bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential Tamoxifen and Aminoglutethimide Versus Tamoxifen Alone in the Adjuvant Treatment of Postmenopausal Breast Cancer Patients: Results of an Italian Cooperative Study
Authors: Boccardo F. , Rubagotti A. , Amoroso D. , Mesiti M. , Romeo D. , Caroti C. , Farris A. , Cruciani G. , Villa E. , Schieppati G. , Mustacchi G.
Published: February 2017

PURPOSE: To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued.

PATIENTS AND METHODS: Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years.

RESULTS: At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P = .02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P = .005) and breast cancer–specific survival (P = .06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P = .0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm.

CONCLUSION: Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.
Preoperative Chemotherapy in Primary Operable Breast Cancer: Results From the European Organization for Research and Treatment of Cancer Trial 10902
Authors: van der Hage Jos A. , van de Velde Cornelis J.H. , Julien Jean-Pierre , Tubiana-Hulin Michelle , Vandervelden Cecile , Duchateau Luc ,   Cooperating Investigators
Published: February 2017

PURPOSE: To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy.

PATIENTS AND METHODS: Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR).

RESULTS: At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P = .38), PFS (hazards ratio, 1.15; P = .27), and time to LRR (hazards ratio, 1.13; P = .61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy.

CONCLUSION: The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality.
Prospective Study of Helicobacter pylori Eradication Therapy in Stage IE High-Grade Mucosa-Associated Lymphoid Tissue Lymphoma of the Stomach
Authors: Chen Li-Tzong , Lin Jaw-Town , Shyu Rong-Yaun , Jan Chang-Ming , Chen Chi-Long , Chiang I-Ping , Liu Shiang-Ming , Su Ih-Jen , Cheng Ann-Lii
Published: February 2017

PURPOSE: High-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach are generally believed to be Helicobacter pylori–independent, autonomously growing tumors. However, anecdotal cases of regression of high-grade lymphomas after the cure of H pylori infection had been described. The present prospective study was conducted to evaluate the effect of anti–H pylori therapy in stage IE high-grade gastric MALT lymphomas.

PATIENTS AND METHODS: Sixteen patients with H pylori infection and stage IE gastric high-grade MALT lymphoma consented to a brief antibiotic therapy as first-line treatment from June 1995 through April 2000. Then, patients underwent intensive endoscopic follow-up examinations (± endoscopic ultrasonography) with biopsy to evaluate tumor response. Patients with significant improvement of gross lesions that accompanied regression of large cells were followed up without additional treatment. Patients without significant improvement were immediately referred to systemic chemotherapy.

RESULTS: Eradication of H pylori was achieved in 15 patients and was accompanied by rapid gross tumor regression and disappearance of large cells in 10. All 10 of these patients with early response had subsequent complete histologic remission of lymphoma. The complete remission rate was 62.5% (95% confidence interval, 35.8% to 89.1%). The response rate was not affected by the tumor grading (proportion of large blast cells within the tumor) but was adversely affected by the depth of tumor invasion. At a median follow-up of 43.5 months (range, 21.1 to 67.4 months), all 10 of these patients remained lymphoma-free. The median duration of complete response was 31.2 months (range, 14.4 to 49.1 months).

CONCLUSION: These results suggest that high-grade transformation is not necessarily associated with the loss of H pyloridependence in early-stage MALT lymphomas of the stomach.
Methodologic Lessons Learned From Hot Flash Studies
Authors: Sloan Jeff A. , Loprinzi Charles L. , Novotny Paul J. , Barton Debra L. , Lavasseur Beth I. , Windschitl Harold
Published: February 2017

PURPOSE: In the course of conducting a series of prospective clinical trials devoted to defining new treatment opportunities for hot flashes in cancer survivors, considerable experience has been acquired with related methodologic issues. This article has been written in response to many queries regarding this methodology.

PATIENTS AND METHODS: A series of seven different clinical trials that involved 968 patients was used for this work. Reliable and valid definitions of hot flash intensity were developed from patient-reported descriptions. Concomitant validity and reliability assessment of patient-completed diaries was undertaken to compare hot flash data with toxicity and quality-of-life (QOL) end points and to examine consistency across patient groups using variability analysis and correlation procedures. Parametric data from this meta-analysis was used to examine relative power considerations for the design of phase II and phase III clinical trials.

RESULTS: Daily diaries used in these studies exhibited consistency and reliability and had few missing data. Hot flash frequency and hot flash score (frequency multiplied by average severity) variables produced almost identical end point results. For phase III placebo-controlled studies, 50 patients per treatment arm seem appropriate to provide sufficient power specifications to detect a clinically meaningful change in hot flash activity. For phase II trials, 25 patients per trial seem to provide reasonable estimates of eventual hot flash efficacy to screen potential agents for more definitive testing.

CONCLUSION: Given the data gained from these experiences, we can plan and carry out more efficient trials to identify efficacious agents for the reduction of hot flash activity.
Clinical Trials: Are They a Good Buy?
Authors: Bennett Charles L. , Adams Jared R. , Knox Kirstin S. , Kelahan Andrew M. , Silver Samuel M. , Bailes Joseph S.
Published: February 2017

PURPOSE: Concern that clinical trials may be too costly has been used to justify traditionally restrictive insurer policies regarding clinical trials. Additionally, fear of insurer reimbursement denial can be a significant barrier to clinical trial participation. In this study, we reviewed the empirical data on costs of clinical trials versus standard care and summarized the current status of policy initiatives related to clinical trial insurance reimbursement.

METHODS: Electronic and print data sources were searched for studies on the costs of oncology clinical trials. Information on policy initiatives for clinical trial reimbursement was obtained from the American Society of Clinical Oncology, the American Society of Hematology, and the Coalition of National Cancer Cooperative Groups and from searches of World Wide Web sites.

RESULTS: Five pilot studies provided information for 377 patients on phase II/III clinical trials matched with controls on standard care. Cost estimates ranged from 10% lower to 23% higher costs/charges for clinical trials in comparison to standard medical care. Medicare, 14 states, and several private insurers now cover the costs of patient care in “qualifying” clinical trials.

CONCLUSION: Findings from small pilot studies suggest that phase II and III clinical trials result in at most modest increases in cost over standard treatment costs. Also, an increasing number of policy makers have decided to support clinical trial reimbursement initiatives. It is hoped that economic data from large observational studies will facilitate widespread and permanent decisions that support reimbursement for phase I, II, and III clinical trial participation.
Benefit of a High-Dose Epirubicin Regimen in Adjuvant Chemotherapy for Node-Positive Breast Cancer Patients With Poor Prognostic Factors: 5-Year Follow-Up Results of French Adjuvant Study Group 05 Randomized Trial
Authors:   By the French Adjuvant Study Group
Published: February 2017

PURPOSE: To determine the influence of the epirubicin dose in operable node-positive breast cancer patients with factors of poor prognosis.

PATIENTS AND METHODS: Between April 1990 and July 1993, 565 operable breast cancer patients with either more than three positive nodes or between one and three positive nodes with Scarff Bloom Richardson grade ≥ 2 and hormone receptor negativity were randomized after surgery to receive either fluorouracil 500 mg/m2, epirubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days for six cycles (FEC 50) or the same regimen except with epirubicin dose of 100 mg/m2 (FEC 100). Postmenopausal patients received tamoxifen 30 mg/d for 3 years at the beginning of chemotherapy. Radiotherapy was delivered at the end of chemotherapy in both groups.

RESULTS: The median follow-up was 67 months. The 5-year disease-free survival (DFS) was 54.8% with FEC 50 and 66.3% with FEC 100 (P = .03). The 5-year overall survival (OS) was 65.3% and 77.4%, respectively (P = .007). The mean relative dose-intensity was similar in the two groups (90.3% and 86.1%, respectively). Neutropenia and anemia were significantly more frequent in FEC 100 (P < 10−3), as were nausea-vomiting (P = .008) and stomatitis and alopecia (P < 10−3). Nine cases of grade 3 infection occurred only with FEC 100, and no toxic deaths occurred. Three cases of acute cardiac toxicity were observed (FEC50 = 1, FEC100 = 2) and 10 patients (FEC50 = 6, FEC100 = 4) presented delayed cardiac dysfunctions. Two cases of secondary leukemia were observed (acute lymphatic leukemia with FEC 50 and acute myelogenous leukemia with FEC 100).

CONCLUSION: After 5 years of follow-up, the increased epirubicin dose led to a significant benefit in terms of DFS and OS, with a high survival rate among patients with poor-prognosis breast cancer.
Results of Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue in 22 Patients With Refractory or Recurrent Primary CNS Lymphoma or Intraocular Lymphoma
Authors: Soussain Carole , Suzan Florence , Hoang-Xuan Khê , Cassoux Nathalie , Levy Vincent , Azar Nabih , Belanger Coralie , Achour Eddine , Ribrag Vincent , Gerber Sophie , Delattre Jean-Yves , Leblond and Véronique
Published: February 2017

PURPOSE: To assess the feasibility and efficacy of intensive chemotherapy with hematopoietic stem-cell rescue (IC + HCR) in patients with refractory or recurrent primary CNS lymphoma (PCNSL) or intraocular lymphoma (IOL).

PATIENTS AND METHODS: IC consisted of thiotepa 250 mg/m2/d days −9 through −7, busulfan 10 mg/kg (total dose) days −6 through −4, and cyclophosphamide 60 mg/kg/d days −3 and −2. Intravenous clonazepam 2 mg/d was given prophylactically from the day before initiation of busulfan therapy to the day after completion of busulfan therapy. Patients with refractory or recurrent PCNSL underwent IC + HCR only if they were chemosensitive to two cycles of salvage treatment with cytarabine (2 g/m2/d days 2 through 5 and 50 mg/m2/d days 1 through 5 in a 12-hour infusion) and etoposide (VP-16; 200 mg/m2/d days 2 through 5) (CYVE). Patients with IOL refractory to high-dose methotrexate (MTX) and cytarabine entered the IC + HCR program directly.

RESULTS: Twenty-two patients (10 with relapses, 12 with refractory disease) were enrolled. Twenty patients entered the IC + HCR program: twelve entered after CYVE treatment, seven entered directly, and one had previously been retreated with high-dose MTX. Before IC, eight patients were in complete remission (CR), four were in partial remission (PR), one had stable disease, and seven had refractory disease. After IC + HCR, 16 patients entered CR, two remained in PR, one had stable disease, and one had disease progression. Fourteen patients remained alive (median follow-up time, 41.5 months). The overall probability of survival at 3 years was 63.7%. After IC, that probability was 60% and the 3-year probability of event-free survival was 53%. Seven patients had neurologic adverse events during the entire procedure.

CONCLUSION: IC + HCR proved feasible and effective in patients with refractory or recurrent PCNSL or IOL. The entire procedure seemed to be most toxic in patients ≥ 60 years. A prospective multicenter study is ongoing.
Clinical Characteristics and Outcome of Patients With Extracutaneous Mycosis Fungoides
Authors: de Coninck Ellen C. , Kim Youn H. , Varghese Anna , Hoppe Richard T.
Published: February 2017

PURPOSE: To identify prognostic factors predictive of outcome in patients with extracutaneous (stage IV) mycosis fungoides (MF) and to evaluate the risk of progression to extracutaneous disease by initial extent of skin involvement.

PATIENTS AND METHODS: One hundred twelve patients with extracutaneous disease at presentation or with progression and 434 patients with initial cutaneous-only disease were identified. Actuarial survival curves were plotted according to the Kaplan-Meier technique.

RESULTS: The median survival of all stage IV patients was 13 months from the date of first treatment for stage IV disease. Sex, race, age, extent of skin involvement, and peripheral blood Sezary cell involvement were not significant to survival outcome. Eleven patients (10%) had a complete response to therapy resulting in a significantly improved median survival compared with patients with a partial or no response (1.70 v 0.91 years, P = .047 and 1.70 v 0.57 years, P = .011, respectively). At 20 years from diagnosis, the risk for progression to extracutaneous disease by initial extent of skin involvement was 0% for limited patch/plaque, 10% for generalized patch/plaque, 35.5% for tumorous disease, and 41% for erythrodermic involvement.

CONCLUSION: This was a larger scale study over a longer time period than had been completed previously on extracutaneous MF. Prognostic factors important in the cutaneous stages of disease are no longer significant once extracutaneous disease develops. Patients who had a more favorable response to therapy may have had a biologically less aggressive disease than their less fortunate counterparts. The risk of developing stage IV MF is highest in patients presenting with tumorous or erythrodermic skin disease and is lowest in patients with limited skin involvement.
Application of a New Multinomial Phase II Stopping Rule Using Response and Early Progression
Authors: Dent S. , Zee B. , Dancey J. , Hanauske A. , Wanders J. , Eisenhauer E.
Published: February 2017

PURPOSE: A multinomial stopping rule had previously been developed that incorporated both objective response and early progression into decisions to stop or continue phase II trials of anticancer agents. The purpose of this study was to apply the multinomial rule to two independent sets of phase II data to assess its utility in appropriately recommending early trial closure as compared with other stopping rules.

MATERIALS AND METHODS: Data from completed phase II trials of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and European Organization for Research and Treatment of Cancer Early Clinical Studies Group (ECSG) formed the basis of the study. Based on observed results for each trial, the recommendation of the multinomial stopping rule was applied, as was the recommendation of the actual stopping rule used (Fleming or Gehan). The appropriateness of the recommendations was evaluated based on interpretation of final study results.

RESULTS: The standard and multinomial rules disagreed on early stopping in one of 16 NCIC CTG trials and in seven of 23 ECSG trials. In all cases, the standard rule advised continuing to the second stage whereas the multinomial rule advised stopping early because of excessive numbers of patients experiencing early disease progression. Final trial results indicated that the multinomial recommendation was appropriate, because in no study did final results lead to conclusions of activity.

CONCLUSION: In this series of trials, the multinomial stopping rule performed more efficiently than the Fleming or Gehan rules in advising early stopping of trials. These results encourage continued exploration of this approach for phase II trials of cytotoxic and noncytotoxic anticancer agents.
Radiation Concurrent With Gemcitabine for Locally Advanced Head and Neck Cancer: A Phase I Trial and Intracellular Drug Incorporation Study
Authors: Eisbruch Avraham , Shewach Donna S. , Bradford Carol R. , Littles James F. , Teknos Theodore N. , Chepeha Douglass B. , Marentette Lawrence J. , Terrell Jeffrey E. , Hogikyan Norman D. , Dawson Laura A. , Urba Susan , Wolf Gregory T. , Lawrence Theodore S.
Published: February 2017

PURPOSE: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level.

PATIENTS AND METHODS: Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured.

RESULTS: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m2/wk, 150 mg/m2/wk, and 50 mg/m2/wk. No DLT was observed at 10 mg/m2/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m2 (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m2.

CONCLUSION: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m2, which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.
Patient Preferences for Adjuvant Interferon Alfa-2b Treatment
Authors: Kilbridge Kerry L. , Weeks Jane C. , Sober Arthur J. , Haluska Frank G. , Slingluff Craig L. , Atkins Michael B. , Sock Dana E. , Kirkwood John M. , Nease Robert F.
Published: February 2017

PURPOSE: Although trials of adjuvant interferon alfa-2b (IFNα-2b) in high-risk melanoma patients suggest improvement in disease-free survival, it is unclear whether treatment offers improvement in overall survival. Widespread use of adjuvant IFNα-2b has been tempered by its significant toxicity. To quantify the trade-offs between IFNα-2b toxicity and survival, we assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a particular health state on a scale of 0 (death) to 1 (perfect health).

PATIENTS AND METHODS: We assessed utilities for health states associated with adjuvant IFN among 107 low-risk melanoma patients using the standard gamble technique. Health states described four IFNα-2b toxicity scenarios and the following three posttreatment outcomes: disease-free health and melanoma recurrence (with or without IFNα-2b) leading to cancer death. We also asked patients the improvement in 5-year disease-free survival they would require to tolerate IFN.

RESULTS: Utilities for melanoma recurrence with or without IFNα-2b were significantly lower than utilities for all IFNα-2b toxicities but were not significantly different from each other. At least half of the patients were willing to tolerate mild-moderate and severe IFNα-2b toxicity for 4% and 10% improvements, respectively, in 5-year disease-free survival.

CONCLUSION: On average, patients rate quality of life with melanoma recurrence much lower than even severe IFNα-2b toxicity. These results suggest that recurrence-free survival is highly valued by patients. The utilities measured in our study can be applied directly to quality-of-life determinations in clinical trials of adjuvant IFNα-2b to measure the net benefit of therapy.
Phase I Safety and Pharmacokinetic Study of Recombinant Human Anti-Vascular Endothelial Growth Factor in Patients With Advanced Cancer
Authors: Gordon M. S. , Margolin K. , Talpaz M. , Sledge G. W. , Holmgren E. , Benjamin R. , Stalter S. , Shak S. , Adelman D. C.
Published: February 2017

PURPOSE: We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer.

PATIENTS AND METHODS: Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72.

RESULTS: Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study.

CONCLUSION: rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of ≥ 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.
How Effective Is Dose-Intensive/Myeloablative Therapy Against Ewing’s Sarcoma/Primitive Neuroectodermal Tumor Metastatic to Bone or Bone Marrow? The Memorial Sloan-Kettering Experience and a Literature Review
Authors: Kushner Brian H. , Meyers Paul A.
Published: February 2017

PURPOSE: Attempts to improve outcomes of patients with Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) metastatic to bone/bone marrow (BM) have focused on chemotherapy dose intensification strategies. We now present results achieved with that approach, as carried out at Memorial Sloan-Kettering Cancer Center (MSKCC) and as reported in the literature.

PATIENTS AND METHODS: Twenty-one unselected MSKCC patients with newly diagnosed ES/PNET metastatic to bone/BM received the “P6” protocol which includes cycles of cyclophosphamide (4.2 g/m2)/doxorubicin (75 mg/m2)/vincristine and cycles of ifosfamide (9 g/m2)/etoposide (500 mg/m2). Patients in complete/very good partial remission (CR/VGPR) after P6 received myeloablative therapy with either total-body irradiation (TBI) (hyperfractionated 15 Gy)/melphalan (180 mg/m2) or thiotepa (900 mg/m2)/carboplatin (1,500 mg/m2). We reviewed the literature.

RESULTS: Only one MSKCC patient became a long-term event-free survivor; all but one relapse was in a distant site. Initial responses to P6 were CR/VGPR in 19 patients, but eight of them plus two others developed PD while receiving or shortly after completing P6. Eight patients were treated with TBI/melphalan: four relapsed 2 to 7 months after transplantation; two died early of toxicity; one died of pulmonary failure 17 months after transplantation (no evidence of ES/PNET); and one remains in CR at more than 7 years. The three patients treated with thiotepa/carboplatin relapsed 3 to 4 months after transplantation. All reports on large series of unselected patients with ES/PNET metastatic to bone/BM showed similarly unsatisfactory results. Poor outcome was seen with use of active agents for ES/PNET–cyclophosphamide, ifosfamide, doxorubicin, dactinomycin, vincristine, etoposide - at standard dosages for prolonged periods of time and at higher dosages in intensive regimens for short or prolonged periods of time. No improvements in event-free survival rates occurred with successive cooperative group or large single-institutional studies that used increasingly aggressive chemotherapeutic approaches. Inclusion of ifosfamide with or without etoposide made no difference nor did consolidation of remission with myeloablative chemoradiotherapy. Secondary leukemia emerged as a major risk with dose-intensive regimens.

CONCLUSION: The MSKCC experience and findings reported in the literature suggest that dose-intensive use of the chemotherapy agents with established activity against ES/PNET is reaching its efficacy and toxicity limits. A major impact on prognosis awaits the development of entirely novel therapies.
Insomnia in the Context of Cancer: A Review of a Neglected Problem
Authors: Savard Josée , Morin Charles M.
Published: February 2017

ABSTRACT: This article reviews the evidence on the diagnosis, epidemiology, etiology, and treatment of insomnia in the context of cancer and proposes several areas for future research. Clinical and diagnostic features of insomnia are described and prevalence estimates of insomnia complaints in cancer patients are summarized. Then, potential etiologic factors (ie, predisposing, precipitating, and perpetuating factors) and consequences of insomnia (ie, psychologic, behavioral, and health impact) in the context of cancer are discussed. Finally, pharmacologic and psychologic treatments previously shown effective to treat insomnia in healthy individuals are discussed as valuable treatment options for cancer patients as well. Because long-term use of hypnotic medications is associated with some risks (eg, dependence), it is argued that psychologic interventions (eg, stimulus control, sleep restriction, cognitive therapy) are the treatment of choice for sleep disturbances in the context of cancer, especially when it has reached a chronic course. However, the efficacy of these treatments has yet to be verified specifically in cancer patients.
Survival and Reproductive Function After Treatment of Malignant Germ Cell Ovarian Tumors
Authors: Zanetta Gerardo , Bonazzi Cristina , Cantù Maria Grazia , Bini† Sergio , Locatelli Anna , Bratina Giorgio , Mangioni Costantino
Published: February 2017

PURPOSE: Germ cell ovarian tumors are curable. The possible sequelae of chemotherapy on long-term survivors are still unknown, but these patients may expect normal lives. The aim of this study was to evaluate the outcome and reproductive function in a population of women treated since 1982.

MATERIALS AND METHODS: Between 1982 and 1996, 169 women with malignant germ cell ovarian tumors were seen (70 dysgerminomas, 28 endodermal sinus tumors, 24 mixed tumors, and 47 immature teratomas). Seventy-one had advanced or recurrent disease. Fertility-sparing surgery was performed in 138 (81%) women, 81 of whom received postoperative chemotherapy.

RESULTS: With a median follow-up of 67 months, the survival rate was 94% for dysgerminoma, 89% for endodermal sinus tumors, 100% for mixed types, and 98% for immature teratoma. For women who were treated conservatively, the survival rate was 98%, 90%, 100%, and 100%, respectively. Two women had adnexal recurrences, and both received salvage treatment. After treatment, all but one postpubertal woman had recovery of menses within 9 months. During follow-up, 12 untreated and 20 treated patients had 55 conceptions. We recorded 40 pregnancies at term, six terminations, and nine miscarriages. Four malformations were observed: one in 14 conceptions of patients who had not received chemotherapy and three in 41 conceptions of treated patients.

CONCLUSION: Irrespective of subtype and stage, conservative surgery should become the standard approach to treating most patients with malignant ovarian germ cell tumors. Fertility seems to be only marginally affected by treatments. Miscarriages are in the expected range for the general population. The malformation rate is slightly higher than in the general population, but no significant difference was seen between patients who did and did not receive chemotherapy.
Phase I Trial of Escalating Doses of Paclitaxel Combined With Fixed Doses of Cisplatin and Doxorubicin in Advanced Endometrial Cancer and Other Gynecologic Malignancies: A Gynecologic Oncology Group Study
Authors: Fleming Gini F. , Fowler Jeffrey M. , Waggoner Steven E. , Copeland Larry J. , Greer Benjamin E. , Horowitz Ira , Sutton Gregory , Schilder Russell J. , Fracasso Paula M. , Ball Harrison G. , McGuire William P.
Published: February 2017

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers.

PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m2 and 45 mg/m2, whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m2. Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not.

RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma.

CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m2, doxorubicin 45 mg/m2, and paclitaxel 160 mg/m2 with G-CSF support is recommended for further testing.
Phase III Comparison of High-Dose Paclitaxel + Cisplatin + Granulocyte Colony-Stimulating Factor Versus Low-Dose Paclitaxel + Cisplatin in Advanced Head and Neck Cancer: Eastern Cooperative Oncology Group Study E1393
Authors: Forastiere Arlene A. , Leong Traci , Rowinsky Eric , Murphy Barbara A. , Vlock Daniel R. , DeConti Ronald C. , Adams George L.
Published: February 2017

PURPOSE: To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck.

PATIENTS AND METHODS: Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m2 (24-hour infusion) + cisplatin 75mg/m2 + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m2 (24-hour infusion) + cisplatin 75 mg/m2. Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival.

RESULTS: No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) was 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm B; febrile neutropenia, 27% of patients in Arm A and 39% in Arm B. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal.

CONCLUSION: This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended.
Accelerated Concomitant Boost Radiotherapy and Chemotherapy for Advanced Nasopharyngeal Carcinoma
Authors: Wolden Suzanne L. , Zelefsky Michael J. , Kraus Dennis H. , Rosenzweig Kenneth E. , Chong Lanceford M. , Shaha Ashok R. , Zhang Haige , Harrison Louis B. , Shah Jatin P. , Pfister David G.
Published: February 2017

PURPOSE: To evaluate the feasibility and efficacy of concomitant boost radiotherapy (RT) plus cisplatin-based chemotherapy compared with standard fractionation RT for patients with advanced nasopharyngeal cancer.

PATIENTS AND METHODS: From 1988 through 1999, 50 patients with American Joint Committee on Cancer stage II-IVb nasopharyngeal carcinoma were treated with 70-Gy concomitant boost RT (1.8 Gy/d, weeks 1 through 6; 1.6 Gy second daily fraction, weeks 5 through 6) and two cycles of concurrent cisplatin 100 mg/m2 days 1 and 22. Thirty-seven patients also received three cycles of cisplatin-based adjuvant chemotherapy. These 50 patients were compared with a nonrandomized cohort of 51 patients with nasopharyngeal cancer treated with 70-Gy standard fractionation RT (1.8 Gy/d) without chemotherapy from 1988 through 1995. The groups were well matched for prognostic factors except stage, for which the concomitant boost RT/chemotherapy group was more advanced (54%, T3-4; 54%, N2-3; 44%, stage IV) compared with the standard RT group (31%, T3-4, P = .03; 22%, N2-3, P < .001; 20%, stage IV, P < .01).

RESULTS: With a median follow-up of 42 months (range, 12 to 129 months), the 3-year actuarial local control, progression-free survival, and survival rates were 89% v 74% (P < .01), 66% v 54% (P = .01), and 84% v 71% (P = .04) for the concomitant boost RT/chemotherapy group and the standard RT patients, respectively. Acute grade 3 mucositis was more prevalent with combined therapy, 84% v 43% (P < .001), resulting in a higher rate of temporary gastrostomy tube placement, 46% v 20% (P < .01).

CONCLUSION: Concomitant boost RT with cisplatin-based chemotherapy is feasible and improves local-regional control as well as survival for patients with advanced nasopharyngeal cancer compared with standard RT alone.
Perspectives on Comorbidity and Cancer in Older Patients: Approaches to Expand the Knowledge Base
Authors: Yancik Rosemary , Ganz Patricia A. , Varricchio Claudette G. , Conley Barbara
Published: February 2017

Abstract : Not only do persons 65 years and older bear a disproportionate burden of cancer, advancing age is associated with increased vulnerability to other age-related health problems. Newly diagnosed older cancer patients who have lived into later years of life may have concurrent ailments (eg, diabetes, chronic obstructive pulmonary disease, heart disease, arthritis, and/or hypertension) that could affect treatment choice, prognosis, and survival. The clinician must often make cancer treatment decisions in the context of an older individual’s pre-existing health problems (ie, comorbidity). Ways to produce reliable information on comorbidity that can be effectively used in evaluation of older cancer patients are urgently needed. What is the nature and severity of the older patient’s comorbid health problems? How do other age-related conditions influence treatment decisions and the cancer course? How do already compromised older patients tolerate the stress of cancer and its treatment? How are concomitant comorbid conditions managed?

At present, no established, valid way to assess comorbidity in older cancer patients exists. Such technology, with a solid conceptual and scientific base, promises a high positive clinical yield to assure quality cancer care for older patients if reliable and valid instruments can be integrated into oncology practice. Much preliminary scientific work must be performed. A synthesis of viewpoints on what to include in comorbidity assessment of older cancer patients and development approaches were expressed in a multidisciplinary working group convened by the National Institute on Aging and the National Cancer Institute. We share the key issues raised regarding complexities of comorbidity assessment and suggestions for scientific inquiry.
CD6+ Donor Marrow T-Cell Depletion as the Sole Form of Graft-Versus-Host Disease Prophylaxis in Patients Undergoing Allogeneic Bone Marrow Transplant From Unrelated Donors
Authors: Soiffer Robert J. , Weller Edie , Alyea Edwin P. , Mauch Peter , Webb Iain L. , Fisher David C. , Freedman Arnold S. , Schlossman Robert L. , Gribben John , Lee Stephanie , Anderson Kenneth C. , Marcus Karen , Stone Richard M. , Antin Joseph H. , Ritz Jerome
Published: February 2017

PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis.

PATIENTS AND METHODS: Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5 Gy (26 points) of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment.

RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 × 106/L was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival was 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P = .002), cytomegalovirus seronegative status (P = .04), and early disease status at bone marrow transplant (P = .05) were associated with superior survival.

CONCLUSION: CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in an incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD.
Computer Program to Assist in Making Decisions About Adjuvant Therapy for Women With Early Breast Cancer
Authors: Ravdin Peter M. , Siminoff Laura A. , Davis Greg J. , Mercer Mary Beth , Hewlett Joan , Gerson Nancy , Parker Helen L.
Published: February 2017

PURPOSE: The goal of the computer program Adjuvant! is to allow health professionals and their patients with early breast cancer to make more informed decisions about adjuvant therapy.

METHODS: Actuarial analysis was used to project outcomes of patients with and without adjuvant therapy based on estimates of prognosis largely derived from Surveillance, Epidemiology, and End-Results data and estimates of the efficacy of adjuvant therapy based on the 1998 overviews of randomized trials of adjuvant therapy. These estimates can be refined using the Prognostic Factor Impact Calculator, which uses a Bayesian method to make adjustments based on relative risks conferred and prevalence of positive test results.

RESULTS: From the entries of patient information (age, menopausal status, comorbidity estimate) and tumor staging and characteristics (tumor size, number of positive axillary nodes, estrogen receptor status), baseline prognostic estimates are made. Estimates for the efficacy of endocrine therapy (5 years of tamoxifen) and of polychemotherapy (cyclophosphamide/methotrexate/fluorouracil–like regimens, or anthracycline-based therapy, or therapy based on both an anthracycline and a taxane) can then be used to project outcomes presented in both numerical and graphical formats. Outcomes for overall survival and disease-free survival and the improvement seen in clinical trials, are reasonably modeled by Adjuvant!, although an ideal validation for all patient subsets with all treatment options is not possible. Additional speculative estimates of years of remaining life expectancy and long-term survival curves can also be produced. Help files supply general information about breast cancer. The program’s Internet links supply national treatment guidelines, cooperative group trial options, and other related information.

CONCLUSION: The computer program Adjuvant! can play practical and educational roles in clinical settings.
BAG-1: A Novel Biomarker Predicting Long-Term Survival in Early-Stage Breast Cancer
Authors: Turner Bruce C. , Krajewski Stanislaw , Krajewska Maryla , Takayama Shinichi , Gumbs Andrew A. , Carter Darryl , Rebbeck Timothy R. , Haffty Bruce G. , Reed John C.
Published: February 2017

PURPOSE: Among women with early-stage breast cancer treated with lumpectomy and radiation therapy, 30% to 40% will develop metastatic disease, which is often fatal. A need exists therefore for biomarkers that distinguish patients at high risk of relapse. We performed a retrospective correlative analysis of BAG-1 protein expression in breast tumors derived from a cohort of early-stage breast cancer patients.

PATIENTS AND METHODS: Archival paraffin blocks from 122 women with stages I to II breast cancer treated with lumpectomy and radiation therapy (median follow-up, 12.1 years) were analyzed by immunohistochemical methods using monoclonal antibodies recognizing BAG-1 and other biomarkers, including Bcl-2, estrogen receptor, progesterone receptor, p53, and HER2/Neu. Immunostaining data were correlated with distant metastasis-free survival (DMFS) and overall survival (OS).

RESULTS: Cytosolic immunostaining for BAG-1 was upregulated in 79 (65%) of 122 invasive breast cancers (P < .001) compared with normal breast. Elevated BAG-1 was significantly associated with longer DMFS and OS, overall (stages 1 and II) and in node-negative (stage I only) patients, on the basis of univariate and multivariate analyses (DMFS, P = .005; OS, P = .01, in multivariate analysis of all patients; DMFS, P = .005; OS, P = .001, in multivariate analysis of node-negative patients). All other biomarkers failed to reach statistical significance in multivariate analysis. Clinical stage was an independent predictor of OS (P = .04) and DMFS (P = .02).

CONCLUSION: These findings provide preliminary evidence that BAG-1 represents a potential marker of improved survival in early-stage breast cancer patients, independent of the status of axillary lymph nodes.
Paclitaxel, an Active Agent in Nonsquamous Carcinomas of the Uterine Cervix: A Gynecologic Oncology Group Study
Authors: Curtin John P. , Blessing John A. , Webster Kenneth D. , Rose Peter G. , Mayer Allan R. , Fowler Wesley C. , Malfetano John H. , Alvarez Ronald D.
Published: February 2017

PURPOSE: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy.

PATIENTS AND METHODS: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m2 and de-escalation to 110 mg/m2 were allowed based on adverse effects.

RESULTS: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia.

CONCLUSION: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.