bluuebunny/crossref_metadata_2025 huggingface dataset:
Benefits and Costs of Screening Ashkenazi Jewish Women for BRCA1 and BRCA2
Authors: Grann Victor R. , Whang William , Jacobson Judith S. , Heitjan Daniel F. , Antman Karen H. , Neugut Alfred I.
Published: February 2017

PURPOSE: To determine the survival benefit and cost-effectiveness of screening Ashkenazi Jewish women for three specific BRCA1/2 gene mutations.

METHODS: We used a Markov model and Monte Carlo analysis to estimate the survival benefit and cost-effectiveness of screening for three specific mutations in a population in which their prevalence is 2.5% and the associated cancer risks are 56% for breast cancer and 16% for ovarian cancer. We assumed that the sensitivity and specificity of the test were 98% and 99%, respectively, that bilateral prophylactic oophorectomy would reduce ovarian cancer risk by 45%, and that bilateral prophylactic mastectomy would reduce breast cancer risk by 90%. We used Medicare payment data for treatment costs and Surveillance, Epidemiology, and End Results data for cancer survival.

RESULTS: Our model suggests that genetic screening of this population could prolong average nondiscounted survival by 38 days (95% probability interval, 22 to 57 days) for combined surgery, 33 days (95% probability interval, 18 to 43 days) for mastectomy, 11 days (95% probability interval, 4 to 25 days) for oophorectomy, and 6 days (95% probability interval, 3 to 8 days) for surveillance. The respective cost-effectiveness ratios per life-year saved, with a discount rate of 3%, are $20,717, $29,970, $72,780, and $134,273.

CONCLUSION: In this Ashkenazi Jewish population, with a high prevalence of BRCA1/2 mutations, genetic screening may significantly increase average survival and, depending on costs and screening/treatment strategies, may be cost-effective by the standards of accepted cancer screening tests. According to our model, screening is cost-effective only if all women who test positive undergo prophylactic surgery. These estimates require confirmation through prospective observational studies and clinical trials.
Gemcitabine in Patients With Relapsed or Cisplatin-Refractory Testicular Cancer
Authors: Bokemeyer C. , Gerl A. , Schöffski P. , Harstrick A. , Niederle N. , Beyer J. , Casper J. , Schmoll H.J. , Kanz L.
Published: February 2017

PURPOSE: Despite generally high cure rates in patients with metastatic testicular germ cell tumors, patients with incomplete response to cisplatin-based first-line therapy or with relapsed disease after high-dose salvage chemotherapy have a very poor prognosis. This phase II study evaluates the use of gemcitabine in patients with intensively pretreated or cisplatin-refractory testicular germ cell cancers.

PATIENTS AND METHODS: Thirty-five patients (median age, 33 years) were enrolled; 31 patients were fully assessable. All patients had metastatic nonseminomatous germ cell tumors; eight patients had extragonadal primary tumors. Twenty patients (63%) had lung metastases, and 12 patients (39%) had liver metastases. The median number of prior cisplatin-based chemotherapy cycles was seven; 22 patients (71%) had received high-dose chemotherapy with autologous stem-cell transplantation, and 19 patients (61%) had received treatment with paclitaxel. Seventeen patients (54%) were considered refractory or absolutely refractory to chemotherapy.

RESULTS: Six of 31 assessable patients (19%) responded favorably to gemcitabine, 11 patients (35%) displayed no change, and 14 patients (45%) had disease progression. The median time to treatment failure was 4 months (range, 2 to 9+ months), and the median survival was 6 months (range, 2 to 23 months). Patients received a median of six gemcitabine applications. Ten patients (32%) required dose reductions, mainly owing to hematologic toxicity. Grade 3/4 granulocytopenia occurred in four patients (13%) and grade 3/4 thrombocytopenia in seven patients (22%). One case of severe sepsis was observed.

CONCLUSION: Gemcitabine displays antitumor activity in intensively pretreated and refractory germ cell tumors. Responses were observed in approximately 20% of patients, including three of 22 patients after previous high-dose chemotherapy and one of four patients with mediastinal tumors. Gemcitabine may be a reasonable palliative option for intensively pretreated patients and should be further investigated to define its role in the risk-adapted treatment strategies for germ cell tumors.
Attitudes, Knowledge, and Risk Perceptions of Women With Breast and/or Ovarian Cancer Considering Testing for BRCA1 and BRCA2
Authors: Bluman Leslie G. , Rimer Barbara K. , Berry Donald A. , Borstelmann Nancy , Iglehart J. Dirk , Regan Katherine , Schildkraut Joellen , Winer Eric P.
Published: February 2017

PURPOSE: This study examined baseline knowledge, beliefs, and risk perceptions among a group of 200 women with breast and/or ovarian cancer who participated in a trial designed to improve decision making about genetic testing for BRCA1 and BRCA2.

PATIENTS AND METHODS: Women were identified by self-referral, physician referral, and tumor registry extraction and invited to participate in a randomized trial in which testing for BRCA1 and BRCA2 was offered free of charge. Subjects completed baseline questionnaires and interviews that assessed knowledge, attitudes, and perceptions of risk of having an alteration in BRCA1 or BRCA2.

RESULTS: Sixty percent of women overestimated their chances of having a BRCA1 or BRCA2 mutation compared with estimates from a BRCA1/BRCA2 risk model. Women who have at least three relatives with breast or ovarian cancer were one third (95% confidence interval, 0.2 to 0.6) as likely to overestimate their risk of having a BRCA1 or BRCA2 mutation compared with women who have two or fewer affected relatives. Knowledge was limited about BRCA1 and BRCA2 mutations and cancer risk associated with gene mutations. Eighty-four percent of the women indicated a probable or definite interest in testing.

CONCLUSION: A high proportion of the high-risk women in this study had knowledge deficits about BRCA1 and BRCA2 and overestimated their risk of having a mutation. Although some degree of caution should be used in generalizing the results of this study to practice settings, the data provide insight into the challenges clinicians will face in communicating with patients about cancer genetics.
Pneumonia in Febrile Neutropenic Patients and in Bone Marrow and Blood Stem-Cell Transplant Recipients: Use of High-Resolution Computed Tomography
Authors: Heussel Claus Peter , Kauczor Hans-Ulrich , Heussel Gudula E. , Fischer Berthold , Begrich Markus , Mildenberger Peter , Thelen Manfred
Published: February 2017

PURPOSE: To obtain statistical data on the use of high-resolution computed tomography (HRCT) for early detection of pneumonia in febrile neutropenic patients with unknown focus of infection.

MATERIALS AND METHODS: One hundred eighty-eight HRCT studies were performed prospectively in 112 neutropenic patients with fever of unknown origin persisting for more than 48 hours despite empiric antibiotic treatment. Fifty-four of these studies were performed in transplant recipients. All patients had normal chest roentgenograms. If pneumonia was detected by HRCT, guided bronchoalveolar lavage was recommended. Evidence of pneumonia on chest roentgenograms during follow-up and micro-organisms detected during follow-up were regarded as documentation of pneumonia.

RESULTS: Of the 188 HRCT studies, 112 (60%) showed pneumonia and 76 were normal. Documentation of pneumonia was possible in 61 cases by chest roentgenography or micro-organism detection (54%) (P < 10-6). Sensitivity of HRCT was 87% (88% in transplant recipients), specificity was 57% (67%), and the negative predictive value was 88% (97%). A time gain of 5 days was achieved by the additional use of HRCT compared to an exclusive use of chest roentgenography.

CONCLUSION: The high frequency of inflammatory pulmonary disease after a suspicious HRCT scan (> 50%) proves that pneumonia is not excluded by a normal chest roentgenogram. Given the significantly longer duration of febrile episodes in transplant recipients, HRCT findings are particularly relevant in this subgroup. Patients with normal HRCT scans, particularly transplant recipients, have a low risk of pneumonia during follow-up. All neutropenic patients with fever of unknown origin and normal chest roentgenograms should undergo HRCT.
Metastasis Stage, Adjuvant Treatment, and Residual Tumor Are Prognostic Factors for Medulloblastoma in Children: Conclusions From the Children's Cancer Group 921 Randomized Phase III Study
Authors: Zeltzer Paul M. , Boyett James M. , Finlay Jonathan L. , Albright A. Lel , Rorke Lucy B. , Milstein Jerrold M. , Allen Jeffrey C. , Stevens Kenneth R. , Stanley Philip , Li Hao , Wisoff Jeffrey H. , Geyer J. Russell , McGuire-Cullen Patsy , Stehbens James A. , Shurin Susan B. , Packer Roger J.
Published: February 2017

PURPOSE: From 1986 to 1992, “eight-drugs-in-one-day” (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB).

PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years.

RESULTS: Survival and progression-free survival (PFS) ± SE at 7 years were 55% ± 5% and 54% ± 5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63% ± 5% versus 45% ± 5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32% ± 10% v 58% ± 4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (M0 v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70% ± 5%, 57% ± 10%, and 40% ± 8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2of residual tumor, versus ≥ 1.5 cm2of residual tumor by scan, were significantly different (P = .023; 78% ± 6% v 54% ± 11%, respectively).

CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, ≥ 3 years with ≤ 1.5 cm2residual tumor, had a 78% ± 6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate.
Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer
Authors: Vanhoefer Udo , Harstrick Andreas , Köhne Claus-Henning , Achterrath Wolf , Rustum Youcef M. , Seeber Siegfried , Wilke Hansjochen
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity.

PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7).

RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response.

CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.
Efficacy and Safety of Prolonged-Release Lanreotide in Patients With Gastrointestinal Neuroendocrine Tumors and Hormone-Related Symptoms
Authors: Wymenga A.N.M. , Eriksson B. , Salmela P.I. , Jacobsen M.B. , Van Cutsem E.J.D.G. , Fiasse R.H. , Välimäki M.J. , Renstrup J. , de Vries E.G.E. , Öberg K.E.
Published: February 2017

PURPOSE: To evaluate the prolonged release (PR) of the long-acting somatostatin analog lanreotide in patients with gastrointestinal neuroendocrine tumors and its effect on hormone-related symptomatology, tumor markers, tumor size, tolerability, and quality of life (QOL).

PATIENTS AND METHODS: Eligible patients had the following substantial daily symptoms: for patients with carcinoid tumors, three or more stools and/or 1.5 or more flushing episodes; for patients with gastrinoma, greater than 50% elevated basic acid output; and for patients with vasoactive intestinal peptide-secreting tumors (VIPomas), four or more stools and/or a stool volume of ≥ 800 mL, a measurable tumor, and an elevated biochemical tumor marker (≥ two times the upper limit of the normal reference range). Lanreotide PR was administered intramuscularly every 14 days at 30 mg for 6 months. We measured efficacy by studying symptoms, tumor markers, tumor size, and QOL. Side effects were scored according to the National Cancer Institute's toxicity grading system and ultrasound examination of the gallbladder.

RESULTS: Fifty-five patients were included in the study (48 patients with carcinoid tumors, six patients with gastrinoma, and one patient with VIPoma). Symptomatic improvement (> 50% reduction) occurred in 38% of the assessable patients with carcinoid tumors, in 67% of the gastrinoma patients, and in the VIPoma patient. Tumor markers normalized in two of 45 assessable patients, 19 patients exhibited a reduction (> 50%), 19 patients exhibited no change, and tumor markers rose by more than 50% in five patients. Tumor size was reduced in two of 31 assessable patients and remained stable in 25 patients; four patients experienced progression. QOL assessments after 1 month showed improvements in emotional and cognitive function, and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones.

CONCLUSION: Lanreotide PR is a well-tolerated somatostatin analog with significant clinical, biochemical, and antitumor effects that bring about a significant improvement in QOL for patients with neuroendocrine tumors.
Comparative Effects of Paclitaxel and Docetaxel on the Metabolism and Pharmacokinetics of Epirubicin in Breast Cancer Patients
Authors: Esposito M. , Venturini M. , Vannozzi M.O. , Tolino G. , Lunardi G. , Garrone O. , Angiolini C. , Viale M. , Bergaglio M. , Del Mastro L. , Rosso R.
Published: February 2017

PURPOSE: To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin.

PATIENTS AND METHODS: We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m2 by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m2 in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m2 followed immediately by docetaxel 70 mg/m2 in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography.

RESULTS: No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1.7-fold and 1.9-fold higher (P < .05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 ± 150 ng/mL*h) was significantly higher (P < .01) than the corresponding values after epirubicin administered either as a single agent (692 ± 46 ng/mL*h) or in combination with docetaxel (848 ± 237 ng/mL*h).

CONCLUSION: There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.
Randomized Comparison of Fluorouracil Plus Cisplatin Versus Hydroxyurea as an Adjunct to Radiation Therapy in Stage IIB-IVA Carcinoma of the Cervix With Negative Para-Aortic Lymph Nodes: A Gynecologic Oncology Group and Southwest Oncology Group Study
Authors: Whitney Charles W. , Sause William , Bundy Brian N. , Malfetano John H. , Hannigan Edward V. , Fowler, Jr Wesley C. , Clarke-Pearson Daniel L. , Liao Shu-Yuan
Published: February 2017

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities.

METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU.

RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018).

CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.
Estrogen Replacement Therapy After Localized Breast Cancer: Clinical Outcome of 319 Women Followed Prospectively
Authors: Vassilopoulou-Sellin Rena , Asmar Lina , Hortobagyi Gabriel N. , Klein Mary Jean , McNeese Marsha , Singletary Sonja E. , Theriault Richard L.
Published: February 2017

PURPOSE: To determine whether estrogen replacement therapy (ERT) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer.

PATIENTS AND METHODS: Potential participants (n = 319) in a trial of ERT after breast cancer were observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not. Of 319 women, 39 were given estrogen and 280 were not given hormones. Tumor size, number of lymph nodes, estrogen receptors, menopausal status at diagnosis, and disease-free interval at the initiation of the observation period were comparable for the trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT (n = 39) versus controls (n = 280). Cancer events were ascertained for both groups.

RESULTS: Patient and disease characteristics were comparable for the trial participants versus nonparticipants, as well as for the women on ERT versus the controls. One patient in the ERT group developed a new lobular estrogen receptor–positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor–negative breast cancer and 27 months after initiation of ERT. In the control group, there were 20 cancer events: 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months.

CONCLUSION: ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer. Results of randomized trials are needed before any changes in current standards of care can be proposed.
Irinotecan Therapy in Adults With Recurrent or Progressive Malignant Glioma
Authors: Friedman Henry S. , Petros William P. , Friedman Allan H. , Schaaf Larry J. , Kerby Tracy , Lawyer Jennifer , Parry Mary , Houghton Peter J. , Lovell Shelley , Rasheed Karima , Cloughsey Tim , Stewart Elizabeth S. , Colvin O. Michael , Provenzale James M. , McLendon Roger E. , Bigner Darell D. , Cokgor Ilkcan , Haglund Michael , Rich Jeremy , Ashley David , Malczyn Joseph , Elfring Gary L. , Miller Langdon L.
Published: February 2017

PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma.

PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (IV) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients.

RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment.

CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.
Improved Outcome With T-Cell–Depleted Bone Marrow Transplantation for Acute Leukemia
Authors: Aversa Franco , Terenzi Adelmo , Carotti Alessandra , Felicini Rita , Jacucci Roberta , Zei Tiziana , Latini Paolo , Aristei Cynthia , Santucci Antonella , Martelli Maria Paola , Cunningham Isabel , Reisner Yair , Martelli Massimo F.
Published: February 2017

PURPOSE: To eliminate the risk of rejection and lower the risk of relapse after T-cell–depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation.

PATIENTS AND METHODS: Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis.

RESULTS: Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status.

CONCLUSION: Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell–depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.
Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients With “Low-Grade” Non-Hodgkin's Lymphoma and B-Cell Chronic Lymphocytic Leukemia
Authors: Foran James M. , Oscier David , Orchard Jennifer , Johnson Stephen A. , Tighe Mary , Cullen Michael H. , de Takats Philippa G. , Kraus Christian , Klein Marcus , Lister T. Andrew
Published: February 2017

PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with “low-grade” non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia.

PATIENTS AND METHODS: Oral F-AMP was incorporated into the “conventional” treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyl-adenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy.

RESULTS: Oral administration of F-AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cmax. The linear increase in mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent.

CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.
Review of the Efficacy of Individualized Chemotherapy Selected by In Vitro Drug Sensitivity Testing for Patients With Cancer
Authors: Cortazar Patricia , Johnson Bruce E.
Published: February 2017

PURPOSE: The purpose of this study is to review the potential efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing (DST) compared with empiric regimens for patients with cancer.

METHODS: MEDLINE and CANCERLIT were searched for articles published (in English) about prospective clinical trials in which patients were treated with chemotherapy that was selected with the use of in vitro DST.

RESULTS: We identified 12 prospective studies that examined the benefit of chemotherapy selected by DST. Five hundred six patients (33%) were treated with chemotherapy that was selected with the use of in vitro DST. The mean response rate for patients treated with in vitro–selected therapy was 27% (range, 10% to 100%; n = 12 studies) compared with 18% (range, 0% to 100%; n = 7 studies) for patients treated with empiric therapy. Five studies (only one randomized) evaluated the impact of chemotherapy selected by in vitro DST on patient survival. Three studies showed that survival was 1 to 4 months longer for the 238 patients treated with empiric chemotherapy compared with that of the 65 patients treated with chemotherapy that was selected by in vitro testing. Two nonrandomized studies showed that survival was 4 or 19 months longer for 27 patients treated with chemotherapy selected by in vitro testing compared with that of 80 patients who were treated with empiric chemotherapy.

CONCLUSION: Only one third of patients entered in prospective trials of in vitro DST were actually treated with an in vitro best regimen. The response rates seem to be better with in vitro selected chemotherapy regimens than with empiric regimens, but the impact on survival has not been adequately addressed.
Health-Related Quality of Life in Men With Metastatic Prostate Cancer Treated With Prednisone Alone or Mitoxantrone and Prednisone
Authors: Osoba David , Tannock Ian F. , Ernst D. Scott , Neville Alan J.
Published: February 2017

PURPOSE: A combination of mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL).

PATIENTS AND METHODS: Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain. HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module–Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients.

RESULTS: At 6 weeks, both groups showed improvement in several HQL domains, and only physicalfunctioning and pain were better in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life (P = .009), four functioning domains, and nine symptoms (.001 < P < .01), and the improvement (> 10 units on a scale of 0 to100) lasted longer than in the prednisone-alone group (.004 < P < .05). The addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life (.001 < P < .003).

CONCLUSION: Treatment with mitoxantrone plus prednisone was associated with greater and longer-lasting improvement in several HQL domains and symptoms than treatment with prednisone alone.
Postmenopausal Hormone Replacement Therapy: Effect on Diagnosis and Outcome in Early-Stage Invasive Breast Cancer Treated With Conservative Surgery and Radiation
Authors: Fowble Barbara , Hanlon Alexandra , Freedman Gary , Patchefsky Art , Kessler Howard , Nicolaou Nicos , Hoffman John , Sigurdson Elin , Boraas Marcia , Goldstein Lori
Published: February 2017

PURPOSE: To compare the pretreatment characteristics and outcome of postmenopausal women with stage I-II breast cancer treated with conservative surgery and radiation who had a history of hormone replacement therapy (HRT) with those who had never received HRT.

MATERIALS AND METHODS: From 1979 to 1993, 485 postmenopausal women underwent excisional biopsy, axillary dissection, and radiation for stage I-II breast cancer. The median follow-up was 5.9 years. One hundred forty-one patients reported a history of HRT. The median length of use was 5 years. Three hundred forty-four patients reported no history of HRT.

RESULTS: Statistically significant differences between the two groups were observed for median age (HRT 60 years v no HRT 64 years; P = .0009), median weight (HRT 142 lbs v no HRT 152 lbs; P = .004), clinical tumor size ≤ 2 cm (HRT 77% v no HRT 66%; P = .02), and the use of re-excision (HRT 62% v no HRT 49%; P = .01). The method of detection by mammogram only (HRT 52% v no HRT 42%; P = .06) was of borderline statistical significance. The HRT patients had a statistically significant increased cumulative incidence of ipsilateral breast tumor recurrence (8% v 2%; P = .02), a statistically significant decreased cumulative incidence of distant metastases (HRT 6% v no HRT 17%; P = .01), and a borderline statistically significant improvement in cause-specific survival at 10 years (HRT 92% v no HRT 86%; P = .07). Postmenopausal women with a history of HRT did not have an increased risk of contralateral breast cancer or second non–breast cancer malignancy.

CONCLUSION: This study failed to identify an adverse effect of HRT on breast cancer mortality in patients with stage I-II disease treated with conservative surgery and radiation.
Expression and Prognostic Significance of Metalloproteinases and Their Tissue Inhibitors in Patients With Small-Cell Lung Cancer
Authors: Michael M. , Babic B. , Khokha R. , Tsao M. , Ho J. , Pintilie M. , Leco K. , Chamberlain D. , Shepherd F. A.
Published: February 2017

PURPOSE: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in tumor development and progression. MMP expression has been correlated with advanced clinical stage and poor survival in some tumors, but data for small-cell lung cancer (SCLC) are lacking. The aim of this study was to assess the expression of MMPs and TIMPs in SCLC and to evaluate their importance relative to standard prognostic factors.

PATIENTS AND METHODS: Expression of MMP-1, -2, -3, -9, -11, -13, and -14 and TIMP-1, -2, -3, and -4 was evaluated by immunohistochemistry (IHC). In situ hybridization was used to confirm expression of specific mRNAs. Clinical data collected included sex, tumor stage, performance status, weight loss, hematology (hemoglobin, WBC, platelets) and biochemistry (sodium, albumin, alkaline phosphatase, lactate dehydrogenase), treatment, and survival.

RESULTS: Samples from 46 patients were evaluated: 30 males, 16 females; 29 limited, 17 extensive stage; 35 Eastern Cooperative Oncology Group performance status 0-1. Positive IHC staining was evident for MMP-1 and -9 in 60% to 70% of tumor cells, and for MMP-11, -13, and -14 and TIMP-2 and -3 in 70% to 100% of tumor cells. Stromal staining of TIMP-1 to -3 was present in less than 30% of specimens. On multivariate analysis, only stage and decreased tumoral expression of TIMP-1 were significant for response (P = .043). Significant factors for survival were tumor stage (P = .0021); weight loss (P = .013); and high tumor cell expression of MMP-3 (P = .077), MMP-11 (P = .031), and MMP-14 (P = .019). MMP and TIMP expression did not differ significantly between stages.

CONCLUSION: MMPs and TIMPs are widely expressed in SCLC. Increased tumoral expression of MMP-3, -11, and -14 were independent negative prognostic factors for survival. The results support the evaluation of synthetic MMP inhibitors in patients with SCLC.
Comparison of Lumbar and Shunt Cerebrospinal Fluid Specimens for Cytologic Detection of Leptomeningeal Disease in Pediatric Patients With Brain Tumors
Authors: Gajjar Amar , Fouladi Maryam , Walter Andrew W. , Thompson Stephen J. , Reardon David A. , Merchant Thomas E. , Jenkins Jesse J. , Liu Aiyi , Boyett James M. , Kun Larry E. , Heideman Richard L.
Published: February 2017

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps.

PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells.

RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P = .0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P = .011). Analysis of the subset of patients with embryonal tumors showed similar results (P = .0008).

CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.
Insufficient Effectiveness of 5-Hydroxytryptamine-3 Receptor Antagonists Due to Oral Morphine Administration in Patients With Cisplatin-Induced Emesis
Authors: Shoji Akira , Toda Mariko , Suzuki Kaneo , Takahashi Hiroshi , Takahashi Kenichi , Yoshiike Yasuhiro , Ogura Takashi , Watanuki Yuji , Nishiyama Harumi , Odagiri Shigeki
Published: February 2017

PURPOSE: To compare the effect of 5-hydroxytryptamine-3 (5HT3) receptor antagonists in cancer patients receiving chemotherapy including cisplatin (CDDP), with or without sustained-release oral morphine (MS Contin; Shionogi Co, Osaka, Japan).

PATIENTS AND METHODS: We retrospectively studied 58 lung cancer patients given chemotherapy including at least 50 mg/m2 CDDP with 5-HT3 receptor antagonists between January 1996 and December 1997. Number of vomiting episodes, average porportions of hospital-supplied meals consumed (0 to 100%, as an index of appetite), and nausea severity scores (0 to 2 points, subjective patient judgment) were compared between oral morphine–administered (+) and morphine-free (−) groups.

RESULTS: Sixteen morphine(+) and 42 morphine(−) cases were used. In cases of acute emesis (within 24 hours after CDDP injection), morphine(+) and morphine(−) groups were significantly different in number of vomiting episodes (1.25 and 0.14, respectively; P < .0001), appetite (58.13% and 90.24%; P < .0001), and nausea severity scores (1.63 and 0.62; P < .0001). In delayed-emesis cases (24 to 120 hours after CDDP), these groups differed significantly in number of vomiting episodes (1.94 and 0.43, respectively; P = .0001), appetite (23.13% and 52.08%; P < .0001), and nausea severity (1.38 and 0.91; P = .009). There were no significant differences in sex, age, anticancer drugs concurrent with CDDP, CDDP dose, corticosteroid administration, clinical stage, or type of 5-HT3 antagonist.

CONCLUSIONS: These data suggest that morphine can markedly reduce the effectiveness of 5-HT3 receptor antagonists in patients receiving chemotherapy that includes CDDP. These results require confirmation by reinvestigation of clinical data on the efficacy of 5-HT3 receptor antagonists and by extensive prospective analyses.
Development and Testing of a Visit-Specific Patient Satisfaction Questionnaire: The Princess Margaret Hospital Satisfaction With Doctor Questionnaire
Authors: Loblaw D. Andrew , Bezjak Andrea , Bunston† Terry
Published: February 2017

PURPOSE: To develop a psychometrically sound patient-satisfaction-with-physician questionnaire that can be used in an outpatient oncology setting.

PATIENTS AND METHODS: The questionnaire was developed by a four-step process involving a total of 277 cancer patients. The item-generation process utilized input from 95 oncology outpatients, three medical researchers, and the relevant literature. Items were tested by 70 of the above patients. Initial item reduction was achieved by input from another eight patients. Factor analysis and validity testing used data derived from a different group of 174 oncology outpatients. Convergent validity was tested by correlating the Princess Margaret Hospital Patient Satisfaction with Doctor Questionnaire (PMH/PSQ-MD) with Rubin et al's Physician subscale of the Patient's Viewpoint Questionnaire (PS-PVQ) and Smith et al's Patient-Doctor Interaction Scale (PDIS). Divergent validity was tested by comparing these questionnaires with Spitzer's quality of life (QOL) questionnaire.

RESULTS: The final PMH/PSQ-MD is a 29-item self-administered questionnaire with four response categories and a “does not apply” category. Four domains were confirmed by factor analysis: (1) information exchange, (2) interpersonal skills, (3) empathy, and (4) quality of time. The questionnaire has an overall Cronbach's alpha of 0.97; the values for each domain are, respectively, 0.92, 0.90, 0.88, and 0.88. The PMH/PSQ-MD correlated well with both the PDIS and the PS-PVQ (P < .001 for both). Divergent validity was confirmed with Spitzer's QOL questionnaire.

CONCLUSION: The PMH/PSQ-MD is an outpatient satisfaction questionnaire specific to the patient-physician interaction that has shown excellent internal consistency, is feasible, and has strong support for validity in this oncology population.
Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry for the Evaluation of HER-2/neu in Breast Cancer
Authors: Jacobs Timothy W. , Gown Allen M. , Yaziji Hadi , Barnes Melissa J. , Schnitt Stuart J.
Published: February 2017

PURPOSE: To compare fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in the determination of HER-2/neu status of breast cancers.

MATERIALS AND METHODS: FISH and IHC for HER-2/neu were performed on formalin-fixed paraffin sections of 100 consecutive invasive breast cancers. FISH was performed at Beth Israel Deaconess Medical Center, Boston, MA, using the Oncor/Ventana INFORM kit (Ventana Medical Systems, Tucson, AZ; formerly sold by Oncor, Inc, Gaithersburg, MD) in a laboratory certified as proficient in this procedure. IHC was performed at PhenoPath Laboratories, Seattle, WA, using a polyclonal antibody to the HER-2/neu protein. FISH and IHC were analyzed in a blinded fashion, and the results were then compared. Procedure and interpretation times and reagent costs for FISH and IHC were also compared.

RESULTS: HER-2/neu was amplified by FISH in 26% of cases, and 23% were HER-2/neu–positive by IHC. FISHand IHC were both assessable in 90 cases. Concordance between FISH and IHC results was seen in 82 of these cases (91%, P < .001). The FISH procedure required more technologist time and more interpretation time per case for the pathologist than IHC. Reagent costs were substantially higher for FISH than for IHC.

CONCLUSION: There is a high level of correlation between FISH and IHC in the evaluation of HER-2/neu status of breast cancers using formalin-fixed paraffin-embedded specimens. Although the choice of which assay to use should be left for individual laboratories to make based on technical and economic considerations, our results may make it difficult to justify the routine use of FISH for determination of HER-2/neu status in breast cancer.
Phase I Trial of Twice-Weekly Gemcitabine and Concurrent Radiation in Patients With Advanced Pancreatic Cancer
Authors: Blackstock A. William , Bernard Stephen A. , Richards Frederick , Eagle Kaye S. , Case L. Douglas , Poole Michael E. , Savage Paul D. , Tepper Joel E.
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer.

PATIENTS AND METHODS: Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m2 by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m2 increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed.

RESULTS: The dose-limiting toxicities at 60 mg/m2 given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m2 dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression.

CONCLUSION: A dose of twice-weekly gemcitabine at 40 mg/m2 produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.