Reversible Acute Toxicity Research Articles

RTRB-08HELICAL TOMOTHERAPY-BASED CRANIOSPINAL IRRADIATION: MATURE OUTCOMES OF A PROSPECTIVE FEASIBILITY STUDY

PURPOSE: To report mature outcomes in a cohort of patients treated on a prospective feasibility study of helical tomotherapy-based craniospinal irradiation (CSI). METHODS: After written informed consent, patients needing neuraxial irradiation were accrued and treated on an Institutional Review Board-approved study. Following CSI, patients received boost irradiation based upon histology and extent of disease. Concurrent chemotherapy was not given during CSI; however patients with high-risk disease received sequential adjuvant systemic chemotherapy. Patients were followed up longitudinally for survival and toxicity. RESULTS: Twenty patients (median age of 15 years) constituted the study cohort. Tomotherapy-based CSI was well tolerated with self-limiting and reversible acute toxicity. Four (20%) patients needed growth factor or platelet support during CSI. Significant late neuro-toxicity was seen in only 1 (5%) patient. None of the patients developed symptomatic radiation pneumonitis or second new malignancy. At a median follow-up of 62 months (inter-quartile range 24-71 months), the 5-year progression-free survival and overall survival (with respective standard error) for the entire cohort was 50% (+11.2%) and 55% (+11.1%) respectively. Outcomes within the cohort varied significantly; patients with favorable biology disease had good outcomes while patients with high-risk, metastatic, or recurrent disease fared poorly reflecting inherently aggressive biology. CONCLUSIONS: Helical tomotherapy is an ideal platform for planning, verification and delivery of supine CSI in clinical practice resulting in moderate, self-limiting, reversible acute toxicity and modest delayed toxicity. Patterns of failure and survival outcomes are largely dependent upon disease biology and are not any different compared to conventional techniques.

Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease.

Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin-resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods ≤3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods ≤9 months after STZ-icv treatment. Male Wistar rats were given vehicle (control)- or STZ (3 mg/kg)-icv injection and killed 0.5, 1, 3, 6 and 9 months afterwards. Insulin-1 (Ins-1), IR, phospho- and total (p/t)-glycogen synthase kinase 3-β (GSK-3β), p/t-tau and insulin degrading enzyme (IDE) mRNA and/or protein were measured. Acute upregulation of tau and IR mRNA (p < 0.05) was followed by a pronounced downregulation of Ins-1, IR and IDE mRNA (p < 0.05) in the course of time. Acute decrement in p/t-tau and p/t-GSK-3β ratios (p < 0.05) was followed by increment in both ratios (3-6 months, p < 0.05) after which p/t-tau ratio demonstrated a steep rise and p/t-GSK-3β ratio a steep fall up to 9 months (p < 0.05). Acute decline in IDE and IR expression (p < 0.05) was followed by a slow progression of the former and a slow recovery of the latter in 3-9 months. Results indicate a biphasic pattern in time dependency of onset and progression of changes in brain insulin signalling of STZ-icv model (partly reversible acute toxicity and chronic AD-like changes) which should be considered when using this model as a tool in translational sAD research.

Keys to Personalized Care in Pancreatic Oncology

Morethanadecadeago,investigatorsfromVirginiaMasonMedical Centerreportedapromising3-yearoverallsurvivalrateof64%(95%CI, 56% to 72%) in a group of 43 patients who received a novel adjuvant regimencomprisinginterferonalfa,infusionalfluorouracil,cisplatin,and external-beamradiationtherapy(45-54Gyover5to6weeks),followedby twomorecyclesoffluorouracil,afterresectionofpancreaticcancer.The GI toxicity in particular was significant, leading to a delay of chemoradiotherapyin70%ofthepatientsandhospitalizationin42%. 1 Two different institutions and one cooperative group have since reported similar findings with this regimen in single-arm prospective studies: potentially clinically relevant improvement in survival at the cost of significant but reversible acute toxicity. 2-4

A preliminary result of concurrent chemoradiation with weekly cisplatin in elderly nasopharyngeal carcinoma patients

Conclusion. A weekly regimen of cisplatin 30 mg/m2 as concurrent chemoradiation (CCRT) was effective in elderly nasopharyngeal carcinoma (NPC) patients, with acceptable and reversible acute toxicity following CCRT therapy. Objectives. The purpose of this retrospective study was to evaluate the efficacy, toxicity, and tolerability of a multi-modal treatment strategy in elderly NPC patients. Subsequent systemic adjuvant chemotherapy was administered to achieve systemic control. Patients and methods. From December 2002 to December 2006, 26 NPC patients over 60 years of age who had stage IIB to IV NPC were evaluated in this retrospective analysis. The CCRT chemotherapy protocol consisted of eight weekly doses of cisplatin 30 mg/m2 administered in an outpatient setting. Adjuvant systemic chemotherapy consisted of four monthly cycles of cisplatin (20 mg/m2/day) plus 5-fluorouracil (1000 mg/m2/day) for 5 consecutive days. Study end points included treatment outcome, compliance, and toxicity. Results. The 2-year overall survival, disease-free survival, local control, and distant metastasis-free rate were 87%, 73%, 92%, and 76%, respectively. Over 80% of patients were able to take more than six doses of weekly cisplatin during CCRT; however, nearly half of the patients had grade 3 hematological toxicity during adjuvant therapy requiring treatment modification or cessation of further adjuvant therapy.

Five year results of a randomized trial comparing hyperfractionated to conventional radiotherapy over four weeks in locally advanced head and neck cancer

Background and Purpose Fractionation strategies delivered over 4 weeks are of clinical and radiobiological interest because treatment is completed before radiotherapy (RT) induced clonogen proliferation commences in earnest approximately 3 to 4 weeks into a course of RT. We wished to test the clinical hypothesis that an increased total dose delivered over 4 weeks with smaller than standard doses per fraction in locally advanced squamous cell carcinoma (SCC) may result in relative protection of late responding tissues and an increased tumor control compared to a conventional daily course in the same overall time. Materials and methods Between 1988 and 1995 a randomized controlled trial employing RT alone was undertaken at the Princess Margaret Hospital that included 331 eligible patients with T3 or T4 N0 or any N-positive oropharynx, hypopharynx, or larynx primary SCC. RT was randomly assigned to one of two 4 week schedules, either 51 Gy in 20 equal daily fractions, termed conventional fractionation (CF), or 58 Gy in 40 equal fractions given twice per day as a hyperfractionated (HF) experimental arm. Results The 5-year local relapse rate was reduced in the HF (41%) compared to the CF arm (49%). This difference was marginally not significant ( p = 0.082) when the effect was not adjusted. When the effect of the treatment was adjusted by Cox model for clinical factors that included N-category, ECOG performance status, site of disease, T-category, age, hemoglobin, and gender the HF achieved a significant effect ( p = 0.02). Survival (40% vs. 30%) was also improved with HF compared to CF arm. This difference was only marginally not significant ( p = 0.069) but again achieved statistical significance when the model was adjusted for clinical factors ( p = 0.01). Similar results were observed for disease free survival. Although reversible acute toxicity was increased with HF, the overall 5-year rate of grade 3 and 4 late toxicity for the CF was 10.5% compared to 7.7% in the higher dose HF arm. Conclusions HF delivered in 4 weeks permits enhanced RT doses achieving improved tumor control, without increased late toxicity, compared to daily fractionated radiotherapy in the same overall time.

Phase I evaluation of hyperthermia equipment--University of Utah institutional report.

At the University of Utah Medical Center the thrusts of the effort with respect to the NCl Hyperthermia Equipment Evaluation Contract have been threefold. The first objective was the development of a reliable thermometry system for collecting temperature information as a function of space as well as time. The second objective was the evaluation and comparison of a number of hyperthermia devices, particularly with respect to deep-heating devices, and specifically as pertains to the BSD annular phased array system (AA) and its various configurations. The third objective was to develop methodology for analysing hyperthermia data which could be easily adapted toward device comparison. In the period from 10/81-1/86, a total of 137 patients were treated with one or more of 10 devices, totalling 199 device evaluations at the University of Utah Medical Center or the subcontracting institution, LDS Hospital. Of these, 132 device evaluations involved deep-seated tumours. The AA was found to be feasible for deep pelvic regional hyperthermia, although the frequency of reversible acute toxicity was high, and achievement of desired temperatures was frequently limited by one of several factors. The radiative electromagnetic wave applicators which were evaluated for treatment of superficial tumours were found to be mostly feasible for tumours of the thoracic and extremities regions, although the heating patterns were frequently too shallow or too small in area, when compared with the size of the lesion.