bluuebunny/crossref_metadata_2025_split huggingface dataset:
Docetaxel and Cisplatin in Combination as First-Line Chemotherapy for Advanced Epithelial Ovarian Cancer
Authors: Vasey P. A. , Paul J. , Birt A. , Junor E. J. , Reed N. S. , Symonds R. P. , Atkinson R. , Graham J. , Crawford S. M. , Coleman R. , Thomas H. , Davis J. , Eggleton S. P.H. , Kaye S. B. 
Published: February 2017

PURPOSE: A prospective, nonrandomized, multicenter, open feasibility study of cisplatin and docetaxel as first-line chemotherapy in International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV epithelial ovarian cancer was conducted. The primary end point was the incidence of severe fluid retention that necessitated treatment withdrawal. PATIENTS AND METHODS: Cisplatin and docetaxel were administered every 3 weeks for six planned cycles, with a 5-day prophylactic dexamethasone regimen (8 mg two times per day). One hundred patients (median age, 53 years; range, 24 to 71 years) received a total of 512 cycles of chemotherapy in two cohorts: cohort 1, 49 patients, 258 cycles (cisplatin 75 mg/m2 and docetaxel 75 mg/m2); cohort 2, 51 patients, 254 cycles (cisplatin 75 mg/m2 and docetaxel 85 mg/m2). RESULTS: No patients were taken off study because of fluid retention. Sixty-six patients completed six cycles of protocol therapy; 16 stopped early because of toxicity (neurotoxicity in six patients, nephrotoxicity in three, neutropenia in two, and hypersensitivity, diarrhea and vomiting, skin rash, clinical deterioration, and patient's wishes in one patient each). Grade 3/4 neutropenia was observed in more than 75% of patients and seemed to be cumulative. Patients in cohort 2 had significantly more severe neutropenia and lethargy than those in cohort 1. In addition, there were five treatment-related deaths in cohort 2 (three neutropenia and two upper gastrointestinal hemorrhage). Neurotoxicity (mainly sensory, > grade 1) was observed in 23 patients. The overall clinical response rate was 69% (complete response, 38%; partial response, 31%); CA-125 response rate was 73%. Median progression-free survival for the group was 12 months. CONCLUSION: Cisplatin and docetaxel can be administered at doses of 75 mg/m2 and 75 mg/m2, respectively, every 3 weeks, and the utility of this regimen is not limited by fluid retention. However, 33 of 100 patients were unable to complete the planned six cycles, which may explain, in part, the poor overall progression-free survival. Increasing the docetaxel dose to 85 mg/m2 adds unacceptable hematologic toxicity and potential risks to the patient.
Complete Surgical Excision Is Effective Treatment for Children With Immature Teratomas With or Without Malignant Elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study
Authors: Marina Neyssa M. , Cushing Barbara , Giller Roger , Cohen Lewis , Lauer Stephen J. , Ablin Arthur , Weetman Robert , Cullen John , Rogers Paul , Vinocur Charles , Stolar Charles , Rescorla Fred , Hawkins Edith , Heifetz Stephen , Rao Pejaver V. , Krailo Mark , Castleberry Robert P. 
Published: February 2017

PURPOSE: To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%. PATIENTS AND METHODS: Patients with immature teratomas treated at Pediatric Oncology Group or Children's Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death. RESULTS: Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. CONCLUSION: Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.
Genetic Prodrug Activation Therapy for Breast Cancer: A Phase I Clinical Trial oferbB-2–Directed Suicide Gene Expression
Authors: Pandha Hardev S. , Martin Lesley-Ann , Rigg Anne , Hurst Helen C. , Stamp Gordon W.H. , Sikora Karol , Lemoine Nicholas R. 
Published: February 2017

PURPOSE: This trial was designed to test the safety and efficacy of a tumor-specific genetic prodrug activation therapy targeted by use of the human erbB-2 gene promoter. The erbB-2 oncogene is overexpressed in approximately 20% of cases of breast cancer and is associated with poor prognosis.PATIENTS AND METHODS: Twelve breast cancer patients received transcriptionally targeted gene therapy in a phase I clinical trial using direct intratumoral injection of plasmid construct combined with systemic administration of prodrug. The genetic prodrug activation therapy is specifically targeted to erbB-2–overexpressing breast cancer cells by use of a therapeutic cassette that contains the Escherichia coli cytosine deaminase gene driven by the tumor-specific erbB-2 promoter, thus allowing activation of fluorocytosine to the active cytotoxic fluorouracil only within tumor cells that express the oncogene.RESULTS: The approach was shown to be safe and to result in targeted gene expression in up to 90% of cases. Using a number of different assays, we demonstrated that significant levels of expression of the suicide gene were specifically restricted to erbB-2–positive tumor cells, confirming the selectivity of the approach.CONCLUSION: The results of this study, the first targeted gene therapy for breast cancer and the first to use the cytosine deaminase system in human subjects, are encouraging for the development of genetic prodrug activation therapies that exploit the transcriptional profile of cancer cells.
Phase I Clinical/Pharmacokinetic and Pharmacodynamic Trial of the c-raf-1 Antisense Oligonucleotide ISIS 5132 (CGP 69846A)
Authors: Stevenson James P. , Yao Kang-Shen , Gallagher Maryann , Friedland David , Mitchell Edith P. , Cassella Amy , Monia Brett , Kwoh T. Jesse , Yu Rosie , Holmlund Jon , Dorr F. Andrew , O'Dwyer Peter J. 
Published: February 2017

PURPOSE: Raf-1 is a protein kinase that plays a broad role in oncogenic signaling and acts as a downstream effector of Ras in the mitogen-activated protein kinase pathway. The present study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-raf-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treated patients was studied using a reverse transcriptase polymerase chain reaction assay. PATIENTS AND METHODS: Patients with refractory malignancies received ISIS 5132 as a 2-hour intravenous infusion three times weekly for 3 consecutive weeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-1 mRNA analysis were collected at baseline and on days 3, 5, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter. RESULTS: Thirty-one patients received ISIS 5132 at one of nine dose levels ranging from 0.5 mg/kg to 6.0 mg/kg. Clinical toxicities included fever and fatigue, but these were not dose limiting. A clinically defined MTD was not reached. The harmonic mean half-life of ISIS 5132 was 59.8 minutes (range, 35.5 to 107.3 minutes). The area under the concentration-time curve increased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (range, 1.21 to 2.41 mL/kg/min). Two patients experienced prolonged stable disease lasting more than 7 months, which was associated with persistent reduction in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expression were identified at time points after the baseline value (P < .05) at doses ≥ 2.5 mg/kg. CONCLUSION: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.
Associations Between Community Income and Cancer Survival in Ontario, Canada, and the United States
Authors: Boyd Chris , Zhang-Salomons Jina Y. , Groome Patti A. , Mackillop William J. 
Published: February 2017

PURPOSE: The objectives of this study were as follows: (1) to compare the magnitude of the association between socioeconomic status (SES) and cancer survival in the Canadian province of Ontario with that in the United States (U.S.), and (2) to compare cancer survival in communities with similar SES in Ontario and in the U.S. METHODS: The Ontario Cancer Registry provided information about all cases of invasive cancer diagnosed in Ontario from 1987 to 1992, and the Surveillance, Epidemiology and End Results Registry (SEER) provided information about all cases diagnosed in the SEER regions of the U.S. during the same time period. Census data provided information about SES at the community level. The product-limit method was used to describe cause-specific survival. Cox proportional hazards models were used to describe the association between SES and the risk of death from cancer. RESULTS: There were significant associations between SES and survival for most cancer sites in both the U.S. and Ontario, but the magnitude of the association was usually larger in the U.S. In the poorest communities, there were significant survival advantages in favor of cancer patients in Ontario for many disease groups, including cancers of the lung, head and neck region, cervix, and uterus. However, in upper- and middle-income communities, there were significant survival advantages in favor of the U.S. for all cases combined and for several individual diseases, including cancers of the breast, colon and rectum, prostate, and bladder. CONCLUSION: The association between SES and cancer survival is weaker in Ontario than it is in the U.S. This is due to a combination of better survival among patients in the poorest communities and worse survival among patients in the wealthier communities of Ontario relative to those in the U.S.
Treatment of Multifocal Primary Cutaneous B-Cell Lymphoma: A Clinical Follow-Up Study of 29 Patients
Authors: Bekkenk Marcel W. , Vermeer Maarten H. , Geerts Marie-Louise , Noordijk Ed M. , Heule Freerk , van Voorst Vader Pieter C. , van Vloten Willem A. , Meijer Chris J.L.M. , Willemze Rein 
Published: February 2017

PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines. PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg). RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis. CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.
Lack of Effect of Adjuvant Chemotherapy on the Elimination of Single Dormant Tumor Cells in Bone Marrow of High-Risk Breast Cancer Patients
Authors: Braun Stephan , Kentenich Christina , Janni Wolfgang , Hepp Florian , de Waal Johann , Willgeroth Fritz , Sommer Harald , Pantel Klaus 
Published: February 2017

PURPOSE: There is an urgent need for markers that can predict the efficacy of adjuvant chemotherapy in patients with solid tumors. This study was designed to evaluate whether monitoring of micrometastases in bone marrow can predict the response to systemic chemotherapy in breast cancer. PATIENTS AND METHODS: Bone marrow aspirates of 59 newly diagnosed breast cancer patients with either inflammatory (n = 23) or advanced (> four nodes involved) disease (n = 36) were examined immunocytochemically with the monoclonal anticytokeratin (CK) antibody A45-B/B3 (murine immunoglobulin G1; Micromet, Munich, Germany) before and after chemotherapy with taxanes and anthracyclines. RESULTS: Of 59 patients, 29 (49.2%) and 26 (44.1%) presented with CK-positive tumor cells in bone marrow before and after chemotherapy, respectively. After chemotherapy, less than half of the previously CK-positive patients (14 of 29 patients; 48.3%) had a CK-negative bone marrow finding, and 11 (36.7%) of 30 previously CK-negative patients were CK-positive. At a median follow-up of 19 months (range, 6 to 39 months), Kaplan-Meier analysis of 55 assessable patients revealed a significantly reduced overall survival (P = .011; log-rank test) if CK-positive cells were detected after chemotherapy. In multivariate analysis, the presence of CK-positive tumor cells in bone marrow after chemotherapy was an independent predictor for reduced overall survival (relative risk = 5.0; P = .016). CONCLUSION: The cytotoxic agents currently used for chemotherapy in high-risk breast cancer patients do not completely eliminate CK-positive tumor cells in bone marrow. The presence of these tumor cells after chemotherapy is associated with poor prognosis. Thus, bone marrow monitoring might help predict the response to systemic chemotherapy.
Outcome Of CNS Disease At Diagnosis in Disseminated Small Noncleaved-Cell Lymphoma and B-Cell Leukemia: A Children’s Cancer Group Study
Authors: Gururangan Sridharan , Sposto Richard , Cairo Mitchell S. , Meadows Anna T. , Finlay Jonathan L. 
Published: February 2017

PURPOSE: To examine the impact of initial CNS involvement on outcome and patterns of failure in patients with disseminated small noncleaved-cell lymphoma and B-cell leukemia who were treated in four successive Children’s Cancer Group trials. PATIENTS AND METHODS: Of 462 patients with disseminated disease, 49 (10.6%) had CNS disease at diagnosis (CNS+). CNS disease included meningeal disease or CNS parenchymal masses with or without cranial neuropathies (CSF+/Mass; CNPs) in 36 patients and isolated CNPs in 13. Of the CNS+ patients, 28 had M2 (5% to 25% blasts) or M3 (> 25% blasts) bone marrow involvement. All patients received protocol-based systemic and intrathecal chemotherapy. Thirty-six patients also received CNS irradiation. RESULTS: Relapses occurred in 21 (43%) of 49 patients, predominantly in the CNS (71%) and bone marrow (52%). The 3-year event-free survival ± SE for all patients with CNS+ disease was 45% ± 7%. Patients with CSF+/Mass had a nominally higher treatment failure rate compared with patients with CNS− after adjusting for marrow status and lactate dehydrogenase (LDH) diagnosis, with a relative failure rate (RFR) of 1.52 (95% confidence interval [CI], 0.88 to 2.6; P = .15). In comparison, the RFRs for patients with M2 or M3 marrow and for those with LDH levels greater than 500 IU/L after adjusting for CNS disease were 1.4 (95% CI, 0.96 to 2.0; P = .029) and 2.2 (95% CI, 1.5 to 3.0; P < .001), respectively. The RFR for patients with isolated CNPs was 0.87 (95% CI, 0.36 to 2.1; P = .76). CONCLUSION: We conclude that, with the treatments used during the period covered by these studies, the presence of CSF+/Mass CNS disease at diagnosis was associated with a nominally worse outcome independent of initial bone marrow status and LDH level, but the effect was not statistically significant.
Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects
Authors: de Jonge Maja J. A. , Loos Walter J. , Gelderblom Hans , Planting André S. Th. , van der Burg Maria E. L. , Sparreboom Alex , Brouwer Eric , van Beurden Vera , Mantel Marijke A. , Doyle Eddie , Hearn Solange , Ross Graham , Verweij Jaap 
Published: February 2017

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m2 either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m2/d × 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m2/d × 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m2/d PO × 5 preceded by cisplatin 75 mg/m2 IV day 1 once every 3 weeks, and topotecan 2.0 mg/m2/d PO followed by cisplatin 75 mg/m2 IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.
Evaluation of Tumor Measurements in Oncology: Use of Film-Based and Electronic Techniques
Authors: Schwartz Lawrence H. , Ginsberg Michelle S. , DeCorato Douglas , Rothenberg Lawrence N. , Einstein Steven , Kijewski Peter , Panicek David M. 
Published: February 2017

PURPOSE: To evaluate the variability in bidimensional computed tomography (CT) measurements obtained of actual tumors and of tumor phantoms by use of three measurement techniques: hand-held calipers on film, electronic calipers on a workstation, and an autocontour technique on a workstation. MATERIALS AND METHODS: Three radiologists measured 45 actual tumors (in the lung, liver, and lymph nodes) on CT images, using each of the three techniques. Bidimensional measurements were recorded, and their cross-products calculated. The coefficient of variation was calculated to assess interobserver variability. CT images of 48 phantoms were measured by three radiologists with each of the techniques. In addition to the coefficient of variation, the differences between the cross-product measurements of tumor phantoms themselves and the measurements obtained with each of the techniques were calculated. RESULTS: The differences between the coefficients of variation were statistically significantly different for the autocontour technique, compared with the other techniques, both for actual tumors and for tumor phantoms. There was no statistically significant difference in the coefficient of variation between measurements obtained with hand-held calipers and electronic calipers. The cross-products for tumor phantoms were 12% less than the actual cross-product when calipers on film were used, 11% less using electronic calipers, and 1% greater using the autocontour technique. CONCLUSION: Tumor size is obtained more accurately and consistently between readers using an automated autocontour technique than between those using hand-held or electronic calipers. This finding has substantial implications for monitoring tumor therapy in an individual patient, as well as for evaluating the effectiveness of new therapies under development.
Correlation Between Docetaxel Clearance and Estimated Cytochrome P450 Activity by Urinary Metabolite of Exogenous Cortisol
Authors: Yamamoto Noboru , Tamura Tomohide , Kamiya Yoshikazu , Sekine Ikuo , Kunitoh Hideo , Saijo Nagahiro 
Published: February 2017

PURPOSE: There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6β-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method. PATIENTS AND METHODS: Thirty patients with advanced non–small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6β-OHF and FC were measured. More than 2 days later, 60 mg/m2 of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed. RESULTS: After cortisol administration, the total amount of 24-hour urinary 6β-OHF (T6β-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 ± 4,076 μg/d (mean ± SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 ± 6.4 L/h/m2 and 2.66 ± 0.91 mg/L 8729· h, respectively. An excellent correlation between docetaxel CL and T6β-OHF was observed (r = .867). In multivariate analysis, T6β-OHF (P < .001), alpha-1-acid glycoprotein (P < .004), AST (P = .007), and age (P = .022) significantly correlated with docetaxel CL. CONCLUSION: The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6β-OHF after cortisol administration.