bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.
Authors: Holmes F A , Madden T , Newman R A , Valero V , Theriault R L , Fraschini G , Walters R S , Booser D J , Buzdar A U , Willey J , Hortobagyi G N 
Published: February 2017

PURPOSE To determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially. PATIENTS AND METHODS Ten patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly. RESULTS Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3. CONCLUSION When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.
Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group.
Authors: Pritchard K I , Paterson A H , Paul N A , Zee B , Fine S , Pater J 
Published: February 2017

PURPOSE AND METHODS Associations between thromboembolism and malignancy, usually widespread, and between thromboembolism and hormonal and/or chemotherapy have been previously reported. We performed a randomized trial of tamoxifen 30 mg/d for 2 years (T) versus T plus 6 months of intravenous chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) for postmenopausal women with involved axillary nodes and positive estrogen receptor (ER) or progesterone receptor (PgR) status following primary therapy for breast cancer. RESULTS We observed one or more thromboembolic events in 48 of 353 women (13.6%) allocated to receive T plus CMF in comparison to five of 352 women (2.6%) randomized to receive T alone (P < .0001). Six women in the T plus CMF arm, but none randomized to receive T alone, suffered two thromboembolic events while an study therapy. There were also significantly more women who developed severe (grade 3 to 5) thromboembolic events in the T plus CMF arm than in the T arm (34 v five; P < .0001). Most thromboembolic events (39 of 54) occurred while women were actually receiving chemotherapy (P < .0001). Thromboembolic complications resulted in more days in hospital and more deaths than any other complication of therapy, including infection, in this trial. CONCLUSION Thromboembolism related to the addition of CMF chemotherapy to tamoxifen as adjuvant therapy in this group of women represents a relatively common and serious complication that may outweigh any benefits offered by this additional therapy.
Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan.
Authors: Perez-Soler R , Glisson B S , Lee J S , Fossella F V , Murphy W K , Shin D M , Hong W K 
Published: February 2017

PURPOSE This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with small-cell lung cancer (SCLC) refractory to etoposide. PATIENTS AND METHODS Refractoriness to etoposide was defined as lack of response to etoposide-containing frontline therapy, or progression during or within 3 months of the last dose of etoposide-containing frontline or second-line therapy. Other eligibility criteria were presence of measurable disease, Zubrod scale performance status (PS) < or = 2, < or = two prior chemotherapy regimens, and adequate renal and liver function. TPT was administered at a dose of 1.25 mg/m2/d for 5 days over 30 minutes every 21 days. RESULTS Thirty-two patients were registered, of whom 28 are fully assessable. All patients had been treated with frontline etoposide and cisplatin. Three patients (11%) achieved a partial remission (PR) (durations, 7, 8, and 19 weeks) and two (7%) achieved a minor response; five patients (17%) had stable disease and 18 (65%) had progressive disease. One of the three patients who achieved a PR had failed to respond to frontline cisplatin and etoposide. The overall median survival duration was 20 weeks. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 70% and 31% of courses administered, respectively. No grade 3 to 4 non-hematological toxicities were observed. Grade 1 or 2 nonhematological toxicities (in percentage of patients) consisted of nausea (41%, 8%) and vomiting (25%, 11%), and alopecia (100%). CONCLUSION TPT at the dose and schedule used has modest antitumor activity in SCLC patients refractory to etoposide and cisplatin, which indicates that clinical resistance to the topoisomerase II poison etoposide does not confer cross-sensitivity to the topoisomerase I poison TPT. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.
Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors.
Authors: Saltz L B , Kanowitz J , Kemeny N E , Schaaf L , Spriggs D , Staton B A , Berkery R , Steger C , Eng M , Dietz A , Locker P , Kelsen D P 
Published: February 2017

PURPOSE To determine the maximum-tolerable dose (MTD) of fluorouracil (5FU) when given with fixed doses of leucovorin and irinotecan (CPT-11), to define the dose-limiting toxicities of this combination, and to evaluate the effect of 5FU on the pharmacokinetics of CPT-11. PATIENTS AND METHODS CPT-11, leucovorin, and 5FU were administered in repeated 6-week cycles that consisted of weekly treatment with all three drugs for 4 consecutive weeks followed by a 2-week break. On day 1 of treatment, CPT-11 alone was given by 90-minute infusion, and pharmacokinetic sampling was performed over 24 hours. Leucovorin and 5FU were administered by brief intravenous injection on day 2. On days 8, 15, and 22, CPT-11 infusion was immediately followed by leucovorin and then 5FU. A second 24-hour pharmacokinetic sampling was performed on day 8, which permitted comparison of the pharmacokinetics of CPT-11 with and without 5FU. For the second 6-week cycle, leucovorin was administered first, followed by 5FU and then CPT-11, and a third pharmacokinetic sampling was performed. RESULTS Forty-two patients were entered onto this trial. The CPT-11 dose was initially fixed at 100 mg/m2. Leucovorin was fixed at 20 mg/m2. 5FU doses of 210, 265, 340, 425, and 500 mg/m2 were studied. When the 500-mg/m2 dose of 5FU was found to be tolerable, this was then maintained and CPT-11 was escalated to 125 and then 150 mg/m2. This final CPT-11 dose exceeded the MTD. Neutropenia was the major dose-limiting toxicity. Diarrhea was common, but was rarely dose-limiting. Coadministration of 5FU had no substantial effect on the pharmacokinetics of CPT-11 or SN-38. Among the 38 patients with colorectal cancer, six partial responses (PRs) were seen in this predominantly 5FU-refractory patient population. CONCLUSION 5FU does not substantially affect the metabolism of CPT-11 to its active metabolite, SN-38. The combination of CPT-11125 mg/m2, 5FU 500 mg/m2, and leucovorin 20 mg/m2 is feasible and tolerable on this schedule.
Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer.
Authors: Jones S E , Schottstaedt M W , Duncan L A , Kirby R L , Good R H , Mennel R G , George T K , Snyder D A , Watkins D L , Denham C A , Hoyes F A , Rubin A S 
Published: February 2017

PURPOSE To determine the effects of sargramostim (recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) on the incidence, duration, and complications of myelosuppression after moderate-dose fluorouracil, doxorubicin, cyclophosphamide (FAC) adjuvant chemotherapy in patients with node-positive breast cancer. PATIENTS AND METHODS In this randomized, double-blind, placebo-controlled study, 142 women with stage II and III breast cancer were to receive four 21-day cycles of chemotherapy that consisted of fluorouracil 600 mg/ m2 intravenously (IV), doxorubicin 60 mg/m2 IV, and cyclophosphamide 750 mg/m2 IV on day 1, followed by placebo or GM-CSF 250 micrograms/m2/d daily subcutaneously (SC) on days 3 through 15. All patients received prophylactic ciprofloxacin by mouth when the absolute neutrophil count (ANC) was less than 1,000/microL. RESULTS Eighty-six percent of GM-CSF patients (n = 62) and 96% of placebo patients (n = 69) completed four assessable cycles of treatment on study. Overall, the median duration of severe neutropenia (ANC < 500/microL) was 2.8 days with GM-CSF and 6.8 days with placebo (P < .001); the duration of ANC less than 1,000/microL was 6.0 versus 9.1 days, respectively (P < .001). Hospitalizations for febrile neutropenia were uncommon in either group: GM-CSF, six; placebo, eight. The only other difference in hematologic toxicity was grade 3/4 thrombocytopenia observed with greater frequency in GM-CSF patients than placebo patients in cycles 3 and 4. GM-CSF increased mean the FAC dose-intensity among patients who completed two or more cycles (P < .001). GM-CSF was generally well tolerated and associated with more injection-site reactions, but less mucositis than placebo. There were no deaths on study. CONCLUSION GM-CSF significantly enhanced ANC recovery after FAC chemotherapy; it decreased the incidence and duration of associated neutropenia and moderately increased the dose-intensity of adjuvant chemotherapy. Whether these effects will ultimately translate into improved long-term outcome remains to be determined.
Ifosfamide and vinorelbine as first-line chemotherapy for metastatic breast cancer.
Authors: Leone B A , Vallejo C T , Romero A O , Perez J E , Cuevas M A , Lacava J A , Sabatini C L , Dominguez M E , Rodriguez R , Barbieri M R , Ortiz E H , Salvadori M A , Acuña L A , Acuña J M , Langhi M J , Amato S , Machiavelli M R 
Published: February 2017

PURPOSE To evaluate the efficacy and toxicity of the combination of ifosfamide (IFX) and vinorelbine (VNB) as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS Between August 1993 and August 1995, 45 patients with untreated MBC received a regimen that consisted of IFX 2 g/m2 by 1-hour intravenous (i.v.) infusion on days 1 to 3, mesna 400 mg/m2 by i.v. bolus at hours 0 and 4 and 800 mg/m2 orally at hour 8 on days 1 to 3, and VNB 35 mg/m2 by 20-minute i.v. infusion on days 1 and 15. Courses were repeated every 28 days. During the first course only, half-dose VNB (17.5 mg/m2) was administered on days 8 and 22. The median age was 53 years and 30 patients (67%) were postmenopausal. Dominant sites of disease were soft tissue in nine patients, bone in seven, and visceral in 29. RESULTS Objective responses (ORs) were recorded in 25 of 43 assessable patients (58%; 95% confidence interval, 43% to 73%). Complete remissions (CRs) occurred in six patients (14%) and partial remissions (PRs) in 19 (44%). No change (NC) was recorded in 10 patients (23%) and progressive disease (PD) in eight patients (19%). The median time to treatment failure was 12 months and the median survival duration 19 months. Myelosuppression was the limiting toxicity, mainly leukopenia in 32 patients (74%). In contrast, anemia and thrombocytopenia were mild. Other significant toxicities included peripheral neuropathy in nine patients (21%), constipation in 15 (35%), and myalgias in 11 (26%). CONCLUSION IFX/VNB is an active combination against MBC with moderate toxicity and deserves further evaluation.
Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541.
Authors: Rosner G L , Hargis J B , Hollis D R , Budman D R , Weiss R B , Henderson I C , Schilsky R L 
Published: February 2017

PURPOSE We examined data from a large clinical trial to determine if chemotherapy dosing according to actual body weight places obese patients at greater risk of toxicity. PATIENTS AND METHODS Cancer and Leukemia Group B (CALGB) study 8541, a randomized study of schedule and dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) for stage II breast cancer patients with positive regional lymph nodes, provided data on 1,435 women for analysis. Using body-mass index (BMI), we classified a woman as obese if her BMI was > or = 27.3 kg/m2; doses were considered weight-based if within 5% of values calculated using actual weight. Our primary analysis concerned toxicity risks during cycle 1. RESULTS Among women who received weight-based doses of the most dose-intensive CAF regimen, 47% of obese and 51% of nonobese women experienced severe hematologic toxicity (grade > or = 3) during cycle 1 (P = .51, two-tailed). The overall risk ratio (obese v nonobese) of treatment failure among women who received weight-based doses during cycle 1 was 1.02 (95% confidence interval, 0.83 to 1.26), stratified by treatment and adjusted for number of positive nodes, menopausal status, hormone receptor status, and tumor size. The overall adjusted failure risk ratio (weight-based v reduced initial doses) was 0.73 (95% confidence interval, 0.53 to 1.00) among obese women. CONCLUSION Obese patients initially dosed (within 5%) by actual weight did not experience excess cycle 1 toxicity or worse outcome compared with nonobese women dosed similarly. The data suggest that obese women who received reduced doses in cycle 1 experienced worse failure-free survival. We recommend that initial doses of CAF be computed according to actual body weight.
Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials.
Authors: Albain K S , Green S R , Lichter A S , Hutchins L F , Wood W C , Henderson I C , Ingle J N , O'Sullivan J , Osborne C K , Martino S 
Published: February 2017

PURPOSE To investigate the frequency of breast-sparing treatment among breast cancer patients subsequently enrolled in national cooperative group studies of adjuvant chemotherapy. PATIENTS AND METHODS A data base was formed of 5,172 patients randomized onto two intergroup trials. Lumpectomy rates were analyzed within study-defined risk strata and across geographic regions. Significant predictors of lower lumpectomy usage were determined in multivariate analyses with variables that described patient and disease characteristics, systemic risk strata, geographic region, and socioeconomic indicators based on zip code of residence. RESULTS Breast-conservation rates were 30% in the node-negative and 15% in the node-positive trials, with a wide geographic variation within each study (range, 14% to 49% and 9% to 31%, respectively). Lumpectomy use declined with increasing tumor size and did not exceed 40% even for tumors < or = 1 cm with negative nodes. With increasing risk of systemic relapse, frequency of lumpectomy declined (rates for five strata in order of increasing systemic risk: 41%, 33%, 24%, 18%, and 11%), even though these strata were not known at the time of the surgical decision. A logistic model confirmed the joint significance of geographic region and systemic risk. An exploratory model that adjusted for all important variables identified the following significant predictors of lower lumpectomy use: positive nodes; many positive nodes, increased systemic risk; tumor size > or = 2.0 cm; older age; South, Central or non-New England regions; and either lack of college degree or lower income levels. CONCLUSION Breast-sparing therapy was used in the minority of women subsequently accrued to two national adjuvant breast cancer studies, even though this cohort and their referring surgeons represented a select population. Although multiple concrete factors were independent predictors of lower lumpectomy rates, prospective research is needed into how patients and their physicians approach the mastectomy versus lumpectomy decision.
Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma.
Authors: Sparano J A , Wiernik P H , Hu X , Sarta C , Schwartz E L , Soeiro R , Henry D H , Mason B , Ratech H , Dutcher J P 
Published: February 2017

PURPOSE To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.
Phase I and pharmacologic study of topotecan in patients with impaired renal function.
Authors: O'Reilly S , Rowinsky E K , Slichenmyer W , Donehower R C , Forastiere A A , Ettinger D S , Chen T L , Sartorius S , Grochow L B 
Published: February 2017

PURPOSE To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions.