Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis.

BACKGROUND: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma. METHODS: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. RESULTS: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. CONCLUSIONS: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

Delayed and intermittent CPR for severe accidental hypothermia.

INTRODUCTION: Cardiac arrest (CA) in patients with severe accidental hypothermia (core temperature <28 °C) differs from CA in normothermic patients. Maintaining CPR throughout the prehospital period may be impossible, particularly during difficult evacuations. We have developed guidelines for rescuers who are evacuating and treating severely hypothermic CA patients. METHODS: A literature search was performed. The authors used the findings to develop guidelines. RESULTS: Full neurological recovery is possible even with prolonged CA if the brain was already severely hypothermic before CA occurred. Data from surgery during deep hypothermic CA and prehospital case reports underline the feasibility of delayed and intermittent CPR in patients who have arrested due to severe hypothermia. CONCLUSIONS: Continuous CPR is recommended for CA due to primary severe hypothermia. Mechanical chest-compression devices should be used when available and CPR-interruptions avoided. Only if this is not possible should CPR be delayed or performed intermittently. Based on the available data, a patient with a core temperature <28 °C or unknown with unequivocal hypothermic CA, evidence supports alternating 5 min CPR and ≤5 min without CPR. With core temperature <20 °C, evidence supports alternating 5 min CPR and ≤10 min without CPR.

Phase I/II study of inhaled doxorubicin combined with platinum-based therapy for advanced non-small cell lung cancer.

PURPOSE: We have shown the feasibility of administering inhaled doxorubicin to patients with cancer. This study evaluated inhaled doxorubicin combined with cisplatin and docetaxel in patients with non-small cell lung cancer. The principal objective was to determine safety and, secondarily, efficacy. EXPERIMENTAL DESIGN: Patients who had chemo-naïve advanced non-small cell lung cancer were enrolled in the study. Adequate organ and pulmonary function was required: diffusing capacity for carbon monoxide/forced expiratory volume in 1 second/forced vital capacity > or =50%, resting/exercise O(2) saturation > or =90%/85%. In phase I, doxorubicin was escalated: dose level 1 (6 mg/m(2)) and level 2 (7.5 mg/m(2)). Escalation was permitted if < or =2 of 6 patients experienced pulmonary dose-limiting toxicity (grade 2 Radiation Therapy Oncology Group lung morbidity; resting O(2) saturation of <85%; decrease in diffusing capacity for carbon monoxide, forced vital capacity, or forced expiratory volume in 1 second of > or =20% from baseline or < or =30% of predicted; or grade 3 Common Terminology Criteria for Adverse Events version 3.0 pulmonary toxicity). Doses of cisplatin and docetaxel were 75 mg/m(2). Treatments and pulmonary function tests were repeated every 21 days, with up to eight cycles for responding patients. RESULTS: Twenty-eight patients were treated at level 1 and eight patients at level 2. Doxorubicin was escalated to 7.5 mg/m(2), however, after two patients developed pulmonary dose-limiting toxicity; the remainder were treated at 6.0 mg/m(2). Twenty-four evaluable patients received at least two courses or had progressive disease following the first course at the phase II dose. Toxicity was associated with i.v. chemotherapy although one patient had delayed pulmonary toxicity responding to corticosteroids and oxygen. Seven (29%) evaluable patients responded (six partial responses and one complete response) and 13 (54%) patients had stable disease for up to eight cycles. CONCLUSION: Although this combination was safe, the primary objective was not met and will not be pursued further.

Eye problems in mountain and remote areas: prevention and onsite treatment--official recommendations of the International Commission for Mountain Emergency Medicine ICAR MEDCOM.

Although eyes are not frequently injured in the mountains, they are exposed to many adverse factors from the environment. This article, intended for first responders, paramedics, physicians, and mountaineers, is the consensus opinion of the International Commission for Mountain Emergency Medicine (ICAR-MEDCOM). Its aim is to give practical advice on the management of eye problems in mountainous and remote areas. Snow blindness and minor injuries, such as conjunctival and corneal foreign bodies, could immobilize a person and put him or her at risk of other injuries. Blunt or penetrating trauma can result in the loss of sight in the eye; this may be preventable if the injury is managed properly. In almost all cases of severe eye trauma, protecting the eye and arranging an immediate evacuation are necessary. The most common eye problems, however, are due to ultraviolet light and high altitude. People wearing contact lenses and with previous history of eye diseases are more vulnerable. Any sight-threatening eye problem or unexplained visual loss at high altitude necessitates descent. Wearing appropriate eye protection, such as sunglasses with sidepieces and goggles with polarized or photochromic lenses, could prevent most of the common eye problems in mountaineering.