibody drug ipilumimab. By relieving this restraint, CTLA-4-blocking antibodies such as ipilumimab can promote tumor rejection, but the full scope of their most suitable applications has yet to be fully determined. In this study, we offer a preclinical proof-of-concept in the TRAMP C2 mouse model of prostate cancer that CTLA-4 blockade cooperates with cryoablation of a primary tumor to prevent the outgrowth of secondary tumors seeded by challenge at a distant site. Although growth of secondary tumors was unaffected by cryoablation alone, the combination treatment was sufficient to slow growth or trigger rejection. In addition, secondary tumors were highly infiltrated by CD4(+) T cells and CD8(+) T cells, and there was a significant increase in the ratio of intratumoral T effector cells to CD4(+)FoxP3(+) T regulatory cells, compared with monotherapy. These findings documented for the first time an effect of this immunotherapeutic intervention on the intratumoral accumulation and systemic expansion of CD8(+) T cells specific for the TRAMP C2-specific antigen SPAS-1. Although cryoablation is currently used to treat a targeted tumor nodule, our results suggest that combination therapy with CTLA-4 blockade will augment antitumor immunity and rejection of tumor metastases in this setting.

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.

Treatment of pulmonary colorectal metastases by radiofrequency ablation.

UNLABELLED We evaluated the local tumor control and the survival benefit achieved with radiofrequency ablation (RFA) for nonoperable lung metastases in 45 patients with colorectal cancer. Median survival from the time of RFA was 46 months. One-, 2- and 3-year local tumor progression (LTP)-free survival rates were 92%, 77%, and 77%, respectively. RFA offers very good local control in patients with pulmonary metastases from colorectal cancer. BACKGROUND Radiofrequency ablation has emerged as a potential, lung function-preserving treatment of colorectal lung metastases. PATIENTS AND METHODS Forty-five patients with colorectal pulmonary metastases underwent computed tomography-guided RFA from December 2004 to June 2010. A baseline posttreatment scan was obtained 4-6 weeks after RFA and follow-up imaging studies every 3 months thereafter were obtained and compared to evaluate the tumor progression at site of ablation or elsewhere. The primary end points were LTP-free survival and overall survival from RFA procedure. The Kaplan-Meier method was used to analyze the end points. A Cox proportional hazard model with robust inference was used to estimate the associations between baseline factors and survival end points. RESULTS Sixty-nine metastases were ablated in 45 patients. Tumor size ranged from 0.4 to 3.5 cm. The median number of metastases ablated per patient was 1 (range, 1-3). Median follow-up after RFA was 18 months. Median survival from the time of RFA was 46 months (95% confidence interval [CI], 27.8-47.3). One-, 2- and 3-year overall survival rates from the time of RFA were 95% (95% CI, 82%-99%), 72% (95% CI, 52%-85%), and 50% (95% CI, 26%-71%), respectively. Nine of 69 lesions (13%) progressed and 4 were retreated with no progression after second RFA. Median time to progression was not reached. LTP-free survival from RFA was 92% (95% CI, 82%-97%) at 1 year, 77% (95% CI, 58%-88%) at 2 years, and 77% (95% CI, 58%-88%) at 3 years. CONCLUSION Radiofrequency ablation of lung metastases is an effective minimally invasive, parenchymal-sparing technique that has very good local control rates in patients with pulmonary metastases from colorectal cancer, with LTP-free survival of 77% at 3 years.

CT-guided Radiofrequency Ablation as a Salvage Treatment of Colorectal Cancer Hepatic Metastases Developing after Hepatectomy

PURPOSE To evaluate the clinical outcomes of percutaneous radiofrequency (RF) ablation of colorectal cancer liver metastases (CLMs) that recur after hepatectomy. MATERIALS AND METHODS From December 2002 to December 2008, 71 CLMs that developed after hepatectomy were ablated in 56 patients. Medical records and imaging were reviewed to determine technique effectiveness/complete ablation (ie, ablation defect covering the entire tumor on 4-6-week postablation computed tomography [CT]), complications, and local tumor progression (LTP) at the site of ablation. LTP-free and overall survival were calculated by using Kaplan-Meier methodology. A modified clinical risk score (CRS) including nodal status of the primary tumor, time interval between diagnoses of the primary tumor and liver metastases, number of tumors, and size of the largest tumor was assessed for its effect on overall survival and LTP. RESULTS Tumor size ranged between 0.5 and 5.7 cm. Complete ablation was documented in 67 of 71 cases (94%). Complications included liver abscess (n = 1) and pleural effusion (n = 1). Median overall survival time was 31 months. One-, 2- and 3-year overall survival rates were 91%, 66%, and 41%, respectively. CRS was an independent factor for overall survival (74% for CRS of 0-2 vs 42% for CRS of 3-4 at 2 y; P = .03) and for LTP-free survival (66% for CRS of 0-2 vs 22% for CRS of 3-4 at 1 y after a single ablation; P <.01). CONCLUSIONS CT-guided RF ablation can be used to treat recurrent CLM after hepatectomy. A low CRS is associated with better clinical outcomes.

Phase I Trial of Selective Internal Radiation Therapy for Chemorefractory Colorectal Cancer Liver Metastases Progressing After Hepatic Arterial Pump and Systemic Chemotherapy

INTRODUCTION This prospective study assessed the safety and outcomes of selective internal radiation therapy (SIRT) using yttrium-90 ((90)Y) resin microspheres as a salvage therapy for liver-predominant metastases of colorectal cancer in patients with documented progression after hepatic arterial chemotherapy (HAC) and systemic chemotherapy. PATIENTS AND METHODS We recruited 19 patients who had received a mean of 2.9 prior lines of chemotherapy and ≥ 1 line of HAC. Dose-limiting toxicities (grade 3 or higher) were catalogued using Common Terminology Criteria for Adverse Events version 3.0. At 4 to 8 weeks and 3 to 4 months post SIRT, responses were assessed by carcinoembryonic antigen (CEA), and quantitative imaging using Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST). Liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. RESULTS Median follow-up was 31.2 months after SIRT. Within 6 weeks of SIRT, 3 patients (15.8%) experienced grade 3 toxicity. There was no incidence of radiation-induced liver disease. Responses by RECIST, PERCIST, and CEA were, respectively, 0%, 20%, and 32% at 4 to 8 weeks and 5%, 33%, and 21% at 3 to 4 months post SIRT; 53% of patients had stable disease (by RECIST) at 3 to 4 months. Of 19 patients, 4 (21.1%) had liver ablation, 9 (47%) received additional HAC, and 17 (89%) received systemic chemotherapy after SIRT. Median LPFS, PFS, and OS after SIRT were 5.2 months, 2.0 months, and 14.9 months, respectively. CONCLUSION SIRT was well tolerated and did not prohibit subsequent treatment, resulting in a median OS of 14.9 months in this heavily pretreated population.

Pulmonary Thermal Ablation in Patients With Prior Pneumonectomy

OBJECTIVE The purpose of this article is to review the safety and efficacy of thermal ablation of lung malignancies after pneumonectomy. MATERIALS AND METHODS We reviewed patients who underwent thermal ablation for malignant lung tumors after pneumonectomy between 1999 and 2009. Patient demographics, complications, procedural success, and oncologic outcomes were recorded. Technique effectiveness was evaluated at imaging 4-6 weeks after ablation. The Kaplan-Meier method was used to evaluate overall survival. A cumulative incidence and competing risk method was used to account for progression-free tumors at the time of patient death. RESULTS Of 619 lung ablations, 17 were performed to treat 13 tumors (nine primary and four metastatic) in 12 patients with a single lung. The median tumor size was 2 cm (range, 1.2-4 cm). Technical success was documented in all 17 cases. Technical effectiveness was documented in 10 of 12 patients. Local tumor progression occurred in five lesions within a median of 12 months (range, 10-22 months) after ablation and was treated with repeat ablation in four lesions. Complications included six (35%) of 17 pneumothoraces requiring thoracostomy. Deaths occurred within 2-12 days after three (19%) of 16 ablation sessions. The median time to primary local tumor progression was 18 months (95% CI, 12 months through not reached), and the median time to assisted (after repeat ablation) local tumor progression was 33 months (95% CI, not reached). Median overall survival was 21 months (95% CI, 18-53 months). After excluding the two early deaths complicating the initial ablation procedure, median overall survival was 37 months. CONCLUSION Thermal ablation can offer local tumor control after pneumonectomy, despite a relatively high postprocedure clinical risk.

Pyogenic abscess after hepatic artery embolization: a rare but potentially lethal complication.

PURPOSE Hepatic artery embolization (HAE) is used commonly to treat liver tumors or hemorrhage. Infectious complications are rare but carry high rates of morbidity and mortality. Identification of clinical factors associated with postembolization abscess may improve management and outcome. MATERIALS AND METHODS Clinical and pathologic variables of patients treated with HAE were collected and analyzed to determine the etiology, incidence, and outcome of pyogenic hepatic abscess. RESULTS From January 1998 to January 2010, 971 patients underwent 2,045 HAE procedures. Fourteen patients developed a pyogenic hepatic abscess after embolization, for an overall rate of 1.4%. Thirty-four patients (4%) had a history of bilioenteric anastomosis (BEA) and 21 patients (2%) lacked a competent sphincter of Oddi because of the presence of a biliary stent (n = 19) or a previous sphincterotomy (n = 2). Eleven of the 34 patients with a BEA (33%) and two of 21 patients with an incompetent sphincter (10%) developed abscesses, in contrast to only one abscess (0.05%) among the 916 patients with apparently normal sphincters (0.1%; odds ratio, 437.6; 95% CI, 54.2-3,533; P < .0001). Gram-negative and Gram-positive aerobes were the most common bacteria isolated after drainage. Percutaneous drainage was the initial management strategy in all patients; two patients (14%) required subsequent surgical drainage and hepatectomy, and three (21%) died. CONCLUSIONS Pyogenic hepatic abscess is rare after HAE. A history of BEA or an incompetent sphincter of Oddi caused by a biliary stent or previous sphincterotomy substantially increases the likelihood of this highly morbid and potentially fatal complication.

Factors Affecting Periprocedural Morbidity and Mortality and Long-term Patient Survival after Arterial Embolization of Hepatic Neuroendocrine Metastases

PURPOSE To identify factors affecting periprocedural morbidity and mortality and long-term survival following hepatic artery embolization (HAE) of hepatic neuroendocrine tumor (NET) metastases. MATERIALS AND METHODS This single-center, institutional review board-approved retrospective review included 320 consecutive HAEs for NET metastases performed in 137 patients between September 1996 and September 2007. Forty-seven HAEs (15%) were performed urgently to manage refractory symptoms in inpatients (urgent group), and 273 HAEs (85%) were elective (elective group). Overall survival (OS) was estimated by Kaplan-Meier methodology. Complications were categorized per Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to determine independent predictors for OS, complications, and 30-day mortality. The independent factors were combined to develop clinical risk score groups. RESULTS Urgent HAE (P = .007), greater than 50% liver replacement by tumor (P < .0001), and extrahepatic metastasis (P = .007) were independent predictors for shorter OS. Patients with all three risk factors had decreased OS versus those with none (median, 8.5 vs 86 mo; P < .001). Thirty-day mortality was significantly lower in the elective (1%) versus the urgent group (8.5%; P = .0009). There were eight complications (3%) in the elective group and five (10.6%) in the urgent group (P = .03). Male sex and urgent group were independent factors for higher 30-day mortality rate (P = .023 and P =.016, respectively) and complications (P = .012 and P =.001, respectively). CONCLUSIONS Urgent HAE, replacement of more than 50% of liver by tumor, and extrahepatic metastasis are strong independent predictors of shorter OS. Male sex and urgent HAE carry higher 30-day mortality and periprocedural morbidity risks.

Ablation for the Management of Pulmonary Malignancies

OBJECTIVE Surgical resection remains the treatment of choice for patients with early-stage primary lung cancer and selected patients with limited metastatic lung disease. However, surgery is a high-risk treatment for patients with coexisting morbidities, severe chronic obstructive pulmonary disease, a single lung, or a history of prior resection. The indications for and outcomes of ablative therapies performed for the management of pulmonary malignancies are discussed. CONCLUSION Preservation of residual lung parenchyma when treating patients with early-stage primary lung cancer and those with limited metastatic lung disease is vital and can be achieved with image-guided thermal ablation therapies.

A comparison of outcomes from treating hepatocellular carcinoma by hepatic artery embolization in patients younger or older than 70 years

The objective of this study was to compare the morbidity, mortality, and survival of patients aged <70 years and aged ≥70 years who underwent hepatic arterial embolization (HAE) for the treatment of hepatocellular carcinoma (HCC).