Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Integrating actors into a simulation program: a primer.

We describe our more than 10 years' experience working with actors and provide a "how-to" guide to recruiting, auditioning, hiring, training, and mentoring actors for work as simulated patients in simulation programs. We contend that trained actors add great realism, richness, and depth to simulation-based training programs. The actors experience satisfaction from their contributions, and their skill and improvisational talent allow programs to offer ethical and relational training, customized to a wide range of practitioners and adapted across a variety of health care conversations. Such learning opportunities can directly address Accreditation Council for Graduate Medical Education core competencies in preparing capable, confident, and empathic health care practitioners.

Exploring the potential of mixed-source brachytherapy for the treatment of cervical cancer using high-dose rate 192Ir and/or 50 kV electronic sources.

PURPOSE: In this study, computer modeling was used to compare the relative doses with the bladder, rectum, and bowel when two different brachytherapy modalities were used to treat cervical cancer with a tandem and ovoid applicator. A standard high-dose rate (HDR) (192)Ir treatment plan was compared with a "mixed-source" brachytherapy (MSB) treatment plan in which a 50 kV electronic brachytherapy X-ray source was substituted for (192)Ir as the tandem source. METHODS AND MATERIALS: A total of 15 three-dimensional CT data sets from cervical cancer patients previously treated with tandem and ovoid applicator were evaluated for the study. Bladder, rectum, bowel, and target volumes were contoured and separate treatment plans were created for MSB and HDR (192)Ir applications. Dose-volume histograms were analyzed for each organ at risk. RESULTS: The mean %V(25) for the bladder was 43% vs. 70% for MSB and HDR (192)Ir methods, respectively. Similarly, for the rectum mean %V(25) was 34% vs. 48% for MSB and HDR (192)Ir. For the bowel, the mean %V(25) was 28% vs. 43% for the MSB and HDR (192)Ir methods, respectively. In 16 of 45 organs at risk, %D(2 cc) values were higher for MSB than HDR (192)Ir. CONCLUSIONS: MSB is capable of providing target coverage to the cervix, uterus, and paracervical regions equivalent to that provided by HDR (192)Ir, while significantly reducing the overall dose to the bladder, rectum, and bowel. This reduction is associated with small regions of increased dose in a significant proportion of patients.

Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma.

PURPOSE: The combination of oxaliplatin, 5-fluorouracil, and leucovorin with concurrent radiotherapy was demonstrated to be a safe regimen for locally advanced esophageal carcinoma in a prior phase I study. We now report the efficacy data for 42 patients treated with this regimen. METHODS: Each chemotherapy cycle lasted 29 days and consisted of 5-fluorouracil, 180 mg/m2 protracted-infusion from days 1 to 29, and oxaliplatin, 85 mg/m2 on days 1, 15, and 29. The first cycle was administered concurrently with radiation. The radiation field included regional lymph nodes as well as the primary tumor or tumor bed to a dose of 50.4 Gy in 28 fractions. After concurrent chemoradiotherapy, 1 to 2 additional cycles of chemotherapy were administered. If esophagectomy was indicated, it occurred 4 weeks after completion of concurrent chemoradiotherapy. In the adjuvant group, concurrent chemoradiotherapy was initiated 4 weeks after surgery. RESULTS: Median age was 61 years (range 38-78 years); 30 (71%) of the patients were male. Thirty-three patients had adenocarcinoma, and 9 had squamous cell carcinoma. Concurrent chemoradiotherapy was administered preoperatively (group 1) in 24 patients, definitively (group 2) in 13 patients, and as adjuvant treatment (group 3) in 5 patients. In group 1, 16 patients were down-staged including 1 patient with minimal residual disease and 5 with a complete pathologic response; 4 patients were not down-staged, and 4 did not undergo esophagectomy (2 progressed, 1 died of unrelated causes, and 1 refused). In group 2, 1 patient had a complete clinical response, 4 others were down-staged, 2 had stable disease, and 6 progressed. Four patients in group 3 progressed. Median survival was 28 months for group 1, 12 months for group 2, and not reached at 14 months for group 3. There was one grade 4 toxicity (anaphylaxis) in group 2. Grade 3 toxicities were reported for 5 patients in group 1 and 1 patient in group 2. They consisted of hypotension (n=1), fatigue (n=2), diarrhea (n=2), neuropathy (n=1), mucositis (n=1), pneumonitis (n=1), dehydration (n=1), emesis (n=1), and weight loss (n=1). CONCLUSIONS: Our study supports the incorporation of oxaliplatin into a multimodal concurrent chemoradiotherapy protocol for locally advanced esophageal cancer.