bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear Morphometry and Prognosis in Favorable Histology Wilms' Tumor: A Prospective Reevaluation
Authors: Breslow Norman E. , Partin Alan W. , Lee Benjamin R. , Guthrie Katherine A. , Beckwith J. Bruce , Green Daniel M.
Published: February 2017

PURPOSE: This study was designed to evaluate the ability of a previously published nuclear morphometry discriminant function to predict disease-free survival in patients with Wilms' tumor.

PATIENTS AND METHODS: We identified 218 patients with stage I-IV Wilms' tumor of favorable histology who were entered onto the National Wilms' Tumor Study (NWTS) between January 1, 1990 and April 15, 1994. The nuclear morphometry score was calculated for each patient as follows: MVf = (0.02 × AGE) + (1.17 × SNRF) + (90.6 × LEFD) − 94, with AGE denoting age at diagnosis in months, SNRF the skewness of the nuclear roundness factor, and LEFD the lowest value of nuclear ellipticity as measured by the feret diameter method. Relative risks of relapse were estimated for the total score and for each of its components. Sensitivity and specificity were determined for the criterion of “MVf is greater than −0.35” as a predictor of relapse.

RESULTS: By contrast with previously published results, neither the SNRF nor the LEFD made any contribution to the prediction of disease-free survival. Sensitivity and specificity of the criterion of “MVf is greater than −0.35” were 71% and 56%, respectively.

CONCLUSION: Re-evaluation of a published nuclear morphometry score showed that it did not predict disease-free survival in patients with Wilms' tumor. The earlier study very likely overestimated the predictive power of nuclear morphometry by using the same data set both to develop the score and to evaluate its properties. Because of the huge number of combinations of nuclear morphometry measurements that may enter into the multivariate discriminant function, use of appropriate statistical methods is essential to estimate accurately the sensitivity and specificity.
Phase I Trial of Multiple Cycles of High-Dose Chemotherapy Supported by Autologous Peripheral-Blood Stem Cells
Authors: Schilder Russell J. , Johnson Steven , Gallo James , Kindsfather Scott , Rogers Barbara , Bookman Michael A. , Millenson Michael M. , Boente Matthew , Rosenblum Norman , Litwin Samuel , Ozols Robert F.
Published: February 2017

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin and paclitaxel with hematopoietic peripheral-blood stem cell (PBSC) support.

PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with cyclophosphamide, etoposide, and granulocyte-macrophage colony-stimulating factor (GM-CSF). After one cycle of conventional-dose carboplatin and cyclophosphamide with GM-CSF, patients received multiple cycles of high-dose carboplatin (area under the concentration-time curve [AUC], 12 to 20) and paclitaxel (250 mg/m2) with PBSC and GM-CSF repeated every 28 days.

RESULTS: Twenty-four of 28 patients were assessable for toxicity and clinical outcome. Dose-limiting toxicitieswere dehydration, diarrhea, and electrolyte imbalances. The maximum-tolerated dose of carboplatin was AUC 16 (equivalent to a median of 1,189 mg/m2). The relationship of target AUC to measured AUC was linear (r2 = .29; P = .0011). The overall response rate was 96%, with a complete clinical response rate of 67%. The median time to progression from the first PBSC reinfusion was 49.5 weeks (range, 8 to 156+ weeks).

CONCLUSION: Multiple cycles of high-dose carboplatin (AUC 16) and paclitaxel (250 mg/m2) can be safely administered with GM-CSF and PBSC support. Although this regimen is safe, feasible, and active, the use of multiple cycles of high-dose chemotherapy as front-line treatment remains experimental and should only be used in the context of a clinical trial.
Phase I and Pharmacologic Study of Oral (PEG-1000) 9-Aminocamptothecin in Adult Patients With Solid Tumors
Authors: de Jonge Maja J.A. , Punt Cornelis J.A. , Gelderblom A. Hans , Loos Walter J. , van Beurden Vera , Planting André S.Th. , van der Burg Maria E.L. , van Maanen Lydia W.G.M. , Dallaire Brian K. , Verweij Jaap , Wagener D.J. Theo , Sparreboom Alex
Published: February 2017

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors.

PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m2/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay.

RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m2/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r2 = 0.86). One partial response was noted in a patient with metastatic colorectal cancer.

CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m2/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.
Cisplatin, Gemcitabine, and Paclitaxel in Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: A Phase I-II Study
Authors: Frasci Giuseppe , Panza Nicola , Comella Pasquale , Nicolella Gianpaolo P. , Natale Michele , Manzione Luigi , Bilancia Domenico , Cioffi Riccardo , Maiorino Luigi , De Cataldis Giuseppe , Belli Mario , Micillo Enrico , Mascia Vittorio , Massidda Bruno , Lorusso Vito , De Lena Mario , Carpagnano Francesco , Contu Antonio , Pusceddu Guido , Comella Giuseppe
Published: February 2017

PURPOSE: Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non–small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen.

PATIENTS AND METHODS: From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m2) and gemcitabine (1,000 mg/m2) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks.

RESULTS: Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m2 in pretreated patients, whereas it continued to 150 mg/m2 in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m2 was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patient's disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%.

CONCLUSION: The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.
Accuracy of Recall in Health-Related Quality-of-Life Assessment Among Men Treated for Prostate Cancer
Authors: Litwin Mark S. , McGuigan Kimberly A.
Published: February 2017

PURPOSE: To determine the accuracy of patient recall of health-related quality of life (HRQOL) in men who have undergone radical prostatectomy for early-stage prostate cancer.

PATIENTS AND METHODS: Patients enrolled onto a longitudinal, observational cohort study of HRQOL after radical prostatectomy for early-stage prostate cancer were asked to assess their baseline HRQOL before surgery. They were later asked to recall their baseline HRQOL at intervals of 7 to 37 months after surgery. The two views of baseline HRQOL (actual and recall) were compared. HRQOL was measured with established instruments (the RAND 12-Item Short-Form Health Survey and a validated short form of the University of California Los Angeles Prostate Cancer Index) that addressed impairment in the physical, mental, urinary, bowel, and sexual domains.

RESULTS: Overall, recall was poor. Patients tended to remember their baseline HRQOL as being better than it actually was. This effect was particularly striking for urinary and sexual function. Greater education and younger age diminished this effect in some domains. The effect did not vary with time since surgery.

CONCLUSION: Men undergoing radical prostatectomy for early-stage prostate cancer do not accurately recall their pretreatment HRQOL when asked several months or years later. This recall bias is constant throughout a period of 6 months to 3 years after surgery. By collecting data before treatment and observing subjects longitudinally, investigators can ensure that HRQOL changes are analyzed in the context of any impairment that may have been present at baseline. If a longitudinal study is not feasible, then great caution must be used if patients are asked to recall their pretreatment HRQOL.
Differential Expression of Nuclear Retinoid Receptors in Normal and Malignant Prostates
Authors: Lotan Yair , Xu Xiao C. , Shalev Moshe , Lotan Reuben , Williams Russell , Wheeler Thomas M. , Thompson Timothy C. , Kadmon Dov
Published: February 2017

PURPOSE: To determine (1) whether nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are differentially expressed in normal and in cancerous human prostate tissues and (2) whether oral fenretinide therapy impacts the expression of these receptors in prostate cancer.

PATIENTS AND METHODS: In situ hybridization with antisense riboprobes was used to probe for RAR and RXR transcripts in prostate tissues in a two-phased study: (1) expression of retinoid receptors in eight normal prostates was compared with their expression in 10 randomly picked radical prostatectomy specimens (group A); (2) expression of retinoid receptors was determined in 22 radical prostatectomy specimens from participants in a clinical study (group B). Twelve patients received oral fenretinide 200 mg/d, and 10 received placebo pills for 28 days before surgery.

RESULTS: RARα, RARγ, RXRα, and RXRγ mRNAs were detected in most normal and cancerous prostates. In group A, RARβ mRNA was expressed in only four of 10 malignant prostates but was present in seven of eight benign prostates (P = .05). RXRβ mRNA was expressed in four of eight benign prostates and in zero of 10 malignant prostates (P = .023). In group B prostates, RARβ and RXRβ mRNAs were markedly reduced in all cancers and in the adjacent, nonmalignant tissue. There were no differences between receptor expression in the fenretinide-treated group and the placebo group.

CONCLUSION: RARβ and RXRβ mRNAs are selectively lost in both prostate cancer and adjacent morphologically normal prostatic tissue, supporting the concept of a field of carcinogenesis. One month of oral fenretinide (200 mg/d) did not influence the expression of retinoid receptors in prostate cancer.
Rifampin Does Not Improve the Efficacy of Quinolone Antibacterial Prophylaxis in Neutropenic Cancer Patients: Results of a Randomized Clinical Trial
Authors: Gomez-Martin Carlos , Solá Claudio , Hornedo Javier , Perea Sofia , Lumbreras Carlos , Valentí Vicente , Arcediano Alberto , Rodriguez Milva , Salazar Ramon , Cortés-Funes Hernán , Hidalgo Manuel
Published: February 2017

PURPOSE: To determine whether the addition of rifampin to a quinolone-based antibacterial prophylactic regimen in patients undergoing high-dose chemotherapy (HDC) with peripheral-blood stem-cell transplantation (PBSCT) decreases the incidence of neutropenia and fever, Gram-positive bacteremia, and infection-related morbidity.

PATIENTS AND METHODS: Patients with solid tumors undergoing HDC with PBSCT were randomized to receive prophylactic antibiotics with either ciprofloxacin 500 mg orally every 8 hours or the same ciprofloxacin regimen with rifampin 300 mg orally every 12 hours. Prophylaxis was started 48 hours before stem-cell reinfusion. Patients were monitored to document the occurrence of neutropenia and fever, incidence and cause of bacterial infection, time to onset and duration of fever, requirement for intravenous antimicrobials, and length of hospital admission.

RESULTS: Sixty-five patients were randomized to receive ciprofloxacin and 65 to receive ciprofloxacin plus rifampin, and from these groups, 62 and 61 were assessable, respectively. The proportion of patients who developed neutropenia and fever was 87% in the group treated with ciprofloxacin and 78% in the group treated with ciprofloxacin and rifampin (P = .25). Although there was a trend toward a reduction in the overall incidence of bacteremia (12 v 4 patients), and Gram-positive bacteremia (8 v 2 patients) with the addition of rifampin, none of these comparisons was statistically significant (P = .05 and P = .09, respectively).

CONCLUSION: The results of this study, which demonstrate that rifampin does not improve ciprofloxacin antibacterial prophylaxis in cancer patients undergoing HDC with PBSCT support but that it does increase the occurrence of undesirable side effects, do not support the routine use of rifampin in this setting.
Phase I/II Trial of Cyclophosphamide, Mitoxantrone, and Escalated Doses of Carboplatin Supported by Peripheral-Blood Stem Cells in Women With Metastatic Breast Cancer
Authors: Patnaik Amita , MacKinnon Janet , Goss Paul , Nagy Tracy , Stewart Keith , Keating Armand , Crump Michael
Published: February 2017

PURPOSE: To intensify a regimen of high-dose cyclophosphamide, mitoxantrone, and carboplatin that had previously produced high complete and overall response rates in metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-four patients with a median age of 43 years (range, 25 to 57 years) and previously untreated MBC who were responding to anthracycline-based or single-agent taxane chemotherapy received cyclophosphamide 1.5 g/m2/d and mitoxantrone 16 mg/m2/d combined with escalating doses of carboplatin 200 to 500 mg/m2/d, each given daily from days −6 to −3. Hematopoiesis was supported by mobilized peripheral-blood stem cells infused on day 0 and by use of granulocyte-macrophage colony-stimulating factor 300 μg/d subcutaneously starting on day 1.

RESULTS: A total of six dose levels of carboplatin were examined. Grades 3 and 4 toxicity occurred in 10 patients and one patient, respectively, with grade 3 toxicity occurring in only five of 31 patients treated with ≤ 400 mg/m2 of carboplatin. Major dose-limiting toxicities were cardiac, pulmonary, and renal. Four patients developed congestive heart failure: two had persistently low ejection fraction 11 and 36 months after peripheral-blood stem-cell transplantation (PBSCT), and two recovered. Hematologic recovery to an absolute neutrophil count of greater than 0.5 × 109/L occurred at a median of 11 days (range, 8 to 25 days) and to a platelet count of greater than 20 × 109/L at a median of 10.5 days (range, 6 to 60 days). There were two toxic deaths from sepsis: one on day 27 (level 5) and one from cardiac arrest on day 42 (level 6).

CONCLUSION: The maximum-tolerated dose of carboplatin was 400 mg/m2/d in combination with mitoxantrone 16 mg/m2/d and cyclophosphamide 1,500 mg/m2, all drugs given over 4 days. This regimen is being tested in a phase III trial of high-dose chemotherapy and PBSCT versus standard treatment.
Mobilization of Peripheral-Blood Stem Cells by Concurrent Administration of Daniplestim and Granulocyte Colony-Stimulating Factor in Patients With Breast Cancer or Lymphoma
Authors: DiPersio John F. , Schuster Michael W. , Abboud Camille N. , Winter Jane N. , Santos Vicki R. , Collins Denise M. , Sherman Jeffrey W. , Baum Charles M.
Published: February 2017

PURPOSE: To evaluate the safety and hematopoietic activity of daniplestim administered concurrently with granulocyte colony-stimulating factor (G-CSF) for peripheral-blood stem-cell (PBSC) mobilization.

PATIENTS AND METHODS: In the initial dose-escalation phase, 25 patients with adenocarcinoma of the breast (AB; 13 patients) or lymphoma (12 patients) were given daniplestim at doses ranging from 0.1 to 3.75 μg/kg/d plus G-CSF 10 μg/kg/d. In the randomized phase, 52 patients with AB (27 patients) or lymphoma (25 patients) were randomized within disease categories to the daniplestim dose chosen in the dose-escalation phase plus G-CSF 10 μg/kg/d (D+G) or placebo plus G-CSF 10 μg/kg/d (P+G) for up to 7 days.

RESULTS: A daniplestim dose of 2.5 μg/kg/d was chosen for further study because it was hematopoietically active and had an acceptable side-effect profile. In the randomized phase, in patients with AB, D+G was associated with a higher probability (P = .0696) of collecting ≥ 2.5 × 106 CD34+ cells/kg and significantly higher circulating CD34+ cell counts (P = .0498) on days 6 through 9 after the initiation of dosing. The target level was more likely to be reached with additional leukaphereses in the patients given D+G. Patients given P+G did not benefit from additional leukaphereses beyond the first procedure. The type of mobilization did show a trend toward a shorter duration of neutropenia in the D+G group. The adverse events with D+G consisted largely of mild to moderate flu-like symptoms, including headache and fever, and occurred more frequently than with P+G.

CONCLUSION: Daniplestim administered at 2.5 μg/kg/d is tolerable and active when combined with G-CSF, and the combination may prove more effective than G-CSF alone in promoting the collection of adequate numbers of CD34+ cells for PBSC infusion in patients with AB.
Phase I and Pharmacologic Study of Docetaxel and Irinotecan in Advanced Non–Small-Cell Lung Cancer
Authors: Masuda Noriyuki , Negoro Shunichi , Kudoh Shinzoh , Sugiura Takahiko , Nakagawa Kazuhiko , Saka Hideo , Takada Minoru , Niitani Hisanobu , Fukuoka Masahiro
Published: February 2017

PURPOSE: We conducted a phase I trial of docetaxel, a new antimicrotubule agent, combined with irinotecan (CPT-11), a topoisomerase I inhibitor. The aim was to determine the maximum-tolerated dose (MTD) of docetaxel combined with CPT-11, as well as the dose-limiting toxicities (DLTs) of this combination in advanced non–small-cell lung cancer (NSCLC) patients.

PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated at 4-week intervals with docetaxel (60 minutes, day 2) plus CPT-11 (90 minutes, days 1, 8, and 15). The starting doses of docetaxel/CPT-11 were 30/40 mg/m2, and doses were escalated in 10-mg/m2 increments until the MTD was reached.

RESULTS: The MTD of docetaxel/CPT-11 was 50/60 mg/m2 (level 5A), or 60/50 mg/m2 (level 5B). Neutropenia and diarrhea were the DLTs. CPT-11 did not affect the pharmacokinetics of docetaxel. There were 11 (37%) partial responses among 30 patients. The median survival time was 48 weeks, and the 1-year survival rate was 44.9%.

CONCLUSION: The combination of docetaxel and CPT-11 seems to be active against NSCLC, with acceptable toxicity. The recommended dose for phase II studies is 50 mg/m2 of CPT-11 (days 1, 8, and 15) and 50 mg/m2 of docetaxel (day 2) administered every 28 days.
Differential Frequencies of p16INK4a Promoter Hypermethylation, p53 Mutation, and K-ras Mutation in Exfoliative Material Mark the Development of Lung Cancer in Symptomatic Chronic Smokers
Authors: Kersting M. , Friedl C. , Kraus A. , Behn M. , Pankow W. , Schuermann M.
Published: February 2017

PURPOSE: The aim of this study was to investigate the frequency of three (epi)genetic alterations (p53 and K-ras mutations and p16INK4a promoter hypermethylation) in symptomatic chronic smokers compared with patients with lung cancer and to evaluate the use of exfoliative material for such analyses.

PATIENTS AND METHODS: Fifty-one patients with histologically confirmed lung cancer and 25 chronic smokers (> 20 pack-years) were investigated for mutations in the K-ras (codon 12) and p53 (codons 248, 249, and 273) genes and for allelic hypermethylation of the p16INK4a gene. DNA was isolated from sputum and bilateral bronchial lavage, and brushings were taken at bronchoscopy.

RESULTS: Forty-one genetic lesions were detected within exfoliative material from the group of 51 patients with lung cancer and 10 lesions in the chronic smoker group. K-ras mutations occurred exclusively in the lung cancer group, whereas p53 mutations and p16INK4a promoter hypermethylation were also found in chronic smokers. Three of eight chronic smokers who harbored an (epi)genetic alteration were subsequently diagnosed with lung cancer. Analysis of sputum yielded information equivalent to that of samples obtained during bronchoscopy.

CONCLUSION: p16INK4a promoter hypermethylation and p53 mutations can occur in chronic smokers before any clinical evidence of neoplasia and may be indicative of an increased risk of developing lung cancer or of early disease. K-ras mutations occur exclusively in the presence of clinically detectable neoplastic transformation. Molecular analysis of sputum for such markers may provide an effective means of screening chronic smokers to enable earlier detection and therapeutic intervention of lung cancer.
Late Effects of Treatment in Survivors of Childhood Acute Myeloid Leukemia
Authors: Leung Wing , Hudson Melissa M. , Strickland Donald K. , Phipps Sean , Srivastava Deo K. , Ribeiro Raul C. , Rubnitz Jeffrey E. , Sandlund John T. , Kun Larry E. , Bowman Laura C. , Razzouk Bassem I. , Mathew Prasad , Shearer Patricia , Evans William E. , Pui Ching-Hon
Published: February 2017

PURPOSE: To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML).

PATIENTS AND METHODS: Of 77 survivors (median follow-up duration, 16.7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed.

RESULTS: Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up.

CONCLUSION: Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.
High-Dose Chemotherapy as Initial Salvage Chemotherapy in Patients With Relapsed Testicular Cancer
Authors: Bhatia S. , Abonour R. , Porcu P. , Seshadri R. , Nichols C.R. , Cornetta K. , Einhorn L.H.
Published: February 2017

PURPOSE: To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.

PATIENTS AND METHODS: From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months).

RESULTS: Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality.

CONCLUSION: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.
Phase II Study of Vinorelbine With Protracted Fluorouracil Infusion as a Second- or Third-Line Approach for Advanced Breast Cancer Patients Previously Treated With Anthracyclines
Authors: Berruti Alfredo , Sperone Paola , Bottini Alberto , Gorzegno Gabriella , Lorusso Vito , Brunelli Antonio , Botta Mario , Tampellini Marco , Donadio Michela , Mancarella Sergio , De Lena Mario , Alquati Palmiro , Dogliotti Luigi
Published: February 2017

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens.

PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m2 administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m2/d given continuously over a 24-hour period.

RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months.

CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.
Rapid Hematopoietic Recovery After Coinfusion of Autologous-Blood Stem Cells and Culture-Expanded Marrow Mesenchymal Stem Cells in Advanced Breast Cancer Patients Receiving High-Dose Chemotherapy
Authors: Koç Omer N. , Gerson Stanton L. , Cooper Brenda W. , Dyhouse Stephanie M. , Haynesworth Stephen E. , Caplan Arnold I. , Lazarus Hillard M.
Published: February 2017

PURPOSE: Multipotential mesenchymal stem cells (MSCs) are found in human bone marrow and are shown to secrete hematopoietic cytokines and support hematopoietic progenitors in vitro. We hypothesized that infusion of autologous MSCs after myeloablative therapy would facilitate engraftment by hematopoietic stem cells, and we investigated the feasibility, safety, and hematopoietic effects of culture-expanded MSCs in breast cancer patients receiving autologous peripheral-blood progenitor-cell (PBPC) infusion.

PATIENTS AND METHODS: We developed an efficient method of isolating and culture-expanding a homogenous population of MSCs from a small marrow-aspirate sample obtained from 32 breast cancer patients. Twenty-eight patients were given high-dose chemotherapy and autologous PBPCs plus culture-expanded MSC infusion and daily granulocyte colony-stimulating factor.

RESULTS: Human MSCs were successfully isolated from a mean ± SD of 23.4 ± 5.9 mL of bone marrow aspirate from all patients. Expansion cultures generated greater than 1 × 106 MSCs/kg for all patients over 20 to 50 days with a mean potential of 5.6 to 36.3 × 106 MSCs/kg after two to six passages, respectively. Twenty-eight patients were infused with 1 to 2.2 × 106 expanded autologous MSCs/kg intravenously over 15 minutes. There were no toxicities related to the infusion of MSCs. Clonogenic MSCs were detected in venous blood up to 1 hour after infusion in 13 of 21 patients (62%). Median time to achieve a neutrophil count greater than 500/μL and platelet count ≥ 20,000/μL untransfused was 8 days (range, 6 to 11 days) and 8.5 days (range, 4 to 19 days), respectively.

CONCLUSION: This report is the first describing infusion of autologous MSCs with therapeutic intent. We found that autologous MSC infusion at the time of PBPC transplantation is feasible and safe. The observed rapid hematopoietic recovery suggests that MSC infusion after myeloablative therapy may have a positive impact on hematopoiesis and should be tested in randomized trials.
Physician Compliance With Warfarin Prophylaxis for Central Venous Catheters in Patients With Solid Tumors
Authors: Carr Karen M. , Rabinowitz Ian
Published: February 2017

PURPOSE: There is an established benefit of prophylactic warfarin in cancer patients with central venous catheters. This study assessed the compliance rate of prophylactic low-dose warfarin prescription in cancer patients with central venous catheters at a single institution.

PATIENTS AND METHODS: Oncology patients with central venous catheters were identified by a retrospective chart review. Information retrieved included whether prophylactic warfarin had been prescribed and whether the patient had suffered a thrombotic or bleeding event. After the initial chart review, physicians were notified of the benefits of warfarin prophylaxis, and subsequently, a physician-independent mechanism of prescribing prophylactic warfarin was instituted. After each of these interventions, we retrospectively reviewed a further two cohorts of patients to assess compliance with warfarin prophylaxis.

RESULTS: During the baseline study, only 10% of patients were prescribed prophylactic warfarin. After physician notification, the compliance rate increased to only 20% (P = .3). After instituting the physician-independent mechanism of prescribing prophylactic warfarin, the compliance rate increased to 95% (P < .001). The rate of catheter-related thrombosis was 11% for patients who were prescribed warfarin compared with 21% in those who were not anticoagulated (P = .2).

CONCLUSION: At our institution, the rate of prescribing prophylactic warfarin was low in this patient population, and there was a reluctance of treating physicians to change their prescribing practice. Mechanisms exist to improve the rate of anticoagulant prophylaxis in this clinical setting. We recommend that institutions review their rate of compliance with prophylactic anticoagulation for patients with central venous catheters and solid tumors.
Identifying Breast Cancer Patients at High Risk for Bone Metastases
Authors: Colleoni Marco , O’Neill Anne , Goldhirsch Aron , Gelber Richard D. , Bonetti Marco , Thürlimann Beat , Price Karen N. , Castiglione-Gertsch Monica , Coates Alan S. , Lindtner Jurij , Collins John , Senn Hans-Jörg , Cavalli Franco , Forbes John , Gudgeon Anne , Simoncini Edda , Cortes-Funes Hernan , Veronesi Andrea , Fey Martin , Rudenstam Carl-Magnus ,   for the International (Ludwig) Breast Cancer Study Group
Published: February 2017

PURPOSE: To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with bisphosphonates.

PATIENTS AND METHODS: We evaluated data from 6,792 patients who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1993. Median follow-up was 10.7 years. A total of 1,275 patients (18.7%) presented with node-negative disease, whereas 3,354 patients (49.4%) had one to three and 2,163 patients (31.9%) had four or more involved axillary lymph nodes. We also assessed the incidence of subsequent bone metastases in the cohort of 1,220 patients who had a first event in local or regional sites or soft tissue alone. Median follow-up for this cohort was 7.7 years from first recurrence.

RESULTS: For the entire population with operable disease, the cumulative incidence of bone metastases at any time was 8.2% at 2 years from randomization and 27.3% at 10 years. The highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at 2 years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at 2 years from first recurrence and 36.7% at 10 years).

CONCLUSION: Treatments to prevent bone metastases may have a major impact on the course of breast cancer and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional recurrence or recurrence in soft tissue.
Phase II Trial of the Antiangiogenic Agent Thalidomide in Patients With Recurrent High-Grade Gliomas
Authors: Fine Howard A. , Figg William D. , Jaeckle Kurt , Wen Patrick Y. , Kyritsis Athanassios P. , Loeffler Jay S. , Levin Victor A. , Black Peter M. , Kaplan Richard , Pluda James M. , Yung W.K. Alfred
Published: February 2017

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas.

PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria.

RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival.

CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.
High-Dose Sequential Chemotherapy With Recombinant Granulocyte Colony-Stimulating Factor and Repeated Stem-Cell Support for Inflammatory Breast Cancer Patients: Does Impact on Quality of Life Jeopardize Feasibility and Acceptability of Treatment?
Authors: Macquart-Moulin Geneviève , Viens Patrice , Palangié Thao , Bouscary Marie-Laure , Delozier Thierry , Roché Henri , Janvier Maud , Fabbro Michel , Moatti Jean-Paul ,   for the Economic/Quality-of-Life/Intensive Therapy Group of the French National Federation of Anticancer Centers
Published: February 2017

PURPOSE: This study was designed to investigate the quality of life (QOL) of patients enrolled onto the High-Dose Chemotherapy for Breast Cancer Study Group trial (PEGASE 02), a French pilot multicenter trial of the treatment of inflammatory breast cancer (IBC) aimed at evaluating (1) toxicity and feasibility of sequential high-dose chemotherapy (HDC) with recombinant human granulocyte colony-stimulating factor (filgrastim) and stem-cell support and (2) response to HDC in terms of pathologic response and survival.

PATIENTS AND METHODS: QOL measures were performed at inclusion and four times subsequently up to 1 year using an ad hoc side-effect questionnaire (19 physical symptoms) and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30).

RESULTS: Of the 95 patients entered, the overall QOL questionnaire completion compliance was 75.6%. During cycle 3 of HDC, the number of symptoms was high (mean ± SD QOL score, 10 ± 3), with fatigue, hair loss, appetite loss, nausea, change in taste, vomiting, fever, and weight loss reported by more than 60% of patients. Toxicity and distress associated with HDC were reflected in the decline of four EORTC QLQ-C30 scores: global QOL (P = .001), and physical, role, and social functioning (P < .001 for all statistics). However, QOL deterioration disappeared after treatment completion, except for physical functioning (P = .025). One year after inclusion, most QOL scores returned to baseline, and both emotional functioning and global QOL scores were even higher than baseline (P = .030 and P = .009, respectively).

CONCLUSION: If it is confirmed that improvements in pathologic response rates with HDC effectively translate into increased probabilities of survival for IBC patients, adoption of such treatment as PEGASE 02 will not involve crucial choices between length of life and QOL and should not be delayed for QOL arguments.
Multi-Institutional Phase I/II Trial of Paclitaxel, Cisplatin, and Etoposide With Concurrent Radiation for Limited-Stage Small-Cell Lung Carcinoma
Authors: Levitan Nathan , Dowlati Afshin , Shina Donald , Craffey Mark , Mackay Wilma , DeVore Russell , Jett James , Remick Scot C. , Chang Alex , Johnson David
Published: February 2017

PURPOSE: To determine the feasibility of adding paclitaxel to standard cisplatin/etoposide (EP) and thoracic radiotherapy.

PATIENTS AND METHODS: Thirty-one patients were enrolled onto this study. During the phase I section of this study, the dose of paclitaxel was escalated in groups of three or more patients. Cycles were repeated every 21 days. For cycles 1 and 2, paclitaxel was administered according to the dose-escalation schema at doses of 100, 135, or 170 mg/m2 intravenously over 3 hours on day 1. Once the maximum-tolerated dose (MTD) of paclitaxel (for cycles 1 and 2, concurrent with radiation) was determined, that dose was used in all subsequent patients entered onto the phase II section of this study. For cycles 3 and 4, the paclitaxel dose was fixed at 170 mg/m2 in all patients. On day 2, cisplatin 60 mg/m2 was administered for all cycles. On days 1, 2, and 3, etoposide 60 mg/m2/d (cycles 1 and 2) or 80 mg/m2/d (cycles 3 and 4) was administered. Chest radiation was given at 9 Gy/wk in five fractions for 5 weeks beginning on day 1 of cycle 1. Granulocyte colony-stimulating factors were used during cycles 3 and 4 only.

RESULTS: Twenty-eight patients were assessable. The MTD of paclitaxel was 135 mg/m2, with the dose-limiting toxicity being grade 4 neutropenia. Cycles 1 and 2 were associated with grade 4 neutropenia in 32% of courses, with fever occurring in 7% of courses and grade 2/3 esophagitis in 13%. Cycles 3 and 4 were complicated by grade 4 neutropenia in 20% of courses, with fever occurring in 6% of courses and grade 2/3 esophagitis in 16%. The overall response rate was 96% (complete responses, 39%; partial responses, 57%). After a median follow-up period of 23 months (range, 9 to 40 months), the median survival time was 22.3 months (95% confidence interval, 15.1 to 34.3 months)

CONCLUSION: The MTD of paclitaxel with radiation and EP treatment is 135 mg/m2 given over 3 hours. In this schedule of administration, a high response rate and acceptable toxicity can be anticipated.
Risk Factors for Severe Neuropsychiatric Toxicity in Patients Receiving Interferon Alfa-2b and Low-Dose Cytarabine for Chronic Myelogenous Leukemia: Analysis of Cancer and Leukemia Group B 9013
Authors: Hensley Martee L. , Peterson Bercedis , Silver Richard T. , Larson Richard A. , Schiffer Charles A. , Szatrowski Ted P.
Published: February 2017

PURPOSE: Recombinant interferon alfa-2b (rIFNα2b) is a standard therapy for chronic myelogenous leukemia (CML). Severe neuropsychiatric toxicity has been described in patients receiving rIFNα2b, although the frequency of and the risk factors for developing this toxicity are not well described. The purpose of this study was to identify predictors for the development of severe neuropsychiatric toxicity in CML patients receiving rIFNα2b-based therapy.

PATIENTS AND METHODS: From a prospective cohort of 91 Philadelphia chromosome–positive, previously untreated, chronic-phase CML patients treated on Cancer and Leukemia Group B (CALGB) 9013, a phase II trial of rIFNα2b plus cytarabine, the following were recorded at baseline: age, sex, race, pretreatment history of neurologic or psychiatric diagnosis, spleen size, blood counts, and peripheral blast count. Best response to treatment, rIFNα2b cumulative dose, dose duration, and dose-intensity were recorded during follow-up. Severe neuropsychiatric toxicity was defined as grade 3 or 4 events, according to CALGB expanded common toxicity criteria. Univariate and multivariate logistic regression analyses were used to identify variables that were associated with the development of severe neuropsychiatric toxicity.

RESULTS: Severe neuropsychiatric toxicity developed in 22 patients (24.0%; 95% confidence interval [CI], 15.2% to 32.8%). Toxicity resolved after withdrawal of treatment in all patients. Five of six patients developed recurrence of symptoms with rechallenge. Twelve (63%) of 19 patients with a pretreatment neurologic or psychiatric diagnosis developed severe neuropsychiatric toxicity, as compared with 10 (14%) of 72 patients without a pretreatment neurologic or psychiatric diagnosis (P = .001), resulting in a relative risk of 4.55 (95% CI, 2.33 to 8.88) for developing severe neuropsychiatric toxicity. No other variables were independently associated with the development of neuropsychiatric toxicity.

CONCLUSION: CML patients with a pretreatment history of a neurologic or psychiatric diagnosis are at significantly increased risk of developing severe neuropsychiatric toxicity during therapy with rIFNα2b plus cytarabine. Monitoring for neuropsychiatric symptoms and avoiding rechallenge are recommended measures for such patients receiving rIFNα2b-based therapy.
Exemestane Is Superior to Megestrol Acetate After Tamoxifen Failure in Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Randomized Double-Blind Trial
Authors: Kaufmann Manfred , Bajetta Emilio , Dirix Luc Yves , Fein Luis Enrique , Jones Stephen E. , Zilembo Nicoletta , Dugardyn Jean-Louis , Nasurdi Cristina , Mennel Robert G. , Cervek Jozica , Fowst Camilla , Polli Anna , di Salle Enrico , Arkhipov Alexei , Piscitelli Gabriella , Miller Langdon L. , Massimini Giorgio ,   for the Exemestane Study Group
Published: February 2017

PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated.

RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P = .039), as were the median duration of overall success (OR or stable disease ≥ 24 weeks; 60.1 v 49.1 weeks; P = .025), time to tumor progression (20.3 v 16.6 weeks; P = .037), and time to treatment failure (16.3 v 15.7 weeks; P = .042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P = .001).

CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.