Michael C. Soulen

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria—A 10-Year Update

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies

Beatty, Haas, and colleagues report antitumor activity in two patients treated with autologous T cells transfected with mRNA encoding a chimeric antigen receptor that recognizes mesothelin and contains the CD3-ζ and 4-1BB costimulatory domains (CARTmeso). The short-lived CARTmeso cells induced novel antiself antibodies and a broadly directed epitope spreading. Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB costimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was shown in both patients, and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel antiself antibodies. These data show the potential of using mRNA-engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors. Cancer Immunol Res; 2(2); 112–20. ©2013 AACR.

Chemoembolization of hepatocellular carcinoma

Transcatheter arterial chemoembolization (TACE) is the mainstay of treatment for patients with unresectable hepatocellular carcinoma (HCC). Chemoembolization involves delivery of some type of chemotherapy combined with some type of arterial embolization to destroy tumor cells. Whereas diffuse tumors may require lobar embolization, smaller tumors may be treated selectively. The goal of TACE is to cause tumor necrosis and control tumor growth while preserving as much functional liver tissue as possible. The ultimate purpose, however, is to prolong life. Several different TACE protocols have been developed, with no consensus as to the most effective techniques. The effect of TACE on patient survival remains unclear. Several nonrandomized studies have demonstrated a beneficial effect of TACE on survival. This result has not been confirmed with randomized trials. It is clear, however, that TACE is a palliative procedure that has been unable to provide a cure for HCC. When combined with other procedures such as percutaneous ethanol injection, TACE has been more successful at achieving survival rates matching those obtained after surgical resection in similar patient populations. Finally, TACE may also be useful as a neoadjuvant therapy by improving the outcomes of potentially curative therapies and as a bridge to liver transplantation.

Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome

Appropriate patient selection is crucial in ensuring acceptable outcomes from orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) has elected to prioritize HCC patients for OLT based on criteria of tumor burden. However, it is unclear whether these criteria correlate with outcome, or with the pathobiological features associated with tumor recurrence. Therefore, we analyzed 109 consecutive patients undergoing OLT for HCC at our center, to determine the utility of present selection criteria in predicting outcome. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified tumor node metastases (pTNM) classification system. Multifocality was defined as >4 tumor nodules on explant. Survival analysis was performed using Kaplan‐Meier and Cox proportional hazards regression methods. At a median follow‐up of 18.9 months, the overall mortality was 19% with 15 patients (14%) dying of recurrent HCC. Kaplan‐Meier 1, 3 and 5‐year survival rates were 89.5%, 68%, and 65%, respectively. Recurrence‐free rates of 1, 3, and 5 years were 89%, 75%, and 65%, respectively. On univariate analysis, the factors found to be significantly associated with recurrence of HCC were explant features of macrovascular invasion, tumor size (per centimeter increase), pTNM stage (per 1‐stage increase), and pre‐transplant serum alphafetoprotein (AFP) >300 ng/mL. In defining a threshold level, we found that explant tumor diameter ≥3 cm, and those tumors classified as at least pT3 on pathological examination, were significantly associated with recurrence (P = .01 and .03, respectively). Tumor size on explant was found to be strongly correlated with multifocality (P = .017) and vascular invasion (P = .02). Patients exceeding pathological UNOS criteria were 3.1 times more likely to have recurrence of HCC (P = .03). In conclusion, we found that tumor size appears to be a surrogate marker for negative pathobiological predictors of outcome, i.e., vascular invasion and multifocality. Present UNOS selection criteria for HCC based on tumor burden appear to provide adequate discriminatory power in predicting outcome of OLT. (Liver Transpl 2004;10:911–918.)

Renal angiomyolipoma: Long-term results after arterial embolization

PURPOSE Selective arterial embolization of renal angiomyolipomas (AMLs) was performed to prevent hemorrhage in patients with AMLs larger than 4 cm. This study was conducted to evaluate the long-term efficacy of AML embolization. MATERIALS AND METHODS Nineteen patients underwent embolization for 30 renal AMLs between July 1991 and June 2002. Of these, 10 patients had tuberous sclerosis (TS) with multiple AMLs and nine patients had a solitary sporadic AML. Embolization was performed with use of ethanol mixed with iodized oil (Ethiodol) in 29 tumors; coils were used in addition to the ethanol/Ethiodol mixture in one case. All tumors were completely embolized according to angiographic criteria including vascular stasis and absence of arterial feeders. The efficacy of embolization was determined over a mean follow-up period of 51.5 months (range, 6-132 months). Recurrence was defined as an increase in tumor size of greater than 2 cm on follow-up imaging and/or recurrent symptoms that required repeat embolization. An institutional review board exemption was obtained to perform this retrospective study. RESULTS Embolization of the renal AMLs was technically successful in all 19 patients and for all 30 lesions. AML recurrence was noted in 31.6% of patients (n = 19) and for 30% of lesions overall (n = 9). Six of 10 patients in the TS group had AML recurrences. No recurrences occurred in the patients with sporadic AML. In the TS group of 10 patients, there was a total of 21 AMLs and the overall tumor recurrence rate was 42.9% (nine of 21). Six lesions in four patients had to be reembolized because of recurrent symptoms, including one hemorrhage, and three lesions in two patients required repeat embolization because of a greater than 2 cm increase in size. The median time interval from embolization to recurrence was 78.7 months (range, 13-132 months). Statistical testing with use of the Fisher exact test demonstrated that patients with TS were significantly more likely to develop recurrence than those without TS (P = .01). CONCLUSIONS Transarterial embolization is effective in preventing hemorrhage in patients with renal AMLs. However, long-term follow-up revealed a high AML recurrence rate in patients with TS. Lifelong surveillance for recurrence after AML embolization is essential in patients with TS.

Transcatheter Therapy for Hepatic Malignancy: Standardization of Terminology and Reporting Criteria

The field of interventional oncology includes tumor ablation as well as the use of transcatheter therapies such as embolization, chemoembolization, and radioembolization. Terminology and reporting standards for tumor ablation have been developed. The development of standardization of terminology and reporting criteria for transcatheter therapies should provide a similar framework to facilitate the clearest communication among investigators and provide the greatest flexibility in comparing established and emerging technologies. An appropriate vehicle for reporting the various aspects of catheter directed therapy is outlined, including classification of therapies and procedure terms, appropriate descriptors of imaging guidance, and terminology to define imaging and pathologic findings. Methods for standardizing the reporting of outcomes toxicities, complications, and other important aspects that require attention when reporting clinical results are addressed. It is the intention of the group that adherence to the recommendations will facilitate achievement of the groups main objective: improved precision and communication for reporting the various aspects of transcatheter management of hepatic malignancy that will translate to more accurate comparison of technologies and results and, ultimately, to improved patient outcomes.

Determinants of Postembolization Syndrome after Hepatic Chemoembolization

PURPOSE Postembolization syndrome (PES) occurs in the majority of patients undergoing hepatic chemoembolization, and is the major reason for hospitalization after the procedure. The ability to identify which groups of patients are at increased or decreased risk of PES would be useful to better counsel patients, to minimize toxicity, and to plan inpatient versus outpatient therapy. MATERIALS AND METHODS Seventy hepatic chemoembolization procedures were performed in 29 patients using cytotoxic drugs mixed with Ethiodol and polyvinyl alcohol. The following procedural variables were retrospectively assessed and evaluated for association with PES and length of postprocedural hospitalization: gallbladder embolization, lobe embolized, percentage liver volume embolized, percentage embolized volume occupied by tumor, previous embolization of the same territory, and dose of chemoembolic emulsion. Logistic regression was used to quantify the relative effect of each procedural variable. RESULTS Gallbladder embolization and dose administered were associated with an increased risk of PES and an extended hospitalization, with odds ratios of 2.8 and 3.0, and 3.0 and 4.6, respectively. Previous embolization was associated with a decreased risk of both PES and extended hospitalization, with odds ratios of 0.5 and 0.4, respectively. There was a statistical trend toward significance for gallbladder embolization (P = .06), dose administered (P = .07), and previous embolization (P = .14). CONCLUSION Clinically relevant predictors of the severity of PES and length of postprocedural hospitalization may exist. Avoiding embolization of the gallbladder reduces the risk of PES. Re-embolization of previously treated vessels is associated with decreased toxicity and may assist in selecting patients for treatment on an outpatient basis, especially when a reduced dose is required.

Sutureless Securement Device Reduces Complications of Peripherally Inserted Central Venous Catheters

PURPOSE This study was conducted to evaluate the performance of a sutureless adhesive-backed device, StatLock, for securement of peripherally inserted central venous catheters (PICCs). Earlier studies have demonstrated that StatLock significantly reduces catheter-related complications when compared to tape. The purpose of this study was to determine whether a sutureless securement device offers an advantage over suture in preventing catheter-related complications. MATERIALS AND METHODS 170 patients requiring PICCs, which were randomized to suture (n = 85) or StatLock (n = 85) securement were prospectively studied. Patients were followed throughout their entire catheter course, and PICC-related complications including dislodgment, infection, occlusion, leakage, and central venous thrombosis were documented. Catheter outcome data were compared to determine if statistically significant differences existed between the suture and StatLock groups. RESULTS The groups had equivalent demographic characteristics and catheter indications. Average securement time with StatLock was significantly shorter (4.7 minutes vs 2.7 minutes;P <.001). Although StatLock was associated with fewer total complications (42 vs 61), this difference did not achieve significance. However, there were significantly fewer PICC-related bloodstream infections in the StatLock group (2 vs 10; P =.032). One securement-related needle-stick injury was documented during suturing of a PICC. CONCLUSION The sutureless anchor pad was beneficial for both patients and health care providers. Further investigation to determine how StatLock helps reduce catheter-related blood stream infections is necessary.

Risk Factors for Liver Abscess Formation after Hepatic Chemoembolization

PURPOSE To assess the frequency and risk factors for liver abscess after hepatic chemoembolization. MATERIALS AND METHODS The authors performed retrospective analysis of 397 chemoembolization procedures in 157 patients. All patients received prophylactic intravenous antibiotics before the procedure and 5 days of oral antibiotics after the procedure. The association between abscess formation and risk factors was determined with use of chi(2) analysis and the Fisher exact test and expressed as an odds ratio. RESULTS Liver abscess occurred in seven of 157 patients (4.5%) after eight of 397 procedures (2.0%) at a mean of 19 d +/- 7 after chemoembolization. No patients had neutropenia. Organisms isolated reflected intestinal flora. Six patients required percutaneous drainage for 35 d +/- 29. The seventh patient required drainage for the remainder of life as a result of a nonhealing biliary fistula. Three of 24 patients with neuroendocrine tumors had abscesses (12.5%; odds ratio, 4.6; 95% CI, 0.96-22.1; P =.07), as did three of 14 patients with gastrointestinal sarcomas (21%; odds ratio, 9.5; 95% CI, 1.9-47.8; P =.016), and one of two with pancreatic adenocarcinoma. Six of the seven patients with abscesses underwent a Whipple procedure before chemoembolization. Only one patient with a history of a Whipple procedure did not develop an hepatic abscess. In the absence of a bilioenteric anastomosis, abscess occurred in only one of 150 patients (0.7%), or one of 383 procedures (0.3%). The odds ratio for liver abscess among patients with a bilioenteric anastomosis was 894 (95% CI, 50-16,000; P <.0001). CONCLUSION Earlier bilioenteric anastomosis is the major determinant of liver abscess formation after hepatic chemoembolization. The prophylaxis regimen used failed to prevent abscess formation in patients with earlier bilioenteric anastomosis.

Treatment of Unresectable Hepatocellular Carcinoma with Intrahepatic Yttrium 90 Microspheres: Factors Associated with Liver Toxicities

PURPOSE Intraarterial injection of yttrium 90 microspheres (TheraSpheres) is used in the treatment of hepatocellular carcinoma (HCC). This article presents an analysis of the incidence of liver toxicities (liver-related events) and pretreatment factors associated with liver toxicities after TheraSphere treatment. PATIENTS AND METHODS Eighty-eight TheraSphere-treated patients with low 90-day mortality risk were selected for analysis, with liver toxicities coded with use of standard oncology criteria. Descriptive and inferential statistical methods were applied to estimate the incidence of liver toxicities and to evaluate the influence of liver radiation dose and various pretreatment factors on the risk of their occurrence. RESULTS Sixty-eight liver toxicities occurred in 37 of the 88 patients (42%). Thirty-two patients (36%) experienced 50 liver toxicities after the first treatment and nine of 23 patients (39%) who received a second treatment experienced 18 liver toxicities. Pretreatment total bilirubin and liver radiation dose were found to be associated with the risk of at least one liver toxicity and with the time to first occurrence of a liver toxicity after first treatment. Pretreatment total bilirubin also was associated with liver toxicities after the second treatment. Most of the toxicities resolved; however, those that did not resolve were attributed to tumor progression or advancing cirrhosis. CONCLUSIONS The risk of liver toxicities in patients with unresectable HCC treated with TheraSpheres increases with increasing pretreatment total bilirubin level and liver radiation dose to a maximum of 150 Gy for a single administration. The toxicities attributed to treatment resolved over time, and none of the patients studied had confirmed radiation-induced liver disease. Consequently, doses as high as 150 Gy on a single administration and as high as 268 Gy on repeated administrations were well tolerated.