bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer.
Authors: Murren J R , Anderson S , Fedele J , Pizzorno G , Belliveau D , Zelterman D , Burtness B A , Tocino I , Flynn S D , Beidler D , Cheng Y C 
Published: February 2017

PURPOSE Based on preclinical data that demonstrated synergy between alkylating agents and topoisomerase (topo) I poisons, we determined the maximum-tolerated dose (MTD) of topotecan, using a 5 day bolus schedule, that could be given in combination with a single, fixed dose of cyclophosphamide. Pharmacodynamics of this combination were explored by analyzing biochemical effects of treatment in peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS Patients with refractory cancer were treated with cyclophosphamide 600 mg/m2 on day 1, followed by topotecan given as a 30-minute infusion for 5 consecutive days. Cycles were repeated every 3 weeks. Once the MTD was defined, granulocyte colony-stimulating factor (G-CSF) was added to the regimen in an attempt to escalate further the dose of topotecan. Plasma concentrations of topotecan were determined during the first treatment cycle by high-performance liquid chromatography. PBMCs were sampled at baseline and throughout the 5-day treatment period for analysis of topo I protein concentrations and to determine drug-induced DNA fragmentation. RESULTS Twenty-six patients were treated with topotecan at doses that ranged from 0.5 mg/m2/d to 1.2 mg/ m2/d for a total of 74 cycles. Reversible neutropenia was dose-limiting, with mild to moderate suppression of the other blood-cell elements commonly occurring. Transfusions of RBCs and platelets were required in 24% and 7% of treatment cycles, respectively. The most prominent nonhematologic toxicities were fatigue and weight loss. Compared with previously published data in which topotecan was administered alone, cyclophosphamide did not appear to alter the pharmacokinetics of topotecan. Significant increases in topo I concentration were identified in PBMCs following the administration of cyclophosphamide on day 1 and there was a significant decrease in topo 1 during the 5-day course of treatment (P < .01, sign test). DNA fragmentation as a result of drug treatment was identified in 11 of 15 (73%) cycles analyzed. CONCLUSION For previously treated patients, the recommended dose of topotecan in this schedule is 0.75 mg/m2/d without growth factor support and 1.0 mg/ m2/d if it is administered with G-CSF. Biochemical changes in cells induced by exposure to camptothecins can be measured in vivo and these effects may have important implication in the design of combination therapies and the optimal scheduling of this class of agents.
Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125.
Authors: Rustin G J , Nelstrop A E , Crawford M , Ledermann J , Lambert H E , Coleman R , Johnson J , Evans H , Brown S , Oster W 
Published: February 2017

PURPOSE A phase II study was performed of oral altretamine in 71 patients with ovarian carcinoma who entered clinical complete remission with CA125 levels less than 35 U/mL after initial or second-line chemotherapy, and relapsed more than 6 months later. Response was compared between standard and CA125-based criteria. PATIENTS AND METHODS Altretamine 260 mg/m2 was given in divided doses daily for 14 days per month. Response was evaluated according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 45 of 66 eligible patients. Response was assessed according to precise CA125 criteria in 51 patients based on either a confirmed > or = 50% or > or = 75% decrease in CA125 levels. RESULTS A combination of domperidone, dexamethasona, and chlorpromazine at night controlled toxicity in most patients, which was mainly nausea (National Cancer Institute criteria grade 2 or 3 in 27), vomiting (grade 2 or 3 in 19, grade 4 in one), and tiredness (grade 2 or 3 in 15). Responses (complete plus partial) were seen in 18 (40%; 95% confidence interval [CI], 25.4% to 54.6%) of those evaluated according to EORTC criteria and in 20 (39%; 95% CI, 25.5% to 52.9%) of those evaluated according to CA125 level. The overall response rate was 26 of 57 (45.6%) and was related to treatment-free interval: 6 to 12 months, 35%; 12 to 24 months, 52%; and greater than 24 months, 67%. The medium duration of response was 8 months. CONCLUSION Oral altretamine is a useful agent in patients-who relapse after previously responsive ovarian cancer. Response evaluation by a strict CA125 definition gave a similar estimate of the efficacy of altretamine as EORTC criteria.
Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial.
Authors: Bartelink H , Rubens R D , van der Schueren E , Sylvester R 
Published: February 2017

PURPOSE To assess the long-term contribution of adjuvant chemotherapy (CT) and hormonal therapy (HT) in patients with locally advanced breast cancer, and to evaluate the impact of time of analysis on the results during accrual and up to 8 years after closure of a randomized phase III trial. MATERIALS AND METHODS In a trial using a factorial design, 410 patients were randomized between radiotherapy (RT) alone, RT plus CT, RT plus HT, and RT plus HT plus CT. RESULTS CT and HT each produced a significant prolongation of the time to locoregional tumor recurrence and to distant progression of disease, with the combined treatments providing the greatest therapeutic effect. At the time of trial closure, a significant improvement of survival was observed in patients who received CT (P = .004); however, with a longer follow-up duration, this effect disappeared (P > .05). HT did not initially appear to improve survival (P = .16); however, in the latest analysis with a long-term follow-up duration, a significant improvement of survival was seen (P = .02). A consistent 25% reduction in the death hazards ratio has been seen at all evaluations since trial closure in patients who received HT. The best survival results were observed in patients who received RT, HT, and CT (P = .02), with a reduction of 35% in the death hazards ratio. CONCLUSION An improvement in survival attributable to HT has been shown in patients with locally advanced breast cancer. The greatest therapeutic effect was seen in the treatment group that received both CT and HT. The improvement obtained with HT became apparent only after long-term follow-up evaluation.
Compliance with practice guidelines for node-negative breast cancer.
Authors: Olivotto A , Coldman A J , Hislop T G , Trevisan C H , Kula J , Goel V , Sawka C 
Published: February 2017

PURPOSE Practice guidelines for cancer management have been in use in the province of British Columbia (BC), Canada, since the mid 1970s. To evaluate practice guideline compliance, treatment received was compared with treatment recommended in a population-based cohort of women with breast cancer. METHODS All incident cases (n = 939) of invasive, pathologically node-negative breast cancer diagnosed in 1991 were identified from the BC Cancer Registry. Treatment details were abstracted from cancer clinic records for cases referred to the BC Cancer Agency (BCCA) (n = 661) and original source documents for nonreferred cases. Management decisions were considered compliant if the patient received the recommended treatment or was entered onto a randomized trial of the modality being assessed. RESULTS Overall compliance with adjuvant therapy guidelines was 97% for radiotherapy, 96% for chemotherapy, and 89% for tamoxifen. An oncology specialist was consulted by 94% of patients with an indication for adjuvant treatment and by 58% of those without an indication (odds ratio [OR] = 10.7; 95% confidence interval, 7.0 to 16.4). Compliance with a guideline to deliver radiotherapy was 95%; with chemotherapy, 77%; and with tamoxifen, 68%. Compliance with a guideline that stated no adjuvant treatment was indicated was 99% for radiotherapy, 98% for chemotherapy, and 92% for tamoxifen. Noncompliance among patients with an indication for treatment was related to nonreferral to an oncology specialist and less complete implementation of guideline changes in the community as compared with cancer center practices. CONCLUSION Compliance was high, but scheduled updating and more effective community implementation could further improve consistency of care.
Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer.
Authors: O'Connell M J , Mailliard J A , Kahn M J , Macdonald J S , Haller D G , Mayer R J , Wieand H S 
Published: February 2017

PURPOSE The goal of this study was to determine the efficacy of intensive-course fluorouracil (5FU) plus low-dose leucovorin given for 6 months following potentially curative resection of colon cancer. PATIENTS AND METHODS Three hundred seventeen patients with high-risk stage II or stage III colon cancer were randomly assigned 3 to 4 weeks following surgery to receive either (1) chemotherapy with six cycles of 5FU (425 mg/m2) plus leucovorin (20 mg/m2) by rapid intravenous injection daily for 5 consecutive days every 4 to 5 weeks, or (2) observation. RESULTS The median follow-up duration is 72 months for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant improvement in time to relapse (P < .01) and survival (P = .02) compared with control patients treated with surgery alone. Stomatitis, diarrhea, and leukopenia were the predominant chemotherapy toxicities. There were no treatment-related deaths. CONCLUSION These results indicate that intensive-course 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients with high-risk colon cancer. These benefits were seen with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient for outpatient administration.
Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study.
Authors: Crinò L , Scagliotti G , Marangolo M , Figoli F , Clerici M , De Marinis F , Salvati F , Cruciani G , Dogliotti L , Pucci F , Paccagnella A , Adamo V , Altavilla G , Incoronato P , Trippetti M , Mosconi A M , Santucci A , Sorbolini S , Oliva C , Tonato M 
Published: February 2017

PURPOSE The nucleoside analog, gemcitabine, has shown activity as a single agent in the treatment of metastatic non-small-cell lung cancer (NSCLC). Its combination with cisplatin in preclinical models suggested synergy between the two drugs. The aim of the study was to evaluate the clinical efficacy and toxicity of the cisplatin-gemcitabine combination in advanced NSCLC. PATIENTS AND METHODS Forty-eight consecutive previously untreated NSCLC patients entered the trial from January to June 1994. The median age was 60 years (range, 37 to 70) and performance status (PS) was 0 or 1; 22 patients had unresectable stage III disease (21 stage IIIB and one stage IIIA) and 26 had stage IV disease. Gemcitabine 1 g/m2 was administered weekly (days 1, 8, and 15) followed by a 1-week rest and cisplatin 100 mg/m2 on day 2 of each 28-day cycle. Survival and response were determined in accordance with the intention-to-treat principle in all enrolled patients. RESULTS Of 48 assessable patients, one (stage IV) had a complete response (CR) and 25 achieved a partial response (PR). The overall response rate was 54% (95% confidence interval [CI], 40% to 68%). Thrombocytopenia was the main side effect, with 52% of patients experiencing grade III to IV toxicity, which was usually short-lived and responsible for the omission of gemcitabine administration on day 15 in 50% of chemotherapy courses. The median survival time was 61.5 weeks (95% CI, 40 to 71). CONCLUSION The combination of gemcitabine and cisplatin induced a high response rate in both stage IIIB and IV NSCLC, with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.
Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.
Authors: Huizing M T , Giaccone G , van Warmerdam L J , Rosing H , Bakker P J , Vermorken J B , Postmus P E , van Zandwijk N , Koolen M G , ten Bokkel Huinink W W , van der Vijgh W J , Bierhorst F J , Lai A , Dalesio O , Pinedo H M , Veenhof C H , Beijnen J H 
Published: February 2017

PURPOSE To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.
Trading treatment toxicity for survival in locally advanced non-small cell lung cancer.
Authors: Brundage M D , Davidson J R , Mackillop W J 
Published: February 2017

PURPOSE To determine how patients weigh potential survival benefits against the potential toxicity of different treatment strategies for locally advanced non-small cell lung cancer (NSCLC). Specifically, we were interested in what improvement in survival probability patients would want to have before accepting more toxic therapy. PATIENTS AND METHODS Fifty-six outpatients who had experienced lung cancer (n = 22) or prostate cancer (n = 34), and 20 clinic nurses and radiation therapy technologists participated. A treatment trade-off interview was conducted with each participant that compared low-dose versus high-dose radiotherapy and high-dose radiotherapy versus combination chemo-radiotherapy. Preferences for treatments were assessed by systematically increasing the hypothetical survival advantage of the more toxic treatment until the person reached his or her threshold for choosing the more toxic treatment. RESULTS A wide range of thresholds was observed for both groups. The distributions of survival advantage thresholds for lung cancer and prostate cancer patients were not significantly different but were generally lower thresholds than those declared by staff. If the 3-year survival advantage was 10%, 60% of patients and 15% of staff would consider combination therapy over high-dose radiotherapy. Within patients, apparent willingness to consider more toxic treatments was not significantly related to age, sex, education, or preferred role in decision making. The treatment trade-off method had good test-retest reliability. CONCLUSION There is great interindividual variability in willingness to accept aggressive treatments for locally advanced NSCLC. When choosing NSCLC treatment, each patient should be provided with comprehensive information about the options so that he or she may express his or her preferences should he or she wish to participate in the decision.
Phase I study of direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7, in patients with metastatic melanoma.
Authors: Stopeck A T , Hersh E M , Akporiaye E T , Harris D T , Grogan T , Unger E , Warneke J , Schluter S F , Stahl S 
Published: February 2017

PURPOSE To determine the safety, toxicity, and efficacy of direct intratumoral injection of an allogeneic major histocompatibility complex (MHC) class I gene, HLA-B7, in a cationic lipid vector (Allovectin-7; Vical Inc, San Diego, CA) in patients with metastatic melanoma. PATIENTS AND METHODS Seventeen HLA-B7-negative patients were treated with intralesional injection of Allovectin-7. Twelve patients received a single intralesional injection containing 10 micrograms (four patients), 50 micrograms (five patients), or 250 micrograms (three patients) of plasmid DNA. Five patients received two or three injections of 10 micrograms DNA to a single tumor site at 2-week intervals. Tumor biopsies pretherapy and 2 and 4 weeks after gene injection were obtained to determine expression of the plasmid by polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, flow cytometry, and immunohistochemistry. RESULTS Toxicities were related to technical aspects of the injections or biopsies. These included pain, hemorrhage, pneumothorax, and hypotension. Two patients were hospitalized overnight for observation. Seven patients (50%) had tumor responses insofar as the injected nodule decreased > or = 25% by radiologic or physical examination. One patient with a single site of disease achieved a complete remission. Ninety-three percent of the patients' post-gene therapy biopsies contained HLA-B7 plasmid DNA, mRNA, or protein. CONCLUSION Intratumoral injection of the allogeneic histocompatibility gene, HLA-B7, in a lipid vector can be performed safely at plasmid DNA doses < or = 250 micrograms. The safety profile and biologic activity of this therapy warrants further studies to define the mechanism of action, predictors of response, and antitumor efficacy of this approach.
Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation.
Authors: Sobrero A F , Aschele C , Bertino J R 
Published: February 2017

PURPOSE To determine if fluorouracil (FUra) has different mechanisms of action as a function of the dose schedule used. DESIGN The preclinical and clinical literature relating toxicity and antitumor effects of FUra as a function of its dose schedule, with and without modulating agents, was reviewed. RESULTS The data support the hypothesis that FUra may be considered to be two different drugs, depending on its dose schedule (bolus v continuous infusion [CI]). CONCLUSION These results suggest that additional therapeutic benefit may be obtained from FUra regimens by (1) appropriate schedule-dependent modulation, (2) the sequential or alternating use of cycles of bolus followed by cycles of CI FUra appropriately modulated, or (3) hybrid regimens, ie, those that contain both pulse and CI schedules.
Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia.
Authors: Saven A , Lee T , Schlutz M , Jacobs A , Ellison D , Longmire R , Piro L 
Published: February 2017

PURPOSE De novo B-cell prolymphocytic leukemia (B-PLL) is a distinct clinicopathologic entity usually characterized by marked lymphocytosis, massive splenomegaly, an aggressive course, and refractoriness to therapy. Cladribine (2-chlorodeoxyadenosine [2-CdA]; Ortho Biotech, Raritan, NJ) is a newer purine analog with potent activity against indolent lymphoproliferative disorders. PATIENTS AND METHODS We treated eight patients with cladribine 0.1 mg/kg/d for 7 days by continuous infusion or 0.14 mg/kg/d over 2 hours for 5 days, every 28 to 35 days, for a median of three courses (range, two to five). There were five men and three women, with a median age of 62 years and a median pretreatment duration of 6 months; four patients were previously untreated. RESULTS All eight patients were assessable: five achieved a complete response with a median response duration of 14 months (range, 1+ to 55+), and three achieved a partial response with a median duration of 3 months (range, 1 to 3). Of four patients who achieved a complete response and in whom a peripheral-blood immunophenotypic analysis was performed, two had no circulating B-PLL cells and one had no residual disease on Southern blot analysis. Myelosuppression and infection were the major toxicities: three patients developed grade 3 or 4 myelosuppression, four had bacterial infections, and two had herpes zoster infections. CONCLUSION In this small study of patients with de novo B-PLL, cladribine was an active agent that induced a high overall and complete response rate. These results require confirmation in larger numbers of B-PLL patients.
Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm.
Authors: Small E J , Vogelzang N J 
Published: February 2017

PURPOSE To discuss the evolution of new concepts in the Use of second-line hormonal therapy for patients with progressive prostate cancer despite androgen deprivation. DESIGN Pertinent contemporary prostate-specific antigen (PSA)-based reports of the utility of secondary hormonal maneuvers after treatment with combined androgen blockade (CAB) were reviewed. RESULTS The use of PSA as an end point in hormonerefractory prostate cancer (HRPC) trials is more widely accepted, but still remains somewhat controversial. Using PSA as an end point, it is clear that a variety of secondary hormonal maneuvers can result in responses. Antiandrogen withdrawal is efficacious in approximately 20% of patients and can be observed with a variety of antiandrogens, including flutamide, bicalutamide, and megestrol acetate. A variety of regimens, including megestrol, bicalutamide, glucocorticoids, aminoglutethimide, and ketoconazole, retain activity (14% to 75% PSA response proportion) even in patients who have failed to respond to CAB and flutamide withdrawal. CONCLUSION Once CAB (suppression of gonadal and adrenal androgen) is undertaken, further hormonal maneuvers remain efficacious in some patients with progressive prostate cancer. Antiandrogen withdrawal is now a mandatory maneuver before proceeding to other regimens. It is clear that certain patients will continue to respond to hormonal maneuvers even after antiandrogen withdrawal. An understanding of the molecular basis of these responses may result in the development of a more targeted therapy in the future.