bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival in Early Breast Cancer Patients Is Favorably Influenced by a Natural Humoral Immune Response to Polymorphic Epithelial Mucin
Authors: von Mensdorff-Pouilly S. , Verstraeten A.A. , Kenemans P. , Snijdewint F.G. M. , Kok A. , Van Kamp G.J. , Paul M.A. , Van Diest P.J. , Meijer S. , Hilgers J.
Published: February 2017

PURPOSE: Polymorphic epithelial mucin (PEM or MUC1) is being studied as a vaccine substrate for the immunotherapy of patients with adenocarcinoma. The present study analyzes the incidence of naturally occurring MUC1 antibodies in early breast cancer patients and relates the presence of these antibodies in pretreatment serum to outcome of disease.

MATERIALS AND METHODS: We measured immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to MUC1 with an enzyme-linked immunoassay (PEM.CIg), which uses a MUC1 triple-tandem repeat peptide conjugated to bovine serum albumin, in pretreatment serum samples obtained from 154 breast cancer patients (52 with stage I disease and 102 with stage II) and 302 controls. The median disease-specific survival time of breast cancer patients was 74 months (range, 15 to 118 months). A positive test result was defined as MUC1 IgG or IgM antibody levels equal to or greater than the corresponding rounded-up median results obtained in the total breast cancer population.

RESULTS: A positive test result for both MUC1 IgG and IgM antibodies in pretreatment serum was associated with a significant benefit in disease-specific survival in stage I and II (P = .0116) breast cancer patients. Positive IgG and IgM MUC1 antibody levels had significant additional prognostic value to stage (P = .0437) in multivariate analysis. Disease-free survival probability did not differ significantly. However, stage II patients who tested positive for MUC1 IgG and IgM antibody and who relapsed had predominantly local recurrences or contralateral disease, as opposed to recurrences at distant sites in the patients with a negative humoral response (P = .026).

CONCLUSION: Early breast cancer patients with a natural humoral response to MUC1 have a higher probability of freedom from distant failure and a better disease-specific survival. MUC1 antibodies may control hematogenic tumor dissemination and outgrowth by aiding the destruction of circulating or seeded MUC1-expressing tumor cells. Vaccination of breast cancer patients with MUC1-derived (glyco)peptides in an adjuvant setting may favorably influence the outcome of disease.
Alterations of Chromosome Arms 1p and 19q as Predictors of Survival in Oligodendrogliomas, Astrocytomas, and Mixed Oligoastrocytomas
Authors: Smith Justin S. , Perry Arie , Borell Thomas J. , Lee Hyun K. , O’Fallon Judith , Hosek Sandra M. , Kimmel David , Yates Allan , Burger Peter C. , Scheithauer Bernd W. , Jenkins Robert B.
Published: February 2017

PURPOSE: A recent report suggests that alterations of chromosome arms 1p and 19q are associated with chemotherapeutic response and overall survival in anaplastic oligodendroglioma patients treated with procarbazine, lomustine, and vincristine chemotherapy. We set out to further clarify the diagnostic and prognostic implications of these alterations in a broader set of diffuse gliomas, including astrocytic neoplasms and low-grade oligodendrogliomas.

PATIENTS AND METHODS: Fluorescence in situ hybridization (FISH) signals from DNA probes mapping to 1p and 19q common deletion regions were enumerated in 162 diffuse gliomas (79 astrocytomas, 52 oligodendrogliomas, and 31 mixed oligoastrocytomas), collected as part of an ongoing prospective investigation of CNS tumors.

RESULTS: The oligodendroglial phenotype was highly associated with loss of 1p (P = .0002), loss of 19q (P < .0001), and combined loss of 1p and 19q (P < .0001). Combined loss of 1p and 19q was identified as a univariate predictor of prolonged overall survival among patients with pure oligodendroglioma (log-rank, P = .03) and remained a significant predictor after adjusting for the effects of patient age and tumor grade (P < .01). This favorable association was not evident in patients with astrocytoma or mixed oligoastrocytoma.

CONCLUSION: Combined loss of 1p and 19q is a statistically significant predictor of prolonged survival in patients with pure oligodendroglioma, independent of tumor grade. Given the lack of this association in patients with astrocytic neoplasms and the previously demonstrated chemosensitivity of oligodendrogliomas, a combined approach of histologic and genotypic assessment could potentially improve existing strategies for patient stratification and management.
Cognitive Function as a Predictor of Survival in Patients With Recurrent Malignant Glioma
Authors: Meyers Christina A. , Hess Kenneth R. , Yung W.K. Alfred , Levin Victor A.
Published: February 2017

PURPOSE: To determine the contribution of cognitive function in predicting the survival of patients with recurrent malignant brain tumors.

PATIENTS AND METHODS: A total of 80 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma were seen for baseline evaluations before beginning a phase I or phase II clinical trial. Each patient received a battery of nine brief tests measuring cognitive function, ability to perform activities of daily living (ADLs), and quality of life (QOL). Tests were given monthly after treatment was begun.

RESULTS: Performance on a test of verbal memory was independently and strongly related to survival after accounting for age, Karnofsky performance status score, histology, and time since diagnosis. Models incorporating three of nine and all nine tests in the battery accounted for significantly more variance in survival than did the clinical variables alone. Measures of QOL and ADLs (bathing, feeding, and so on) were not independently related to survival, although they provide clinical information that is important for patient care.

CONCLUSION: These results indicate that a multifaceted assessment of cognition, QOL, and patient function is practical for brain tumor patients in clinical trials and can provide information regarding the relative risks versus benefits of new treatment regimens that supplements the information from the usual clinical variables.
Phase I and Pharmacologic Study of Irinotecan Administered as a 96-Hour Infusion Weekly to Adult Cancer Patients
Authors: Takimoto Chris H. , Morrison Geraldine , Harold Nancy , Quinn Mary , Monahan Brian P. , Band Roger A. , Cottrell Jeff , Guemei Aida , Llorens Victor , Hehman Hilary , Ismail Abdel Salam , Flemming Donald , Gosky David M. , Hirota Haruyo , Berger Sosamma J. , Berger Nathan A. , Chen Alice P. , Shapiro Jeremy D. , Arbuck Susan G. , Wright John , Hamilton J. Michael , Allegra Carmen J. , Grem Jean L.
Published: February 2017

PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites.

PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed.

RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m2/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m2/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer.

CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m2/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.
Research on Complementary/Alternative Medicine for Patients With Breast Cancer: A Review of the Biomedical Literature
Authors: Jacobson Judith S. , Workman Sara B. , Kronenberg Fredi
Published: February 2017

PURPOSE: This article reviews English-language articles published in the biomedical literature from 1980 to 1997 that reported results of clinical research on complementary and alternative medical treatments (CAM) of interest to patients with breast cancer.

METHODS: We searched 12 electronic databases and the bibliographies of the retrieved papers, review articles, and books on CAM and breast cancer. The retrieved articles were grouped by end point: breast cancer (eg, tumor size, survival), disease-related symptoms, side effects of treatment, and immune function. Within each end point, we organized the articles by modality and assessed study design, findings, and qualitative aspects.

RESULTS: Of the more than 1,000 citations retrieved, 51 fit our criteria for review. Of the articles reviewed, 17 were randomized clinical trials; three of these were trials of cancer-directed interventions, two of which involved the same treatment (melatonin). Seven articles described observational studies, and the remainder were reports of phase I or II trials. Relatively few CAM modalities reportedly used by many breast cancer patients were mentioned in articles retrieved by this process. Most articles had shortcomings.

CONCLUSION: Although many studies had encouraging results, none showed definitively that a CAM treatment altered disease progression in patients with breast cancer. Several modalities seemed to improve other outcomes (eg, acupuncture for nausea, pressure treatments for lymphedema). If CAM studies are well-founded, well-designed, and meticulously conducted, and their hypotheses, methods, and results are reported clearly and candidly, research in this controversial area should acquire credibility both in the scientific community and among advocates of unconventional medicine.
Phase I Clinical Trial Design in Cancer Drug Development
Authors: Eisenhauer E.A. , O’Dwyer P.J. , Christian M. , Humphrey J.S.
Published: February 2017

ABSTRACT: The past decade has seen the publication of a number of new proposals for the design of phase I trials of anticancer agents. The purpose of these proposals has been to address ethical concerns about treating excessive numbers of patients at subtherapeutic doses of a new agent and to increase the overall efficiency of the process while enhancing the precision of the recommended phase II dose. In early 1998, a workshop of phase I investigators was held under the sponsorship of Bristol-Myers Squibb Pharmaceutical Research Institute (Wallingford, CT) to review the experience to date with novel phase I methodologies, with a particular focus on their efficiency and safety. This report summarizes the material presented. It was concluded that for phase I trials of antineoplastics (cytotoxics), which begin at 0.1 mouse-equivalent LD10 doses, evidence to date suggests that the historic approach of using a modified Fibonacci escalation and three patients per dose level is not necessary and is seldom used. One patient per dose level and more rapid escalation schemes, both empirically based and statistically based, are commonly used with apparent safety. There remain questions, however: Which of the dose escalation schemes is optimal? Are there alternatives to toxicity as a phase I end point, and will these end points be reliable in defining active doses? Answering these questions in a reasonable time frame will be important if new anticancer agents are not to suffer undue delays in phase I evaluation.
Granulocyte Colony-Stimulating Factor After Intensive Consolidation Chemotherapy in Acute Myeloid Leukemia: Results of a Randomized Trial of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques
Authors: Harousseau J.L. , Witz B. , Lioure B. , Hunault-Berger M. , Desablens B. , Delain M. , Guilhot F. , Le Prise P.Y. , Abgrall J.F. , Deconinck E. , Guyotat D. , Vilque J.P. , Casassus P. , Tournilhac O. , Audhuy B. , Solary E.
Published: February 2017

PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR).

PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 μg/kg.

RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 × 109/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P < .001) and after ICC 2 (20 v 28 days, P < .001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P < .001; 29 v 34 days after ICC 2, P < .001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm.

CONCLUSION: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.
Evaluation of Minimal Residual Disease Using Reverse-Transcription Polymerase Chain Reaction in t(8;21) Acute Myeloid Leukemia: A Multicenter Study of 51 Patients
Authors: Morschhauser F. , Cayuela J.M. , Martini S. , Baruchel A. , Rousselot P. , Socié G. , Berthou P. , Jouet J.P. , Straetmans N. , Sigaux F. , Fenaux P. , Preudhomme C.
Published: February 2017

PURPOSE: Most studies using various reverse-transcription polymerase chain reaction (RT-PCR) techniques reported that the detection of the AML1-ETO fusion transcript was a common finding in long-term complete remission (CR) in acute myeloid leukemia (AML) with t(8;21) translocation. However, larger prospective studies with interlaboratory quality control may be important to investigate more precisely the clinical usefulness of studying minimal residual disease with RT-PCR in t(8;21) AML.

PATIENTS AND METHODS: We collected 223 marrow samples from 51 patients with t(8;21) AML diagnosed in five centers and tested all samples by two different RT-PCR techniques (a nested technique and a one-step technique, with a sensitivity of 10−6 and 10−5, respectively) in two different laboratories.

RESULTS: Samples from 14 patients in long persistent CR (median follow-up duration, 112 months) were taken at least twice, and all were PCR-negative by both techniques. Samples were prospectively taken from 37 patients after achievement of first CR and/or second CR, before intensive consolidation treatment, and every 3 to 6 months after completion of therapy. Patients who converted to PCR negativity with the one-step technique (60%) or both techniques (48%) after CR achievement had a longer CR duration than those with persistently positive PCR results (two-sided log-rank test, P = .0001). Patients who became PCR-negative with the one-step technique before intensive consolidation (23%) had a lower relapse rate (11% v 72%) and a longer CR duration than those who remained persistently PCR-positive at that point (two-sided log-rank test, P = .0015).

CONCLUSION: Patients with AML with t(8;21) in long-term remission were all PCR-negative. In prospectively studied patients, a good correlation was found between negative PCR results and absence of relapse. Early negative results with the one-step RT-PCR technique, before consolidation treatment, seemed to carry an especially good prognosis, suggesting that RT-PCR analysis could help in choosing the type of consolidation therapy in patients with t(8;21) AML.
Enteropathy-Type Intestinal T-Cell Lymphoma: Clinical Features and Treatment of 31 Patients in a Single Center
Authors: Gale Joanna , Simmonds Peter D. , Mead Graham M. , Sweetenham John W. , Wright Dennis H.
Published: February 2017

PURPOSE: We report the clinical features and treatment of 31 patients with a diagnosis of enteropathy-type intestinal T-cell lymphoma treated at the Wessex Regional Medical Oncology Unit in Southampton between 1979 and 1996 (23 men, eight women).

PATIENTS AND METHODS: Patients were identified from our lymphoma database. Details of history, physical examination, staging investigations, treatment, and outcome were taken from patient records.

RESULTS: Twelve patients (35%) had a documented clinical history of adult-onset celiac disease, and a further three had histologic features consistent with celiac disease in resected areas of the small bowel not infiltrated with lymphoma. After diagnosis, 24 (77%) of the 31 patients were treated with chemotherapy; the remaining seven had surgical treatment alone. More than half were unable to complete their planned chemotherapy courses, often because of poor nutritional status; 12 patients required enteral or parenteral feeding. A response to initial chemotherapy was observed in 14 patients (complete response, n = 10; partial response, n = 4). Observed complications of treatment were gastrointestinal bleeding, small-bowel perforation, and the development of enterocolic fistulae. Relapses occurred 1 to 60 months from diagnosis in 79% of those who responded to initial therapy. Of the total 31 patients, 26 (84%) have died, all from progressive disease or from complications of the disease and/or its treatment. The actuarial 1- and 5-year survival rates are 38.7% and 19.7%, respectively, with 1- and 5-year failure-free survival rates of 19.4% and 3.2%, respectively.

CONCLUSION: The prognosis for these patients is poor. This, in part, reflects late diagnosis and poor performance status at the time of presentation. The role of salvage treatments and high-dose chemotherapy at relapse is not clear. However, it is encouraging that there are five long-term survivors in our patient population.
Hormonal Predictors of Prostate Cancer: A Meta-Analysis
Authors: Shaneyfelt Terrence , Husein Rozita , Bubley Glenn , Mantzoros Christos S.
Published: February 2017

PURPOSE: Although there is strong circumstantial evidence that androgens are implicated in the etiology of prostate cancer, epidemiologic investigations have failed to demonstrate consistently that one or more steroid hormones are implicated. In contrast, recent epidemiologic studies unequivocally link serum insulin-like growth factor 1 (IGF-1) levels with risk for prostate cancer.

METHODS: We have performed the first meta-analysis of all previously published studies on hormonal predictors of risk for prostate cancer.

RESULTS: A meta-analysis restricted to studies that performed mutual adjustment for all measured serum hormones, age, and body mass index indicated that men whose total testosterone is in the highest quartile are 2.34 times more likely to develop prostate cancer (95% confidence interval, 1.30 to 4.20). In contrast, levels of dihydrotestosterone and estradiol do not seem to play a role of equal importance. The only study that provides multivariably adjusted sex hormone–binding globulin data indicates that this binding protein is inversely related to prostate cancer risk (odds ratio, 0.46; 95% confidence interval, 0.24 to 0.89). Finally, all three studies that examined the role of serum IGF-1 have consistently demonstrated a positive and significant association with prostate cancer risk that is similar in magnitude to that of testosterone.

CONCLUSION: Men with either serum testosterone or IGF-1 levels in upper quartile of the population distribution have an approximately two-fold higher risk for developing prostate cancer.
Phase II Evaluation of Preoperative Chemoradiation and Postoperative Adjuvant Chemotherapy for Squamous Cell and Adenocarcinoma of the Esophagus
Authors: Heath Elisabeth I. , Burtness Barbara A. , Heitmiller Richard F. , Salem Ronald , Kleinberg Lawrence , Knisely Jonathan P. S. , Yang Stephen C. , Talamini Mark A. , Kaufman Howard S. , Canto Marcia I. , Topazian Mark , Wu Tsung-Teh , Olukayode Koleoso , Forastiere Arlene A.
Published: February 2017

PURPOSE: This phase II trial evaluated continuous-infusion cisplatin and fluorouracil (5-FU) with radiotherapy followed by esophagectomy. The objectives of this trial were to determine the complete pathologic response rate, survival rate, toxicity, pattern of failure, and feasibility of administering adjuvant chemotherapy in patients with resectable cancer of the esophagus treated with preoperative chemoradiation.

PATIENTS AND METHODS: Patients were staged using computed tomography, endoscopic ultrasound, and laparoscopy. The preoperative treatment plan consisted of continuous intravenous infusion of cisplatin and 5-FU and a total dose of 44 Gy of radiation. Esophagogastrectomy was planned for approximately 4 weeks after the completion of chemoradiotherapy. Paclitaxel and cisplatin were administered as postoperative adjuvant therapy.

RESULTS: Forty-two patients were enrolled onto the trial. Of the 39 patients who proceeded to surgery, 29 responded to preoperative treatment: 11 achieved pathologic complete response (CR) and 18 achieved a lower posttreatment stage. Five patients had no change in stage, whereas eight had progressive disease (four with distant metastases and four with increases in the T and N stages). At a median follow-up of 30.2 months, the median survival time has not been reached and the 2-year survival rate is 62%. The median survival of pathologic complete responders has not been reached, whereas the 2-year survival rate of this group is 91% compared with 51% in patients with complete tumor resection with residual tumor (P = .03).

CONCLUSION: An excellent survival rate, comparable to that of our prior preoperative trial, was achieved with lower doses of preoperative cisplatin and 5-FU concurrent with radiotherapy.
Proton Magnetic Resonance Spectroscopic Imaging in Children With Recurrent Primary Brain Tumors
Authors: Warren Katherine E. , Frank Joseph A. , Black Jeanette L. , Hill Rene S. , Duyn Josef H. , Aikin Alberta A. , Lewis Bobbi K. , Adamson Peter C. , Balis Frank M.
Published: February 2017

PURPOSE: Proton magnetic resonance spectroscopic imaging (1H-MRSI) is a noninvasive technique for spatial characterization of biochemical markers in tissues. We measured the relative tumor concentrations of these biochemical markers in children with recurrent brain tumors and evaluated their potential prognostic significance.

PATIENTS AND METHODS: 1H-MRSI was performed on 27 children with recurrent primary brain tumors referred to our institution for investigational drug trials. Diagnoses included high-grade glioma (n = 10), brainstem glioma (n = 7), medulloblastoma/peripheral neuroectodermal tumor (n = 6), ependymoma (n = 3), and pineal germinoma (n = 1). 1H-MRSI was performed on 1.5-T magnetic resonance imagers before treatment. The concentrations of choline (Cho) and N-acetyl-aspartate (NAA) in the tumor and normal brain were quantified using a multislice multivoxel method, and the maximum Cho:NAA ratio was determined for each patient’s tumor.

RESULTS: The maximum Cho:NAA ratio ranged from 1.1 to 13.2 (median, 4.5); the Cho:NAA ratio in areas of normal-appearing brain tissue was less than 1.0. The maximum Cho:NAA ratio for each histologic subtype varied considerably; approximately equal numbers of patients within each tumor type had maximum Cho:NAA ratios above and below the median. Patients with a maximum Cho:NAA ratio greater than 4.5 had a median survival of 22 weeks, and all 13 patients died by 63 weeks. Patients with a Cho:NAA ratio less than or equal to 4.5 had a projected survival of more than 50% at 63 weeks. The difference was statistically significant (P = .0067, log-rank test).

CONCLUSION: The maximum tumor Cho:NAA ratio seems to be predictive of outcome in children with recurrent primary brain tumors and should be evaluated as a prognostic indicator in newly diagnosed childhood brain tumors.
Androgen Deprivation and Four Courses of Fixed-Schedule Suramin Treatment in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Southwest Oncology Group Study
Authors: Hussain Maha , Fisher Emily I. , Petrylak Daniel P. , O’Connor John , Wood David P. , Small Eric J. , Eisenberger Mario A. , Crawford E. David
Published: February 2017

PURPOSE: To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment.

PATIENTS AND METHODS: Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity.

RESULTS: Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity.

CONCLUSION: Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.
Neoadjuvant Chemotherapy and Hormonal Therapy Followed by Radical Prostatectomy: Feasibility and Preliminary Results
Authors: Pettaway Curtis A. , Pisters Louis L. , Troncoso Patricia , Slaton Joel , Finn Laury , Kamoi Kazumi , Logothetis Christopher J.
Published: February 2017

PURPOSE: We assessed the feasibility and efficacy of integrating chemotherapy and androgen ablation with radical prostatectomy in patients with locally advanced prostate cancer. The neoadjuvant approach was adopted because it allows an in situ assessment of antitumoral activity.

PATIENTS AND METHODS: Thirty-three patients were enrolled who met the clinical criteria of stage T1–2, Gleason score of ≥ 8 or T2b-T2c, Gleason score of 7 and prostate-specific antigen (PSA) level greater than 10 ng/mL (n = 15), or clinical stage T3 (n = 18). Therapy consisted of 12 weeks of ketoconazole and doxorubicin alternating with vinblastine, estramustine, and androgen ablation followed by prostatectomy. The ability of neoadjuvant chemotherapy and hormonal therapy to induce a 20% rate of pT0 in the prostatectomy specimen as well as surgical feasibility were assessed.

RESULTS: Chemotherapy complications were comparable to those reported with this regimen previously. No major intraoperative complications occurred. Postoperative complications occurred in 10 (33%) of 30 patients. One patient died at home after discharge (postoperative day 17; no autopsy was performed). Ten (33%) of the 30 patients had organ-confined disease, and 20 (70%) of 30 had extraprostatic extension; 11 (37%) of the 30 had positive lymph nodes. Only five (17%) of 30 exhibited positive surgical margins. All patients achieved an undetectable PSA level postoperatively, and 20 of the surviving 29 patients remain without disease recurrence with a median follow-up of 13 months (range, 9 to 18 months).

CONCLUSION: Chemotherapy and androgen ablation followed by radical prostatectomy was feasible in patients with locally advanced prostate cancer. Although the goal of achieving a 20% rate for pT0 status was not achieved, we believe this type of integrated therapeutic strategy should be investigated further for its ability to alter the course of regionally advanced prostate cancer.
Phase I and Pharmacokinetic Study of Irinotecan and Docetaxel in Patients With Advanced Solid Tumors: Preliminary Evidence of Clinical Activity
Authors: Adjei Alex A. , Klein Cheri E. , Kastrissios Helen , Goldberg Richard M. , Alberts Steven R. , Pitot Henry C. , Sloan Jeff A. , Reid Joel M. , Hanson Lorelei J. , Atherton Pamela , Rubin Joseph , Erlichman Charles
Published: February 2017

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity.

PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m2, 160/65 mg/m2, 200/65 mg/m2, and 200/75 mg/m2) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel.

RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non–small-cell lung cancer, achieved partial remissions.

CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m2 and docetaxel 65 mg/m2.
Phase I Study of Paclitaxel in Combination With a Multidrug Resistance Modulator, PSC 833 (Valspodar), in Refractory Malignancies
Authors: Fracasso Paula M. , Westerveldt Peter , Fears Carole A. , Rosen D. Marc , Zuhowski Eleanor G. , Cazenave Lorraine A. , Litchman Manuel , Egorin Merrill J.
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of paclitaxel when given with PSC 833 (valspodar) to patients with refractory solid tumors.

PATIENTS AND METHODS: Patients were initially treated with paclitaxel 175 mg/m2 continuous intravenous infusion (CIVI) over 3 hours. Subsequently, 29 hours of treatment with CIVI PSC 833 was started 2 hours before paclitaxel treatment was initiated. In this combination, the starting dose of paclitaxel was 52.5 mg/m2. Paclitaxel doses were escalated by 17.5 mg/m2 increments for four subsequent cohorts. Each cohort consisted of three patients with the exception of the last cohort, which consisted of six patients. Data for the pharmacokinetics of paclitaxel with and without concurrent PSC 833 administration were obtained.

RESULTS: All 18 patients completed at least one course of concurrent treatment (median, two courses; range, one to six) and were evaluable for toxicity. The MTD for paclitaxel with PSC 833 was 122.5 mg/m2. Neutropenia was the DLT. All patients had PSC 833 blood concentrations greater than 1,000 ng/mL before, during, and 24 hours after the paclitaxel infusion. PSC 833 produced small increases in the paclitaxel peak plasma concentrations and areas under the concentration-time curve. However, PSC 833 greatly prolonged the terminal phase of paclitaxel, resulting in plasma paclitaxel concentrations of more than 0.05 μmol/L for much longer than expected. As a result, myelosuppression was comparable to that produced by full-dose paclitaxel given without PSC 833. Of the 16 patients who were assessable for response, one patient experienced a partial response and an additional nine patients experienced disease stabilization after paclitaxel treatment alone.

CONCLUSION: Treatment with paclitaxel 122.5 mg/m2 as a 3-hour CIVI concurrent with a 29-hour CIVI of PSC 833 results in acceptable toxicity. The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination.
Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After High-Dose Therapy With Autologous Hematopoietic Progenitor-Cell Support for Lymphoid Malignancies
Authors: Micallef Ivana N. M. , Lillington Debra M. , Apostolidis John , Amess John A. L. , Neat Michael , Matthews Janet , Clark Taane , Foran James M. , Salam Ashiq , Lister T. Andrew , Rohatiner Ama Z. S.
Published: February 2017

PURPOSE: To evaluate the incidence of and risk factors for therapy-related myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML), after high-dose therapy (HDT) with autologous bone marrow or peripheral-blood progenitor-cell support, in patients with non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: Between January 1985 and November 1996, 230 patients underwent HDT comprising cyclophosphamide therapy and total-body irradiation, with autologous hematopoietic progenitor-cell support, as consolidation of remission. With a median follow-up of 6 years, 27 (12%) developed tMDS or sAML.

RESULTS: Median time to development of tMDS or sAML was 4.4 years (range, 11 months to 8.8 years) after HDT. Karyotyping (performed in 24 cases) at diagnosis of tMDS or sAML revealed complex karyotypes in 18 patients. Seventeen patients had monosomy 5/5q−, 15 had −7/7q−, seven had −18/18q−, seven had −13/13q−, and four had −20/20q−. Twenty-one patients died from complications of tMDS or sAML or treatment for tMDS or sAML, at a median of 10 months (range, 0 to 26 months). Sixteen died without evidence of recurrent lymphoma. Six patients were alive at a median follow-up of 6 months (range, 2 to 22 months) after diagnosis of tMDS or sAML. On multivariate analysis, prior fludarabine therapy (P = .009) and older age (P = .02) were associated with the development of tMDS or sAML. Increased interval from diagnosis to HDT and bone marrow involvement at diagnosis were of borderline significance (P = .05 and .07, respectively).

CONCLUSION: tMDS and sAML are serious complications of HDT for NHL and are associated with very poor prognosis. Alternative strategies for reducing their incidence and for treatment are needed.
Allogeneic Bone Marrow Transplantation for Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Long-Term Study of 70 Patients—Report of the French Society of Bone Marrow Transplantation
Authors: Yakoub-Agha I. , de La Salmonière P. , Ribaud P. , Sutton L. , Wattel E. , Kuentz M. , Jouet J.P. , Marit G. , Milpied N. , Deconinck E. , Gratecos N. , Leporrier M. , Chabbert I. , Caillot D. , Damaj G. , Dauriac C. , Dreyfus F. , François S. , Molina L. , Tanguy M.L. , Chevret S. , Gluckman E.
Published: February 2017

PURPOSE: To identify predictive factors of survival, relapse, and transplantation-related mortality (TRM) among patients with therapy-related myelodysplastic syndrome (t-MDS) or acute leukemia (t-AML) who underwent allogeneic bone marrow transplantation (BMT).

PATIENTS AND METHODS: From 1980 to 1998, 70 patients underwent allogeneic BMT for t-MDS (n = 31) or t-AML (n = 39) after prior cytotoxic exposure. Thirty-three patients had received induction-type chemotherapy before BMT. At the time of transplantation, there were 24 patients in complete remission (CR) and 46 with active disease.

RESULTS: With a median follow-up of 7.9 years (range, 1.1 to 18.8 years) after BMT, 16 patients are alive, whereas 19 died of relapse, 34 of TRM, and one of relapse of the primary disease. The estimated 2-year overall survival, event-free survival, relapse, and TRM rates were 30% (95% confidence interval [CI], 19% to 40%), 28% (95% CI, 18% to 39%), 42% (95% CI, 26% to 57%), and 49% (95% CI, 36% to 62%), respectively. In multivariable analysis, age greater than 37 years, male sex, positive recipient cytomegalovirus (CMV) serology, absence of CR at BMT, and intensive schedules used for conditioning were associated with poor outcome.

CONCLUSION: BMT is an effective treatment for patients with t-MDS or t-AML who have responsive disease and, in particular, who have no poor-risk cytogenetic features. The poor results of the other patients, especially those with active disease at BMT, emphasize the need to delineate indications and perform prospective protocols.
Clinical Utility of the Percentage of Positive Prostate Biopsies in Defining Biochemical Outcome After Radical Prostatectomy for Patients With Clinically Localized Prostate Cancer
Authors: D’Amico Anthony V. , Whittington Richard , Malkowicz S. Bruce , Schultz Delray , Fondurulia Julia , Chen Ming-Hui , Tomaszewski John E. , Renshaw Andrew A. , Wein Alan , Richie Jerome P.
Published: February 2017

PURPOSE: To determine the clinical utility of the percentage of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) for men with PSA-detected or clinically palpable prostate cancer.

METHODS: A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men while accounting for the previously established risk groups that are defined according to pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Committee on Cancer (AJCC) clinical T stage. The findings were then tested using an independent surgical database that included data for 823 men.

RESULTS: Controlling for the known prognostic factors, the percentage of positive prostate biopsies added clinically significant information (P < .0001) regarding time to PSA failure after RP. Specifically, 80% of the patients in the intermediate-risk group (1992 AJCC T2b, or biopsy Gleason 7 or PSA > 10 ng/mL and ≤ 20 ng/mL) could be classified into either an 11% or 86% 4-year PSA control cohort using the preoperative prostate biopsy data. These findings were validated in the intermediate-risk patients using an independent surgical data set.

CONCLUSION: The validated stratification of PSA outcome after RP using the percentage of positive prostate biopsies in intermediate-risk patients is clinically significant. This information can be used to identify men with newly diagnosed and clinically localized prostate cancer who are at high risk for early (≤ 2 years) PSA failure and, therefore, may benefit from the use of adjuvant therapy.
Examining the Role of Neoadjuvant Androgen Deprivation in Patients Undergoing Prostate Brachytherapy
Authors: Potters Louis , Torre Taryn , Ashley Richard , Leibel Steven
Published: February 2017

PURPOSE: To assess the role of neoadjuvant androgen deprivation (NAAD) and transperineal interstitial permanent prostate brachytherapy (TIPPB) using a matched-pair analysis selected from a large cohort of patients undergoing TIPPB.

PATIENTS AND METHODS: Six hundred twelve consecutive patients with clinically confined prostate cancer were treated between June 1992, and January 1997, with permanent ultrasound-guided TIPPB with either palladium-103 or iodine-125 as monotherapy or combined with external radiation. Patients with prostate glands ≥ 60 g underwent treatment with NAAD before TIPPB to reduce the prostate volume (n = 163). The median duration of NAAD was 3.4 months before TIPPB (range, 1 to 8 months). To assess the benefit of NAAD, a matched-pair analysis was performed. The American Society of Therapeutic Radiology and Oncology Consensus Group definition of prostate-specific antigen (PSA) relapse-free survival (RFS) was used with the added caveat of an absolute increase of ≥ 1.0 ng/mL. Differences in pretreatment PSA, Gleason scores, and stage were analyzed by Kaplan-Meier curves and the log-rank test.

RESULTS: Two hundred sixty-three patients were matched, with a median follow-up duration of 46 months (range, 24 to 76 months). The actuarial 5-year PSA-RFS rate for all 263 patients is 86.5%. The 5-year PSA-RFS rate for patients treated with NAAD and TIPPB was 87.1% compared with 86.9% for those treated with TIPPB only (P = .935). Subgroup analysis by Gleason score groupings, pretreatment PSA, or stage of disease failed to identify any factors for which androgen ablation was beneficial.

CONCLUSION: We were unable to identify any improvement with the addition of NAAD to TIPPB in patients with localized prostate cancer in this retrospective matched-pair analysis. Furthermore, there was no subset for which the addition of NAAD was found to be beneficial. Clarification of the role and duration of NAAD in patients with early-stage prostate cancer will require prospective data.
Sucralfate in the Prevention of Treatment-Induced Diarrhea in Patients Receiving Pelvic Radiation Therapy: A North Central Cancer Treatment Group Phase III Double-Blind Placebo-Controlled Trial
Authors: Martenson James A. , Bollinger John W. , Sloan Jeff A. , Novotny Paul J. , Urias Rodolfo E. , Michalak John C. , Shanahan Thomas G. , Mailliard James A. , Levitt Ralph
Published: February 2017

PURPOSE: Randomized studies have suggested that sucralfate is effective in mitigating diarrhea during pelvic radiation therapy (RT). This North Central Cancer Treatment Group study was undertaken to confirm the antidiarrheal effect of sucralfate. Several other measures of bowel function were also assessed.

PATIENTS AND METHODS: Patients receiving pelvic RT to a minimum of 45 Gy at 1.7 to 2.1 Gy/d were eligible for the study. Patients were assigned randomly, in double-blind fashion, to receive sucralfate (1.5 g orally every 6 hours) or an identical looking placebo during pelvic RT.

RESULTS: One hundred twenty-three patients were randomly assigned and found assessable. Overall, there was no significant difference in patient characteristics between those receiving sucralfate and those receiving placebo. Moderate or worse diarrhea was observed in 53% of patients receiving sucralfate versus 41% of those receiving placebo. Compared with patients receiving placebo, more sucralfate-treated patients reported fecal incontinence (16% v 34%, respectively; P = .04) and need for protective clothing (8% v 23%, respectively; P = .04). The incidence and severity of nausea were worse among those taking sucralfate (P = .03). Analysis of patient-reported symptoms 10 to 12 months after RT showed a nonsignificant trend toward more problems in patients taking sucralfate than in those taking placebo (average, 2.3 v 1.9 problems, respectively; P = .34).

CONCLUSION: Sucralfate did not decrease pelvic RT-related bowel toxicity by any of the end points measured and seems to have aggravated some gastrointestinal symptoms.
Single-Arm, Open-Label Phase II Study of Intravenously Administered Tirapazamine and Radiation Therapy for Glioblastoma Multiforme
Authors: Del Rowe J. , Scott C. , Werner-Wasik M. , Bahary J.P. , Curran W.J. , Urtasun R.C. , Fisher B.
Published: February 2017

PURPOSE: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model.

PATIENTS AND METHODS: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m2. A second dose level, 260 mg/m2, was opened, and 69 patients were entered.

RESULTS: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m2 dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m 2 dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m2 were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m2 were 16.2 months (class III), 10.3 months (class IV), 5.1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m2 dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level.

CONCLUSION: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m2 dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.