PubMed | Wichita Community Clinical Oncology Program, Toledo Community Hospital Oncology Program CCOP, Michigan Cancer Research Consortium, Meritcare Hospital CCOP and 4 more.
Type: Clinical Trial, Phase II | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016
Carboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients.A tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m(2)) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy.Of 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade 3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard.Everolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens.NCT00936702.
PubMed | Toledo Community Hospital Oncology Program CCOP, Mayo Medical School, Carle Cancer Center, University of New Mexico and 3 more.
Type: Journal Article | Journal: International journal of radiation oncology, biology, physics | Year: 2016
To provide confirmatory evidence on the use of sulfasalazine to reduce enteritis during pelvic radiation therapy (RT), following 2 prior single-institution trials suggestive that benefit existed.A multi-institution, randomized, double-blind, placebo-controlled phase 3 trial was designed to assess the efficacy of sulfasalazine versus placebo in the treatment of RT-related enteritis during RT including the posterior pelvis (45.0-53.5Gy) and conducted through a multicenter national cooperative research alliance.Patients received 1000mg of sulfasalazine or placebo orally twice daily during and for 4weeks after RT. The primary endpoint was maximum severity of diarrhea (Common Terminology Criteria for Adverse Events version 4.0). Toxicity and bowel function were assessed by providers through a self-administered bowel function questionnaire taken weekly during RT and for 6weeks afterward.Eighty-seven patients were enrolled in the trial between April 29, 2011, and May 13, 2013, with evenly distributed baseline factors. At the time of a planned interim toxicity analysis, more patients with grade 3 diarrhea received sulfasalazine than received placebo (29% vs 11%, P=.04). A futility analysis showed that trial continuation would be unlikely to yield a positive result, and a research board recommended halting study treatment. Final analysis of the primary endpoint showed no significant difference in maximum diarrhea severity between the sulfasalazine and placebo arms (P=.41).Sulfasalazine does not reduce enteritis during pelvic RT and may be associated with a higher risk of adverse events than placebo. This trial illustrates the importance of confirmatory phase 3 trials in the evaluation of symptom-control agents.
PubMed | University of Michigan, Toledo Community Hospital Oncology Program CCOP, University of Pennsylvania, Radiation Therapy Oncology Group Statistical Center and 8 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2015
GSK3 is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3 causes stabilization and nuclear translocation of -catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes.Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3 was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3 was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3 groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3 and OS/DFS.The 3-year OS rates for GSK3Q3 versus GSK3 >Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P = 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value = 0.0081. On multivariable analysis, GSK3 was a significant predictor of OS. Patients with GSK3 >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31-0.96, P value = 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value = 0.092).GSK3 expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9. Clin Cancer Res; 21(24); 5612-8. 2015 AACR.
Jatoi A.,Mayo Medical School |
Soori G.,Missouri Valley Cancer Consortium |
Foster N.R.,Mayo Medical School |
Hiatt B.K.,Iowa Oncology Research Association CCOP |
And 6 more authors.
Journal of Thoracic Oncology | Year: 2010
Based on favorable preliminary clinical data and the need to identify effective, well-tolerated neoadjuvant regimens for patients with locally advanced esophageal cancer, this clinical trial was undertaken. Methods: This phase II study tested 500 mg/m2 neoadjuvant pemetrexed intravenously and carboplatin with an area under the curve of 6 intravenously on days 1 and 22 in conjunction with concomitant radiation of 5040 centigray, which was given in 28 daily fractions of 180 centigray. The primary endpoint was the rate of pathologic complete response. Results: This trial closed early because, during an interim analysis, the primary endpoint fell short. However, 26 eligible patients were accrued. Twenty (74%) were men. Performance scores of 0, 1, and 2 were seen in 16 (59%), 9 (33%), and 2 (7%), respectively. Among eligible patients, 6 of 26 (23%; 95% confidence interval 9-44%) demonstrated a pathologic complete response. Twenty-two underwent a complete cancer resection. The median survival was 17.8 months (95% confidence interval: 12.2-30.7 months). In the neoadjuvant setting, 22 patients had at least one grade 3 or worse adverse event, and 8 patients had at least one grade 4 event. Postoperatively (within 30 days of surgery), there were three deaths, one grade 4 event (thrombosis), and three grade 3 events. Conclusions: The neoadjuvant regimen tested within this phase II trial demonstrated antineoplastic activity but fell short of yielding a complete pathologic response rate that merits further testing. Copyright © 2010 by the International Association for the Study of Lung Cancer.
Jatoi A.,Mayo Medical School |
Nieva J.J.,Montana Cancer Consortium |
Qin R.,Mayo Medical School |
Loprinzi C.L.,Mayo Medical School |
And 7 more authors.
Oncology (Switzerland) | Year: 2012
Background: Effective, non-invasive, palliative strategies for symptomatic malignant ascites are unavailable. This trial explored whether octreotide, an inhibitor of vascular endothelial growth factor, a putative mediator of ascites, prolongs the interval to next paracentesis. Methods: After a baseline paracentesis and a test of short-acting agent, patients with symptomatic ascites were randomly assigned to long-acting octreotide (Sandostatin LAR®) depot 30 mg intramuscularly every month versus 0.9% sodium chloride administered similarly. Patients were then monitored for recurrent, symptomatic ascites. Results: Thirty-three patients were enrolled: 16 assigned to the octreotide and 17 to the control arm. The median time to next paracentesis was 28 and 14 days in the octreotide and placebo arm, respectively (p = 0.17). After adjustment for extracted ascites volume and abdominal girth change, no statistically significant difference between the groups was observed (hazard ratio = 0.52, with a 95% confidence interval of 0.21-1.28; p = 0.15, per Cox model). Octreotide-treated patients described less of abdominal bloating (p = 0.01), abdominal discomfort (p = 0.02), and shortness of breath (p = 0.007) at one month, although other quality of life symptoms were comparable between the arms. Long-acting octreotide was reasonably well tolerated. Conclusion: As prescribed in this trial, octreotide did not seem effective in prolonging the time to next paracentesis, although improvements in symptoms suggest that vascular endothelial growth factor inhibition merits further investigation. Copyright © 2012 S. Karger AG, Basel.
Uhm J.H.,Mayo Medical School |
Ballman K.V.,Mayo Medical School |
Wu W.,Mayo Medical School |
Giannini C.,Mayo Medical School |
And 9 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011
Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS. © 2011 Elsevier Inc.
Moraska A.R.,Mayo Medical School |
Atherton P.J.,Metro Minnesota Community Clinical Oncology Program |
Szydlo D.W.,Michigan Cancer Research Consortium |
Barton D.L.,Carle Cancer Center |
And 6 more authors.
Journal of Supportive Oncology | Year: 2010
Hot flashes are a complication of androgen deprivation therapy for prostate cancer. A phase III study showed that use of low-dose gabapentin was well tolerated and moderately decreased the frequency of hot flashes due to androgen deprivation therapy when taken for 4 weeks. The current study, an open-label continuation of the randomized study, examined the efficacy and toxicity of gabapentin when taken for (an additional) 8 weeks. Patients were allowed to start, or continue, gabapentin and to titrate the dose to maximum efficacy, up to 900 mg/d. They were asked to complete a hot flash diary daily and keep weekly logs of toxicity, satisfaction with hot flash control, and quality of life. The moderate reduction in hot flash frequency and severity in the randomized phase of the study appeared to be maintained during this continuation phase. Men originally receiving the placebo or lowest dose of gabapentin (300 mg/d) had improved hot flash control relative to that at the end of the randomized phase. Minimal adverse effects were reported. These findings suggest that low-dose gabapentin is moderately efficacious for at least 12 weeks of hot flash treatment in men undergoing androgen deprivation therapy for prostate cancer and seems to be well tolerated. (NCT00028572) © 2010 Elsevier Inc.
PubMed | Toledo Community Hospital Oncology Program CCOP, Iowa Oncology Research Association Community Clinical Oncology Program, Cedar Rapids Oncology Project Community Clinic Oncology Program, Mayo Medical School and 3 more.
Type: Journal Article | Journal: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer | Year: 2016
Radiotherapy-related dermatological toxicities over time have not been well quantified. We examined during and immediately following radiation therapy skin toxicities over time in a randomized study of mometasone furoate vs placebo during breast radiotherapy.Patients with breast cancer undergoing radiotherapy to the breast or chest wall were randomized. Symptoms related to skin toxicity were addressed weekly using provider-reported Common Terminology Criteria for Adverse Events (CTCAE v3.0) and 4 patient-reported outcomes (PRO) surveys. We applied repeated measures and risk analysis methodologies.One hundred seventy-six patients were enrolled. By CTCAE, significant differences favoring mometasone were detected over time in all toxicities except skin striae, atrophy, and infection. Statistically significant differences between arms at baseline but not over time occurred for all Linear Analog Self-Assessment. Statistically significant differences occurred for all symptoms in the temporal profile of symptoms as measured by PRO surveys (all P<.001).The use of longitudinal methods enhanced the ability of PRO tools to detect differences between study arms. Our results strengthened the conclusions of the original report that mometasone reduced acute skin toxicities. PRO surveys can accurately assess patients experiences of symptom type and intensity over time and should be included in future clinical trials. For radiotherapy-related dermatological toxicity, we hypothesized that clinically significant differences over time, if any, can be found by repeated measures. We examined the acute skin toxicities in a randomized study of mometasone vs placebo during breast radiotherapy. For secondary end points, we showed that longitudinal methods enhanced the detection of differences between study arms and strengthened the conclusions from the original report. Frequent patient-reported outcome surveys over time should be included in future clinical trials.
Older versus younger patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and stomach: A pooled analysis of eight consecutive North Central Cancer Treatment Group (NCCTG) trials
Jatoi A.,Mayo Medical School |
Foster N.R.,Mayo Medical School |
Egner J.R.,Carle Cancer Center |
Burch P.A.,Mayo Medical School |
And 6 more authors.
International Journal of Oncology | Year: 2010
Whether elderly patients with metastatic esophageal, gastroesophageal, and gastric cancer do as well with chemotherapy as their younger counterparts was investigated in this pooled analysis. In total, 367 patients from 8 consecutive, first-line trials were included: i) etoposide + cisplatin; ii) 5-fluorourucil + leucovorin; iii) 5-fluorouracil + levamisole; iv) irinotecan; v) docetaxel + irinotecan; vi) oxaliplatin + capecitabine; vii) docetaxel + capecitabine; and viii) bortezomib + paclitaxel + carboplatin. One hundred and fifty-four (42%) patients were ≥65 years old (range: 65-86), and 213 younger (range: 20-64). Elderly patients had worse performance scores (2-3): 19 vs. 8% (p<0.0001). Rates of grade 3+ adverse events across all chemotherapy cycles in univariate and multivariate analyses (adjusted for gender, performance score, and stratified by individual study) were higher among elderly patients. Rates of neutropenia, fatigue, infection, and stomatitis in elderly vs. younger patients were 31 vs. 29% (p=0.02 by multivariate analyses); 15 vs. 5% (p=0.01); 9 vs. 4% (p=0.03); 6 vs. 1% (p=0.04). In contrast, duration of chemotherapy, overall survival, and progression-free survival were comparable. Although age should not preclude trial entry, these adverse event rates suggest a need to develop more tolerable regimens for older patients with these malignancies.
Jatoi A.,Mayo Medical School |
Ritter H.L.,Toledo Community Hospital Oncology Program CCOP |
Dueck A.,Mayo Medical School |
Nguyen P.L.,Mayo Medical School |
And 4 more authors.
Lung Cancer | Year: 2010
Purpose: This study tested whether infliximab, a chimeric IgG1kappa monoclonal antibody that blocks tumor necrosis factor (TNF) alpha, improves/stabilizes weight loss in elderly and/or poor performance status patients with metastatic non-small cell lung cancer (NSCLC). Methods: This double-blind trial randomly assigned patients to infliximab/docetaxel (n=32) versus placebo/docetaxel (n=29). The primary endpoint was ≥10% weight gain. Results: Groups were balanced with respect to age, number of prior chemotherapy regimens, baseline weight loss, and performance status. No patient gained ≥10% baseline weight, and early evidence of the lack of efficacy prompted early trial closure. Appetite improvement was negligible in both arms. However, infliximab-/docetaxel-treated patients developed greater fatigue and worse global quality of life scores. Other outcomes, such as tumor response rate (<10% in both groups) and overall survival, were not statistically different between groups. There were no statistically significant differences in adverse events, although one death was attributed to infliximab. Genotyping for the TNF alpha -238 and -308 polymorphisms revealed no clinical significance of these genotypes, as relevant to the loss of weight or appetite. Conclusions: This trial closed early because infliximab did not prevent or palliate cancer-associated weight loss. Infliximab was associated with increased fatigue and inferior global quality of life. © 2009 Elsevier Ireland Ltd.