Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Biodistribution and Efficacy of Low Temperature-Sensitive Liposome Encapsulated Docetaxel Combined with Mild Hyperthermia in a Mouse Model of Prostate Cancer.

PURPOSE: Low temperature sensitive liposome (LTSL) encapsulated docetaxel were combined with mild hyperthermia (40-42°C) to investigate in vivo biodistribution and efficacy against a castrate resistant prostate cancer. METHOD: Female athymic nude mice with human prostate PC-3 M-luciferase cells grown subcutaneously into the right hind leg were randomized into six groups: saline (+/- heat), free docetaxel (+/- heat), and LTSL docetaxel (+/- heat). Treatment (15 mg docetaxel/kg) was administered via tail vein once tumors reached a size of 200-300 mm(3). Mice tumor volumes and body weights were recorded for up to 60 days. Docetaxel concentrations of harvested tumor and organ/tissue homogenates were determined by LC-MS. Histological evaluation (Mean vessel density, Ki67 proliferation, Caspase-3 apoptosis) of saline, free Docetaxel and LTSL docetaxel (+/- heat n = 3-5) was performed to determine molecular mechanism responsible for tumor cell killing. RESULT: LTSL/heat resulted in significantly higher tumor docetaxel concentrations (4.7-fold greater compared to free docetaxel). Adding heat to LTSL Docetaxel or free docetaxel treatment resulted in significantly greater survival and growth delay compared to other treatments (p < 0.05). Differences in body weight between all Docetaxel treatments were not reduced by >10% and were not statistically different from each other. Molecular markers such as caspase-3 were upregulated, and Ki67 expression was significantly decreased in the chemo-hyperthermia group. Vessel density was similar post treatment, but the heated group had reduced vessel area, suggesting thermal enhancement in efficacy by reduction in functional perfusion. CONCLUSION: This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment.

A prognostic model of early breast cancer relapse after standard adjuvant therapy and comparison with metastatic disease on initial presentation.

Breast cancer can metastasize at any time during its course, but timing of systemic relapse cannot be predicted by traditional TNM staging. Characteristics of distant recurrence within the first 3 years of diagnosis may identify a group of patients who could benefit from novel strategies to prevent systemic relapse. Of 1,089 patients with breast cancer treated at our institution between January 2007 and May 2011, we identified 76 with de novo metastases (on presentation) and 40 with systemic relapse after a median follow up of 2.2 years. Compared to relapse, de novo metastatic disease was more likely to be grade 1 or 2 (43.1 vs. 18.4 %, p = 0.032), estrogen receptor (ER) positive (69.7 vs. 47.5 %, p = 0.019), progesterone receptor (PgR) positive (56.6 vs. 32.5 %, p = 0.014), and HER2-positive (27.5 vs. 10.3 %, p = 0.035). In the 815 patients with stage I-III disease who were at risk of systemic relapse, univariate analyses were performed for age, tumor size, grade, ER, PgR, HER2, lymph nodes, and TNM stage. A multivariate Cox regression model was built using step-wise model selection and identified 4 covariates that were significantly associated with risk of early relapse: stage-III (p < 0.001), grade-III (p = 0.002), PgR-negative status (p = 0.014), and HER2-negative status (p = 0.033). A risk-score was developed based on the linear combination of these covariates and time-dependent predictive curves were used to evaluate the predictive accuracy of the proposed risk-score. The highest risk-score group had a 1, 2, and 3-year relapse probabilities of 11.5, 41.2, and 52.5 %, respectively. The corresponding 1, 2, and 3-year relapse probabilities for the overall population were 1.2, 4.4, and 6.3 %, respectively. Our proposed model can be used to select patients at high-risk of early relapse who could benefit from enrollment on clinical trials with novel therapies designed for this group.

Single-Agent Therapies After Standard Combination Regimens.

Increasingly prolonged survival in metastatic colorectal cancer has paralleled the approval of new agents alone and in combination. Most recently, several new agents have sought approval in the heavily pretreated setting, after treatment with standard chemotherapies, alone and in combination, and with anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor (for patients with RAS wild-type tumors). These agents have included the multitargeted tyrosine kinase inhibitor (TKI), regorafenib, and the novel antimetabolite combination, TAS-102. Both of these showed improvement in progression-free survival and overall survival compared with placebo controls and were approved in the United States and the rest of the world. Benefits of treatment and toxicities are discussed. Nintedanib, another multitargeted TKI, is already approved by the European Medicines Evaluation Agency for non-small cell lung cancer and has been studied in a similar phase III trial. Results are pending. The risks and benefits of each agent are discussed.

Impact of comorbidity on initial treatment and overall survival in elderly head and neck cancer patients.

BACKGROUND: Comorbidity is a determinant of treatment selection and survival in various cancers including head and neck cancer (HNC) and is often associated with a higher utilization of non-curative intent treatment. PATIENTS AND METHODS: In this retrospective study we analyzed 182 consecutively treated HNC patients >65 years old at the Dallas Veterans Affairs Medical Center from January 2000-June 2007. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). Treatment was classified as curative vs. non-curative intent. RESULTS: Median overall survival was 883 days. Patients with a CCI score 0-2 had non-significant higher rate of curative intent treatment than patients with CCI score >2 (83.8% vs. 74.6%, p=0.13). In multivariate analysis, only stage had significant prognostic importance (hazard ratio (HR) 1.66; 95% confidence interval (CI) 1.29-2.14; p<0.0005). In separate multivariate analyses of patients treated with surgery or chemoradiation, CCI was not a significant predictor of survival with HR of 0.88 (95% CI 0.69-1.11; p=0.29) and 1.13 (95% CI 0.83-1.53; p=0.44), respectively. CONCLUSION: In our elderly HNC population, CCI was not an independent predictor of selection of curative intent treatment or overall survival.