bluuebunny/crossref_metadata_2025 huggingface dataset:
Pentostatin Therapy of T-Cell Lymphomas With Cutaneous Manifestations
Authors: Kurzrock Razelle , Pilat Susan , Duvic Madeleine
Published: February 2017

PURPOSE: To determine the side effects of and response to pentostatin in patients with T-cell lymphomas with cutaneous manifestations.

PATIENTS AND METHODS: Pentostatin was administered to 28 patients who had relapsed cutaneous T-cell lymphoma or peripheral T-cell lymphoma with prominent cutaneous disease. The starting dose was between 3.75 to 5.0 mg/m2/d intravenous for 3 days every 3 weeks.

RESULTS: Of the 24 patients assessable for response, 17 (71%) achieved a partial remission (46%) or complete remission (25%). The patients had a median number of three (range, one to 12) prior therapies. Of the 86 courses of pentostatin given, 39 were administered at doses of 5.0 mg/m2/d and 30 at doses of 3.75 mg/m2/d. Dose escalation to 6.25 mg/m2/d was possible in only five courses, and toxicity necessitated dose reduction to 2.8 mg/m2/d in 12 courses. The most common side effects were granulocytopenia, nausea, and nonneutropenic fever. Most patients developed significant lowering of CD4 counts. Herpes zoster was seen within 1 year after pentostatin in five patients (19%).

CONCLUSION: Pentostatin is an active agent in heavily pretreated T-cell lymphomas with cutaneous manifestations.
Outcome in Patients With Myelodysplastic Syndrome After Autologous Bone Marrow Transplantation for Non-Hodgkin's Lymphoma
Authors: Friedberg Jonathan W. , Neuberg Donna , Stone Richard M. , Alyea Edwin , Jallow Haddy , LaCasce Ann , Mauch Peter M. , Gribben John G. , Ritz Jerome , Nadler Lee M. , Soiffer Robert J. , Freedman Arnold S.
Published: February 2017

PURPOSE: The absolute risk of myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for non–Hodgkin's lymphoma (NHL) exceeds 5% in several reported series. We report the outcome of a large cohort of patients who developed MDS after ABMT for NHL.

PATIENTS AND METHODS: Between December 1982 and December 1997, 552 patients underwent ABMT for NHL, with a uniform ablative regimen of cyclophosphamide and total body irradiation followed by reinfusion of obtained marrow purged with monoclonal antibodies. MDS was strictly defined, using the French-American-British classification system, as requiring bone marrow dysplasia in at least two cell lines, with associated unexplained persistent cytopenias.

RESULTS: Forty-one patients developed MDS at a median of 47 months after ABMT. The incidence of MDS was 7.4%, and actuarial incidence at 10 years is 19.8%, without evidence of a plateau. Patients who developed MDS received significantly fewer numbers of cells reinfused per kilogram at ABMT (P = .0003). Karyotypes were performed on bone marrow samples of 33 patients, and 29 patients had either del(7) or complex abnormalities. The median survival from diagnosis of MDS was 9.4 months. The International Prognostic Scoring System for MDS failed to predict outcome in these patients. Thirteen patients underwent allogeneic BMT as treatment for MDS, and all have died of BMT-related complications (11 patients) or relapse (two patients), with a median survival of only 1.8 months.

CONCLUSION: Long-term follow-up demonstrates a high incidence of MDS after ABMT for NHL. The prognosis for these patients is uniformly poor, and novel treatment strategies are needed for this fatal disorder.
Accelerated Radiotherapy, Carbogen, and Nicotinamide in Glioblastoma Multiforme: Report of European Organization for Research and Treatment of Cancer Trial 22933
Authors: Miralbell Raymond , Mornex Françoise , Greiner Richard , Bolla Michel , Storme Guy , Hulshof Maarten , Bernier Jacques , Denekamp Juliana , Rojas Ana M. , Pierart Marianne , van Glabbeke Martine , Mirimanoff René O.
Published: February 2017

PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme.

PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg.

RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively.

CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.
Phase II Trial of N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl and Doxorubicin Chemotherapy in Metastatic Breast Cancer: A National Cancer Institute of Canada Clinical Trials Group Study
Authors: Khoo K. , Brandes L. , Reyno L. , Arnold A. , Dent S. , Vandenberg T. , Lebwohl D. , Fisher B. , Eisenhauer E.
Published: February 2017

PURPOSE: This multicenter phase II trial investigated the efficacy and toxicity of a combination of the novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE), and doxorubicin in patients with anthracycline-naïve metastatic breast cancer. Preclinical models and early single institutional studies suggested DPPE could potentiate the cytotoxicity of doxorubicin.

PATIENTS AND METHODS: Forty-two women, 32 to 77 years old (median, 59 years), with anthracycline-naïve metastatic breast cancer were treated. Patients may have had one previous regimen of nonanthracycline chemotherapy, either in the adjuvant or metastatic disease treatment setting. DPPE (6 mg/kg) was administered as an 80 minute intravenous infusion with doxorubicin (60 mg/m2) given intravenously over the last 20 minutes of the DPPE infusion. Patients were premedicated with an antiemetic and sedating regimen. The DPPE/doxorubicin treatment was given every 21 days for a maximum of seven cycles.

RESULTS: All 42 patients were assessable. Overall, toxicity was comparable to that expected with doxorubicin alone, with the exception of DPPE-related motion sickness, mild hallucinations, and cerebellar signs at the time of the infusion. These CNS side effects were manageable in an ambulatory care setting, improved with subsequent cycles of treatment, and did not usually require hospitalization. Four patients developed febrile neutropenia. Thirty-five patients received four or more cycles of chemotherapy. The overall response rate was 52.5% (95% confidence interval, 36% to 68%), with 9.5% complete responses (n = 4), 43% partial responses (n = 18), and 38% of patients with stable disease (n = 16).

CONCLUSION: The antitumour effects of DPPE/doxorubicin the 52.5% response rate seems encouraging, particularly in consideration of the fact that a recently reported randomized National Cancer Institute of Canada Clinical Trials Group trial using single-agent doxorubicin 60 mg/m2in one of the treatment arms achieved a 31% response rate. Thus, a randomized phase III trial of doxorubicin versus doxorubicin plus DPPE is being conducted in this clinical setting.
First-Line High-Dose Chemotherapy Compared With Standard-Dose PEB/VIP Chemotherapy in Patients With Advanced Germ Cell Tumors: A Multivariate and Matched-Pair Analysis
Authors: Bokemeyer C. , Kollmannsberger C. , Meisner C. , Harstrick A. , Beyer J. , Metzner B. , Hartmann J. T. , Schmoll H.-J. , Einhorn L. , Kanz L. , Nichols C.
Published: February 2017

PURPOSE: To compare first-line high-dose chemotherapy (HD-CT) with autologous blood stem-cell transplantation to standard-dose chemotherapy (SD-CT) in male patients with advanced germ cell tumors (GCTs), a matched-pair analysis was performed within a homogenous group of patients classified as having either Indiana advanced disease or a poor prognosis according to International Germ Cell Cancer Consensus Group (IGCCCG) criteria.

PATIENTS AND METHODS: A multivariate analysis was performed that included 147 consecutive patients who had received sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) therapy (HD-CT) in a German multicenter trial between 1993 and 1997 and 309 patients who had been treated with standard-dose cisplatin, etoposide, and bleomycin (PEB) or VIP chemotherapy (SD-CT) within two randomized trials at Indiana University between 1984 and 1992.

RESULTS: Multivariate analysis demonstrated HD-CT to be significantly superior to SD-CT when adjustments were made for prognostic factors (P = .021). Primary tumor site (mediastinal v retroperitoneal/gonadal, P = .035) and presence of visceral metastases (P = .0004) were shown to be significant prognostic factors for overall survival. On the basis of these factors, as well as on tumor marker levels (good, intermediate, or poor, according to IGCCCG criteria), 146 of 147 HD-CT patients were fully matched to an SD-CT patient. Median follow-up was 21 months (range, 0 to 70 months) for the HD-CT patients and 22 months (range, 0 to 90 months) for the SD-CT patients. Two-year progression-free survival (75% v 59%) and overall survival (82% v 71%) were significantly prolonged in HD-CT patients (P = .0056 and P = .0184, respectively).

CONCLUSION: The results indicate that first-line HD-CT in patients with poor-prognosis GCT may result in a significant improvement of progression-free and overall survival as compared with SD-CT. Salvage HD-CT seems not to compensate this survival advantage.
Clinical Trial to Assess the Relative Efficacy of Fluorouracil and Leucovorin, Fluorouracil and Levamisole, and Fluorouracil, Leucovorin, and Levamisole in Patients With Dukes' B and C Carcinoma of the Colon: Results From National Surgical Adjuvant Breast and Bowel Project C-04
Authors: Wolmark Norman , Rockette Howard , Mamounas Eleftherios , Jones Judy , Wieand Sam , Wickerham D.L. , Bear Harry D. , Atkins James N. , Dimitrov Nikolay V. , Glass Andrew G. , Fisher Edwin R. , Fisher Bernard
Published: February 2017

PURPOSE: To compare the efficacy of leucovorin-modulated fluorouracil (FU+LV) with that of fluorouracil and levamisole (FU+LEV) or with the combination of FU+LV and levamisole (FU+LV+LEV).

PATIENTS AND METHODS: Between July 1989 and December 1990, 2,151 patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the colon were entered onto National Surgical Adjuvant Breast and Bowl Project protocol C-04. Patients were randomly assigned to receive FU+LV (weekly regimen), FU + LEV, or the combination of FU+LV+LEV. The average time on study was 86 months.

RESULTS: A pairwise comparison between patients treated with FU+LV or FU+LEV disclosed a prolongation in disease-free survival (DFS) in favor of the FU+LV group (65% v 60%; P = .04); there was a small prolongation in overall survival that was of borderline significance (74% v 70%; P = .07). There was no difference in the pairwise comparison between patients who received FU+LV or FU+LV+LEV for either DFS (65% v 64%; P = .67) or overall survival (74% v 73%; P = .99). There was no interaction between Dukes' stage and the effect of treatment.

CONCLUSION: In patients with Dukes' B and C carcinoma of the colon, treatment with FU+LV seems to confer a small DFS advantage and a borderline prolongation in overall survival when compared with treatment with FU+LEV. The addition of LEV to FU+LV does not provide any additional benefit over and above that achieved with FU+LV. These findings support the use of adjuvant FU+LV as an acceptable therapeutic standard in patients with Dukes' B and C carcinoma of the colon.
Management of Acute Myeloid Leukemia in Elderly Patients
Authors: Hiddemann Wolfgang , Kern Wolfgang , Schoch Claudia , Fonatsch Christa , Heinecke Achim , Wörmann Bernhard , Büchner Thomas
Published: February 2017

ABSTRACT: Acute myeloid leukemia (AML) at older age is associated with several biologic and clinical characteristics. Hence, it may arise from an early level of hematopoietic stem cells and has a high frequency of blast cells with multidrug resistance glycoprotein MDR1 expression and particularly a high incidence of poor prognostic karyotypes. These factors, rather than age per se, underlie the poorer outcome as compared with younger cases. Prospective randomized studies clearly demonstrate, however, that elderly patients benefit from more intensive induction therapy and particularly from full-dose application of anthracyclines and possibly also cytarabine. Hematopoietic growth factors accelerate the recovery from treatment-induced neutropenia and may improve the remission rate, remission duration, and even overall survival. New treatment strategies need to be developed, however, for poor-prognosis AML subtypes in order to further improve the therapeutic perspectives for elderly patients with AML.
Phase I Evaluation of ISIS 3521, an Antisense Oligodeoxynucleotide to Protein Kinase C-Alpha, in Patients With Advanced Cancer
Authors: Nemunaitis J. , Holmlund J. T. , Kraynak M. , Richards D. , Bruce J. , Ognoskie N. , Kwoh T. J. , Geary R. , Dorr A. , Von Hoff D. , Eckhardt S. G.
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha.

PATIENTS AND METHODS: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites.

RESULTS: Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (Cmax), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in Cmax, AUC, and elimination half-life.

CONCLUSION: No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.
Assessing the Reliability of Patient, Nurse, and Family Caregiver Symptom Ratings in Hospitalized Advanced Cancer Patients
Authors: Nekolaichuk Cheryl L. , Maguire Thomas O. , Suarez-Almazor Maria , Rogers W. Todd , Bruera Eduardo
Published: February 2017

PURPOSE: The purpose of this study was to examine the reliability of symptom assessments in advanced cancer patients under various conditions, including multiple raters (patients, nurses, and family caregivers), occasions, and symptoms.

PATIENTS AND METHODS: The study sample consisted of 32 advanced cancer patients admitted to a tertiary palliative care unit. Symptom assessments were completed for each patient on two separate occasions, approximately 24 hours apart. On each occasion, the patient, the primary care nurse, and a primary family caregiver independently completed an assessment using the Edmonton Symptom Assessment System (ESAS). The ESAS is a nine-item visual analogue scale for assessing symptoms in palliative patients. The reliability of the assessments (r) was examined using generalizability theory.

RESULTS: Three important findings emerged from this analysis. First, the analysis of individual symptom ratings provided a more meaningful representation of the symptom experience than total symptom distress ratings. Secondly, patients, nurses, and caregivers varied in their ratings across different patients, as well as in their ratings of shortness of breath, which may have been a result of individual rater variability. Finally, reliability estimates (r), based on a single rater and one occasion, were less than .70 for all symptoms, except appetite. These estimates improved substantially (r ≥ .70) for all symptoms except anxiety and shortness of breath, using three raters on a single occasion or two raters across two occasions.

CONCLUSION: The findings from this study reinforce the need for the development of an integrated symptom assessment approach that combines patient and proxy assessments. Further research is needed to explore individual differences among raters.
Improved Survival of Children With Isolated CNS Relapse of Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study
Authors: Ritchey A. Kim , Pollock Brad H. , Lauer Stephen J. , Andejeski Yvonne , Buchanan George R.
Published: February 2017

PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation.

PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy.

RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% ± 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission ≥ 18 months was 83.3% ± 5.3%, and for those with a first complete remission less than 18 months, it was 46.2% ± 10.2% (P = .0002.) There was a low incidence of neurologic toxicity and an unexpectedly high rate of allergic reactions to l-asparaginase. Five patients developed secondary malignancies: two with acute nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy, and two with brain tumors 1.5 to 2 years after cessation of therapy.

CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission ≥ 18 months is comparable to that at the time of original diagnosis of ALL.
Ifosfamide, Carboplatin, and Etoposide: A Highly Effective Cytoreduction and Peripheral-Blood Progenitor-Cell Mobilization Regimen for Transplant-Eligible Patients With Non-Hodgkin's Lymphoma
Authors: Moskowitz Craig H. , Bertino Joseph R. , Glassman Jill R. , Hedrick Eric E. , Hunte Sonia , Coady-Lyons Nancy , Agus David B. , Goy Andre , Jurcic Joseph , Noy Ariela , O'Brien James , Portlock Carol S. , Straus David S. , Childs Barrett , Frank Richard , Yahalom Joachim , Filippa Daniel , Louie Diane , Nimer Stephen D. , Zelenetz Andrew D.
Published: February 2017

PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granuloctye colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34+ cells collected after treatment with ICE and G-CSF were evaluated.

RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P = .003). The median number of CD34+ cells/kg collected was 8.4 × 106. The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects.

CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.
Clinical Course of Breast Cancer Patients With Complete Pathologic Primary Tumor and Axillary Lymph Node Response to Doxorubicin-Based Neoadjuvant Chemotherapy
Authors: Kuerer Henry M. , Newman Lisa A. , Smith Terry L. , Ames Fred C. , Hunt Kelly K. , Dhingra Kapil , Theriault Richard L. , Singh Gurpreet , Binkley Susan M. , Sneige Nour , Buchholz Thomas A. , Ross Merrick I. , McNeese Marsha D. , Buzdar Aman U. , Hortobagyi Gabriel N. , Singletary S. Eva
Published: February 2017

PURPOSE: To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC).

PATIENTS AND METHODS: Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months).

RESULTS: The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P > .05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)–negative (P < .01), and anaplastic (P = .01) but of smaller size (P < .01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P < .01). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P < .01).

CONCLUSION: Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.
Multicenter Phase II Study of Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer
Authors: Blum Joanne L. , Jones Stephen E. , Buzdar Aman U. , LoRusso Patricia Mucci , Kuter Irene , Vogel Charles , Osterwalder Bruno , Burger Hans-Ulrich , Brown Cheryl Stoner , Griffin Tom
Published: February 2017

PURPOSE: Capecitabine is a novel, oral, selectively tumor-activated fluoropyrimidine carbamate. This large multicenter phase II trial tested the efficacy and safety of twice-daily oral capecitabine at 2,510 mg/m2/d given for 2 weeks followed by a 1-week rest period and repeated in 3-week cycles, in patients with paclitaxel-refractory metastatic breast cancer.

PATIENTS AND METHODS: Patients were to have received at least two but not more than three prior chemotherapeutic regimens, one of which had to have contained paclitaxel given for metastatic disease. One hundred sixty-three patients were entered onto the study at 25 centers, and 162 patients received capecitabine. One hundred thirty-five patients had bidimensionally measurable disease, and 27 patients had assessable disease.

RESULTS: The overall response rate was 20% (95% confidence interval, 14% to 28%). All responding patients were resistant to or had failed paclitaxel, and all had received an anthracycline. Three complete responses were seen, with complete response durations of 106, 109, and 194+ days. Median duration of response was 8.1 months, median survival time was 12.8 months, and the median time to disease progression was 93 days. The most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Diarrhea (14%) and hand-foot syndrome (10%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity in more than 10% of patients.

CONCLUSION: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home.
Phase II Trial of Gemcitabine in Refractory Germ Cell Tumors
Authors: Einhorn Lawrence H. , Stender Michael J. , Williams Stephen D.
Published: February 2017

PURPOSE: This phase II study was designed to determine the toxicity and activity of single-agent gemcitabine in heavily pretreated patients with germ cell tumors.

PATIENTS AND METHODS: From March 1996 through November 1997, 21 patients were enrolled onto a phase II study of gemcitabine 1,200 mg/m2, given on days 1, 8, and 15 every 4 weeks. One patient was unassessable because he never received any gemcitabine. Thirteen of 20 patients had received three prior regimens, and 13 patients were platinum refractory (progression during or within 4 weeks of platinum treatment). There were five extragonadal cases and two patients with late relapse (relapse beyond 2 years).

RESULTS: Gemcitabine was well tolerated. Only one patient had grade 3 or 4 nonhematologic toxicity (grade 3 nausea). Six of 20 patients had grade 3 leukopenia. There were no episodes of granulocytopenic fever, and no patient required platelet transfusion. Three (15%) of 20 patients achieved an objective response, including one complete remission. Three additional patients had a minor radiographic or serologic response.

CONCLUSION: Gemcitabine had definite activity in this heavily pretreated germ cell tumor patient population.
Autotransplants for Hodgkin's Disease in Patients Never Achieving Remission: A Report From the Autologous Blood and Marrow Transplant Registry
Authors: Lazarus By Hillard M. , Rowlings Philip A. , Zhang Mei-Jie , Vose Julie M. , Armitage James O. , Bierman Philip J. , Gajewski James L. , Gale Robert Peter , Keating Arm , Klein John P. , Miller Carole B. , Phillips Gordon L. , Reece Donna E. , Sobocinski Kathleen A. , van Besien Koen , Horowitz Mary M.
Published: February 2017

PURPOSE: Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (ie, those with primary induction failure) have a poor prognosis. Some subjects who receive high-dose therapy with autologous hematopoietic progenitor-cell infusion experience prolonged progression-free survival.

PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 122 Hodgkin's disease patients who failed to achieve complete remission after one or more conventional therapy regimens and subsequently received an autotransplant between 1989 and 1995 were reviewed.

RESULTS: Median age was 27 years (range, 7 to 57 years). Median time from diagnosis to transplantation was 14 months (range, 5 to 38 months). Most patients received high-dose chemotherapy without radiation for pretransplantation conditioning (n = 107). The regimen most frequently used was cyclophosphamide, carmustine, and etoposide (n = 47). Fifteen patients received total-body irradiation (n = 15). The graft consisted ofbone marrow (n = 86), blood stem cells (n = 25), or both (n = 11). The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Sixty patients (50%) were considered to have achieved complete remission after autotransplantation; 37 of these had negative imaging studies, whereas scan abnormalities of unknown significance persisted in 23 patients. Twenty-seven patients (22%) had no response or progressive disease after transplantation. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, “B” symptoms at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome.

CONCLUSION: Autotransplants should be considered for patients with Hodgkin's disease who do not achieve complete remission with conventional therapy.
Secondary Leukemia or Myelodysplastic Syndrome After Treatment With Epipodophyllotoxins
Authors: Smith Malcolm A. , Rubinstein Lawrence , Anderson James R. , Arthur Diane , Catalano Paul J. , Freidlin Boris , Heyn Ruth , Khayat Anita , Krailo Mark , Land Vita J. , Miser James , Shuster Jonathan , Vena Don
Published: February 2017

PURPOSE: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment.

METHODS: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (< 1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (≥ 3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group.

RESULTS: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively.

CONCLUSION: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.
Role of Transforming Growth Factor-β1 in Invasion and Metastasis in Gastric Carcinoma
Authors: Maehara Yoshihiko , Kakeji Yoshihiro , Kabashima Akira , Emi Yasunori , Watanabe Akihiro , Akazawa Kohei , Baba Hideo , Kohnoe Shunji , Sugimachi Keizo
Published: February 2017

PURPOSE: Transforming growth factor-beta1 (TGF-β1) is a major modulator of cellular proliferation and extracellular matrix formation. We determined the role of TGF-β1 in invasion and metastasis in gastric cancer.

MATERIALS AND METHODS: We detected TGF-β1 expression in primary and lymph node metastatic lesions of gastric cancer, using an antibody and in situ hybridization. The plasma TGF-β1 levels in the peripheral vein and in the tumor drainage vein were assayed.

RESULTS: In the cytoplasm of cancer cells, TGF-β1 was immunostained in 35.9% (78 of 217) of primary gastric carcinomas, and this expression was confirmed by in situ hybridization. Of 59 gastric carcinomas with a TGF-β1–negative primary tumor, metastatic lymph nodes were positive for TGF-β1 staining in 32 cases (54.2%). Positive staining of TGF-β1 in gastric cancer tissues was closely related to serosal invasion, infiltrative growth, and lymph node metastasis. Multivariate analysis showed that the expression of TGF-β1 was an independent risk factor for serosal invasion and infiltrative growth of the tumor. The plasma level of TGF-β1 did not differ between TGF-β1–negative and –positive groups. There were also no differences in plasma TGF-β1 levels among each tumor stage, between the peripheral and the tumor drainage veins, and between preoperative and postoperative testings.

CONCLUSION: Transforming growth factor-β1 is closely related to the invasion and metastasis of gastric cancer, and production of TGF-β1 in the tumor does not contribute to the total amount of TGF-β1 in the blood circulation. We interpret our observations to mean that in a tumor microenvironment, TGF-β1 alters the biologic behavior of the tumor.
Topotecan Versus Cyclophosphamide, Doxorubicin, and Vincristine for the Treatment of Recurrent Small-Cell Lung Cancer
Authors: von Pawel Joachim , Schiller Joan H. , Shepherd Frances A. , Fields Scott Z. , Kleisbauer J.P. , Chrysson Nick G. , Stewart David J. , Clark Peter I. , Palmer Martin C. , Depierre Alain , Carmichael James , Krebs Jacqueline B. , Ross Graham , Lane Stephen R. , Gralla Richard
Published: February 2017

PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy.

PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review.

RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P ≤ .043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P < .001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P < .001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens.

CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.
Natural History of Stage IV Epithelial Ovarian Cancer
Authors: Bonnefoi H. , A'Hern R. P. , Fisher C. , Macfarlane V. , Barton D. , Blake P. , Shepherd J. H. , Gore M. E.
Published: February 2017

PURPOSE: In this report we present the natural history, prognostic factors, and therapeutic implications of stage IV epithelial ovarian cancer (EOC).

PATIENTS AND METHODS: We reviewed 192 patients with stage IV EOC as defined in 1985 by the International Federation of Gynecology and Obstetrics.

RESULTS: The site of stage IV–defining disease was cytologically positive pleural effusion in 63 patients, liver in 50 patients, lymph nodes in 26 patients, lung in six patients, other sites in 15 patients, and disease at multiple stage IV–defining metastatic sites in 32 patients. Surgery was performed before chemotherapy in 169 patients; 25 patients (14.8%) were left with only microscopic residual disease or less than 2 cm of macroscopic residual disease. The overall response rate to chemotherapy was 56%; the complete response rate was 18%. The median progression-free survival was 7.1 months, and the median overall survival was 13.4 months. The median overall survival of patients with positive pleural effusions only was 13.4 months as compared with 10.5 months for patients with visceral disease only, but this difference was not statistically significant. The 5-year survival rate was 7.6%, with only six patients surviving more than 5 years. Univariate and multivariate analysis showed that two parameters were associated with a shorter survival time: visceral involvement (lung or liver) and diagnosis before 1984.

CONCLUSION: Patients with stage IV EOC initially respond to chemotherapy as often as those with less advanced disease, but the long-term prognosis is very poor. The size of residual disease is not a prognostic factor in this group of patients, and, therefore, the role of debulking surgery in these patients needs to be reconsidered.
Clinical Presentation, Course, and Prognostic Factors in Lymphocyte-Predominant Hodgkin's Disease and Lymphocyte-Rich Classical Hodgkin's Disease: Report From the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease
Authors: Diehl Volker , Sextro Michael , Franklin Jeremy , Hansmann Martin-Leo , Harris Nancy , Jaffe Elaine , Poppema Sibr , Harris Martin , Franssila Kaarle , van Krieken Jan , Marafioti Theresa , Anagnostopoulos Ioannis , Stein Harald
Published: February 2017

PURPOSE: Recent studies have suggested that lymphocyte-predominant Hodgkin's disease (LPHD) is both clinically and pathologically distinct from other forms of Hodgkin's disease, including classical Hodgkin's disease (CHD). However, large-scale clinical studies were lacking. This multicenter, retrospective study investigated the clinical characteristics and course of LPHD patients and lymphocyte-rich classical Hodgkin's disease (LRCHD) patients classified according to morphologic and immunophenotypic criteria.

MATERIALS AND METHODS: Clinical data and biopsy material of all available cases initially submitted as LPHD were collected from 17 European and American centers, stained, and reclassified by expert pathologists.

RESULTS: The 426 assessable cases were reclassified as LPHD (51%), LRCHD (27%), CHD (5%), non–Hodgkin's lymphoma (3%), and reactive lesion (3%); 11% of cases were not assessable. Patients with LPHD and LRCHD were predominantly male, with early-stage disease and few risk factors. Patients with LRCHD were significantly older. Survival and failure-free survival rates with adequate therapy were similar for patients with LPHD and LRCHD, and were stage-dependent and not significantly better than stage-comparable results for CHD (German trial data). Twenty-seven percent of relapsing LPHD patients had multiple relapses, which is significantly more than the 5% of relapsing LRCHD patients who had multiple relapses. Lymphocyte-predominant Hodgkin's disease patients had significantly superior survival after relapse compared with LRCHD or CHD patients; however, this was partly due to the younger average age of LPHD patients.

CONCLUSION: The two subgroups of LPHD and LRCHD bore a close clinical resemblance that was distinct from CHD; the course was similar to that of comparable nodular sclerosis and mixed cellularity patients. Thorough staging is necessary to detect advanced disease in LPHD and LRCHD patients. The question of how to treat such patients, either by reducing treatment intensity or following a “watch and wait” approach, remains unanswered.
Primary Mediastinal Large B-Cell Lymphoma: A Clinicopathologic Study of 43 Patients From the Nebraska Lymphoma Study Group
Authors: Abou-Elella Ashraf A. , Weisenburger Dennis D. , Vose Julie M. , Kollath Jeffrey P. , Lynch James C. , Bast Martin A. , Bierman Philip J. , Greiner Timothy C. , Chan Wing C. , Armitage James O.
Published: February 2017

PURPOSE: To investigate whether primary mediastinal large B-cell lymphoma (PMLBL) is a distinct clinicopathologic entity with a more aggressive course than other diffuse large B-cell lymphomas (DLBL).

MATERIALS AND METHODS: All patients with CD20-positive DLBL who presented with a mediastinal mass measuring at least 5.0 cm and were treated with curative intent were identified. A control group of 352 patients with nonmediastinal DLBL was selected for comparison.

RESULTS: The 43 patients with PMLBL had a male to female ratio of 20:23 and a median age of 42 years. Stage I/II disease was present in 58% of the patients, with only 9% having bone marrow involvement. A complete remission was achieved in 63% of the patients, and the 5-year overall and failure-free survivals were 46% and 38%, respectively. Among the clinical variables, an elevated serum lactate dehydrogenase level, a low performance score, more than one extranodal site, and an intermediate or high International Prognostic Index score were predictive of poor survival. When compared with the DLBL group, a younger median age was the only clinical feature that was significantly different in the PMLBL group.

CONCLUSION: The clinical features of PMLBL do not appear to be significantly different from those of nonmediastinal DLBL. Although the younger age of onset, slight female predominance, mediastinal location, and size of the mass may justify the recognition of PMLBL as a clinical syndrome, additional evidence is needed to define it as a distinct disease entity.
Phase I-II Study of Gemcitabine and Carboplatin in Stage IIIB-IV Non–Small-Cell Lung Cancer
Authors: Iaffaioli Rosario Vincenzo , Tortoriello Anna , Facchini Gaetano , Caponigro Francesco , Gentile Maria , Marzano Nicola , Gravina Adriano , Dimitri Paolo , Costagliola Giuseppina , Ferraro Alessandro , Ferrante Giovanni , De Marino Valeria , Illiano Alfonso
Published: February 2017

PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non–small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non–small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study.

PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non–small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m2, subsequently escalated by 100 mg/m2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity.

RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m2. Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m2 plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months).

CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.