Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer.

Importance: Direct intratumoral delivery of immunotherapies is a compelling approach to overcoming barriers to systemic immunotherapy efficacy. While the use of intratumoral delivery of immunotherapy drugs is increasing rapidly in both the investigational and standard of care domains, the feasibility and safety of these interventions, particularly for deeper lesions that require image-guidance, remain unknown. Objective: To address current knowledge gaps in image-guided techniques for intratumoral immunotherapy delivery and the safety of these interventions. Design, Setting, and Participants: This case series study was performed at a single tertiary cancer center over a 2-year period from January 2016 to January 2018. Patients were followed until January 2019. All patients who underwent image-guided intratumoral delivery of immunotherapy agents in the standard of care, off-label, or investigational setting during the study period were included. Data were analyzed from February 1 to June 1, 2019. Exposures: Image-guided biopsies and intratumoral injections of immunotherapies across several clinical trials as well as standard of care talimogene laherparepvec therapy. Main Outcomes and Measures: Technical success, defined as the delivery of the prescribed injectate volume in its entirety, for image-guided biopsy and injections and procedure-related adverse events. Results: A total of 85 patients (median [interquartile range] age, 61 [47-71] years; 42 [52%] men) underwent 498 encounters during the study period. These encounters comprised 327 image-guided intratumoral investigational agent injections in 67 patients in clinical trials, including 33 patients with melanoma (50%), 14 patients with sarcoma (21%), 3 patients with ovarian cancer (4.5%), 2 patients with breast cancer (3%), and 2 patients with colon cancer (3%). An additional 18 patients with melanoma underwent 113 image-guided talimogene laherparepvec injections. There were no adverse events reported related to the technical component of the procedure, specifically needle insertion or biopsy. Serious adverse events (Common Terminology Criteria for Adverse Events score ≥3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 3 of 327 investigational agent injections (2%) and 4 of 113 talimogene laherparepvec injections (4%). Conclusions and Relevance: The findings of this case series study suggest that intratumoral injections of immunotherapies were feasible across a range of histological conditions and target organs. Immediate postdelivery anticipated adverse events occurred in a small number of instances. Performing physicians should have the necessary safeguards in place to respond as needed. Optimal methods for intratumoral drug delivery remain unresolved, and efforts to standardize drug delivery techniques are required.

Assessment of Reported Trial Characteristics, Rate of Publication, and Inclusion of Mandatory Biopsies of Research Biopsies in Clinical Trials in Oncology.

Importance: Research biopsies are frequently incorporated within clinical trials in oncology and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting. Objectives: To determine the rate of research biopsy reporting for clinical trials registered in ClinicalTrials.gov and determine the clinical trial factors that correlated with research biopsy reporting. Design, Setting, and Participants: ClinicalTrials.gov (CTG) was searched for all oncologic therapeutic clinical trials with completion dates between January 1, 2000, and January 1, 2015, with end point category terms including biopsy, biopsies, or tissue. The date of the final publication search was March 12, 2018. Trials conducting only diagnostic biopsies or trials using bone marrow biopsies or liquid biopsies were excluded. Credit for biopsy reporting was given for any mention of performing or results from tissue biopsies in publications. Clinical trials were compared with the highest level of corresponding publication or registry report. Fisher exact test was used for analysis. Results: A total of 301 clinical trials were identified, with a median of 37 patients (range, 1-1310 patients) enrolled per trial. After a median follow-up time of 5.8 years from trial completion, 244 of 301 trials (81.1%) reported results: publications in 195 (64.8%) and CTG registry in 49 (16.3%). Reporting of trial results was associated with later-stage trials (phase 2/3) (137 of 153 [89.5%] for phase 2/3 vs 107 of 148 [72.3%] for phase 1 or 1/2 trials; P < .001). Results from research biopsies were reported in 153 of 301 (50.8%) trials or in 153 of 244 (62.7%) trials with published results. Rates varied by type of presentation: 142 of 195 publications (72.8%) vs 11 of 49 CTG reports (22.4%) (P < .001). Conducting mandatory biopsies (82.1% [101 of 123] vs 43.0% [52 of 121]; P < .001), early-phase clinical trials (70.1% [75 of 107] vs 56.9% [78 of 137]; P = .03), and listing the biopsy as a primary objective in CTG (76.3% [45 of 59] vs 58.4% [108 of 185]; P = .01) was associated with improved biopsy reporting. Trials that met their primary end point (71.9% [115 of 160] vs 45.2% [38 of 84]; P < .001) and those published in higher-impact journals (81.1% [77 of 95] vs 65.0% [65 of 100]; P = .01) had improved biopsy reporting. Mandatory biopsies and biopsy reporting increased over time with similar slopes (P = .58). Conclusions and Relevance: Despite ethical obligations to report research biopsies, only 50.8% of all trials that included a research biopsy-related end point in CTG reported on these biopsy-related results. Improved efforts are needed to report results obtained from research biopsies.

Transarterial hepatic chemoembolization with 70-150 µm drug-eluting beads: assessment of clinical safety and liver toxicity profile.

PURPOSE: To assess the incidence and severity of adverse events (AEs) in the form of clinical symptoms and liver/biliary injuries (LBI) in patients with hepatic malignancies treated with transarterial chemoembolization using 70-150 µm drug-eluting beads (DEBs). MATERIALS AND METHODS: A single-institution retrospective analysis was performed in 37 patients (25 patients with hepatocellular carcinoma and 12 patients with metastatic disease) who underwent 43 sessions of segmental/subsegmental 70-150 µm DEB transarterial chemoembolization with doxorubicin (38 sessions) or irinotecan (5 sessions). Patient inclusion criteria included the presence of the following lesion features: small diameter (≤ 3 cm), hypovascular, or with areas of residual disease after other locoregional therapies. Mean tumor diameter was 3.4 cm. Mean imaging and clinical follow-up periods were 171 days and 373 days, respectively. Clinical, laboratory, and imaging data were used to identify and classify clinically symptomatic AEs per session and LBI per patient according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Predictors for the occurrence of LBI were evaluated by logistic regression analysis. RESULTS: No grade 4 or 5 AEs were recorded. Clinically symptomatic AEs occurred in 29 (67.4%) sessions (grade 1-2, 28 sessions; grade 3, 1 session), all constituting postembolization syndrome. Asymptomatic LBI occurred in 11 (29.7%) patients (grade 1, 8 patients; grade 2, 3 patients). The mean time between 70-150 µm DEB transarterial chemoembolization session and appearance of LBI was 71 days (range, 21-223 d). No predictive factors for the development of LBI were identified. CONCLUSIONS: Transarterial chemoembolization with 70-150 µm DEBs was considered safe in the present study population given the acceptably low incidence and severity of AEs.