bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Topotecan as Single-Agent Second-Line Chemotherapy in Patients With Advanced Ovarian Cancer
Authors: Clarke-Pearson D. L. , Van Le L. , Iveson T. , Whitney C. W. , Hanjani P. , Kristensen G. , Malfetano J. H. , Beckman R. A. , Ross G. A. , Lane S. R. , DeWitte Mark H. , Fields S. Z.
Published: February 2017

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen.

PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age ≥ 18 years, performance status ≤ 2, and life expectancy ≥ 12 weeks.

RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting.

CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.
Solid Cancers After Bone Marrow Transplantation
Authors: Bhatia Smita , Louie Andrew D. , Bhatia Ravi , O’Donnell Margaret R. , Fung Henry , Kashyap Ashwin , Krishnan Amrita , Molina Arturo , Nademanee Auayporn , Niland Joyce C. , Parker Pablo A. , Snyder David S. , Spielberger Ricardo , Stein Anthony , Forman Stephen J.
Published: February 2017

PURPOSE: To evaluate the incidence and associated risk factors of solid cancers after bone marrow transplantation (BMT).

PATIENTS AND METHODS: We analyzed 2,129 patients who had undergone BMT for hematologic malignancies at the City of Hope National Medical Center between 1976 and 1998. A retrospective cohort and nested case-control study design were used to evaluate the role of pretransplantation therapeutic exposures and transplant conditioning regimens.

RESULTS: Twenty-nine patients developed solid cancers after BMT, which represents a two-fold increase in risk compared with a comparable normal population. The estimated cumulative probability (± SE) for development of a solid cancer was 6.1% ± 1.6% at 10 years. The risk was significantly elevated for liver cancer (standardized incidence ratio [SIR], 27.7; 95% confidence interval [CI], 1.9 to 57.3), cancer of the oral cavity (SIR, 17.4; 95% CI, 6.3 to 34.1), and cervical cancer (SIR, 13.3; 95% CI, 3.5 to 29.6). Each of the two patients with liver cancer had a history of chronic hepatitis C infection. All six patients with squamous cell carcinoma of the skin had chronic graft-versus-host disease. The risk was significantly higher for survivors who were younger than 34 years of age at time of BMT (SIR, 5.3; 95% CI, 2.7 to 8.6). Cancers of the thyroid gland, liver, and oral cavity occurred primarily among patients who received total-body irradiation.

CONCLUSION: The risk of radiation-associated solid tumor development after BMT is likely to increase with longer follow-up. This underscores the importance of close monitoring of patients who undergo BMT.
Phase I Trial of Concurrent Tirapazamine, Cisplatin, and Radiotherapy in Patients With Advanced Head and Neck Cancer
Authors: Rischin Danny , Peters Lester , Hicks Rodney , Hughes Peter , Fisher Richard , Hart Rosetta , Sexton Maree , D’Costa Ieta , von Roemeling Reinhard
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose of tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck.

PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy.

RESULTS: We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 tirapazamine doses were omitted. This resulted in less neutropenia and only one dose-limiting toxicity (DLT) (febrile neutropenia), and eight out of 10 patients completed treatment without any dose omissions. In these 10 patients, the acute radiation toxicities were not obviously enhanced compared with chemoradiotherapy regimens using concurrent platinum and fluorouracil. 18F misonidazole scans detected hypoxia in 14 of 15 patients at baseline, with only one patient having detectable hypoxia at the end of treatment. With a median follow-up of 2.7 years, the 3-year failure-free survival rate was 69% (SE, 12%), the 3-year local progression-free rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%).

CONCLUSION: DLT was due unexpectedly to febrile neutropenia, which could be overcome by omitting tirapazamine in weeks 5 and 6. The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers. It warrants further investigation.
Can We Predict Radiation-Induced Changes in Pulmonary Function Based on the Sum of Predicted Regional Dysfunction?
Authors: Fan Ming , Marks Lawrence B. , Hollis Donna , Bentel Gunilla G. , Anscher Mitchell S. , Sibley Gregory , Coleman R. Edward , Jaszczak Ronald J. , Munley Michael T.
Published: February 2017

PURPOSE: To determine whether changes in whole-lung pulmonary function test (PFT) values are related to the sum of predicted radiation therapy (RT)-induced changes in regional lung perfusion.

PATIENTS AND METHODS: Between 1991 and 1998, 96 patients (61% with lung cancer) who were receiving incidental partial lung irradiation were studied prospectively. The patients were assessed with pre- and post-RT PFTs (forced expiratory volume in one second [FEV1] and diffusion capacity for carbon monoxide [DLCO]) for at least a 6-month follow-up period, and patients were excluded if it was determined that intrathoracic recurrence had an impact on lung function. The maximal declines in PFT values were noted. A dose-response model based on RT-induced reduction in regional perfusion (function) was used to predict regional dysfunction. The predicted decline in pulmonary function was calculated as the weighted sum of the predicted regional injuries:

equation [Formula: see text]

where Vd is the volume of lung irradiated to dose d, and Rd is the reduction in regional perfusion anticipated at dose d.

RESULTS: The relationship between the predicted and measured reduction in PFT values was significant for uncorrected DLCO (P = .005) and borderline significant for DLCO (P = .06) and FEV1 (P = .08). However, the correlation coefficients were small (range, .18 to .30). In patients with lung cancer, the correlation coefficients improved as the number of follow-up evaluations increased (range, .43 to .60), especially when patients with hypoperfusion in the lung adjacent to a central mediastinal/hilar thoracic mass were excluded (range, .59 to .91).

CONCLUSION: The sum of predicted RT-induced changes in regional perfusion is related to RT-induced changes in pulmonary function. In many patients, however, the percentage of variation explained is small, which renders accurate predictions difficult.
Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’Adulto
Authors: Specchia Giorgina , Lo Coco Francesco , Vignetti Marco , Avvisati Giuseppe , Fazi Paola , Albano Francesco , Di Raimondo Francesco , Martino Bruno , Ferrara Felicetto , Selleri Carmine , Liso Vincenzo , Mandelli Franco
Published: February 2017

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy.

PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA).

RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse.

CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.
Pilot Study of Low-Dose Interleukin-11 in Patients With Bone Marrow Failure
Authors: Kurzrock Razelle , Cortes Jorge , Thomas Deborah A. , Jeha Sima , Pilat Susan , Talpaz Moshe
Published: February 2017

PURPOSE: Interleukin-11 (IL-11) is a thrombopoietic cytokine that attenuates postchemotherapy thrombocytopenia at doses of 50 μg/kg/d subcutaneously. Very little is known about the activity of IL-11 in patients with bone marrow failure states.

PATIENTS AND METHODS: Our preliminary experience with IL-11 at doses of 50 μg/kg/d suggested that patients with bone marrow failure developed significant peripheral and pulmonary edema after the prolonged dosing necessary for treating these conditions. We, therefore, initiated a study of low-dose IL-11 (starting dose, 10 μg/kg/d).

RESULTS: Sixteen patients were assessable for response. Six patients had diploid cytogenetics; the others had a variety of chromosomal abnormalities. Six (38%) of 16 patients showed a platelet response to IL-11, and two had a multilineage response (to IL-11 alone, n = 1; to IL-11 plus G-CSF and erythropoietin, n = 1). The median increase in peak platelet counts was 95 × 109/L above baseline in the responders (range, increase of 55 × 109/L to 130 × 109/L above baseline). Responders included five of 11 patients with myelodysplasia and one of four patients with aplastic anemia. Response durations were 12, 13, 14+, 25, 30, and 30+ weeks. Side effects of IL-11 were mild (peripheral edema, n = 7; conjunctival injection, n = 7; myalgia, n = 1; all grade 1). Seven patients had no side effects.

CONCLUSION: Our pilot study suggests that administration of low-dose IL-11 (10 μg/kg/d) can raise platelet counts without significant toxicity in selected thrombocytopenic patients with bone marrow failure.
Second Cancers Occurring in Patients With Early Stage Non–Small-Cell Lung Cancer Treated With Chest Radiation Therapy Alone
Authors: Jeremic Branislav , Shibamoto Yuta , Acimovic Ljubisa , Nikolic Nebojsa , Dagovic Aleksandar , Aleksandrovic Jasna , Radosavljevic-Asic Gordana
Published: February 2017

PURPOSE: To investigate the incidence of second cancers occurring in patients with early stage (I/II) non–small-cell lung cancer (NSCLC) treated with radiation therapy (RT) alone.

PATIENTS AND METHODS: Seventy-eight patients had been treated with conventionally fractionated (CF) RT (1982 to 1987), and 116 patients had been treated with hyperfractionated (Hfx) RT (1988 to 1993). Tumor doses were 60 Gy for CF and 69.6 Gy (1.2 Gy bid) for Hfx.

RESULTS: A total of 26 patients developed second cancers. The cumulative incidence of second cancer was 21.8% (SE, 4.7%) at 5 years and 34.8% (SE, 6.7%) at 10 years. For second lung cancers, it was 6.0% (SE, 2.8%) at 5 years and 14.2% (SE, 5.2%) at 10 years, and for second nonlung cancers, it was 16.3% (SE, 4.2%) at 5 years and 22.2% (SE, 5.7%) at 10 years. The rate of developing second cancer per patient per year was 4.3% (95% confidence intervals [CI], 2.7% to 5.9%), with the rates being 1.4% (CI, 0.5% to 2.3%) for the second lung cancers and 2.8% (CI, 1.5% to 4.1%) for second nonlung cancers. The rate of developing second cancers during the first and second 5-year period after RT (0 to 5 and 5 to 10 years) was 4.3% (CI, 2.4% to 6.2%) and 4.2% (CI, 0.6% to 7.8%), respectively, for all cancers. These rates were 1.0% (CI, 0.1% to 1.9%) and 2.2% (CI, 0% to 4.6%), respectively, for second lung cancers, and 3.2% (CI, 1.6% to 4.8%) and 1.5% (CI, 0% to 3.6%), respectively, for second nonlung cancers.

CONCLUSION: Long-term survivors after RT alone for early stage NSCLC carry the same risk of developing second cancer, either lung or nonlung, as their counterparts treated surgically when the results of this study are compared with those of the published literature.
Phase I Trial of Multiple Cycles of High-Dose Carboplatin, Paclitaxel, and Topotecan With Peripheral-Blood Stem-Cell Support as Front-Line Therapy
Authors: Schilder Russell J. , Gallo James M. , Millenson Michael M. , Bookman Michael A. , Weiner Louis M. , Rogatko André , Rogers Barbara , Padavic-Shallers Kristin , Boente Matthew , Rosenblum Norman , Adams Andrea L. , Ciccotto Suzanne , Ozols Robert F.
Published: February 2017

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

PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m2), and topotecan (10-15 mg/m2), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days.

RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m2 when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m2. The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded.

CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m2, and topotecan 10 mg/m2. Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.
Dose-Intensive Epirubicin-Based Chemotherapy Is Superior to an Intensive Intravenous Cyclophosphamide, Methotrexate, and Fluorouracil Regimen in Metastatic Breast Cancer: A Randomized Multinational Study
Authors: Ackland Stephen P. , Anton Antonio , Breitbach George Peter , Colajori Elena , Tursi Jennifer M. , Delfino Carlos , Efremidis Anna , Ezzat Adnan , Fittipaldo Alberto , Kolaric Kristo , Lopez Massimo , Viaro Donatella ,   the HEPI 013 Study Group
Published: February 2017

PURPOSE: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer.

PATIENTS AND METHODS: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m2 IV, epirubicin 50 mg/m2 IV, and fluorouracil 500 mg/m2 IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m2 IV, methotrexate 40 mg/m2 IV, and fluorouracil 600 mg/m2 IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles.

RESULTS: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P = .01) and in the assessable subset (66% v 52%, respectively; P = .005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P = .0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P = .01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P = .23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF.

CONCLUSION: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.
Serum Prostate-Specific Antigen Decline as a Marker of Clinical Outcome in Hormone-Refractory Prostate Cancer Patients: Association With Progression-Free Survival, Pain End Points, and Survival
Authors: Small Eric J. , McMillan Alex , Meyer Mark , Chen Liang , Slichenmyer William J. , Lenehan Peter F. , Eisenberger Mario
Published: February 2017

PURPOSE: Validated end points are lacking for clinical trials in hormone-refractory prostate cancer (HRPC). Controversy remains regarding the utility of a posttreatment decline of prostate-specific antigen (PSA). The purpose of this study was to determine whether posttreatment declines in PSA were associated with clinical measures of improvement in a randomized phase III trial of suramin plus hydrocortisone versus placebo plus hydrocortisone.

PATIENTS AND METHODS: A total of 460 HRPC patients were randomized to receive suramin plus hydrocortisone (n = 229) or placebo plus hydrocortisone (n = 231). All patients had symptomatic, metastatic HRPC requiring opioid analgesics. Clinical end points evaluated included overall survival, objective progression-free survival (OPFS), and time to pain progression (TTPP). An evaluation of overall survival, OPFS, and TTPP as a function of a PSA decline of ≥ 50%, lasting at least 28 days, was undertaken by using a landmark analysis at 6, 9, and 12 weeks. A multivariate analysis of the impact of PSA decline was performed on these clinical end points.

RESULTS: A decline in PSA of ≥ 50% lasting ≥ 28 days was significantly associated with a prolonged median overall survival, OPFS, and TTPP, both in the entire group and the suramin plus hydrocortisone group at all three landmarks in both univariate and multivariate analysis.

CONCLUSION: In this prospective, randomized trial of suramin plus hydrocortisone versus placebo plus hydrocortisone, a posttherapy decline in PSA of ≥ 50%, lasting 28 days, was associated with prolonged median overall survival, improved median progression-free survival, and median TTPP. This analysis suggests that a posttreatment decline in PSA may be a reasonable intermediate end point in HRPC trials and calls into question the clinical utility of preclinical assays evaluating the in vitro effect of given agents on PSA secretion.
Factors Affecting the Risk of Brain Metastases After Definitive Chemoradiation for Locally Advanced Non–Small-Cell Lung Carcinoma
Authors: Robnett Theodore J. , Machtay Mitchell , Stevenson James P. , Algazy Kenneth M. , Hahn Stephen M.
Published: February 2017

PURPOSE: As therapy for locally advanced non–small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site.

METHODS: Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing.

RESULTS: Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P < .04) versus stage II/IIIA. Histology alone was not significant (P < .12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P < .01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P < .05). On multivariate analysis, timing of chemotherapy (P < .01) and stage IIIA versus IIIB (P < .01) remained significant.

CONCLUSION: Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.
Safety of the Synthetic Retinoid Fenretinide: Long-Term Results From a Controlled Clinical Trial for the Prevention of Contralateral Breast Cancer
Authors: Camerini Tiziana , Mariani Luigi , De Palo Giuseppe , Marubini Ettore , Di Mauro Maria Gaetana , Decensi Andrea , Costa Alberto , Veronesi Umberto
Published: February 2017

PURPOSE: To describe the pattern of occurrence of adverse events commonly arising during treatment with fenretinide, a synthetic retinoid under investigation for cancer prevention.

PATIENTS AND METHODS: The series includes 2,867 women accrued in a trial aimed at assessing the effect of fenretinide on the prevention of second breast malignancy. Women were randomly assigned to receive no treatment (1,435 patients) or 5-year fenretinide treatment (1,432 patients). In terms of disease recurrence in the breast, the trial showed a possible beneficial effect of the compound in premenopausal women, and an opposite trend in postmenopausal women. End points considered for safety assessment were the occurrence of diminished dark adaptation, dermatologic disorders, gastrointestinal symptoms, disorders of the ocular surface, and abnormal laboratory values.

RESULTS: The most common adverse events were diminished dark adaptation (cumulative incidence, 19.0%) and dermatologic disorders (18.6%). Less common events were gastrointestinal symptoms (13.0%) and disorders of the ocular surface (10.9%). In comparison, incidence figures in the control arm were 2.9% for diminished dark adaptation, 2.9% for dermatologic disorders, 5.4% for gastrointestinal symptoms, and 3.2% for disorders of the ocular surface. Symptoms occurring during fenretinide treatment tended to recover with time. No between-group difference was observed for the occurrence of laboratory data abnormalities. Overall, 63 (4.4%) treatment discontinuations were caused by adverse events.

CONCLUSION: Given the number of patients involved in the study and the prolonged intake of the drug, the experience on fenretinide tolerability can be considered sufficiently reassuring to justify further testing of the retinoid.
Reliability and Validity of the Functional Assessment of Cancer Therapy–Ovarian
Authors: Basen-Engquist Karen , Bodurka-Bevers Diane , Fitzgerald Mary A. , Webster Kimberly , Cella David , Hu Shaohua , Gershenson David M.
Published: February 2017

PURPOSE: To report the reliability and validity of the Functional Assessment of Cancer Therapy–Ovarian (FACT-O) in a consecutive series of outpatients with epithelial ovarian cancer.

PATIENTS AND METHODS: Two hundred thirty-two ovarian cancer patients attending an outpatient gynecologic oncology clinic completed questionnaires at baseline. The patients’ FACT-O scores were compared with their performance status, disease stage, treatment status, and other factors hypothesized to be related to quality of life. Patients received a second questionnaire either one week after baseline to assess the instrument’s test-retest reliability and/or two months after baseline to evaluate its sensitivity to change in performance status.

RESULTS: Internal consistency and test-retest reliability of the FACT-O were adequate. Overall, the scales correlated with other measures as expected; all correlations were in the hypothesized direction. Patients with advanced disease, poor performance status, and who were receiving active treatment had lower scores on physical, functional, and ovarian cancer-specific scales. The total FACT-O and emotional well-being scores were lower for patients with poor performance status and patients in active treatment. The FACT-O total and all subscale scores except emotional well-being were sensitive to decreases in performance status.

CONCLUSION: Overall, the FACT-O provides a reliable and valid assessment of the quality of life of women with ovarian cancer, and is appropriate as a brief quality of life assessment in clinical trials and descriptive studies.
Tamoxifen for the Prevention of Breast Cancer: Psychosocial Impact on Women Participating in Two Randomized Controlled Trials
Authors: Fallowfield Lesley , Fleissig Anne , Edwards Rob , West Andrea , Powles Trevor J. , Howell Anthony , Cuzick Jack
Published: February 2017

PURPOSE: The purpose of this study was to evaluate the psychosocial implications of tamoxifen versus placebo in women who are at increased risk of breast cancer.

PATIENTS AND METHODS: The 488 women in the psychosocial study were recruited from participants in two placebo-controlled, double-blind, randomized, controlled trials that investigated the efficacy of tamoxifen in the prevention of breast cancer in women who are at high familial risk. During a 5-year period, repeated assessments were made of anxiety, psychological distress, and sexual functioning using standardized questionnaires before treatment at baseline and at 6-month intervals during the trial.

RESULTS: Questionnaire completion over 5 years was good, with 71.1% of women returning at least 8 of 10 follow-up assessments. Although scores from individuals showed considerable fluctuation and variation over time, changes in anxiety, mood, and sexual functioning were not associated with treatment group. The number of symptoms reported at 48 months via a self-report cheklist were not associated with treatment group, but vasomotor symptoms were more frequent among tamoxifen-treated women. Symptoms of low energy, breast sensitivity, and visual blurring were reported most frequently in the placebo group.

CONCLUSION: In general, these results are comparable to those from the National Surgical Adjuvant Breast and Bowel Project psychosocial study despite differences in study populations, methodology, and instruments. The long-term use of tamoxifen and other selective estrogen response modulators as preventive agents in high-risk groups has been questioned, but we found no evidence of treatment-related side effects that affect women’s psychosocial and sexual functioning.
Clinical Evidence for Topotecan-Paclitaxel Non–Cross-Resistance in Ovarian Cancer
Authors: Gore Martin , ten Bokkel Huinink Wim , Carmichael James , Gordon Alan , Davidson Neville , Coleman Robert , Spaczynski Marek , Héron Jean-François , Bolis Giorgio , Malmström Henric , Malfetano John , Scarabelli Claudio , Vennin Phillipe , Ross Graham , Fields Scott Z.
Published: February 2017

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non–cross-resistance between these two compounds.

PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m2/d) × 5 every 21 days (n = 112) or paclitaxel (175 mg/m2 over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy.

RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P = .638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients).

CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non–cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.
Accelerated Treatment of Breast Cancer
Authors: Vicini Frank A. , Baglan Kathy L. , Kestin Larry L. , Mitchell Chris , Chen Peter Y. , Frazier Robert C. , Edmundson Greg , Goldstein Neal S. , Benitez Pamela , Huang Raywin R. , Martinez Alvaro
Published: February 2017

PURPOSE: Radiation therapy (RT) restricted to the tumor bed, by means of an interstitial implant, and lasting 4 to 5 days after lumpectomy was prospectively evaluated in early-stage breast cancer patients treated with breast-conserving therapy (BCT). The goals of the study were to determine whether treatment time can be reduced and whether elective treatment of the entire breast is necessary.

MATERIALS AND METHODS: Between January 1993 and January 2000, 174 cases of early-stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant. Each brachytherapy patient was matched with one external-beam RT (ERT) patient derived from a reference group of 1,388 patients treated with standard BCT. Patients were matched for age, tumor size, histology, margins of excision, absence of an extensive intraductal component, nodal status, estrogen receptor status, and tamoxifen use. Median follow-up for both the ERT and brachytherapy groups was 36 months.

RESULTS: No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT and brachytherapy patients (1% v 0%, P = .31 and 2% v 1%, P = .63, respectively). In addition, there were no statistically significant differences noted in rates of distant metastasis (6% v 3%, P = .24), disease-free survival (87% v 91%, P = .55), overall survival (90% v 93%, P = .66), or cause-specific survival (97% v 99%, P = .28).

CONCLUSION: Accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach.
Non-Hodgkin’s Lymphoma After Primary Hodgkin’s Disease in the German Hodgkin’s Lymphoma Study Group: Incidence, Treatment, and Prognosis
Authors: Rueffer Ulrich , Josting Andreas , Franklin Jeremy , May Michael , Sieber Markus , Breuer Kai , Engert Andreas , Diehl for the German Hodgkin’s Lymphoma Study Group Volker
Published: February 2017

PURPOSE: The cumulative incidence for non-Hodgkin lymphoma’s (NHL) after primary Hodgkin’s disease (HD) ranges between 1% and 6%. To investigate the course of disease for secondary NHL, we retrospectively analyzed patients treated within clinical trials of the German Hodgkin’s Lymphoma Study Group (GHSG) since 1981.

PATIENTS AND METHODS: From 1981 to 1998, the GHSG conducted three generations of clinical trials for the treatment of primary HD involving a total of 5,406 patients. Reference histology by an expert panel was obtained for 4,104 of the patients. Data on incidence, treatment, and outcome of secondary NHL were updated in March 1999.

RESULTS: At first diagnosis of HD, the pathologists rejected 114 (2.1%) of 5,520 cases initially diagnosed as HD and rediagnosed them as primary NHL. Fifty-two (0.9%) of the remaining 5,406 patients developed a secondary NHL. One patient was excluded from further analyses because of insufficient documentation. Six patients had no further therapy because of patient refusal (n = 1) or rapidly progressive disease (n = 5). For the remaining 45 patients, overall response rate was 43% (36% complete response and 7% partial response). The actuarial 2-year freedom from treatment failure (FFTF) and overall survival (OS) for all patients was 24% and 30%, respectively, and for patients with diffuse large-cell lymphoma, it was 28% and 35%, respectively. Time of occurrence of secondary NHL after first diagnosis of HD and variables employed in the age-adjusted International Prognostic Factor Index (IPFI) significantly influenced treatment outcome.

CONCLUSION: In the GHSG, the incidence of secondary NHL with 0.9% is relatively low compared with previously reported series. The prognosis of secondary NHL seems dismal and is significantly influenced by time of occurrence and the age-adjusted IPFI. In a subset of patients with secondary NHL, long-term disease-free survival could be achieved.
Multicenter Phase Ib/II Trial of the Radiation Enhancer Motexafin Gadolinium in Patients With Brain Metastases
Authors: Carde Patrice , Timmerman Robert , Mehta Minesh P. , Koprowski Christopher D. , Ford Judith , Tishler Roy B. , Miles Dale , Miller Richard A. , Renschler Markus F.
Published: February 2017

PURPOSE: Motexafin gadolinium is a magnetic resonance imaging (MRI)–detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival.

PATIENTS AND METHODS: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range.

RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium’s tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%.

CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.
Phase I Clinical and Pharmacogenetic Study of Weekly TAS-103 in Patients With Advanced Cancer
Authors: Ewesuedo Reginald B. , Iyer Lalitha , Das Soma , Koenig Annette , Mani Sridhar , Vogelzang Nicholas J. , Schilsky Richard L. , Brenckman Wayne , Ratain Mark J.
Published: February 2017

PURPOSE: TAS-103 is an inhibitor of both topoiso-merase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103.

PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m2) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m2 dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques.

RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m2 and in 3 of 6 patients at 200 mg/m2. At 160 mg/m2, there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P < .05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = −0.63, P < .05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103.

CONCLUSION: We recommend a dose of 130 to 160 mg/m2, or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.
Individualized Patient Education and Coaching to Improve Pain Control Among Cancer Outpatients
Authors: Oliver Jennifer Wright , Kravitz Richard L. , Kaplan Sherrie H. , Meyers Frederick J.
Published: February 2017

PURPOSE: An estimated 42% of cancer patients suffer from poorly controlled pain, in part because of patient-related barriers to pain control. The objective of this study was to evaluate the effect of an individualized education and coaching intervention on pain outcomes and pain-related knowledge among outpatients with cancer-related pain.

PATIENTS AND METHODS: English-speaking cancer patients (18 to 75 years old) with moderate pain over the past 2 weeks were randomly assigned to the experimental (n = 34) or control group (n = 33). Experimental patients received a 20-minute individualized education and coaching session to increase knowledge of pain self-management, to redress personal misconceptions about pain treatment, and to rehearse an individually scripted patient-physician dialog about pain control. The control group received standardized instruction on controlling pain. Data on average pain, functional impairment as a result of pain, pain frequency, and pain-related knowledge were collected at enrollment and 2-week follow-up.

RESULTS: At baseline, there were no significant differences between experimental and control groups in terms of average pain, functional impairment as a result of pain, pain frequency, or pain-related knowledge. At follow-up, average pain severity improved significantly more among experimental group patients than among control patients (P = .014). The intervention had no statistically significant impact on functional impairment as a result of pain, pain frequency, or pain-related knowledge.

CONCLUSION: Compared with provision of standard educational materials and counseling, a brief individualized education and coaching intervention for outpatients with cancer-related pain was associated with improvement in average pain levels. Larger studies are needed to validate these effects and elucidate their mechanisms.
T-Cell/Histiocyte–Rich Large B-Cell Lymphoma: A Distinct Clinicopathologic Entity
Authors: Achten R. , Verhoef G. , Vanuytsel L. , De Wolf-Peeters C.
Published: February 2017

PURPOSE: Although it has proven difficult to delineate diagnostically reproducible and clinically relevant subgroups, the heterogeneity of diffuse large B-cell lymphomas (DLBCL) is widely acknowledged. In 1992, we reported on six cases that suggested that large B-cell lymphoma rich in stromal histiocytes and T cells may be identified as a distinct clinicopathologic entity within DLBCL.

PATIENTS AND METHODS: An integrated clinicopathologic study of 40 cases of this DLBCL subtype is presented.

RESULTS: Distinguishing a DLBCL rich in histiocytes and reactive T cells, designated T-cell/histiocyte–rich large B-cell lymphoma (THR-BCL), may be justified from a clinical point of view. The disease typically affects middle-aged male patients who usually present with advanced-stage disease that is not adequately managed with current therapeutic strategies. Whereas proliferation fraction and p53 overexpression, in addition to the clinical variables incorporated in the International Prognostic Index (IPI), significantly correlate with response to treatment and survival in a univariate analysis, only the IPI score identifies relevant prognostic THR-BCL subpopulations in a multivariate model. The morphologic and immunophenotypic profile of the neoplastic B cells in THR-BCL suggests that they may originate from a germinal center ancestor.

CONCLUSION: THR-BCL constitutes a distinct clinicopathologic entity that is characterized by an aggressive behavior. Experimental therapeutic strategies may be indicated to obtain a more favorable response to treatment in this disease.
Quality-of-Life–Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data
Authors: Kilbridge Kerry L. , Cole Bernard F. , Kirkwood John M. , Haluska Frank G. , Atkins Michael A. , Ruckdeschel John C. , Sock Dana E. , Nease Robert F. , Weeks Jane C.
Published: February 2017

PURPOSE: High-dose adjuvant interferon alfa-2b (IFNα2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life–adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNα2b treatment and melanoma recurrence.

PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNα2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS.

RESULTS: Using E1684 data, IFNα2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P < .05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFNα2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFNα2b may detract from QAS.

CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFNα2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFNα2b toxicity than members of the general population and will tend to favor IFNα2b treatment as a result.
Treatment Decision Making in Early-Stage Breast Cancer: Should Surgeons Match Patients’ Desired Level of Involvement?
Authors: Keating Nancy L. , Guadagnoli Edward , Landrum Mary Beth , Borbas Catherine , Weeks Jane C.
Published: February 2017

PURPOSE: To describe desired and actual roles in treatment decision making among patients with early-stage breast cancer, identify how often patients’ actual roles matched their desired roles, and examine whether matching of actual and desired roles was associated with type of treatment received and satisfaction.

PATIENTS AND METHODS: We surveyed 1,081 women (response, 70%) diagnosed with early-stage breast cancer in Massachusetts or Minnesota about their desired and actual roles in treatment decision making with their surgeon and used logistic regression to assess whether matching of actual to desired roles was associated with type of surgery and satisfaction.

RESULTS: Most patients (64%) desired a collaborative role in decision making, but only 33% reported actually having such a collaborative role when they discussed treatments with their surgeons. Overall, 49% of women reported an actual role that matched the desired role they reported, 25% had a less active role than desired, and 26% had a more active role than desired. In adjusted analyses, patients whose reported actual role matched their desired role were no more likely than others to undergo breast-conserving surgery (P > .2), but these women were more satisfied with their treatment choice (83.5% very satisfied; reference) than those whose role was less active than desired (72.9% very satisfied; P = .02) or more active than desired (72.2% very satisfied; P = .005).

CONCLUSION: Only approximately half of patients reported an actual role in decision making that matched the desired role they reported. These patients were more satisfied with their treatment choice than other patients, suggesting that women with early-stage breast cancer may benefit from surgeons’ efforts to identify their preferences for participation in decisions and tailor the decision-making process to them.