Mechanisms of Efficacy of the FGFR1-3 Inhibitor AZD4547 in Pediatric Solid Tumor Models.

Children with aggressive pediatric solid tumors have poor outcomes and novel treatments are needed. Pediatric solid tumors demonstrate aberrant expression and activity of the fibroblast growth factor receptor (FGFR) family, suggesting FGFR inhibitors may be effective therapeutic agents. AZD4547 is a multikinase inhibitor of the FGFR1-3 kinases, and we hypothesized that AZD4547 would be effective in pediatric solid tumor preclinical models. We evaluated the effects of AZD4547 on neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma cells alone and in combination with STAT3 inhibition. Continuous live cell imaging was used to measure induction of apoptosis and effects on migration. Receptor inhibition and intracellular signaling were examined by western blotting. AZD4547 treatment resulted in decreased cell confluence, increased apoptosis and reduced cell migration in all tested cell lines. AZD4547 treatment led to decreased phosphorylation of signaling proteins involved in cell survival and apoptotic pathways and increased phosphorylation of STAT3, and treatment of cell lines with AZD4547 combined with STAT3 inhibition demonstrated increased efficacy. Sensitivity to AZD4547 appears to be mediated by effects on the Ras/MAPK and JAK/STAT pathways, and AZD4547 represents a potential novel therapeutic agent for children with solid tumors.

Technological advances in cancer and future spending by the elderly.

This paper forecasts the consequences of scientific progress in cancer for total Medicare spending between 2005 and 2030. Because technological advance is uncertain, widely varying scenarios are modeled. A baseline scenario assumes that year 2000 technology stays frozen. A second scenario incorporates recent cancer treatment advances and their attendant discomfort. Optimistic scenarios analyzed include the discovery of an inexpensive cure, a vaccine that prevents cancer, and vastly improved screening techniques. Applying the Future Elderly Model, we find that no scenario holds major promise for guaranteeing the future financial health of Medicare.

Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms.

PURPOSE: In a single-institution, double-blind, prospective, randomized trial, we determined whether oral aloe vera gel can reduce radiation-induced mucositis in head-and-neck cancer patients. METHODS AND MATERIALS: We randomized 58 head-and-neck cancer patients between oral aloe vera and placebo. To be included in this Phase II protocol, patients had to be treated with radiotherapy with curative intent at Stanford University between February 1999 and March 2002. We examined patients biweekly for mucositis at 15 head-and-neck subsites and administered quality-of-life questionnaires. RESULTS: Patients in the aloe and placebo groups were statistically identical in baseline characteristics. By the end of treatment, the two groups were also statistically identical in maximal grade of toxicity, duration of Grade 2 or worse mucositis, quality-of-life scores, percentage of weight loss, use of pain medications, hydration requirement, oral infections, and prolonged radiation breaks. CONCLUSION: In our randomized study, oral aloe vera was not a beneficial adjunct to head-and-neck radiotherapy. The mean quality-of-life scores were greater in the aloe vera group, but the differences were not statistically significant. Oral aloe vera did not improve tolerance to head-and-neck radiotherapy, decrease mucositis, reduce soreness, or otherwise improve patient well-being.

Prognostic value of Chinese race in nasopharyngeal cancer.

PURPOSE: Nasopharyngeal carcinoma is rare in the United States and common in southern China. Evaluating American patients treated using a uniform technique and staged with CT scanning, we determined whether Chinese and non-Chinese patients differ in presentation and outcome. METHODS AND MATERIALS: Between 1979 and 1996, 172 patients treated at Massachusetts General Hospital received primary radiotherapy with curative intent for nasopharyngeal carcinoma. Forty-one patients (24%) were of Chinese descent, and 41% of cancers were classified as having lymphoepithelioma histologic features. Most patients received twice-daily radiotherapy and a brachytherapy boost, receiving a median dose of 72 Gy to the nasopharynx. RESULTS: At the initial presentation, the Chinese patients were significantly younger, less likely to smoke, more likely to have Stage IV disease, and more likely to have cancer with lymphoepithelioma histologic features. After controlling for stage, age, histologic type, and treatment variables, Chinese patients were significantly more likely to develop distant metastases (p <0.05). Although Chinese race does not predict for local control or overall survival, a younger age, continued tobacco use, total radiation dose, and lymphoepithelioma histologic features do. CONCLUSION: In a large retrospective analysis of nasopharyngeal carcinoma, Chinese and non-Chinese patients differed significantly in presentation-age, stage, and histologic features-and outcome. We suggest as an explanation differences in intrinsic tumor biology rather than differences in treatment techniques or staging systems. Additional trials in endemic countries are needed to confirm the optimal treatment of Chinese and Chinese-American patients.

Role of neck surgery in conjunction with radiation in regional control of node-positive cancer of the oropharynx.

For patients with clinically node-positive oropharynx cancer treated with radiotherapy, planned neck dissection is controversial. We investigated whether neck surgery after radiation reduces nodal recurrence. Between 1970 and 1995, 263 patients at Massachusetts General Hospital received radiotherapy for clinically node-positive base of tongue or tonsil carcinomas. Patients received three different types of treatment: neck surgery followed by radiation (SR)-50 patients; radiation alone (RT)-160 patients; and radiation followed by surgery (RS)-53 patients. Median patient follow-up was 28 months. SR patients have an 84% complete response (CR) rate, RT patients 76%, and RS patients 13%. In multivariate analysis, among patients with a CR, the three treatment groups have the same regional control rates. Among patients with an incomplete response, the RS treatment group is 67% (p < 0.01) and 86% (p < 0.01) less likely to have recurrence than the RT and SR groups, respectively. Neck dissection after radiation therapy improves regional control for patients without a complete clinical response to radiation therapy but not for those with a CR. Despite higher CR rates, neck dissection before radiation confers no regional control benefit. We therefore recommend that primary radiotherapy with neck dissection be reserved for those without a complete clinical response.