bluuebunny/crossref_metadata_2025 huggingface dataset:
Late Medical Complications and Fatigue in Hodgkin’s Disease Survivors
Authors: Knobel Heidi , Loge Jon Håvard , Lund May Brit , Forfang Kolbjørn , Nome Ole , Kaasa Stein
Published: February 2017

PURPOSE: Long-term medical complications, such as cardiac, pulmonary, and thyroid dysfunction, are frequent among Hodgkin’s disease survivors (HDSs). Chronic fatigue is also highly prevalent among HDSs. Few studies have explored possible etiologic explanations for fatigue. The aim of this study was to explore whether late cardiac, pulmonary, and thyroid complications after curative treatment for Hodgkin’s disease (HD) may explain the high level of fatigue among HDSs.

PATIENTS AND METHODS: Four-hundred fifty-nine patients treated for HD at the Norwegian Radium Hospital from 1971 to 1991 were included in a cross-sectional, follow-up study of subjective health status. Fatigue (physical [PF] and mental), was measured by the Fatigue Questionnaire. A subcohort of the HDSs (116 patients) treated from 1980 to 1988 were included in a separate study in which long-term cardiac, pulmonary, and thyroid complications were assessed. All patients had received radiotherapy, and 63 patients had received additional chemotherapy. The present study comprised 92 patients (mean age, 37 years; range, 23 to 56 years) who participated in both studies.

RESULTS: HDSs with pulmonary dysfunction were more fatigued than HDSs with normal pulmonary function (PF 10.9 v 8.9; P < .05). Gas transfer impairment was the most prevalent pulmonary dysfunction, and three times as many patients with gas transfer impairment reported chronic fatigue (duration, 6 months or longer), compared with patients without pulmonary dysfunction (48% v 17%, P < .01). No associations were found between cardiac sequelae or hypothyroidism and fatigue.

CONCLUSION: Pulmonary dysfunction is associated with fatigue in HDSs. Cardiac sequelae was not associated with fatigue in HDSs. We question the absence of an association between thyroid complications and fatigue.
Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid Malignancies
Authors: Hidalgo Manuel , Siu Lillian L. , Nemunaitis John , Rizzo Jinee , Hammond Lisa A. , Takimoto Chris , Eckhardt S. Gail , Tolcher Anthony , Britten Carolyn D. , Denis Louis , Ferrante Karen , Von Hoff Daniel D. , Silberman Sandra , Rowinsky Eric K.
Published: February 2017

PURPOSE: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized.

RESULTS: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL).

CONCLUSION: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.
Extending Positron Emission Tomography Scan Utility to High-Risk Neuroblastoma: Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography as Sole Imaging Modality in Follow-Up of Patients
Authors: Kushner Brian H. , Yeung Henry W.D. , Larson Steven M. , Kramer Kim , Cheung Nai-Kong V.
Published: February 2017

PURPOSE: Although positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (18F-FDG) has a major impact on the treatment of adult cancer, the reported experience with extracranial tumors of childhood is limited. We describe a role for PET in patients with neuroblastoma (NB).

PATIENTS AND METHODS: In 51 patients with high-risk NB, 92 PET scans were part of a staging evaluation that included iodine-123 or iodine-131 metaiodobenzylguanidine (MIBG) scan, bone scan, computed tomography (and/or magnetic resonance imaging), urine catecholamine measurements, and bone marrow (BM) examinations. The minimum number of tests sufficient to detect NB was determined.

RESULTS: Of 40 patients who were not in complete remission, only 1 (2.5%) had NB that would have been missed had a staging evaluation been limited to PET and BM studies, and 13 (32.5%) had NB detected by PET but not by BM and urine tests. PET was equal or superior to MIBG scans for identifying NB in soft tissue and extracranial skeletal structures, for revealing small lesions, and for delineating the extent and localizing sites of disease. In 36 evaluations of 22 patients with NB in soft tissue, PET failed to identify only two long-standing MIBG-negative abdominal masses. PET and MIBG scans showed more skeletal lesions than bone scans, but the normally high physiologic brain uptake of FDG blocked PET visualization of cranial vault lesions. Similar to MIBG, FDG skeletal uptake was diffusely increased with extensive or progressing BM disease but faint or absent with minimal or nonprogressing BM disease.

CONCLUSION: In the absence or after resolution of cranial vault lesions, and once the primary tumor is resected, PET and BM tests suffice for monitoring NB patients at high risk for progressive disease in soft tissue and bone/BM.
Cationic Liposome-MediatedE1AGene Transfer to Human Breast and Ovarian Cancer Cells and Its Biologic Effects: A Phase I Clinical Trial
Authors: Hortobagyi Gabriel N. , Ueno Naoto T. , Xia Weiya , Zhang Su , Wolf Judith K. , Putnam Joe B. , Weiden Paul L. , Willey Jie S. , Carey Mary , Branham Donna L. , Payne Joy Y. , Tucker Stanley D. , Bartholomeusz Chandra , Kilbourn Robert G. , De Jager Robert L. , Sneige Nour , Katz Ruth L. , Anklesaria Pervin , Ibrahim Nuhad K. , Murray James L. , Theriault Richard L. , Valero Vicente , Gershenson David M. , Bevers Michael W. , Huang Leaf , Lopez-Berestein Gabriel , Hung Mien-Chie
Published: February 2017

PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu–overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu–overexpressing and low HER-2/neu–expressing breast and ovarian cancers in a phase I clinical trial.

PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12).

RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase–polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites.

CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.
Factors Associated With Response to High-Dose Interleukin-2 in Patients With Metastatic Melanoma
Authors: Phan Giao Q. , Attia Peter , Steinberg Seth M. , White Donald E. , Rosenberg Steven A.
Published: February 2017

PURPOSE: The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma.

PATIENTS AND METHODS: We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute.

RESULTS: The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2= .000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 ± 0.3 doses v 14.5 ± 0.2 doses; P2= .0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2= .27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2= .0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2= .01; free T4, P2= .0049; vitiligo, P2< 10−6), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response.

CONCLUSION: The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.
Screening Sensitivity and Sojourn Time From Breast Cancer Early Detection Clinical Trials: Mammograms and Physical Examinations
Authors: Shen Yu , Zelen Marvin
Published: February 2017

PURPOSE: To estimate sensitivities of breast cancer screening modalities and preclinical duration of the disease from eight breast cancer screening clinical trials.

PATIENTS AND METHODS: Screening programs invariably lead to diagnosis of disease before signs or symptoms are present. Two key quantities of screening programs are the sensitivity of the disease detection modality and the mean sojourn time (MST). The observed screening histories in a periodically screened cohort make it possible to estimate these quantities of interest. We applied recently developed statistical methods to data from eight randomized breast cancer screening trials to estimate the sensitivities of early detection modalities and MST. Moreover, when a screening trial involved two screening modalities, our methods enabled the estimation of the individual sensitivity of each screening modality.

RESULTS: We analyzed breast cancer data from several screening trials and have relatively complete data from the Health Insurance Plan (HIP), Edinburgh, and two Canadian studies. The screening sensitivity for mammography, physical examination, and MST were, respectively, HIP: 0.39, 0.47, and 2.5 years; Edinburgh: 0.63, 0.40, and 4.3 years; Canadian (age 40 to 49 at entry): 0.61, 0.59, and 1.9 years; Canadian (age 50 to 59 at entry): 0.66, 0.39, and 3.1 years.

CONCLUSION: The public debate on early breast cancer detection is mainly centered on mammograms. However, the current study indicates that a physical examination is of comparable importance. Cautious interpretation of trial differences is required as a result of various experimental designs and the age dependency of screening sensitivity and MST.
Multicenter Phase II Trial of Paclitaxel, Cisplatin, and Etoposide With Concurrent Radiation for Limited-Stage Small-Cell Lung Cancer
Authors: Bremnes Roy M. , Sundstrøm Stein , Vilsvik Jan , Aasebø Ulf ,   for the Norwegian Lung Cancer Study Group
Published: February 2017

PURPOSE: To investigate the feasibility, efficacy, and safety of adding paclitaxel to cisplatin/etoposide chemotherapy and concurrent thoracic radiotherapy (TRT) in treatment of limited-stage small-cell lung cancer (LD-SCLC).

PATIENTS AND METHODS: Patients received five courses of chemotherapy (paclitaxel 175 mg/m2 1-hour intravenous [IV] infusion day 1; cisplatin 50 mg/m2 IV day 1; etoposide 100 mg/m2 IV day 1; oral etoposide 100 mg bid days 2 to 5) at 3-week intervals. TRT (42 Gy administered in 15 fractions) was administered concurrent with chemotherapy cycle 3. All patients were evaluated before starting TRT and 4 weeks after termination of chemotherapy. Patients achieving complete remission (CR) were administered prophylactic cranial irradiation.

RESULTS: Thirty-nine patients were included, and the median age was 63 years. The median follow-up was 36 months (range, 19 to 57 months). The overall response rate was 92% (CR, 81%; partial response, 11%), and the median survival was 21 months. The 1- and 2-year disease-specific survival rates were 69% and 37%, respectively. Of 29 CR patients, 83% have relapsed. Brain metastasis was as frequent as local recurrences (42%). Hematologic toxicity included grade 3 to 4 leukopenia in 74% of patients and grade 3 thrombocytopenia in 10%. One treatment-related death occurred as a result of severe neutropenia and septicemia. Hematotoxicity caused dose reductions in 31% of courses. One patient had an anaphylactic reaction during the first paclitaxel infusion. Paclitaxel-related neuropathy and myalgia were reversible. Grade 3 esophagitis was seen in five patients during and shortly after TRT.

CONCLUSION: This novel multimodal regimen is effective and well tolerated in patients with LD-SCLC. It compares favorably with previously published phase II studies.
A Simple Stratification Factor Prognostic for Survival in Advanced Cancer: The Good/Bad/Uncertain Index
Authors: Sloan Jeff A. , Loprinzi Charles L. , Laurine John A. , Novotny Paul J. , Vargas-Chanes Delfino , Krook James E. , O’Connell Michael J. , Kugler John W. , Tirona Maria Tria , Kardinal Carl G. , Wiesenfeld Martin , Tschetter Loren K. , Hatfield Alan K. , Schaefer Paul L.
Published: February 2017

PURPOSE: This article summarizes the third step of a research program to identify variables that supplement the predictive power of the the Eastern Cooperative Oncology Group (ECOG) performance status (PS) for survival. The objective was to produce a simple, practical, stratification factor for phase III oncology clinical trials involving patients with advanced malignant disease.

PATIENTS AND METHODS: A questionnaire was administered to 729 patients with metastatic colorectal or lung cancers. Patients provided a Karnofsky index and appetite rating while physicians provided a survival estimate and the ECOG-PS. Scores for each item were categorized as having a positive, neutral, or negative indication for survival. A patient was classified as having a relatively good prognosis if three or more of the four items showed a positive indication, a bad prognosis if three or more items were negative, and an uncertain prognosis otherwise (Good/Bad/Uncertain [GBU] index).

RESULTS: The GBU index improved on the prognostic power of a Cox model quartile index and PS alone and increased the accuracy of survival classification estimates by 5% to 10% more than ECOG-PS alone. For patients with PS of 0 or 1, significant survival patterns exist between GBU groups (P= .002 and .0001, respectively).

CONCLUSION: The GBU index may be recommended as a supplementary stratification factor for certain future phase III trials in metastatic lung or colorectal cancer where patient heterogeneity is a particular concern. The GBU represents a relatively modest increase to the cost and patient burden of a clinical trial given the additional control that is achieved over the potentially confounding concomitant to the treatment variable.
Randomized Clinical Trials in Oncology: Understanding and Attitudes Predict Willingness to Participate
Authors: Ellis Peter M. , Butow Phyllis N. , Tattersall Martin H.N. , Dunn Stewart M. , Houssami Nehmat
Published: February 2017

PURPOSE: To explore the association at different time points in the trajectory of breast cancer care, between anxiety, knowledge, and attitudes, on women’s willingness to participate in randomized clinical trials.

MATERIALS AND METHODS: A cross-sectional survey was undertaken among women attending a breast clinic for screening mammography or diagnostic assessment plus women with newly diagnosed breast cancer to assess attitudes toward and willingness to participate in randomized clinical trials of breast cancer treatment.

RESULTS: Five hundred forty-five women completed questionnaires assessing knowledge of and attitudes toward randomized clinical trials. The mean age of respondents was 48.9 years (SD, 11.3 years). Thirty-three percent of women would consider participating in a clinical trial if they had breast cancer. Women with breast cancer (31%) were significantly more likely to decline to participate than women attending for screening mammography (15%) or diagnostic assessment (15%, P = .0002). Women who might consider participating in a randomized clinical trial were more knowledgeable about randomized trials (mean difference, 0.7; 95% confidence interval [CI], 0.2 to 1.2; P = .003). In a multivariate analysis, women who would consider participating in a randomized trial were younger (odds ratio [OR], 0.96; 95% CI, 0.93 to 0.99), more likely to want an active role in decision-making (OR, 3.2; 95% CI, 1.3 to 7.6), and reported a greater impact from the positive aspects of clinical trials (OR, 2.2; 95% CI, 1.3 to 3.8) and less impact from the negative aspects of clinical trials (OR, 2.2; 95% CI, 1.3 to 3.2).

CONCLUSION: These findings suggest that women who have a better understanding of issues about clinical trials have more favorable attitudes toward randomized trials and are more willing to consider participation in a clinical trial.
Acute and Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell and Bone Marrow Transplantation: A Meta-Analysis
Authors: Cutler Corey , Giri Satyendra , Jeyapalan Suriya , Paniagua David , Viswanathan Akila , Antin Joseph H.
Published: February 2017

PURPOSE: Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures.

METHODS: An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed.

RESULTS: Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P= .006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P < .001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P < .001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05).

CONCLUSION: Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.
Body-Surface Area–Based Dosing Does Not Increase Accuracy of Predicting Cisplatin Exposure
Authors: de Jongh Felix E. , Verweij Jaap , Loos Walter J. , de Wit Ronald , de Jonge Maja J.A. , Planting André S.T. , Nooter Kees , Stoter Gerrit , Sparreboom Alex
Published: February 2017

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population.

PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m2 (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non–protein-bound cisplatin in plasma by atomic absorption spectrometry.

RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CLfree) was 57.1 ± 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m2 (mean, 1.86 ± 0.19 m2), with an interpatient variability of 10.4%. When CLfree was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CLfree and BSA (r = 0.42). Intrapatient variability in CLfree, calculated from 90 patients was 12.1% ± 7.8% (range, 0.30% to 32.7%).

CONCLUSION: In view of the high interpatient variability in CLfree relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.
Primary Chemotherapy for Operable Breast Cancer: Incidence and Prognostic Significance of Ipsilateral Breast Tumor Recurrence After Breast-Conserving Surgery
Authors: Rouzier Roman , Extra Jean-Marc , Carton Mathieu , Falcou Marie-Christine , Vincent-Salomon Anne , Fourquet Alain , Pouillart Pierre , Bourstyn Edwige
Published: February 2017

PURPOSE: To determine the incidence and the prognostic value of ipsilateral breast tumor recurrence (IBTR) in patients treated with primary chemotherapy and breast-conserving surgery.

PATIENTS AND METHODS: Between January 1985 and December 1994, 257 patients with invasive T1 to T3 breast carcinoma were treated with primary chemotherapy, lumpectomy, and radiation therapy. The median follow-up time was 93 months. To evaluate the role of IBTR in metastase-free survival, a Cox regression multivariate analysis was performed using IBTR as a time-dependent covariate.

RESULTS: The IBTR rates were 16% (± 2.4%) at 5 years and 21.5% (± 3.2%) at 10 years. Multivariate analysis showed that the probability of local control was decreased by the following independent factors: age ≤ 40 years, excision margin ≤ 2 mm, S-phase fraction more than 4%, and clinical tumor size more than 2 cm at the time of surgery. In patients with excision margins of more than 2 mm, the IBTR rates were 12.7% at 5 years and 17% at 10 years. Nodal status, age ≤ 40 years, and negative estrogen receptor status were predictors of distant disease in the Cox multivariate model with fixed covariates. The contribution of IBTR was highly significant (relative risk = 5.34) when added to the model, whereas age ≤ 40 years was no longer significant. After IBTR, 31.4% (± 7.0%) of patients developed metastases at 2 years and 59.7% (± 8.1%) at 5 years. Skin involvement, size at initial surgery, and estrogen receptor status were predictors of metastases after IBTR.

CONCLUSION: IBTR is a strong predictor for distant metastases. There are implications for conservative surgery after downstaging of the tumor and therapy at the time of IBTR.
United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia
Authors: Soignet Steven L. , Frankel Stanley R. , Douer Dan , Tallman Martin S. , Kantarjian Hagop , Calleja Elizabeth , Stone Richard M. , Kalaycio Matt , Scheinberg David A. , Steinherz Peter , Sievers Eric L. , Coutré Steven , Dahlberg Steve , Ellison Ralph , Warrell Raymond P.
Published: February 2017

PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL).

PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or ≥ second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study.

RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/μL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes.

CONCLUSION: This study establishes ATO as a highly effective therapy for patients with relapsed APL.
Primary Gastrointestinal Non-Hodgkin’s Lymphoma: II. Combined Surgical and Conservative or Conservative Management Only in Localized Gastric Lymphoma—Results of the Prospective German Multicenter Study GIT NHL 01/92
Authors: Koch Peter , del Valle Francisco , Berdel Wolfgang E. , Willich Normann A. , Reers Berthold , Hiddemann Wolfgang , Grothaus-Pinke Bernward , Reinartz Gabriele , Brockmann Jens , Temmesfeld Altfried , Schmitz Rudolf , Rübe Christian , Probst Andreas , Jaenke Gert , Bodenstein Heinrich , Junker Arved , Pott Christiane , Schultze Jürgen , Heinecke Achim , Parwaresch Reza , Tiemann Markus ,   for the German Multicenter Study Group
Published: February 2017

PURPOSE: The aim of the study was to obtain data on anatomic and histologic distribution, clinical features, and treatment results of patients with primary gastrointestinal non-Hodgkin’s lymphomas, particularly combined surgical and conservative treatment (CSCT) versus conservative treatment (CT) alone for primary gastric lymphoma (PGL) in localized stages.

PATIENTS AND METHODS: Whether the treatment included surgery was left to the discretion of each participating center. Radiotherapy (Rx) and chemotherapy were stratified according to histologic grading, stage, and the inclusion or omission of surgery as follows: patients with low-grade PGL were treated with extended-field (EF) Rx (30 Gy). In case of residual tumor after surgery or in case of CT only (in stage IIE after six cycles of cyclophosphamide, vincristine, and prednisone), an additional boost of 10 Gy was given. All patients with high-grade PGL were treated with four (stage IE) or six (stage IIE) cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by EF Rx (stage IE) or involved-field (IF) Rx (stage IIE). Rx dosage corresponded to low-grade NHL.

RESULTS: Between October 1992 and November 1996, 106 patients had CT only. The survival rate (SR) after 5 years was 84.4% and was influenced neither by patients’ characteristics nor by stage or histologic grade. Seventy-nine patients had CSCT. Their SR was 82.0%. Complete resection of the tumor (R0) was prognostic for the overall survival (P = .0165) as compared with incomplete resection.

CONCLUSION: Although the study was not randomized, a stomach-conserving approach may be favored.
Quality of Life in Palliative Cancer Care: Results From a Cluster Randomized Trial
Authors: Jordhøy Marit S. , Fayers Peter , Loge Jon Håvard , Ahlner-Elmqvist Marianne , Kaasa Stein
Published: February 2017

PURPOSE: To assess the impact of comprehensive palliative care on patients’ quality of life. The intervention was based on cooperation between a palliative medicine unit and the community service and was compared with conventional care.

PATIENTS AND METHODS: A cluster randomized trial was carried out, with community health care districts defined as the clusters. Patients from these districts who had malignant disease and survival expectancy between 2 to 9 months were entered onto the trial. The main quality-of-life end points were physical and emotional functioning, pain, and psychologic distress assessed monthly by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) questionnaire and Impact of Event scale (IES). In total, 235 intervention patients and 199 controls were included.

RESULTS: During the initial 4 months of follow-up, the compliance was good (72%) and comparable among treatment groups. No significant differences on any of the quality-of-life scores were found. At later assessments and for scores that were made within 3 months before death, there was also no consistent tendency in favor of any treatment group on the main outcomes or other EORTC QLQ-C30 scales/items.

CONCLUSION: A general program of palliative care may be important to ensure flexibility and to meet the needs of terminally ill patients. However, to achieve improvements on a group level of the various dimensions of quality of life, specific interventions directed toward specific symptoms or problems may have to be defined, evaluated, and included in the program.
Efficacy of Contralateral Prophylactic Mastectomy in Women With a Personal and Family History of Breast Cancer
Authors: McDonnell Shannon K. , Schaid Daniel J. , Myers Jeffrey L. , Grant Clive S. , Donohue John H. , Woods John E. , Frost Marlene H. , Johnson Joanne L. , Sitta Diana L. , Slezak Jeffrey M. , Crotty Thomas B. , Jenkins Robert B. , Sellers Thomas A. , Hartmann Lynn C.
Published: February 2017

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy.

RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%).

CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.
Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study
Authors: Percesepe Antonio , Borghi Francesca , Menigatti Mirco , Losi Lorena , Foroni Moira , Di Gregorio Carmela , Rossi Giuseppina , Pedroni Monica , Sala Elisa , Vaccina Fabiana , Roncucci Luca , Benatti Piero , Viel Alessandra , Genuardi Maurizio , Marra Giancarlo , Kristo Paula , Peltomäki Paivi , Ponz de Leon Maurizio
Published: February 2017

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer.

PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1.

RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differentiation (P = .002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations.

CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.
K-ras and p16 Aberrations Confer Poor Prognosis in Human Colorectal Cancer
Authors: Esteller M. , González S. , Risques R. A. , Marcuello E. , Mangues R. , Germà J. R. , Herman J. G. , Capellà G. , Peinado M. A.
Published: February 2017

PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways.

PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated.

RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered.

CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.
Adjuvant Tamoxifen: Predictors of Use, Side Effects, and Discontinuation in Older Women
Authors: Demissie Serkalem , Silliman Rebecca A. , Lash Timothy L.
Published: February 2017

PURPOSE: To identify predictors of adjuvant tamoxifen use, side effects, and discontinuation in older women.

PATIENTS AND METHODS: We followed a cohort of 303 women ≥ 55 years of age diagnosed with stage I or stage II breast cancer for nearly 3 years. Data were collected from women’s surgical records and from computer-assisted telephone interviews at 5, 21, and 33 months after primary tumor therapy.

RESULTS: Two hundred ninety-two (96%) of 303 patients in the study provided information about tamoxifen use. Tamoxifen use was reported by 189 patients (65%); 26 (15%) discontinued use during the follow-up period. Patients who were 65 to 74 years of age (relative to those 55 to 64 years of age), had stage II disease, were estrogen receptor–positive, saw a greater number of breast cancer physicians, and had better perceptions of their abilities to discuss treatment options with physicians had greater odds of tamoxifen use. Those who had better physical function, had received standard primary tumor therapy, and had obtained helpful breast cancer information from books or magazines had lesser odds of tamoxifen use. Patients ≥ 75 years of age (relative to those 55 to 64 years of age) and patients with better emotional health had significantly lesser odds of reporting side effects. Patients who were estrogen receptor–positive were less likely to stop taking tamoxifen; patients who experienced side effects were more likely to stop taking tamoxifen.

CONCLUSION: Deviations from a prescribed course of adjuvant tamoxifen occur relatively frequently. The clinical consequences of this deviation need to be identified.
Efficacy of Docetaxel 60 mg/m2 in Patients With Metastatic Breast Cancer According to the Status of Anthracycline Resistance
Authors: Ando Masashi , Watanabe Toru , Nagata Kazuhiro , Narabayashi Masaru , Adachi Isamu , Katsumata Noriyuki
Published: February 2017

PURPOSE: To evaluate the efficacy of docetaxel 60 mg/m2 in metastatic breast cancer (MBC) according to the status of anthracycline resistance.

PATIENTS AND METHODS: Ninety-nine patients with anthracycline-resistant MBC were treated with docetaxel 60 mg/m2 intravenously for a 90-minute period every 3 to 4 weeks. Anthracycline resistance was defined as primary and secondary resistance. Primary resistance was defined as progression during or within 6 months after completion of adjuvant anthracycline, and no MBC response to a first-line regimen that contained anthracycline. Secondary resistance was defined as progression after a documented clinical response to a first-line anthracycline treatment for MBC. Secondary resistance was further divided into three categories: (1) absolute resistance, or progression during treatment with anthracycline after a period of response; (2) relative resistance, or progression within 6 months after anthracycline administration ended; and (3) sensitive regrowth, or progression more than 6 months after the conclusion of anthracycline administration.

RESULTS: The response rate in the 99 patients was 35.4% (95% confidence interval, 30.1% to 44.8%). The response rates according to the status of anthracycline resistance were as follows: primary resistance (n = 46), 19.6%; secondary resistance (n = 53), 49.1% (absolute resistance [n = 16], 56.3%); relative resistance (n = 17), 47.1%; and sensitive regrowth (n = 20), 45.0%. The median time to treatment failure in patients with primary resistance was 2.9 months, compared with 5.2 months in patients with secondary resistance (P = .0022).

CONCLUSION: Docetaxel at a dose of 60 mg/m2 seemed to be effective in MBC with secondary resistance to anthracycline. The status of anthracycline resistance is important for the prediction of response to second-line treatment with docetaxel.
Combined Tamoxifen and Luteinizing Hormone-Releasing Hormone (LHRH) Agonist Versus LHRH Agonist Alone in Premenopausal Advanced Breast Cancer: A Meta-Analysis of Four Randomized Trials
Authors: Klijn J. G.M. , Blamey R.W. , Boccardo F. , Tominaga T. , Duchateau L. , Sylvester R.
Published: February 2017

PURPOSE: The logic behind the application of luteinizing hormone-releasing hormone (LHRH) agonists in combination with tamoxifen in premenopausal women is that LHRH agonists on the one hand suppress the tamoxifen-induced stimulation of the pituitary-ovarian function and, on the other hand, seem as effective as surgical castration. This meta-analysis combines all randomized evidence to compare the combined treatment with LHRH agonist alone with respect to overall survival, progression-free survival, and objective response in premenopausal women with advanced breast cancer.

PATIENTS AND METHODS: Four clinical trials randomizing a total of 506 premenopausal women with advanced breast cancer to LHRH agonist alone or to the combined treatment of LHRH agonist plus tamoxifen were identified. Meta-analytic techniques were used to analyze individual patient data from these trials.

RESULTS: With a median follow-up of 6.8 years, there was a significant survival benefit (stratified log-rank test, P = .02; hazards ratio [HR] = 0.78) and progression-free survival benefit (stratified log-rank test, P = .0003; HR = 0.70) in favor of the combined treatment. The overall response rate was significantly higher on combined endocrine treatment (stratified Mantel Haenszel test, P = .03; odds ratio = 0.67).

CONCLUSION: The combination of LHRH agonist plus tamoxifen is superior to LHRH agonist alone in premenopausal women with advanced breast cancer. Therefore, if a premenopausal woman with advanced breast cancer is thought to be suitable for endocrine treatment, it is proposed that the combination of a LHRH agonist plus tamoxifen be considered as the new standard treatment.
Autologous Transplantation for Diffuse Aggressive Non-Hodgkin’s Lymphoma in Patients Never Achieving Remission: A Report from the Autologous Blood and Marrow Transplant Registry
Authors: Vose Julie M. , Zhang Mei-Jie , Rowlings Philip A. , Lazarus Hillard M. , Bolwell Brian J. , Freytes Cesar O. , Pavlovsky Santiago , Keating Armand , Yanes Burhan , van Besien Koen , Armitage James O. , Horowitz Mary M. ,   Others of the Autologous Blood and Marrow Transplant Registry Lymphoma Working Committee
Published: February 2017

PURPOSE: To evaluate the results of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (autotransplants) in patients with diffuse aggressive non-Hodgkin’s lymphoma (NHL) who never achieve a complete remission with conventional chemotherapy.

PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 184 patients with diffuse aggressive NHL who never achieved a complete remission with conventional chemotherapy and subsequently received an autotransplant were evaluated. Transplants were performed between 1989 and 1995 and were reported to the ABMTR by 48 centers in North and South America.

RESULTS: Seventy-nine (44%) of 184 patients achieved a complete remission or a complete remission with residual imaging abnormalities of unknown significance after autotransplantation. Thirty-four (19%) of 184 had a partial remission and 55 (31%) of 184 had no response or progressive disease. Eleven patients (6%) were not assessable for response because of early death. The probabilities of progression-free and overall survival at 5 years after transplantation were 31% (95% confidence interval [CI], 24% to 38%) and 37% (95% CI, 30% to 45%), respectively. In multivariate analysis, chemotherapy resistance, Karnofsky performance status score less than 80 at transplantation, age ≥ 55 years at transplantation, receiving three or more prior chemotherapy regimens, and not receiving pre- or posttransplant involved-field irradiation therapy were adverse prognostic factors for overall survival.

CONCLUSION: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation should be considered for patients with diffuse aggressive NHL who never achieve a complete remission but who are still chemotherapy-sensitive and are otherwise transplant candidates.
Phase I/II Study of Escalating Doses of Vinorelbine in Combination With Oxaliplatin in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Monnet Isabelle , Soulié Patrick , de Cremoux Hubert , Saltiel-Voisin Sabine , Bekradda Mohammed , Saltiel Jean-Claude , Brain Etienne , Dupont-André Ghislaine , Cvitkovic Esteban
Published: February 2017

PURPOSE: Oxaliplatin is a platinum compound active in non–small-cell lung cancer (NSCLC) patients, and vinorelbine (VNB) is an active reference agent. This phase I/II study was performed to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the recommended dose (RD) of a VNB/oxaliplatin combination given to previously untreated patients with advanced NSCLC.

PATIENTS AND METHODS: Oxaliplatin was given at the fixed dose of 130 mg/m2 (2-hour intravenous [IV] infusion) on day 1. VNB was administered on days 1 and 8 (10-minute IV infusion), with doses starting at 22 mg/m2/d and escalated by 2 mg/m2 increments until MTD. Treatment was repeated every 3 weeks. No special hydration measures or prophylactic granulocyte colony-stimulating factors were used.

RESULTS: Twenty-seven patients (20 men, 7 women) received 110 cycles total at six different VNB dose levels. Neutropenia was the DLT. Although no patient experienced DLT at the highest dose level (32 mg/m2/d), multiple treatment delays (54% of cycles) and dose reductions (34% of cycles) were required at this dose level. Others toxicities were mainly limited to grade 1 peripheral neuropathy and grade 1/2 nausea/vomiting. The relative dose-intensity of administered VNB from dose levels 3 to 6 (26 to 32 mg/m2) remained stable, whereas grade 3/4 neutropenia increased. All patients were assessable for activity; there were 10 objective responses, including one complete response (37% response rate).

CONCLUSION: The present combination can be safely administered in an outpatient setting. The RD is VNB 26 mg/m2 days 1 and 8 with oxaliplatin 130 mg/m2 day 1 every 3 weeks.