Carboplatin and Paclitaxel Chemoradiation for Localized Anal Cancer in Patients Not Eligible for Mitomycin and 5-Fluorouracil.

BACKGROUND: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. METHODS: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. RESULTS: Ten patients were included; eight were female, and the median age was 75.5 years (54-87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40-100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4-50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). CONCLUSIONS: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

Impact of baseline culture conditions of cancer organoids when determining therapeutic response and tumor heterogeneity.

Representative models are needed to screen new therapies for patients with cancer. Cancer organoids are a leap forward as a culture model that faithfully represents the disease. Mouse-derived cancer organoids (MDCOs) are becoming increasingly popular, however there has yet to be a standardized method to assess therapeutic response and identify subpopulation heterogeneity. There are multiple factors unique to organoid culture that could affect how therapeutic response and MDCO heterogeneity are assessed. Here we describe an analysis of nearly 3500 individual MDCOs where individual organoid morphologic tracking was performed. Change in MDCO diameter was assessed in the presence of control media or targeted therapies. Individual organoid tracking was identified to be more sensitive to treatment response than well-level assessment. The impact of different generations of mice of the same genotype, different regions of the colon, and organoid specific characteristics including baseline size, passage number, plating density, and location within the matrix were examined. Only the starting size of the MDCO altered the subsequent growth. These results were corroborated using ~ 1700 patient-derived cancer organoids (PDCOs) isolated from 19 patients. Here we establish organoid culture parameters for individual organoid morphologic tracking to determine therapeutic response and growth/response heterogeneity for translational studies.

Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation.

PURPOSE: Cancer treatment is limited by inaccurate predictors of patient-specific therapeutic response. Therefore, some patients are exposed to unnecessary side effects and delays in starting effective therapy. A clinical tool that predicts treatment sensitivity for individual patients is needed. EXPERIMENTAL DESIGN: Patient-derived cancer organoids were derived across multiple histologies. The histologic characteristics, mutation profile, clonal structure, and response to chemotherapy and radiation were assessed using bright-field and optical metabolic imaging on spheroid and single-cell levels, respectively. RESULTS: We demonstrate that patient-derived cancer organoids represent the cancers from which they were derived, including key histologic and molecular features. These cultures were generated from numerous cancers, various biopsy sample types, and in different clinical settings. Next-generation sequencing reveals the presence of subclonal populations within the organoid cultures. These cultures allow for the detection of clonal heterogeneity with a greater sensitivity than bulk tumor sequencing. Optical metabolic imaging of these organoids provides cell-level quantification of treatment response and tumor heterogeneity allowing for resolution of therapeutic differences between patient samples. Using this technology, we prospectively predict treatment response for a patient with metastatic colorectal cancer. CONCLUSIONS: These studies add to the literature demonstrating feasibility to grow clinical patient-derived organotypic cultures for treatment effectiveness testing. Together, these culture methods and response assessment techniques hold great promise to predict treatment sensitivity for patients with cancer undergoing chemotherapy and/or radiation.