Ironwood Cancer and Research Centers

South Tucson, AZ, United States

Ironwood Cancer and Research Centers

South Tucson, AZ, United States

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Allison R.R.,21st Century Oncology Carolina Radiation Medicine | Ambrad A.A.,Ironwood Cancer and Research Centers | Arshoun Y.,Allegheny General Hospital | Carmel R.J.,John Muir Health Medical Center | And 16 more authors.
Cancer | Year: 2014

BACKGROUND The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format. METHODS A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis. RESULTS Of 120 subjects enrolled, 78 (SC, N = 41; MuGard, N = 37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P = .034) and WHO scores on the last day of radiation therapy (P = .038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts. CONCLUSIONS Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability. Cancer 2014;120:1433-1440. © 2014 Access Pharmaceuticals, Inc. Cancer published by Wiley Periodicals. Inc. on behalf of American Cancer Society. In a randomized, double-blind, placebo-controlled trial, the mucoadhesive hydrogel MuGard proved to be superior to saline-bicarbonate rinse in mitigating oral mucositis (OM) symptoms and delaying OM progression. MuGard was safe and well-tolerated, and favorably affected the rate and incidence of ulcerative lesions, consistent with the patient-reported outcomes. © 2014 American Cancer Society. Access Pharmaceuticals, Inc. Cancer published by Wiley Periodicals. Inc. on behalf of American Cancer Society.


Sechopoulos I.,Emory University | Sechopoulos I.,Ironwood Cancer and Research Centers | Ali E.S.M.,Carleton University | Ali E.S.M.,Ironwood Cancer and Research Centers | And 11 more authors.
Medical Physics | Year: 2015

The use of Monte Carlo simulations in diagnostic medical imaging research is widespread due to its flexibility and ability to estimate quantities that are challenging to measure empirically. However, any new Monte Carlo simulation code needs to be validated before it can be used reliably. The type and degree of validation required depends on the goals of the research project, but, typically, such validation involves either comparison of simulation results to physical measurements or to previously published results obtained with established Monte Carlo codes. The former is complicated due to nuances of experimental conditions and uncertainty, while the latter is challenging due to typical graphical presentation and lack of simulation details in previous publications. In addition, entering the field of Monte Carlo simulations in general involves a steep learning curve. It is not a simple task to learn how to program and interpret a Monte Carlo simulation, even when using one of the publicly available code packages. This Task Group report provides a common reference for benchmarking Monte Carlo simulations across a range of Monte Carlo codes and simulation scenarios. In the report, all simulation conditions are provided for six different Monte Carlo simulation cases that involve common x-ray based imaging research areas. The results obtained for the six cases using four publicly available Monte Carlo software packages are included in tabular form. In addition to a full description of all simulation conditions and results, a discussion and comparison of results among the Monte Carlo packages and the lessons learned during the compilation of these results are included. This abridged version of the report includes only an introductory description of the six cases and a brief example of the results of one of the cases. This work provides an investigator the necessary information to benchmark his/her Monte Carlo simulation software against the reference cases included here before performing his/her own novel research. In addition, an investigator entering the field of Monte Carlo simulations can use these descriptions and results as a self-teaching tool to ensure that he/she is able to perform a specific simulation correctly. Finally, educators can assign these cases as learning projects as part of course objectives or training programs. © 2015 American Association of Physicists in Medicine.


Ramalingam S.S.,Emory University | Janne P.A.,Dana-Farber Cancer Institute | Mok T.,Chinese University of Hong Kong | O'Byrne K.,Princess Alexandra Hospital | And 14 more authors.
The Lancet Oncology | Year: 2014

Background: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. Methods: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. Findings: Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2.6 months (95% CI 1.9-2.8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0.941, 95% CI 0.802-1.104, one-sided log-rank p=0.229). For patients with wild-type KRAS, median progression-free survival was 2.6 months for dacomitinib (95% CI 1.9-2.9) and erlotinib (95% CI 1.9-3.0; stratified HR 1.022, 95% CI 0.834-1.253, one-sided p=0.587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. Interpretation: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. Funding: Pfizer. © 2014 Elsevier Ltd.


PubMed | Institute Of Cancerologie Of Iouest, Princess Alexandra Hospital, Hospital Universitario 12 Of Octubre, Center of Oncology of Poland and 8 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2014

Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study.In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554.Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 26 months (95% CI 19-28) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0941, 95% CI 0802-1104, one-sided log-rank p=0229). For patients with wild-type KRAS, median progression-free survival was 26 months for dacomitinib (95% CI 19-29) and erlotinib (95% CI 19-30; stratified HR 1022, 95% CI 0834-1253, one-sided p=0587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib.Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations.Pfizer.


PubMed | Osaka National Hospital, Jules Bordet Cancer Institute, AZ Nikolaas, Sloan Kettering Cancer Center and 8 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

LBA509 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HRExon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models.NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting.This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HRNCT00863655.


PubMed | Complutense University of Madrid, Institute Of Cancerologie Of Louest, Petrov Research Institute of Oncology, Centro Oncologico Of Galicia and 12 more.
Type: | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models.BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after 125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility.As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 vs 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 vs 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia.Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.


PubMed | Osaka National Hospital, Novartis, University of Houston, Sloan Kettering Cancer Center and 9 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

142 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit.Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox models.NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 in EVE + EXE arm and 70 in EXE arm) whose baseline characteristics and clinical outcome were comparable to the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE + EXE over EXE was maintained in the subgroups defined by each of the 9 genes with a mutation rate >10% (e.g., PIK3CA, FGFR1, CCND1) or when less frequently mutated genes (e.g., PTEN, AKT1) were included in their respective pathways. Patients with 0 or 1 genetic alteration in PI3K or FGFR pathways or CCND1 had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to EVE in this setting.This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. The preliminary results suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated.NCT00863655.


Dragun A.E.,University of Louisville | Harper J.L.,Medical University of South Carolina | Olyejar S.E.,Ironwood Cancer and Research Centers | Zunzunegui R.G.,Tanner Medical Center | Wazer D.E.,Brown University
Brachytherapy | Year: 2011

Purpose: To analyze toxicity and cosmesis in patients with collagen vascular disease (CVD) treated with accelerated partial breast irradiation (APBI) via high-dose-rate (HDR) brachytherapy. Methods and Materials: This is a pooled analysis of patients with early stage and in situ breast cancer with CVD treated with adjuvant multicatheter or balloon brachytherapy. Physicians at multiple institutions were asked to review their experience and report data regarding toxicity and cosmesis in patients with CVD. All patients fit American Society of Breast Surgeons recommendations for APBI and were treated with HDR brachytherapy with ≥3 months followup. Results: Nine cases from five institutions are the subject of this analysis. The median patient age was 54 years and median followup was 31 months. All patients had documented history and active signs/symptoms of rheumatoid arthritis, systemic lupus erythematosis, psoriatic arthritis, or scleroderma. All patients had received medical therapy for CVD in the past, and 78% were under active treatment at the time of brachytherapy. All the patients were treated with multicatheter or balloon (MammoSite [Hologic, Inc., Marlboro, MA], MammoSite ML [Hologic, Inc., Marlboro, MA], or Contura [Senorx, Irvine, CA]) brachytherapy with a median volume of 45.5. cc and a median skin distance of 7.5. mm. Acute toxicity included Grade 1 skin erythema (5) and catheter-site wound dehiscence (1). Late toxicity included seroma (5), induration (5), pain (2), telangectasia (2), and superficial infection (1). Cosmesis was excellent or good for all the patients. Conclusions: Women with CVD have a toxicity and cosmesis profile consistent with other APBI series. Although confirmatory data is needed, it may not be necessary to exclude these patients from clinical trials of APBI. © 2011 American Brachytherapy Society.


PubMed | Swedish Cancer Institute and Ironwood Cancer and Research Centers
Type: Journal Article | Journal: Medical physics | Year: 2017

In this study, we evaluated the performance of an Elekta linac in the delivery of gated radiotherapy. We examined whether the use of either a short gating window or a long beam hold impacts the accuracy of the delivery METHODS: The performance of an Elekta linac in the delivery of gated radiotherapy was assessed using a 20cmX 20cm open field with the radiation delivered using a range of beam-on and beam-off time periods. Two SBRT plans were used to examine the accuracy of gated beam delivery for clinical treatment plans. For the SBRT cases, tests were performed for both free-breathing based gating and for gated delivery with a simulated breath-hold. A MatriXX 2D ion chamber array was used for data collection, and the gating accuracy was evaluated using gamma score.For the 20cmX20cm open field, the gated beam delivery agreed closely with the non-gated delivery results. Discrepancies in the agreement, however, began to appear with a 5-to-1 ratio of the beam-off to beam-on. For these tight gating windows, each beam-on segment delivered a small number of monitor units. This finding was confirmed with dose distribution analysis from the delivery of the two VMAT plans where the gamma score(1%,2%/1mm) showed passing rates in the range of 95% to 100% for gating windows of 25%, 38%, 50%, 63%, 75%, and 83%. Using a simulated sinusoidal breathing signal with a 4 second period, the gamma score of freebreathing gating and breath-hold gating deliveries were measured in the range of 95.7% to 100%.The results demonstrate that Elekta linacs can be used to accurately deliver respiratory gated treatments for both free-breathing and breath-hold patients. The accuracy of beams delivered in a gated delivery mode at low small MU proved higher than similar deliveries performed in a non-gated (manually interrupted) fashion.


Shtivelband M.I.,Ironwood Cancer and Research Centers
Breast | Year: 2013

Although patients with hormone receptor (HR)-positive breast cancer are successfully treated with endocrine therapy, many tumors go on to develop resistance to these agents. Studies have determined that mechanisms of resistance to endocrine therapy are quite complex and can involve a multitude of signal transduction pathways, either through direct association with the estrogen receptor or through cross-talk with other pathways. Preclinical studies have suggested the therapeutic importance of the mammalian target of rapamycin (mTOR) pathway and that inhibiting this pathway may restore sensitivity to endocrine therapy. The oral mTOR inhibitor everolimus has been extensively studied for breast cancer. Clinical studies suggest that everolimus in combination with endocrine therapy improves progression-free survival and is well tolerated. A combined approach, targeting both mTOR signal transduction and the HR pathways, promises to take clinical research in a new direction for the treatment of HR-positive advanced breast cancer. © 2013 Elsevier Ltd.

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