bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of continuous infusion carboplatin and etoposide in children with refractory acute leukemia: a Pediatric Oncology Group study.
Authors: Sadowitz P D , Dubowy R , Souid A , Pollock B H , Weinstein H , Parmley R T , Bowman W P , Land V , Vats T , Pratt C 
Published: February 2017

PURPOSE The purpose of this phase I study was to determine the toxicities and response to continuous infusion carboplatin in combination with a fixed dose of etoposide (VP-16) in children with refractory acute leukemia. PATIENTS AND METHODS From January 1989 to February 1992, 20 patients received 28 courses of treatment. Each course of treatment consisted of a 1-hour intravenous (IV) infusion of VP-16 100 mg/m2/d for 5 days, followed by a 23-hour IV infusion of carboplatin each day. The initial, total 5-day dose of carboplatin (1,000 mg/m2) was escalated by 250- to 375-mg increments to a final, total dose of 1,875 mg/m2 over 5 days. RESULTS Significant marrow suppression was observed in all patients, with prolonged marrow aplasia at the 1,875-mg/m2 dose level. Grade III diarrhea occurred in three patients; 10 patients experienced life-threatening infection and three had severe thrombocytopenic bleeding. Major marrow responses (two complete remissions and two partial remissions) occurred in four patients (20%). CONCLUSION In view of the apparent antileukemic efficacy and minimal extramedullary toxicity, carboplatin deserves further study in a phase II trial.
Chronic lymphocytic leukemia: an updated review.
Authors: Faguet G B 
Published: February 2017

PURPOSE To review recent advances in the pathogenesis, biology, diagnosis, and management of chronic lymphocytic leukemia (CLL). DESIGN A literature search restricted to English-language articles, abstracts, book chapters, and reports published between 1975 and 1993 was conducted both electronically using MEDLINE and CANCERLIT and manually using the bibliographies of the electronically retrieved data base. Of approximately 1,000 publications identified for analysis, 233 were selected as representative of important advances in CLL. RESULTS The last 10 years have witnessed renewed interest in the biology and treatment of CLL, a disease long viewed by clinicians as following an indolent course and perceived by investigators as uninspiring. This interest, based on advances in understanding the lineage and biology of CLL and on the advent of new and more efficacious chemotherapeutic agents, has led to improvements in patient survival and, for the first time, to complete remissions (CRs) in large subsets of patients. As we learn to use these agents better, especially in combination chemotherapy, alternative therapeutic modalities, are being vigorously pursued, including high-dose ablative chemotherapy with allogeneic or autologous bone marrow transplantation (BMT) rescue and the use of powerful tumor-cell target-specific immunoreagents. These therapeutic advances, coupled with the recent availability of molecular probes to ascertain objectively minimal remnant disease posttreatment, provide a basis for developing and assessing ever more efficacious and potentially curative treatment strategies for the management of this disease. CONCLUSION For the first time since the original 1924 monograph by Minot and Isaacs, the cure of subsets of patients with CLL appears not to be an unreasonable goal.
Timed sequential chemotherapy for previously treated patients with acute myeloid leukemia: long-term follow-up of the etoposide, mitoxantrone, and cytarabine-86 trial.
Authors: Archimbaud E , Thomas X , Leblond V , Michallet M , Fenaux P , Cordonnier C , Dreyfus F , Troussard X , Jaubert J , Travade P 
Published: February 2017

PURPOSE To confirm and extend encouraging preliminary results of timed sequential chemotherapy (TSC) in patients with previously treated acute myelogenous leukemia (AML). PATIENTS AND METHODS We report the results of the regimen of mitoxantrone on days 1 to 3, etoposide on days 8 to 10, and cytarabine on days 1 to 3 and 8 to 10 (EMA) in 133 patients, with a median follow-up of 40 months. RESULTS Sixty percent of patients, with a 95% confidence interval (CI) ranging from 51% to 68%, achieved complete remission (CR), including 44% (CI, 32% to 57%) of refractory patients and 76% (CI, 64% to 86%) of late first-relapse patients (P = .0002). Twenty-nine percent of patients did not respond to therapy, and 11% died from toxicity. Median duration of neutropenia and thrombocytopenia was 31 days and 29 days, respectively. Severe nonhematologic toxicity included sepsis in 54% of patients and mucositis in 23%. Postinduction therapy included a second course of EMA in 27 patients, maintenance in 10, autologous bone marrow transplantation (BMT) in 12, and allogeneic BMT in 13. Median survival of patients who did not have transplantation performed is 7 months, with 11% (CI, 4% to 18%) survival at 5 years. Median disease-free survival (DFS) is 8 months with 20% (CI, 8% to 32%) DFS at 5 years. Twenty-eight percent (CI, 15% to 44%) of nontransplanted patients who achieved CR had an inversion of CR duration. Previous refractoriness was the main factor associated with poor prognosis for CR achievement, DFS, and survival. CONCLUSION These results confirm initial reports on TSC and show that approximately 20% of patients with first relapse after therapy can enjoy prolonged DFS using chemotherapy only.
Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem.
Authors: Freifeld A G , Walsh T , Marshall D , Gress J , Steinberg S M , Hathorn J , Rubin M , Jarosinski P , Gill V , Young R C 
Published: February 2017

PURPOSE To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem. PATIENTS AND METHODS Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection. RESULTS Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P < .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients. CONCLUSION Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.
Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.
Authors: Gianni L , Kearns C M , Giani A , Capri G , Viganó L , Lacatelli A , Bonadonna G , Egorin M J 
Published: February 2017

PURPOSE To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy. PATIENTS AND METHODS Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models. RESULTS Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (Cmax). Neutropenia was related to the duration that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well described by a sigmoid maximum response (Emax) model. CONCLUSION The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.
Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.
Authors: Abigerges D , Chabot G G , Armand J P , Hérait P , Gouyette A , Gandia D 
Published: February 2017

PURPOSE A phase I study was undertaken to determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacokinetics of the novel topoisomerase I inhibitor irinotecan (CPT-11). PATIENTS AND METHODS Sixty-four patients meeting standard phase I eligibility criteria were included (24 women, 40 men; median age, 51 years; primary sites: colon, head and neck, lung, pleura; 60 of 64 had been previously treated). Pharmacokinetics was determined by high-performance liquid chromatography (HPLC). RESULTS One hundred ninety CPT-11 courses were administered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to 750 mg/m2). Grade 3 to 4 nonhematologic toxicities included diarrhea (16%; three hospitalizations), nausea and vomiting (9%), asthenia (14%), alopecia (53%), elevation of hepatic transaminases (8%), and one case of skin toxicity. An acute cholinergic syndrome was observed during CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg/m2, but this was circumvented by using a high-dose loperamide protocol that allowed dose escalation. Dose-dependent, reversible, noncumulative granulocytopenia was the dose-limiting toxicity (nadir, days 6 to 9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in 9% of patients. One patient died during the study, 8 days after CPT-11 treatment. Two complete responses (cervix, 450 mg/m2; head and neck, 750 mg/m2) and six partial responses in fluorouracil (5-FU)-refractory colon cancer were observed (260 to 600 mg/m2). Pharmacokinetics of CPT-11 and active metabolite SN-38 were performed in 60 patients (94 courses). CPT-11 plasma disposition was bi- or triphasic, with a mean terminal half-life of 14.2 +/- 0.9 hours (mean +/- SEM). The mean volume of distribution (Vdss) was 157 +/- 8 L/m2, and total-body clearance was 15 +/- 1 L/m2/h. The CPT-11 area under the plasma concentration versus time curves (AUC) and SN-38 AUC increased linearly with dose. SN-38 plasma decay had an apparent half-life of 13.8 +/- 1.4 hours. Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granulocytopenia, with grade 2 diarrhea, and with nausea and vomiting. CONCLUSION The MTD of CPT-11 administered as a 30-minute IV infusion every 3 weeks is 600 mg/m2, with granulocytopenia being dose-limiting. At 350 mg/m2, diarrhea appeared dose-limiting, but high-dose loperamide reduced this toxicity and allowed dose escalation. For safety reasons, the recommended dose is presently 350 mg/m2 every 3 weeks; more experience must be gained to establish the feasibility of a higher dose in large multicentric phase II studies. However, when careful monitoring of gastrointestinal toxicities is possible, a higher dose of 500 mg/m2 could be recommended in good-risk patients. The activity of this agent in 5-FU-refractory colorectal carcinoma makes it unique and mandates expedited phase II testing.
Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.
Authors: Wadler S , Haynes H , Wiernik P H 
Published: February 2017

PURPOSE Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting. PATIENTS AND METHODS Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days. RESULTS A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses. CONCLUSION Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.
Ciprofloxacin versus trimethoprim/sulfamethoxazole for prophylaxis of bacterial infections in bone marrow transplant recipients: a randomized, controlled trial.
Authors: Lew M A , Kehoe K , Ritz J , Antman K H , Nadler L , Kalish L A , Finberg R 
Published: February 2017

PURPOSE To compare the efficacy and safety of ciprofloxacin (CIP) and trimethoprim/sulfamethoxazole (TMS) for the prevention of bacterial infections in patients who received bone marrow transplantation (BMT) for the treatment of solid and hematopoietic neoplasms. PATIENTS AND METHODS Adult inpatients about to undergo BMT for lymphoma, leukemia, or solid tumors were enrolled onto a prospective, randomized, double-blinded, controlled trial that compared CIP (750 mg orally twice per day) with TMS (160 mg trimethoprim and 800 mg sulfamethoxazole orally twice per day). Subjects were stratified before randomization according to tumor and BMT type. Prophylaxis was begun within 96 hours of initiation of the BMT preparative regimen and continued until the onset of fever, signs or symptoms of infection, serious adverse effects, or recovery of the absolute granulocyte count (AGC) to > or = to 400/microL. RESULTS Seventy-five CIP recipients and 71 TMS recipients were assessable for efficacy. No difference was noted between the two groups in occurrence of fever during neutropenia, time to onset of first fever, or overall infection rates. Ten bacteremias occurred in CIP recipients versus six in TMS recipients (P = .43). Ten episodes of Clostridium difficile enterocolitis occurred in TMS recipients versus no episodes in CIP recipients (P = .001). Four infections caused by gram-negative bacilli, including one bacteremia, occurred in TMS recipients versus none in CIP recipients (P = .06). No differences were noted in the incidence of rash or organ toxicity. TMS recipients had longer durations of granulocytopenia at AGC levels < or = to 500/microL and < or = to 100/microL than did CIP recipients (P = .08 for both comparisons). Mean peak and trough serum levels of CIP decreased significantly between weeks 1 and 2 of prophylaxis. CONCLUSION CIP and TMS were equally safe and effective in the prevention of bacterial infections in BMT patients when the overall infection rate was used as the principal end point. TMS prophylaxis was associated with a higher incidence of C difficile enterocolitis and infections caused by gram-negative bacilli, as well as a trend toward prolongation of granulocytopenia.
Are axillary recurrence and overall survival affected by axillary extranodal tumor extension in breast cancer? Implications for radiation therapy.
Authors: Leonard C , Corkill M , Tompkin J , Zhen B , Waitz D , Norton L , Kinzie J 
Published: February 2017

PURPOSE To determine the overall survival and local recurrence significance of axillary lymph node extranodal tumor extension (ETE) and whether axillary/chest-wall irradiation influenced any of these outcomes. MATERIALS AND METHODS The records of 81 breast cancer patients treated with radical or modified radical mastectomy at a single surgical practice were eligible for study. Thirty-four patients had ETE: 17 with focal ETE (< 10 x high-power field) and 17 with extensive ETE (> 10 x high-power field). RESULTS With a median follow-up duration of 92 months, only two patients had an axillary recurrence (2%): one had focal ETE and one had no ETE. Neither of these patients received axillary radiation therapy. Overall survival and recurrence-free survival were significantly decreased with ETE in patients whether axillary radiation therapy had been administered or not. Analysis showed that the age of the patient correlated significantly with extensive ETE (P = .04) and that the number of positive lymph nodes (< or = three v > three) correlated significantly with ETE (whether focal or extensive) (P = .0001). A multivariate analysis of extranodal tumor extension and number of positive lymph nodes showed that ETE was associated with decreased survival (P = .05), although to a lesser degree than number of positive lymph nodes (P = .003). CONCLUSION These results show that ETE is associated with decreased survival and increased recurrence rates regardless of the extent of the radiation therapy field. Also, ETE does not necessarily indicate a significantly increased incidence of axillary recurrence. Therefore, axillary irradiation based on this pathologic finding may not be indicated.
Pubertal growth in young adult survivors of childhood leukemia.
Authors: Didcock E , Davies H A , Didi M , Ogilvy Stuart A L , Wales J K , Shalet S M 
Published: February 2017

PURPOSE To determine the effect of cranial irradiation (18 Gy and 24 Gy) on pubertal growth in young adult survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Final height (FH) and pubertal growth were retrospectively examined in 142 young adult survivors of childhood ALL. All were in first remission and had received either 18 or 24 Gy of cranial irradiation. Eighty-four children (48 girls) were treated with 24 Gy and 58 (35 girls) with 18 Gy. None had received either testicular or spinal irradiation. Timing and duration of puberty were studied in 110 patients. RESULTS Significant reduction in height standard deviation score (SDS) from diagnosis to FH was seen in both sexes and in both dose groups. In girls, in both dose groups, mean age at peak height velocity (PHV) and mean age at menarche occurred significantly earlier than in the normal population. In boys, there was a normal timing of PHV. The amplitude of PHV was significantly reduced in both sexes and in both dose groups. Parameters of pubertal duration (PHV to menarche, PHV to FH, and menarche to FH) were not significantly different from normal population values. CONCLUSION In conclusion, puberty occurred early in girls, but not in boys. Amplitude of PHV was reduced in both sexes, with no reduction in the duration of puberty. It is likely that disturbances of both timing and quality of growth during puberty contribute to the loss of standing height and body disproportion seen in these children.
Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer.
Authors: Seidman A D , Tiersten A , Hudis C , Gollub M , Barrett S , Yao T J , Lepore J , Gilewski T , Currie V , Crown J 
Published: February 2017

PURPOSE To evaluate the efficacy and safety of paclitaxel administered by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. PATIENTS AND METHODS Forty-nine patients with metastatic breast cancer received paclitaxel via 3-hour intravenous infusion after standard premedication. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used, and chemotherapy was cycled every 3 weeks. For 25 patients who received paclitaxel as initial therapy (group I), the starting dose was 250 mg/m2. Twenty-four patients who had received two or more prior regimens, including an anthracycline (group II), started at 175 mg/m2. Paclitaxel pharmacokinetics were evaluated in 23 patients in group I. RESULTS Grade 3 and 4 toxicities included (groups I/II) neutropenia (36%/33%), thrombocytopenia (0%/8%), anemia (0%/13%), neuropathy (8%/0%), arthralgia/myalgia (16%/4%), and mucositis (4%/4%). No significant hypersensitivity-type reactions or cardiac arrhythmias were seen. Six patients who received paclitaxel at > or = 250 mg/m2 experienced transient photopsia, without apparent chronic neuro-ophthalmologic sequelae. The mean peak plasma paclitaxel concentration was 5.87 mumol/L (range, 1.99 to 7.89) for these patients, and 6.08 mumol/L (range, 0.81 to 13.81) for 17 of 19 patients who did not experience visual symptoms. In 25 assessable patients in group I at a median follow-up time of 12 months, one complete response (CR) and seven partial responses (PRs) have been observed, for a total response rate of 32% (95% confidence interval [CI], 15% to 53%). In group II, five PRs were noted in 24 assessable patients (20.8%; 95% CI, 7% to 42%). Median response durations were 7 months for group I and 4 months for group II. CONCLUSION Paclitaxel via 3-hour infusion, without prophylactic G-CSF, is active and safe as initial and subsequent therapy for metastatic breast cancer. The transient visual symptoms noted at higher doses seem unrelated to peak plasma paclitaxel concentration. Further studies that compare 3- and 24 hour (or other) infusion schedules are necessary to determine the optimal administration of paclitaxel in metastatic breast cancer.