bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days
Authors: Dowlati Afshin , Hoppel Charles L. , Ingalls Stephen T. , Majka Susan , Li Xiaolin , Sedransk Nell , Spiro Timothy , Gerson Stanton L. , Ivy Percy , Remick Scot C. 
Published: February 2017

PURPOSE: Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily × 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions. PATIENTS AND METHODS: Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m2/d × 5 days. RESULTS: Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m2/d × 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 ± 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve∞. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression. CONCLUSION: The recommended phase II dose for NSC 665649 on a daily × 5 every 3 weeks schedule is 141 and 165 mg/m2/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.
Addition of Oxaliplatin to Continuous Fluorouracil, l-Folinic Acid, and Concomitant Radiotherapy in Rectal Cancer: The Lyon R 97-03 Phase I Trial
Authors: Freyer Gilles , Bossard Nadine , Romestaing Pascale , Mornex Françoise , Chapet Olivier , Trillet-Lenoir Véronique , Gérard Jean-Pierre 
Published: February 2017

PURPOSE: Oxaliplatin could increase the efficacy of fluorouracil (5-FU)/folinic acid chemoradiotherapy in rectal cancer. We tested three dose levels to identify a feasible oxaliplatin dose for combination therapy. PATIENTS AND METHODS: Between February 1998 and April 2000, we included 17 rectal adenocarcinoma patients in a single-center phase I study. Patients had T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentially operable T2/T3 M1 requiring local treatment. Pelvic radiotherapy was 45 Gy over 5 weeks, 1.8 Gy/fraction, with concomitant chemotherapy weeks 1 and 5. Chemotherapy was oxaliplatin 80, 100, or 130 mg/m2 2-hour infusion on day 1 followed by l-folinic acid 100 mg/m2/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1). Six patients refusing surgery received additional contact radiotherapy +/− brachytherapy. Dose escalation proceeded if less than two of six patients had dose-limiting toxicity (DLT) at a given dose-level. RESULTS: All except two patients completed treatment; patients at level 1 (prolonged grade 1 thrombocytopenia) and level 3 (prolonged cold-related dysesthesia) had no second chemotherapy course. Median follow-up is 14 months (range, 2 to 28 months). One elderly patient at dose level 1 had DLT asthenia, severe diarrhea and vomiting, and more than 10% weight loss. There were no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Eight patients underwent radical surgery after chemoradiotherapy. Two had complete pathologic responses. CONCLUSION: FolfoR1 seems feasible and effective. Dose escalation did not increase toxicity. Although the MTD was not reached in this study, we recommend oxaliplatin 130 mg/m2 for phase II studies because it is the dose determined from studies in metastatic patients with no toxicity when given concurrently with radiation.
Melanoma Information on the Internet: Often Incomplete—A Public Health Opportunity?
Authors: Bichakjian Christopher K. , Schwartz Jennifer L. , Wang Timothy S. , Hall Janette M. , Johnson Timothy M. , Sybil Biermann J. 
Published: February 2017

PURPOSE: To assess the accuracy and completeness of information regarding melanoma on the Internet, retrieved by use of search engines. METHODS: The first 30 uniform/universal resource locators (URLs) from each of eight search engines using the search term “melanoma” were retrieved for evaluation of accuracy and completeness using a 35-point checklist rating system instrument. Four reviewers independently rated each of 35 sites, and one reviewer rated all 74 assessable sites. Kappa statistics were used to evaluate interrater variability. RESULTS: A total of 74 assessable Web sites were evaluated. The remainder were inaccessible, link pages only, or duplicates. Thirty-five Web sites were each independently rated by four reviewers. The remaining 39 Web sites were each rated by one reviewer. The mean kappa statistic for all variables and all rater pairs for which a kappa could be calculated was 0.824, indicating excellent overall inter-rater reliability. The majority of Web sites failed to include complete information on general information, risk factors, diagnosis, treatment, prevention, and prognosis. Ten Web sites (14%) contained a total of 13 inaccuracies, most relatively minor. CONCLUSION: Medical information retrieved with the search term melanoma was likely to lack complete basic melanoma information and contained inaccuracies in 14% of sites. Health care providers can help patients by recommending comprehensive and accurate Web sites for patient review, by working to create accurate and thorough Web-based health information material, and by educating patients and the public about the variability in completeness and accuracy.
Cooperative Role of Telomerase Activity and p16 Expression in the Prognosis of Non–Small-Cell Lung Cancer
Authors: González-Quevedo Rosa , Iniesta Pilar , Morán Alberto , de Juan Carmen , Sánchez-Pernaute Andrés , Fernández C. , Torres Antonio , Díaz-Rubio E. , Balibrea Jose-Luis , Benito Manuel 
Published: February 2017

PURPOSE: Telomerase activity and p16 expression can be considered two of the most important molecular markers implicated in tumorigenesis. Our main aim was to study the cooperative role of both molecular alterations in the prognosis of patients surgically resected for non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We have determined telomerase activity and p16 expression in a series of 98 prospectively collected NSCLC specimens obtained from patients who had undergone surgery without other treatment. Telomerase activity was investigated by a telomeric repeat amplification protocol enzyme-linked immunosorbent assay–based procedure, and p16 expression was examined by Western blot. Associations with survival were evaluated. RESULTS: Positive results for telomerase activity were found in 82% of the cases, and this variable correlated with poor differentiation and recurrence of tumors. Lack of p16 expression was observed in 61% of tumors, and a significant association with tumor recurrence was also observed. By univariate analysis, both negative telomerase activity and p16-positive expression were significantly correlated with a better prognosis. Moreover, statistics for equality of survival distributions for telomerase, adjusted for p16, indicated a positive interaction between both parameters. For telomerase-positive tumors, p16 expression emerged as a significant independent protective variable, as indicated by Cox multivariate analysis (relative risk [RR], 0.214; P = .014). This protective effect was maintained only for stage I and II tumors (RR, 0.108; P = .046). CONCLUSION: These results suggest that the combined telomerase activity and p16 expression analyses may be of prognostic importance in NSCLC, especially for patients affected by stage I and II tumors.
Outcomes and Cost-Effectiveness of Alternative Staging Strategies for Non–Small-Cell Lung Cancer
Authors: Esnaola Nestor F. , Lazarides Sophia N. , Mentzer Steven J. , Kuntz Karen M. 
Published: February 2017

PURPOSE: To identify the optimal strategy for staging the mediastinum of patients with known non–small-cell lung cancer (NSCLC), stratified by tumor (T) classification. METHODS: We used a decision-analytic model to compare the health outcomes and cost-effectiveness of three staging strategies: (1) chest computed tomography alone, (2) selective mediastinoscopy, and (3) routine mediastinoscopy. The overall effectiveness and cost of each strategy was a function of the proportion of patients accurately staged and the risks, benefits, and costs of the diagnostic tests and treatments used. Probability estimates and costs were derived from primary data and the literature. We adopted a societal perspective and calculated incremental cost-effectiveness ratios (ICERs) as cost per quality-adjusted life year (QALY) gained. RESULTS: Both mediastinoscopy strategies correctly identified more patients with mediastinal involvement (N2/N3 disease) and assigned them to multimodal regimens. Routine mediastinoscopy maximized quality-adjusted life expectancy in all patients, irrespective of T classification, and this result was robust to varying the model estimates over their reported ranges. In T1 patients, selective mediastinoscopy cost $24,500 per QALY gained, compared with $78,800 per QALY gained for routine mediastinoscopy. In T2 and T3 patients, the ICER of routine mediastinoscopy was more favorable ($42,800 and $53,400 per QALY gained, respectively). CONCLUSION: Routine mediastinoscopy maximizes quality-adjusted life expectancy in patients with known NSCLC, and its ICER compares favorably with other currently accepted medical technologies. The survival benefit and cost-effectiveness of this strategy are greater in patients with T2 and T3 tumors and are likely to improve with advances in multimodal therapy.
Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Bacik Jennifer , Murphy Barbara A. , Russo Paul , Mazumdar Madhu 
Published: February 2017

PURPOSE: To define outcome data and prognostic criteria for patients with metastatic renal cell carcinoma (RCC) treated with interferon-alfa as initial systemic therapy. The data can be applied to design and interpretation of clinical trials of new agents and treatment programs against this refractory malignancy. PATIENTS AND METHODS: Four hundred sixty-three patients with advanced RCC administered interferon-α as first-line systemic therapy on six prospective clinical trials were the subjects of this retrospective analysis. Three risk categories for predicting survival were identified on the basis of five pretreatment clinical features by a stratified Cox proportional hazards model. RESULTS: The median overall survival time was 13 months. The median time to progression was 4.7 months. Five variables were used as risk factors for short survival: low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and time from initial RCC diagnosis to start of interferon-α therapy of less than one year. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two (intermediate risk), and those with three or more (poor risk). The median time to death of patients deemed favorable risk was 30 months. Median survival time in the intermediate-risk group was 14 months. In contrast, the poor-risk group had a median survival time of 5 months. CONCLUSION: Progression-free and overall survival with interferon-α treatment can be compared with new therapies in phase II and III clinical investigations. The prognostic model is suitable for risk stratification of phase III trials using interferon-α as the comparative treatment arm.
Phase II Trial of Thalidomide for Patients With Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Berg William , Ginsberg Michelle , Russo Paul , Vuky Jacqueline , Yu Richard , Bacik Jennifer , Mazumdar Madhu 
Published: February 2017

PURPOSE: To assess efficacy and toxicity of thalidomide in patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: Twenty-six patients with RCC were treated with thalidomide at a starting dose of 200 mg daily. Thalidomide was increased by 200 mg every 2 weeks until a maximum dose of 800 mg or prohibitive toxicity was reached. Fifteen patients had prior nephrectomy, 11 patients had no prior systemic therapy, and 15 had received one prior systemic regimen. RESULTS: A maximum dose of 800 mg, 600 mg, 400 mg, and 200 mg was reached in five, 10, eight, and three patients, respectively. Grade 2 and 3 dyspnea occurred in four and three patients, respectively. Grade 2 and 3 neurologic toxicity was observed in five and two patients, respectively. Of the 25 assessable patients, the best response was stable disease in 16 (95% confidence interval [CI], 43% to 82%) patients. The 6-month progression-free survival rate was 32% (95% CI, 14% to 50%). Three patients achieved prolonged stable disease of 16, 16+, and 18+ months, including two patients who were refractory to previous cytokine therapy. Fifty-seven percent were alive at 1 year (95% CI, 37% to 76%). CONCLUSION: This trial does not support the routine use of thalidomide to induce partial response for metastatic RCC. Because disease stabilization occurs as a part of the natural history of metastatic RCC, the potential effect of thalidomide on progression-free and overall survival for patients with advanced RCC is being addressed in a randomized phase III trial. New immunomodulatory analogs of thalidomide that have shown potentially greater antitumor effects in preclinical models warrant study in metastatic RCC.
Phase II Trial of Biweekly Administration of Vinorelbine and Gemcitabine in Pretreated Advanced Breast Cancer
Authors: Stathopoulos George P. , Rigatos Sotiris K. , Pergantas Nikos , Tsavdarides Dimitris , Athanasiadis Ilias , Malamos Nikos A. , Stathopoulos John G. 
Published: February 2017

PURPOSE: To determine the efficacy of gemcitabine (GEM) plus vinorelbine (VRL) administered biweekly in pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Advanced breast cancer patients without response, with stable disease, or with recurrence within 6 months of prior treatment were given GEM 1,000 mg/m2 and VRL 25 mg/m2, once every 2 weeks for at least six cycles. RESULTS: Of the 51 patients enrolled, 50 (median, age 58 years; range, 34 to 76 years) were assessable. All patients had prior chemotherapy with an anthracycline-related regimen that included taxanes in 50% of the cases. Four patients (8%) had a complete response (CR) and 23 (46%) had a partial response (PR), for an overall response rate of 54%; 16 (32%) had stable disease and 7 (14%) experienced disease progression. Response occurred mainly in patients with soft tissue (83.3%) and lung metastasis (66.7%). Response duration was 4 to 8+, 4 to 9+, and 4 to 9 months for those with CR, PR, and stable disease, respectively. The regimen was well tolerated, with grade 1 to 2 myelotoxicity and asthenia reported. No patient required a dose reduction. Gastrointestinal side effects were negligible. Patients received 99.7% (range, 93.0% to 100.0%) of the planned dose-intensity of each drug. CONCLUSION: GEM in combination with VRL is an active regimen for advanced breast cancer patients, and biweekly administration significantly reduces myelotoxicity.
Troxacitabine, an l-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies
Authors: de Bono Johann S. , Stephenson Joseph , Baker Sharyn D. , Hidalgo Manuel , Patnaik Amita , Hammond Lisa A. , Weiss Geoffrey , Goetz Andrew , Siu Lillian , Simmons Cecelia , Jolivet Jacques , Rowinsky Eric K. 
Published: February 2017

PURPOSE: To assess the feasibility of administering troxacitabine, a unique l-nucleoside that is not a substrate for deoxycytidine deaminase–mediated catabolism, as a 30-minute intravenous (IV) infusion daily for 5 days. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of troxacitabine as a 30-minute IV infusion daily for 5 days. Plasma and urine sampling was performed to characterize the pharmacokinetics and pharmacodynamics of troxacitabine. RESULTS: Thirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m2/d. Severe neutropenia that was protracted (> 5 days) and/or associated with fever, and skin rashes were consistently experienced by heavily (HP) and minimally pretreated (MP) patients at doses exceeding 1.2 and 1.5 mg/m2/d, respectively. At troxacitabine doses ≥ 1.2 mg/m2/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to 4 weeks. Skin rash, palmar-plantar erythrodysesthesia, and thrombocytopenia were also observed and were occasionally severe, particularly at the highest doses. A patient with metastatic ocular melanoma experienced a partial response. Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cls) were 60 (32) L and 161 (33) mL/min, respectively, on day 1. After treatment on the fifth day, terminal half-life values averaged 39 (63) hours, and Cls was reduced by approximately 20%, averaging 127 (27) mL/min. The principal mode of drug elimination was renal. CONCLUSION: Recommended doses for phase II studies of troxacitabine as a 30-minute infusion daily for 5 days every 4 weeks are 1.5 and 1.2 mg/m2/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.
Phase II and Biologic Study of Interferon Alfa, Retinoic Acid, and Cisplatin in Advanced Squamous Skin Cancer
Authors: Shin Dong M. , Glisson Bonnie S. , Khuri Fadlo R. , Clifford John L. , Clayman Gary , Benner Steven E. , Forastiere Arlene A. , Ginsberg Lawrence , Liu Diane , Lee J. Jack , Myers Jeffrey , Goepfert Helmuth , Lotan Reuben , Hong Waun Ki , Lippman Scott M. 
Published: February 2017

PURPOSE: The purpose of this study was to test interferon alfa (IFNα), 13-cis-retinoic acid (13cRA), and cisplatin biochemotherapy in advanced squamous cell carcinoma (SCC) of the skin. PATIENTS AND METHODS: Patients with advanced skin SCC received IFNα (5 × 106 IU/m2, subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m2, intravenous injection, weekly) in a phase II trial. The growth inhibition, cell-cycle, and apoptosis activity of these agents was evaluated in two skin SCC cell lines (SRB1-m7 and SRB12-p9). RESULTS: Thirty-nine patients were enrolled. All were assessable for survival, 35 for response and toxicity (median follow-up was 38 months). The overall and complete response rates were 34% and 17%, respectively, with median durations of 9 and 35.4 months, respectively. The response rate was higher in locally advanced (67%) than metastatic (17%) disease (P = .007). Median survival was 14.6 months. One-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively. Toxicity included generally mild to moderate fatigue and mucocutaneous dryness, moderate to severe neutropenia (38%), and neutropenic fever (6%). There were no treatment-related deaths. In vitro growth inhibition and apoptosis effects of cisplatin were differential and inversely associated with those of retinoic acid and especially IFNα in two skin SCC lines. CONCLUSION: The rising incidence, morbidity, and mortality of advanced skin SCC are a major challenge for clinical oncologists. Combined 13cRA, IFNα, and cisplatin was clinically active in extensive locally advanced disease. Each agent had independent, non–cross-resistant biologic effects in vitro, which may account for the combination’s clinical activity.
Beneficial Effects of Adenosine Triphosphate on Nutritional Status in Advanced Lung Cancer Patients: A Randomized Clinical Trial
Authors: Agteresch Hendrik J. , Rietveld Trinet , Kerkhofs Leon G.M. , van den Berg J. Willem O. , Wilson J. H. Paul , Dagnelie Pieter C. 
Published: February 2017

PURPOSE: In a randomized clinical trial in patients with advanced non–small-cell lung cancer (NSCLC), infusion with adenosine 5′-triphosphate (ATP) inhibited loss of body weight and quality of life. In the present article, the effects of ATP on body composition, energy intake, and energy expenditure as secondary outcome measures in the same patients are reported. PATIENTS AND METHODS: Patients with NSCLC, stage IIIB or IV, were randomized to receive either 10 intravenous, 30-hour ATP infusions every 2 to 4 weeks or no ATP. Fat mass (FM), fat-free mass (FFM), and arm muscle area were assessed at 4-week intervals for 28 weeks. Food intake, body cell mass (BCM), and resting energy expenditure (REE) were assessed at 8-week intervals for 16 weeks. Between-group differences were tested for statistical significance by repeated-measures analysis of covariance. RESULTS: Fifty-eight patients were randomized (28 ATP, 30 control). No change in body composition over the 28-week follow-up period was found in the ATP group, whereas, per 4 weeks, the control group lost 0.6 kg of FM (P = .004), 0.5 kg of FFM (P = .02), 1.8% of arm muscle area (P = .02), and 0.6% of BCM/kg body weight (P = .054) and decreased 568 KJ/d in energy intake (P = .0001). Appetite also remained stable in the ATP group but decreased significantly in the control group (P = .0004). No significant differences in REE between the ATP and control groups were observed. CONCLUSION: The inhibition of weight loss by ATP infusions in patients with advanced NSCLC is attributed to counteracting the loss of both metabolically active and inactive tissues. These effects are partly ascribed to maintenance of energy intake.