Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. OBJECTIVE: To determine the safety of iCRT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. INTERVENTION: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). RESULTS AND LIMITATIONS: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. CONCLUSIONS: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. PATIENT SUMMARY: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.

Large German Multicenter Experience on the Treatment Outcome of 207 Patients With Adenoid Cystic Carcinoma of the Major Salivary Glands.

INTRODUTION: We aimed to evaluate treatment outcome of combined radiotherapy (RT) including photon intensity modulated radiotherapy (IMRT) and carbon ion boost for adenoid cystic carcinomas (ACCs) of the major salivary glands, the currently available largest German collective for this cohort. MATERIALS AND METHODS: Overall, 207 patients who were irradiated with combined RT between 2009 and 2019 at Heidelberg University Hospital were analyzed retrospectively for local control (LC), progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimates. The majority of patients received postoperative RT (n=176/207, 85%) after previous surgery in large German hospitals mainly Mainz, Freiburg, Mannheim and Heidelberg University Hospitals and 15% received primary RT (n=31/207). RESULTS: After a median follow-up time of 50 months, 84% of the patients were still alive (n=174/207). Disease progression occurred in 32% of the patients (n=66/207) while local recurrence was diagnosed in 12% (n=25/207), and distant relapse in 27% (n=56/207). Estimated 5-year LC, PFS and OS rates were 84%, 56% and 83% for OS, respectively. In multivariate analysis, we could identify two prognostic subgroups: one subgroup resulting in decreased LC, PFS and OS rates and another subgroup having an additional survival disadvantage in PFS and OS. Patients with a macroscopic tumor disease (yes vs. no; p<0.001 for LC, p=0.010 for PFS and p=0.040 for OS) treated in a definitive setting (vs. postoperative setting; p=0.001 for LC, p=0.006 for PFS, p=0.049 for OS) and tumors of upper T stage (T1-4; p=0.004 for LC, p<0.001 for PFS, p<0.001 for OS) showed significantly more local relapses and a decreased PFS and OS. Upper Age (p<0.001 for both PFS and OS), lower Karnofsky Performance Score (<80% vs. ≥80%; p<0.001 for both PFS and OS) and solid histology (vs. non-solid; p=0.049 for PFS and p=0.003 for OS) were in addition associated with worse survival outcome. Toxicity was moderate with 18% late grade 2 and 3 toxicity. CONCLUSIONS: Combined RT results in superior LC rates compared to photon data with moderate toxicity. In multivariate analysis, upper T stage, the existence of a macroscopic tumor before RT and definitive RT setting were identified as major prognostic factors affecting LC negatively.

Image Guided Brachytherapy for Cancer of the Nasal Vestibule: Local Control and Cosmesis.

PURPOSE: To evaluate the efficacy of modern image guided brachytherapy for squamous cell carcinoma of the nasal vestibule, to explore tumor volume as a prognostic factor for local and regional recurrence, and to assess patient satisfaction with nasal function and appearance after treatment. METHODS AND MATERIALS: In a retrospective analysis, we reviewed the medical records of 102 patients with Wang T1-T2 nasal vestibule cancer treated at a single institution with brachytherapy as the sole treatment. Median follow-up time was 42 months (range, 3-210 months). A patient satisfaction study using the validated Nasal Appearance and Function Evaluation Questionnaire was conducted among 42 patients more than 1 year after treatment. A statistically significant cutoff point for tumor volume as a prognostic factor of local control was established using Youden's index method. RESULTS: Seventy-seven of 102 patients were treated with interstitial implants, and 25 patients were treated by an intracavitary mould technique. The 5-year control rates were 95%, 91%, and 83% for local, regional, and locoregional control, respectively. Tumor volume ≥2.3 cm3 resulted in worse 3-year regional control compared to tumor volume <2.3 cm3 (62% vs 96%; P = .01). Ultimate regional control after salvage treatment was 96%, with no significant difference observed between subgroups by tumor volume (92% for ≥2.3 cm3 vs 96% for <2.3 cm3; P = .57). Three patients with regional failure developed distant metastases. Five-year disease-specific survival and overall survival were 94% and 74%, respectively. Patient-assessed cosmetic and functional satisfaction were both rated high (mean 3.7 and 4.0 of 5, respectively). CONCLUSION: We report the largest cohort to date treated with brachytherapy as the sole treatment for nasal vestibule carcinoma. Brachytherapy offers excellent local control for Wang T1-T2 tumors with high patient satisfaction. Tumor volume is an adequate predictive factor for patients at risk of regional recurrence, but ultimate control rates after salvage treatment are high. Therefore, we do not recommend elective treatment of the neck.

Outcome and toxicity profile after brachytherapy for squamous cell carcinoma of the nasal vestibule.

BACKGROUND: The purpose of this study was to evaluate outcome and toxicity profile after primary brachytherapy for squamous cell carcinoma of the nasal vestibule. METHODS: A retrospective study was conducted for patients with Wang classification T1 to 2 cN0 squamous cell carcinoma of the nasal vestibule who received primary treatment with brachytherapy between 1992 and 2010. Tumor control, acute skin, mucosal, and late cartilage toxicity were scored. RESULTS: Of 60 patients (T1, 50; T2, 10), 38 were treated with an interstitial implant and 22 by a mold technique. The 3-year local, regional, and locoregional control rates were 91%, 93%, and 84%, respectively. Tumor diameter <1.5 cm resulted in a better local (p = .02) and regional (p = .05) control. The cumulative incidence of moist skin desquamation and confluent mucositis was 64% and 82%, respectively. The actuarial incidence of chondritis and/or chondronecrosis was 19%. CONCLUSION: Primary brachytherapy for Wang T1 to 2 squamous cell carcinoma of the nasal vestibule offers excellent tumor control rates with acceptable toxicity and preservation of anatomy.