A Phase 1b Clinical Study of Intravesical Photodynamic Therapy in Patients with Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer.

Background: A phase 1b study of photosensitizer TLD-1433-mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. Objective: The primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design setting and participants: Six BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysis: Patients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitations: PDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. Conclusions: PDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summary: Photodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

Pulmonary rehabilitation compared with brief advice given for severe chronic obstructive pulmonary disease.

PURPOSE: The objective of this study was to compare the effectiveness of a short-term pulmonary rehabilitation program with brief advice given to patients with severe ventilatory impairment due to chronic obstructive pulmonary disease (COPD). METHODS: One hundred three patients with severe COPD, defined as having forced expiratory volume in 1 second < 40% predicted, were randomly assigned to rehabilitation or to brief advice. Fifty-four patients attended a rehabilitation program twice a week for 6 weeks. Forty-nine patients attended a single session during which they were given printed educational materials and verbal advice and guidance about exercise. Subjects were reassessed at 3 months. RESULTS: The shuttle walking distance increased significantly in the rehabilitation group by 43 meters. The increase of 23 meters in the brief advice group was significantly less than in the rehabilitation group. Improvements in quality of life in the rehabilitation group were small and not clinically significant. CONCLUSIONS: In these patients with severe COPD, a short outpatient rehabilitation program of low intensity achieved small but significant improvement in shuttle walking distance, compared with brief advice. The improvements in quality of life were modest and did not reach statistical significance, although in some instances the confidence limits include differences that approach clinical significance. The relatively small effect may be due to the low intensity of the program or to the severity of the subjects' ventilatory impairment.

Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial.

OBJECTIVE: To determine whether patients with locally advanced non-small cell lung cancer unsuitable for resection or radical radiotherapy, and with minimal thoracic symptoms, should be given palliative thoracic radiotherapy immediately or as needed to treat symptoms. DESIGN: Multicentre randomised controlled trial. SETTING: 23 centres in the United Kingdom, Ireland, and South Africa. PARTICIPANTS: 230 patients with previously untreated, non-small cell lung cancer that is locally too advanced for resection or radical radiotherapy with curative intent, with minimal thoracic symptoms, and with no indication for immediate thoracic radiotherapy. INTERVENTIONS: All patients were given supportive treatment and were randomised to receive palliative thoracic radiotherapy either immediately or delayed until needed to treat symptoms. The recommended regimens were 17 Gy in two fractions one week apart or 10 Gy as a single dose. MAIN OUTCOME MEASURES: Primary--patients alive and without moderate or severe cough, chest pain, haemoptysis, or dyspnoea six months from randomisation, as recorded by clinicians. Secondary--quality of life, adverse events, survival. RESULTS: From December 1992 to May 1999, 230 patients were randomised. 104/115 of the patients in the immediate treatment group received thoracic radiotherapy (90 received one of the recommended regimens). In the delayed treatment group, 48/115 (42%) patients received thoracic radiotherapy (29 received one of the recommended regimens); 64 (56%) died without receiving thoracic radiotherapy; the remaining three (3%) were alive at the end of the study without having received the treatment. For patients who received thoracic radiotherapy, the median time to start was 15 days in the immediate treatment group and 125 days in the delayed treatment group. The primary outcome measure was achieved in 28% of the immediate treatment group and 26% of patients from the delayed treatment group (27/97 and 27/103, respectively; absolute difference 1.6%, 95% confidence interval -10.7% to 13.9%). No evidence of a difference was observed between the two treatment groups in terms of activity level, anxiety, depression, and psychological distress, as recorded by the patients. Adverse events were more common in the immediate treatment group. Neither group had a survival advantage (hazard ratio 0.95, 0.73 to 1.24; P=0.71). Median survival was 8.3 months and 7.9 months, and the survival rates were 31% and 29% at 12 months, for the immediate and delayed treatment groups, respectively. CONCLUSION: In minimally symptomatic patients with locally advanced non-small cell lung cancer, no persuasive evidence was found to indicate that giving immediate palliative thoracic radiotherapy improves symptom control, quality of life, or survival when compared with delaying until symptoms require treatment.