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IntroductionPatients developing acute radiotherapy induced dermatitis or oral mucositis commonly experience pain. When severe, this radiotherapy-associated pain (RAP) can necessitate treatment breaks; unfortunately, in a variety of cancers, prolongation of the radiotherapy course has been associated with early cancer relapse and/or death. This is often attributed to accelerated repopulation, but it is unknown whether pain or pain signaling constituents might alter tumor behavior and hasten metastatic disease progression. We studied this by testing the hypothesis that severe acute RAP at one site can hasten tumor growth at a distant site.MethodsMice underwent single fraction tongue irradiation (27 Gy, or 0 Gy “sham” control) to induce severe glossitis. At the time of maximal oral RAP, one of three luciferase-transfected tumor cell lines were injected via tail vein (4T1, B16F10, MOC2; each paired to their syngeneic host: BALB/c or C57BL/6); tumor burden was assessed via in vivo transthoracic bioluminescence imaging and ex vivo pulmonary nodule quantification. Survival was compared using Kaplan-Meier statistics.ResultsTongue irradiation and resultant RAP promoted lung tumor growth of 4T1-Luc2 cells in BALB/c mice. This effect was not a result of off-target radiation, nor an artefact of environmental stress caused by standard (subthermoneutral) housing temperatures. RAP did not affect the growth of B16F10-Luc2 cells, however, C57BL/6 mice undergoing tail vein injection of MOC2-Luc2 cells at the time of maximal RAP experienced early lung tumor-attributable death. Lung tumor growth was normalized when RAP was reduced by treatment with resiniferatoxin (300 µg/kg, subcutaneously, once).DiscussionThis research points towards radiation-induced activation of capsaicin-responsive (TRPV1) neurons as the cause for accelerated growth of tumors at distant (unirradiated) sites.

BackgroundPatients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear.MethodsPatients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type.ResultsPatients who underwent surgery were younger (P=.02) and had more appendicular tumors (P

PurposeChemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.Patients and methodsThis was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).ResultsFive hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.ConclusionFor localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.