bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flavopiridol, A Novel Cyclin-Dependent Kinase Inhibitor, in Metastatic Renal Cancer: A University of Chicago Phase II Consortium Study
Authors: Stadler Walter M. , Vogelzang Nicholas J. , Amato Robert , Sosman Jeffery , Taber David , Liebowitz David , Vokes Everett E. 
Published: February 2017

PURPOSE: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population. PATIENTS AND METHODS: Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m2/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed. RESULTS: There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs. CONCLUSION: Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.
Sex Differences in Fluorouracil-Induced Stomatitis
Authors: Sloan Jeff A. , Loprinzi Charles L. , Novotny Paul J. , Okuno Scott , Nair Suresh , Barton Debra L. 
Published: February 2017

PURPOSE: A meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)–based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis. PATIENTS AND METHODS: Data were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation. RESULTS: Women reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P = .002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P = .0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P < .00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade ≥ 1, (70% v 59%, respectively; P < .00001) and grade 3+ (18% v 11%, respectively; P = .004). CONCLUSION: More women than men reported 5-FU–induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.
HER-2/neu and p53 Expression Versus Tamoxifen Resistance in Estrogen Receptor–Positive, Node-Positive Breast Cancer
Authors: Berry Donald A. , Muss Hyman B. , Thor Ann D. , Dressler Lynn , Liu Edison T. , Broadwater Gloria , Budman Dan R. , Henderson I. Craig , Barcos Maurice , Hayes Daniel , Norton Larry 
Published: February 2017

PURPOSE: An association between the overexpression of proto-oncogene HER-2/neu and resistance to tamoxifen in estrogen receptor (ER)–positive primary and metastatic breast cancer has been suggested. We examine a possible interaction between HER-2/neu or p53 expression and tamoxifen effectiveness in patients with ER-positive, node-positive disease treated with cyclophosphamide, doxorubicin, and fluorouracil in a large adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB] 8541). Tamoxifen assignment was not randomized—physician discretion was used for premenopausal and postmenopausal women. Trial protocol then specified assignment to postmenopausal women with ER-positive tumors, although not all took tamoxifen. PATIENTS AND METHODS: CALGB 8541 assessed HER-2/neu expression in patients with ER-positive disease by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and amplification by differential polymerase chain reaction (PCR). IHC assessed expression of p53. Univariate and multivariate proportional hazards models assessed tamoxifen–HER-2/neu status interactions and tamoxifen-p53 status interactions. RESULTS: HER-2/neu status was available for 651 patients with ER-positive disease; 650, 608, and 353 patients were assessed by IHC, PCR, and FISH, respectively. Approximately one half received tamoxifen. Reduction in risk of disease recurrence or death resulting from tamoxifen was approximately 37% (32% with overexpression and 39% with normal expression of HER-2/neu; n = 155 by IHC). The tamoxifen–HER-2/neu status interaction was not significant in multivariate analysis of all three HER-2/neu assessment methods. Tamoxifen-p53 interaction did not significantly predict outcome. CONCLUSION: Disease-free and overall survival benefit of tamoxifen in patients with ER-positive, node-positive breast cancer does not depend on HER-2/neu or p53 status. Our data suggest that neither HER-2/neu nor p53 expression should be used to determine assignment of tamoxifen.
Tamoxifen Adjuvant Treatment Duration in Early Breast Cancer: Initial Results of a Randomized Study Comparing Short-Term Treatment With Long-Term Treatment
Authors: Delozier Thierry , Spielmann Marc , Macé-Lesec’h Josette , Janvier Maud , Hill Catherine , Asselain Bernard , Julien Jean-Pierre , Weber Béatrice , Mauriac Louis , Petit Jean-Christophe , Kerbrat Pierre , Malhaire Jean-Pierre , Vennin Philippe , Leduc B. , Namer for the Moïse ,   Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group
Published: February 2017

PURPOSE: In 1986, The Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group initiated a multicenter randomized trial to assess the usefulness of long-term adjuvant tamoxifen treatment. Short-term adjuvant tamoxifen treatment was to be compared with lifelong adjuvant tamoxifen treatment. PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen treatment were eligible for the trial. From September 1986 to May 1995, 3,793 patients were randomized from France, Belgium, and Argentina. A total of 1,882 patients stopped tamoxifen (short-term group), and 1,911 patients were to continue tamoxifen for life (long-term group) at the same dose as previously prescribed. The protocol was modified in February 1997, limiting tamoxifen treatment to 10 years after randomization, thus giving a comparison between a 2- to 3-year treatment and a 12- to 13-year treatment. To date, the median duration of tamoxifen treatment is 30 months in the short-term group, and 70 months in the long-term group. RESULTS: Overall, longer tamoxifen treatment induced a 23% reduction in relapse rates, leading to a 7-year disease-free survival rate of 78%, compared with 72% in the shorter-treatment group. In contrast, overall survival did not differ between the two groups, with a 79% overall survival rate in both groups. This improvement in disease-free survival could be observed in node-positive patients (P = .001); however, it was not found in node-negative patients. Prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in estrogen receptor–positive patients (P = .03) as well as in estrogen receptor–negative patients (P = .05). Furthermore, longer treatment reduced contralateral breast cancers and did not increase the number of endometrial cancers. CONCLUSION: : Although no survival advantage was noted, patients did benefit from longer tamoxifen treatment over 3 years and had significantly better disease-free survival compared with patients who stopped hormonal treatment. Long-term follow-up is needed to assess these results. Most patients in the long-term group are still receiving treatment. Comparison of results as time passes will enable conclusions to be made on the value of long-term treatment over 5 years compared with 2 to 3 years.
Homoharringtonine and Low-Dose Cytarabine in the Management of Late Chronic-Phase Chronic Myelogenous Leukemia
Authors: Kantarjian Hagop M. , Talpaz Moshe , Smith Terry L. , Cortes Jorge , Giles Francis J. , Rios Mary Beth , Mallard Susie , Gajewski James , Murgo Anthony , Cheson Bruce , O’Brien Susan 
Published: February 2017

PURPOSE: : To evaluate the efficacy andtoxicity profiles of a combination regimen of homoharringtonine (HHT)and low-dose cytarabine (ara-C) in patients with Philadelphiachromosome (Ph)–positive chronic myelogenous leukemia (CML) whohad experienced treatment failure with interferon alfa (IFNα)therapy. PATIENTS AND METHODS: One hundred five patients were treated: 100 in chronicphase (15 with cytogenetic clonal evolution) and five in acceleratedphase. Their median age was 52 years; all had been treatedunsuccessfully with IFNα; 94% were in late chronic phase; 43% hadbeen exposed to ara-C and 11% had been exposed to HHT. Patientsreceived HHT 2.5 mg/m2 by continuousinfusion daily for 5 days and ara-C 15mg/m2 daily in two subcutaneous injectionsfor 5 days every 4 weeks. The outcome of the 100 patients in chronicphase was compared with a previous study group of 73 patients treatedwith HHT alone. RESULTS: Overall, the complete hematologic response (CHR) rate in chronic phasewas 72%; the cytogenetic response rate was 32% (major response, 15%;complete response, 5%). Toxicities were acceptable, mostly related tomoderate diarrhea (3%), headaches (3%), cardiovascular events (3%),and myelosuppression-associated complications (3% to 14%). With amedian follow-up period of 25 months, the estimated 4-year survivalrate was 55%. Response rates were identical with HHT plus ara-C versusHHT alone, but the survival was significantly longer with thecombination after accounting for differences in the study groups andby multivariate analysis. CONCLUSION: The combination regimen of HHT and ara-C is effective andsafe in patients with CML who have experienced treatment failure withIFNα and needs to be investigated together with IFNα as partof front-line CML therapy. The addition of ara-C did not improve theresponse rates but may have improved survival, perhaps throughsuppression of clones related to diseasetransformation.
Phase I Chemotherapy Study of Biochemical Modulation of Folinic Acid and Fluorouracil by Gemcitabine in Patients With Solid Tumor Malignancies
Authors: Madajewicz S. , Hentschel P. , Burns P. , Caruso R. , Fiore J. , Fried M. , Malhotra H. , Ostrow S. , Sugarman S. , Viola M. 
Published: February 2017

PURPOSE: This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m2 over 1 hour and a 5-FU 450 mg/m2 IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m2/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest. RESULTS: The MTD of gemcitabine was established at 900 mg/m2 given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m2. One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months. CONCLUSION: The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.
Prospective Trial of the Herbal Supplement PC-SPES in Patients With Progressive Prostate Cancer
Authors: Small Eric J. , Frohlich Mark W. , Bok Robert , Shinohara Katsuto , Grossfeld Gary , Rozenblat Zinovi , Kelly Wm. Kevin , Corry Michele , Reese David M. 
Published: February 2017

PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti–prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies. RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of ≥ 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of ≥ 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea. CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.
High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation for Advanced Soft Tissue Sarcoma in Adults
Authors: Blay J-Y. , Bouhour D. , Ray-Coquard I. , Dumontet C. , Philip T. , Biron P. 
Published: February 2017

PURPOSE: Patients with metastatic or locally advanced, unresectable soft tissue sarcoma (ASTS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDCT) with hematopoietic stem-cell support in this disease is not established. PATIENTS AND METHODS: Between 1988 and 1994, 30 patients with ASTS who responded to a standard chemotherapy regimen were included in a prospective pilot study of HDCT as consolidation therapy using ifosfamide (12 g/m2), etoposide (800 mg/m2), and cisplatin (200 mg/m2) (VIC). RESULTS: The median duration of grade 4 neutropenia and thrombocytopenia was 14 and 10 days, respectively. Nineteen patients (63%) experienced grade 1 or higher renal toxicity. All eight patients in complete remission (CR) before HDCT were still in CR at day 60. Of the 22 patients in partial remission (PR) or with a minor response to conventional chemotherapy, CR, PR, and stable disease were achieved in four (18%), three (13%), and 12 patients (54%), respectively, by day 60, while three patients (14%) progressed. With a median follow-up of 94 months, overall and progression-free survival rates at 5 years after HDCT were 23% and 21%, respectively. Patients in CR before HDCT had a significantly superior 5-year overall survival rate compared with other patients (75% v 5%; P = .001). CONCLUSION: Despite the toxicity of the VIC regimen, a high survival rate was observed in HDCT-treated patients who were in CR after conventional chemotherapy. A phase III randomized trial is required to establish the role of HDCT in ASTS.
Time to Clinical Response: An Outcome of Antibiotic Therapy of Febrile Neutropenia With Implications for Quality and Cost of Care
Authors: Elting Linda S. , Rubenstein Edward B. , Rolston Kenneth , Cantor Scott B. , Martin Charles G. , Kurtin Danna , Rodriguez Saul , Lam Tony , Kanesan Krishnakumari , Bodey Gerald 
Published: February 2017

PURPOSE: To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia. METHODS: The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs. RESULTS: Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P = .003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P = .01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P < .04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P = .03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P < .001). CONCLUSION: Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non–low-risk patients with febrile neutropenia.
Fenretinide Therapy in Prostate Cancer: Effects on Tissue and Serum Retinoid Concentration
Authors: Thaller Christina , Shalev Moshe , Frolov Anna , Eichele Gregor , Thompson Timothy C. , Williams Russel H. , Dillioglugil Ozdal , Kadmon Dov 
Published: February 2017

PURPOSE: To examine the feasibility of using fenretinide (4-HPR) for the prevention and treatment of prostate cancer. MATERIALS AND METHODS: We measured the impact of 4-HPR therapy on retinoid concentrations in vivo, in a mouse model of prostate cancer and clinically, in patients with prostate cancer who were given oral 4-HPR (200 mg/d) or placebo for 4 weeks before undergoing a radical prostatectomy. RESULTS: Prostate tumors in mice treated with 4-HPR contained high levels of 4-HPR and of all-trans-retinoic acid (RA) and reduced levels of retinol (ROH). Patients given 4-HPR were found to have significantly higher concentrations of 4-HPR in the cancerous prostate as compared with the serum levels (463 nmol/L v 326 nmol/L; P = .049), but they were only 1/10 the levels found in mice and were far below the concentrations reported in human breast tissue. Serum and tissue ROH levels were reduced to less than half the concentrations found in untreated controls. RA concentrations in human serum and in cancerous prostates were not significantly affected by 4-HPR treatment, in contrast with the findings in mice. CONCLUSION: The standard oral dose of 4-HPR proposed for breast cancer (200 mg/d) achieved only modest drug levels in the prostate and is unlikely to be effective for prostate cancer prevention or treatment. Higher doses need to be explored.
Preliminary Results of a Randomized Radiotherapy Dose-Escalation Study Comparing 70 Gy With 78 Gy for Prostate Cancer
Authors: Pollack Alan , Zagars Gunar K. , Smith Lewis G. , Lee J. Jack , von Eschenbach Andrew C. , Antolak John A. , Starkschall George , Rosen Isaac 
Published: February 2017

PURPOSE: To determine the effect of radiotherapy dose on prostate cancer patient outcome and biopsy positivity in a phase III trial. PATIENTS AND METHODS: A total of 305 stage T1 through T3 patients were randomized to receive 70 Gy or 78 Gy of external-beam radiotherapy between 1993 and 1998. Of these, 301 were assessable; stratification was based on pretreatment prostate-specific antigen level (PSA). Dose was prescribed to the isocenter at 2 Gy per fraction. All patients underwent planning pelvic computed tomography scan to confirm prostate position. Treatment failure was defined as an increasing PSA on three consecutive follow-up visits or the initiation of salvage treatment. Median follow-up was 40 months. RESULTS: One hundred fifty patients were randomized to the 70-Gy arm and 151 to the 78-Gy arm. The difference in freedom from biochemical and/or disease failure (FFF) rates of 69% and 79% for the 70-Gy and 78-Gy groups, respectively, at 5 years was marginally significant (log-rank P = .058). Multiple-covariate Cox proportional hazards regression showed that the study randomization was an independent correlate of FFF, along with pretreatment PSA, Gleason score, and stage. The patients who benefited most from the 8-Gy dose escalation were those with a pretreatment PSA of more than 10 ng/mL; 5-year FFF rates were 48% and 75% (P = .011) for the 70-Gy and 78-Gy arms, respectively. There was no difference between the arms (∼80% 5-year FFF) when the pretreatment PSA was ≤ 10 ng/mL. CONCLUSION: A modest dose increase of 8 Gy using conformal radiotherapy resulted in a substantial improvement in prostate cancer FFF rates for patients with a pretreatment PSA of more than 10 ng/mL. These findings document that local persistence of prostate cancer in intermediate- to high-risk patients is a major problem when doses of 70 Gy or less are used.