bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized Study of CODE Versus Alternating CAV/EP for Extensive-Stage Small-Cell Lung Cancer: An Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group
Authors: Murray Nevin , Livingston Robert B. , Shepherd Frances A. , James Keith , Zee Benny , Langleben A. , Kraut Michael , Bearden James , Goodwin J. Wendall , Grafton Clive , Turrisi Andrew , Walde David , Croft Herbert , Osoba David , Ottaway Jon , Gandara David
Published: February 2017

PURPOSE: To determine whether an intensive weekly chemotherapy regimen plus thoracic irradiation is superior to standard chemotherapy in the treatment of extensive-stage small-cell lung cancer (ESCLC).

PATIENTS AND METHODS: Patients with ESCLC were considered eligible for the study if they were younger than 68 years, had a performance status of 0 to 2, and were free of brain metastases. Patients were randomized to receive cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Consolidative thoracic irradiation and prophylactic cranial irradiation were given to patients responding to CODE and according to investigator discretion on the CAV/EP arm.

RESULTS: The fidelity of drug delivery on both drug regimens was equal, and more than 70% of all patients received the intended protocol chemotherapy. Although rates of neutropenic fever were similar, nine (8.2%) of 110 patients on the CODE arm died during chemotherapy, whereas one (0.9%) of 109 patients died on the CAV/EP arm. Response rates after chemotherapy were higher (P = .006) with CODE (87%) than with CAV/EP (70%). However, progression-free survival (median of 0.66 years on both arms) and overall survival (median, 0.98 years for CODE and 0.91 years for CAV/EP) were not statistically different.

CONCLUSION: The CODE regimen increased two-fold the received dose-intensity of four of the most active drugs in small-cell lung cancer compared with the standard CAV/EP regimen while maintaining an approximately equal total dose. Despite supportive care (but not routine prophylactic use of granulocyte colony-stimulating factor), there was excessive toxic mortality with the CODE regimen. The response rate with CODE was higher than that of CAV/EP, but progression-free and overall survival were not significantly improved. In view of increased toxicity and similar efficacy, the CODE chemotherapy regimen is not recommended for treatment of ESCLC.
Prospective Randomized Trial of Docetaxel Versus Doxorubicin in Patients With Metastatic Breast Cancer
Authors: Chan Stephen , Friedrichs Kay , Noel Daniel , Pintér Tamàs , Van Belle Simon , Vorobiof Daniel , Duarte Ricardo , Gil Gil Miguel , Bodrogi Istvan , Murray Elizabeth , Yelle Louise , von Minckwitz Gunter , Korec Stefan , Simmonds Peter , Buzzi Franco , González Mancha Rosario , Richardson Gary , Walpole Euan , Ronzoni Monica , Murawsky Michael , Alakl May , Riva Alessandro , Crown John
Published: February 2017

PURPOSE: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent–containing chemotherapy.

PATIENTS AND METHODS: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m2 or doxorubicin 75 mg/m2 every 3 weeks for a maximum of seven treatment cycles.

RESULTS: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P = .008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel.

CONCLUSION: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.
Predictors of Sexual Health in Women After a Breast Cancer Diagnosis
Authors: Ganz Patricia A. , Desmond Katherine A. , Belin Thomas R. , Meyerowitz Beth E. , Rowland Julia H.
Published: February 2017

PURPOSE: To identify variables that might be predictive of sexual health (interest, dysfunction, and satisfaction) in a large sample of breast cancer survivors, with a validation conducted in a second, independent sample.

PATIENTS AND METHODS: On the basis of a conceptual framework of sexual health in breast cancer survivors, we performed multivariable regression analyses to estimate sexual interest, dysfunction, and satisfaction in both samples. Additional analyses were performed using stepwise regression and recursive partitioning to explore in each sample the relative contributions of the independent variables toward predicting the outcome measures.

RESULTS: The models for sexual interest accounted for at least 33% of the variance, and the significant predictors common to the two samples were having a new partner since the diagnosis of breast cancer, mental health score, and body image score. For sexual dysfunction, the models in the two samples explained at least 33% of the variance, and the common significant predictors were vaginal dryness, past chemotherapy use, and having a new partner since diagnosis. The sexual satisfaction models explained at least 27% of the variance, with the common significant predictors being the quality of the partnered relationship and sexual problems in the partner.

CONCLUSION: Among the predictors of sexual health, several are mutable (vaginal dryness, emotional well-being, body image, the quality of the partnered relationship, and sexual problems in the partner), and these should be considered for future interventions to address the sexual health and well-being of breast cancer survivors.
Early Detection and Accurate Description of Extent of Metastatic Bone Disease in Breast Cancer With Fluoride Ion and Positron Emission Tomography
Authors: Schirrmeister Holger , Guhlmann Albrecht , Kotzerke Jörg , Santjohanser Claudia , Kühn Thorsten , Kreienberg Rolf , Messer Peter , Nüssle Karin , Elsner Klaus , Glatting Gerhard , Träger Harald , Neumaier Bernd , Diederichs Christoph , Reske Sven N.
Published: February 2017

PURPOSE: Previous studies have shown that bone metastases are revealed by magnetic resonance imaging (MRI) or bone marrow scintigraphy several months before they are visible by conventional bone scintigraphy (BS). We present a new approach for detecting bone metastases in patients with breast cancer. We compared findings obtained with fluoride ion (F-18) and positron emission tomography (PET) with those obtained with conventional BS.

PATIENTS AND METHODS: Thirty-four breast cancer patients were prospectively examined using F-18–PET and conventional BS. F-18–PET and BS were performed within 3 weeks of each other. Metastatic bone disease was previously known to be present in six patients and was suspected (bone pain or increasing levels of tumor markers, Ca2+, alkaline phosphatase) in 28 patients. Both imaging modalities were compared by patient-by-patient analysis and lesion-by-lesion analysis, using a five-point scale for receiver operating characteristic (ROC) curve analysis. A panel of reference methodswas used, including MRI (28 patients), planar x-ray (17 patients), and spiral computed tomography (four patients).

RESULTS: With F-18–PET, 64 bone metastases were detected in 17 patients. Only 29 metastases were detected in 11 patients with BS. As a result of F-18–PET imaging, clinical management was changed in four patients (11.7%). For F-18–PET, the area under the ROC curve was 0.99 on a lesion basis (for BS, it was 0.74; P < .05) and 1.00 on a patient basis (for BS, it was 0.82; P < .05).

CONCLUSION: F-18–PET demonstrates a very early bone reaction when small bone marrow metastases are present, allowing accurate detection of breast cancer bone metastases. This accurate detection has a significant effect on clinical management, compared with the effect on management brought about by detection with conventional BS.
Hyper-CVAD Program in Burkitt's-Type Adult Acute Lymphoblastic Leukemia
Authors: Thomas Deborah A. , Cortes Jorge , O'Brien Susan , Pierce Sherry , Faderl Stefan , Albitar Maher , Hagemeister Frederick B. , Cabanillas Fernando F. , Murphy Sharon , Keating Michael J. , Kantarjian Hagop
Published: February 2017

PURPOSE: To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were ≥ 60 years. Patients received Hyper-CVAD alternated with courses of high-dose methotrexate and cytarabine. Granulocyte colony-stimulating factor and prophylactic antibiotics were administered for all eight planned courses. CNS prophylaxis alternated intrathecal methotrexate and cytarabine on days 2 and 7 of each course.

RESULTS: Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (± 11%); the 3-year continuous CR rate was 61% (± 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age ≥ 60 years, poor performance status, anemia, thrombocytopenia, peripheral blasts, and increased lactate dehydrogenase level. The 3-year survival rate was 77% for 14 patients younger than 60 years and 17% for 12 patients ≥ 60 years (P < .01). Regression analysis identified older age, anemia, and presence of peripheral blasts as independent factors associated with shorter survival. Patients could be stratified according to (1) no or one adverse feature, (2) two adverse features, and (3) all adverse features. The 3-year survival rates were 89%, 47%, and 0%, respectively (P < .01).

CONCLUSION: Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.
Marginal Zone B-Cell Lymphoma: A Clinical Comparison of Nodal and Mucosa-Associated Lymphoid Tissue Types
Authors: Nathwani Bharat N. , Anderson James R. , Armitage James O. , Cavalli Franco , Diebold Jacques , Drachenberg Milton R. , Harris Nancy L. , MacLennan Kenneth A. , Müller-Hermelink H. Konrad , Ullrich Fred A. , Weisenburger Dennis D.
Published: February 2017

PURPOSE: In the International Lymphoma Study Group classification of lymphoma, extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) type is listed as a distinctive entity. However, nodal MZL is listed as a provisional entity because of questions as to whether it is truly a disease or just an advanced stage of MALT-type MZL. To resolve the issue of whether primary nodal MZL without involvement of mucosal sites exists and whether it is clinically different from extranodal MALT-type lymphoma, we compared the clinical features of these two lymphomas.

PATIENTS AND METHODS: Five expert hematopathologists reached a consensus diagnosis of MZL in 93 patients. Seventy-three were classified as having MALT-type MZL because of involvement of a mucosal site at the time of diagnosis, and 20 were classified as having nodal MZL because of involvement of lymph nodes without involvement of a mucosal site.

RESULTS: A comparison of the clinical features of nodal MZL and MALT-type MZL showed that more patients with nodal MZL presented with advanced-stage disease (71% v 34%; P = .02), peripheral lymphadenopathy (100% v 8%; P < .001), and para-aortic lymphadenopathy (56% v 14%; P < .001) than those with MALT-type MZL. However, fewer patients with nodal MZL had a large mass (≥ 5 cm) than those with MALT-type MZL (31% v 68%; P = .03). The 5-year overall survival of patients with nodal MZL was lower than that for patients with MALT-type MZL (56% v 81%; P = .09), with a similar result for failure-free survival (28% v 65%; P = .01). Comparisons of patients with International Prognostic Index scores of 0 to 3 showed that those with nodal MZL had lower 5-year overall survival (52% v 88%; P = .025) and failure-free survival (30% v 75%; P = .007) rates than those with MALT-type MZL.

CONCLUSION: Nodal MZL seems to be a distinctive disease entity rather than an advanced stage of MALT-type MZL because the clinical presentations and survival outcomes are different in these two types of MZL. Clinically, nodal MZL is similar to other low-grade, node-based B-cell lymphomas, such as follicular and small lymphocytic lymphomas.
Assessment and Significance of Mediastinal Bulk in Hodgkin's Disease: Comparison Between Computed Tomography and Chest Radiography
Authors: Bradley A. J. , Carrington B. M. , Lawrance J. A.L. , Ryder W. D.J. , Radford J. A.
Published: February 2017

PURPOSE: In Hodgkin's disease (HD), mediastinal bulk is currently defined from chest radiograph (CXR) measurements as a ratio of the maximum transverse mass diameter to the internal thoracic diameter at T5/6 level ≥ 0.33. We evaluated how computed tomographic (CT) measurements of bulk correspond to those obtained from the CXR and correlated nodal mass long axis diameter with freedom from progression.

METHODS: Ninety-five adult patients who had a CXR thoracic ratio of greater than 0.3 and a CT scan within 28 days of the CXR were included in the study, provided that both investigations were performed before the start of treatment. Measurements of the widest mediastinal diameter and internal thoracic diameter were made on both CXR and CT scan. The thoracic ratio (TR) was calculated for each modality and compared using paired t tests. The longest diameter of the largest individual nodal mass (LIMCT) was also measured from the CT and correlated with freedom from progression using Cox regression.

RESULTS: There was excellent correlation between CT and CXR for measurement of TR, with TRCT greater than TRCXR (mean difference of 2%). A TRCT of 0.35 was found to be equivalent to a TRCXR of 0.33. No single measurement of nodal size correlated with the current definition of bulk. However LIMCT greater than 10 cm did correlate with increased risk of progressive HD (P = .03), even after adjustment for other prognostic variables (chemotherapy regimen and Hasenclever Prognostic Index).

CONCLUSION: Excellent correlation was observed between assessment of TR by CXR and CT scan. The longest diameter of the LIMCT greater than 10 cm was found to be associated with an increased risk of disease progression.
Low-Grade Stage III-IV Follicular Lymphoma: Multivariate Analysis of Prognostic Factors in 484 Patients—A Study of the Groupe d'Etude des Lymphomes de l'Adulte
Authors: Decaudin Didier , Lepage Eric , Brousse Nicole , Brice Pauline , Harousseau Jean-Luc , Belhadj Karim , Tilly Hervé , Michaux Lucienne , Chèze Stéphane , Coiffier Bertrand , Solal-Céligny Philippe
Published: February 2017

PURPOSE: To identify the prognostic factors that influence overall survival (OS) in patients with stage III-IV follicular lymphomas and evaluate the clinical usefulness and the prognostic value of the International Prognostic Index (IPI).

PATIENTS AND METHODS: Four hundred eighty-four patients with Ann Arbor stage III-IV follicular lymphomas treated in two phase III trials from 1986 to 1995 were screened for this study. All histologic slides were reviewed by two hematopathologists. The influence of the initial parameters on survival was defined by univariate (log-rank test) and multivariate (Cox model) analyses.

RESULTS: The poor prognostic factors for OS (age > 60 years, “B” symptom(s), ≥ two extranodal sites, stage IV disease, tumor bulk > 7 cm, at least three nodal sites > 3 cm, liver involvement, serous effusion-compression or orbital/epidural involvement, and erythrocyte sedimentation rate > 30 mm/h) that were significant in univariate analysis were subjected to multivariate analysis. Three factors remained significant: B symptom(s) (risk ratio = 1.80), age greater than 60 years (risk ratio = 1.60), and at least three nodal sites greater than 3 cm (risk ratio = 1.71). When the IPI was applied to these patients, the score was 1, 2, 3, and 4-5 in 49%, 39%, 11%, and 2%, respectively, and it was significant for progression-free survival (P = .002) and OS (P = .0001).

CONCLUSION: Three prognostic factors for poor OS were identified: B symptoms, age greater than 60 years, and at least three nodal sites greater than 3 cm. The IPI was prognostic for OS, but in this population, a very low number of patients belonged to the high-risk groups.
Survival and Prognostic Stratification of 670 Patients With Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Mazumdar Madhu , Bacik Jennifer , Berg William , Amsterdam Alison , Ferrara Joseph
Published: February 2017

PURPOSE: To identify prognostic factors and a model predictive for survival in patients with metastatic renal-cell carcinoma (RCC).

PATIENTS AND METHODS: The relationship between pretreatment clinical features and survival was studied in 670 patients with advanced RCC treated in 24 Memorial Sloan-Kettering Cancer Center clinical trials between 1975 and 1996. Clinical features were first examined univariately. A stepwise modeling approach based on Cox proportional hazards regression was then used to form a multivariate model. The predictive performance of the model was internally validated through a two-step nonparametric bootstrapping process.

RESULTS: The median survival time was 10 months (95% confidence interval [CI], 9 to 11 months). Fifty-seven of 670 patients remain alive, and the median follow-up time for survivors was 33 months. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status (<80%), high serum lactate dehydrogenase (> 1.5 times upper limit of normal), low hemoglobin (< lower limit of normal), high “corrected” serum calcium (> 10 mg/dL), and absence of prior nephrectomy. These were used as risk factors to categorize patients into three different groups. The median time to death in the 25% of patients with zero risk factors (favorable-risk) was 20 months. Fifty-three percent of the patients had one or two risk factors (intermediate-risk), and the median survival time in this group was 10 months. Patients with three or more risk factors (poor-risk), who comprised 22% of the patients, had a median survival time of 4 months.

CONCLUSIONS: Five prognostic factors for predicting survival were identified and used to categorize patients with metastatic RCC into three risk groups, for which the median survival times were separated by 6 months or more. These risk categories can be used in clinical trial design and interpretation and in patient management. The low long-term survival rate emphasizes the priority of clinical investigation to identify more effective therapy.
Multi-Institutional Study of the Angiogenesis Inhibitor TNP-470 in Metastatic Renal Carcinoma
Authors: Stadler Walter M. , Kuzel Timothy , Shapiro Charles , Sosman Jeffery , Clark Joseph , Vogelzang Nicholas J.
Published: February 2017

PURPOSE: Renal cell carcinoma is resistant to most chemotherapy, and only a minority of patients respond to immunotherapy. Its highly vascular nature suggests that antiangiogenesis therapy might be useful. We thus performed a phase II study of the fumigillin analog TNP-470 in previously treated patients with metastatic renal cell carcinoma.

PATIENTS AND METHODS: Metastatic renal cell carcinoma patients with good organ function were entered onto the study through five separate institutions. There were no exclusion criteria for prior therapy. All patients were treated at a dose of 60 mg/m2of TNP-470 infused over 1 hour three times per week.

RESULTS: Thirty-three patients were enrolled. Therapy was generally well tolerated, but asthenia, fatigue, vertigo, dizziness, sense of imbalance, and loss of concentration were common and severe enough to lead to therapy discontinuation in five patients. There was only one partial response of short duration (response rate, 3%, 95% confidence interval, 0% to 16%), but six patients (18%) remained on study for 6 or more months without toxicity or disease progression.

CONCLUSION: Long-term therapy with TNP-470 has manageable toxicities and is feasible in patients with metastatic renal cell carcinoma but does not lead to any significant objective responses. Further studies in this population using TNP-470 schedules that produce more prolonged drug levels and clinical trial end points other than objective tumor regression may be indicated.
Activity and Pharmacodynamics of 21-Day Topotecan Infusion in Patients With Ovarian Cancer Previously Treated With Platinum-Based Chemotherapy
Authors: Hochster Howard , Wadler Scott , Runowicz Carolyn , Liebes Leonard , Cohen Henry , Wallach Robert , Sorich Joan , Taubes Beth , Speyer James
Published: February 2017

PURPOSE: Twenty-one–day topotecan infusion was administered as second-line therapy in patients with previously treated ovarian cancer (based on our prior favorable phase I experience) to determine its activity, time to progression, and pharmacodynamics.

PATIENTS AND METHODS: Ovarian cancer patients with measurable lesions and one prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m2/d 21-day continuous ambulatory intravenous infusion, with appropriate dose modifications for toxicity, was administered every 28 days. Weekly blood levels of topotecan and topoisomerase-1 (topo-1) levels in peripheral-blood mononuclear cells (PBMCs) were determined for pharmacodynamic correlation.

RESULTS: Twenty-four patients were entered onto the study (six cisplatin-refractory, five relapsing within < 6 months and 13 relapsing > 6 months after platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One episode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the patients had anemia that required transfusions. Eight of 23 patients with measurable disease (35%; 95% confidence interval [CI], 15% to 54%) had partial responses (PRs) lasting longer than 1 month. Two of these patients had minor residual computed tomographic changes but had clinical complete remissions that lasted up to 53 weeks while they were not undergoing further therapy. One patient with nonmeasurable disease had a PR (by CA-125 criteria) that lasted 6 months, for an overall response rate of 38% in nine of 24 patients (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pharmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo-1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) for topotecan. This was confirmed in a pharmacodynamic model.

CONCLUSION: Twenty-one–day infusion is a well-tolerated method of administering topotecan. Pharmacodynamic studies demonstrate correlations between (1) the week of infusion and the PBMC topo-1 level, (2) the AUC of topotecan and the decrease in topo-1 levels, and (3) the change in topo-1 level and the neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level for topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administration therefore warrants further investigation in larger, randomized studies comparing this 21-day schedule with the once-daily-for-5-days schedule.
KRN8602 (MX2-Hydrochloride): An Active New Agent for the Treatment of Recurrent High-Grade Glioma
Authors: Clarke Kerrie , Basser Russell L. , Underhill Craig , Mitchell Peter , Bartlett Jane , Cher Lawrence , Findlay Michael , Dalley David , Pell Malcolm , Byrne Michael , Geldard Howard , Hill John S. , Maher Darryl , Fox Richard M. , Green Michael D. , Kaye Andrew H.
Published: February 2017

PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma.

PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score ≤ 2) were treated with an intravenous bolus of 40 mg/m2 KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles.

RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting.

CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.
Frequency of First Metastatic Events in Breast Cancer: Implications for Sequencing of Systemic and Local-Regional Treatment
Authors: Thames Howard D. , Buchholz Thomas A. , Smith Cynthia D.
Published: February 2017

PURPOSE: The sequencing of treatment for early breast cancer is controversial. The purpose of this study was to quantify the risk of delaying surgery, using estimates of the frequency of first metastases from breast primary tumors.

PATIENTS AND METHODS: The probability that 560 (node-negative), 657 (with one to three positive nodes), and 505 (with more than three positive nodes) women treated without adjuvant chemotherapy would be free of distant disease at presentation was fit to a mathematical model of the seeding of distant metastases and combined with estimates of the growth rate to calculate the frequency of first distant disseminations per month.

RESULTS: Frequencies of first distant metastases were approximately 1% to 2% per month, 2% to 4% per month, and 3% to 6% per month in T1 patients who were node-negative, had one to three positive nodes, or more than three positive nodes, respectively. As a result, the typical patient with T1 disease, who has a 70% to 80% chance of being free of distant disease, runs a 1% to 4% risk of distant dissemination for each month surgery is delayed. Assuming a 30% reduction in mortality caused by adjuvant chemotherapy, the model predicts that T1 patients treated with neoadjuvant chemotherapy would potentially have a higher rate of distant metastasis development than those treated with an initial surgical resection followed by adjuvant chemotherapy.

CONCLUSION: We formulate the hypothesis that optimal sequencing of surgery and systemic treatment of breast cancer may be size-dependent, with a disadvantage or no benefit from neoadjuvant treatment for T1 patients but an increasing benefit with increasing size of the primary tumor.
Health-Related Quality of Life and Tamoxifen in Breast Cancer Prevention: A Report From the National Surgical Adjuvant Breast and Bowel Project P-1 Study
Authors: Day Richard , Ganz Patricia A. , Costantino Joseph P. , Cronin Walter M. , Wickerham D. Lawrence , Fisher Bernard
Published: February 2017

PURPOSE: This is the initial report from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting.

PATIENTS AND METHODS: This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies–Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist.

RESULTS: No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar.

CONCLUSION: Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated.
Prognostic Value of Nucleolar Protein p120 in Patients With Resected Lung Adenocarcinoma
Authors: Sato George , Saijo Yasuo , Uchiyama Bine , Kumano Nobuko , Sugawara Shun-ichi , Fujimura Shigefumi , Sato Masami , Sagawa Motoyasu , Ohkuda Kazuhiro , Koike Kaoru , Minami Yuko , Satoh Ken , Nukiwa Toshihiro
Published: February 2017

PURPOSE: In this study we investigated the prognostic significance of proliferation-associated nucleolar protein p120 in primary resected lung adenocarcinoma because it reflects tumor growth fractions in vitro.

PATIENTS AND METHODS: Expression levels of p120 in tumors were assessed by immunohistochemistry in 74 patients who underwent radical resection. With clinical follow-up data, the prognostic significance of p120 calculated by labeling indices was evaluated using the Cox proportional hazards model.

RESULTS: p120 protein was clearly detected in nucleoli of adenocarcinoma cells. Its expression levels widely varied in each sample from 8.5% to 67.2%, with a mean ± SD of 35.2% ± 15.1%. No significant correlation was found between expression levels of p120 and clinicopathologic factors. However, the expression levels of p120 were negatively correlated with the tumor doubling time calculated with retrospective chest roentgenograms. Using a cutoff value of 35% in the labeling index of p120, patients with high expression of p120 experienced early recurrence and shorter survival compared with those who had low expression of p120. Multivariate analysis showed that p120 served as an independent, as well as the strongest, prognostic factor for resected lung adenocarcinoma.

CONCLUSION: This report provides the first evidence that expression levels of p120 in tumor tissues can be used as an independent and powerful prognostic marker for resected lung adenocarcinoma.
Prognostic Significance of Apoptotic Index in Completely Resected Non–Small-Cell Lung Cancer
Authors: Tanaka Fumihiro , Kawano Yozo , Li Mio , Takata Tetsuya , Miyahara Ryo , Yanagihara Kazuhiro , Ohtake Yohsuke , Fukuse Tatsuo , Wada Hiromi
Published: February 2017

PURPOSE: To evaluate the significance of apoptotic index (AI) as a prognostic factor after surgery for non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: A total of 236 patients who underwent surgery for previously untreated pathologic stage I to IIIa NSCLC between 1985 and 1990 were reviewed. AI was defined as the number of apoptotic cells, detected by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling, per 1,000 tumor cells. Proliferative index (PI) and aberrant p53 expression were also evaluated immunohistochemically.

RESULTS: The 5-year survival rate for the lowest-AI group (AI < 5.0) was 74.7%; those for the lower-AI group (5.0 ≤ AI < 11.0) and the higher-AI group (11.0 ≤ AI < 25.0) were 51.6% and 57.8%, respectively. These survival rates were significantly lower than that of the lowest-AI group (P = .021 and P = .043, respectively). The highest-AI group (25.0 ≤ AI), however, showed the most favorable prognosis, with a 5-year survival rate of 83.2%. Multivariate analysis confirmed that a moderate AI (5.0 ≤ AI < 11.0 or 11.0 ≤ AI < 25.0) was a significant factor to predict poor prognosis. The PIs for the lowest-, the lower-, the higher-, and the highest-AI groups were 32.3%, 48.0%, 54.3%, and 50.7%, respectively. The lowest-AI group showed a favorable prognosis because of its low PI, whereas the lower- and the higher-AI groups had a poor prognosis caused by increased cancer-cell proliferation. The highest-AI group showed the most favorable prognosis because apoptotic cell death overcame cell proliferation. No significant correlation was observed between AI and aberrant p53 expression.

CONCLUSION: AI proved to be an independent prognostic factor in NSCLC.
Long-Term Outcome of Patients With American Joint Committee on Cancer Stage IIB Extremity Soft Tissue Sarcomas
Authors: Fleming Jason B. , Berman Russell S. , Cheng Su-Chun , Chen Nancy P. , Hunt Kelly K. , Feig Barry W. , Respondek Paula M. , Yasko Alan W. , Pollack Alan , Patel Shreyaskumar R. , Burgess Michael A. , Papadopoulos Nicholas E. , Plager Carl , Zagars Gunar , Benjamin Robert S. , Pollock Raphael E. , Pisters Peter W.T.
Published: February 2017

PURPOSE: It has been suggested that patients with small (< 5 cm), high-grade extremity soft tissue sarcomas (STS) have an excellent overall prognosis and, consequently, may not require adjuvant therapies.

PATIENTS AND METHODS: A comprehensive review of all patients with extremity STS treated at a tertiary care cancer hospital over a 9-year period (January 1984 to December 1992) was performed. Prognostic factors, treatment data, and long-term outcome were evaluated in the subset of 111 patients with American Joint Committee on Cancer stage IIB (G3/4, T1a/b) disease.

RESULTS: The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm), and 55 tumors (50%) were deep in location. All patients underwent surgical resection; 68 (61%) received pre- or postoperative radiotherapy, and 32 (29%) received doxorubicin-based chemotherapy. The median follow-up was 76 months. Forty patients (36%) experienced 59 recurrences. First recurrences occurred at local, regional, and distant sites in 21, five, and 14 patients, respectively. The 5-year actuarial local recurrence-free, distant recurrence-free, disease-free, and overall survival rates were 82%, 83%, 68%, and 83%, respectively. The presence of a microscopically positive surgical margin was an independent adverse prognostic factor for both local recurrence (relative risk [RR] = 3.75; 95% confidence interval [CI], 1.25 to 11.25; P = .02) and disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P = .005).

CONCLUSION: Event-free outcome for this subset of patients with high-grade STS does not seem as favorable as previously reported by other investigators. Patients who undergo maximal surgical resection with microscopically positive margins represent a subset of T1 STS patients who warrant consideration for adjuvant therapies.
Outcome of Radiation-Related Osteosarcoma After Treatment of Childhood and Adolescent Cancer: A Study of 23 Cases
Authors: Tabone Marie-Dominique , Terrier Philippe , Pacquement Hélène , Brunat-Mentigny Maud , Schmitt Claudine , Babin-Boilletot Annie , Mahmoud Hazem H. , Kalifa Chantal
Published: February 2017

PURPOSE: We analyzed the clinical features and outcome of patients with radiation-associated osteosarcoma treated during the era of contemporary chemotherapy.

PATIENTS AND METHODS: The characteristics and outcome of 23 patients (17 males and six females) treated during childhood or adolescence for a solid tumor who later developed osteosarcomas within the radiation field between 1981 and 1996 were reviewed.

RESULTS: The median dose of radiation delivered to the first cancer was 47 Gy. Nineteen patients also received chemotherapy. The median time between radiotherapy and the diagnosis of secondary osteosarcoma was 8 years. Histologic slide review showed conventional central osteosarcoma with various differentiation patterns in 21 cases, together with one case of high-grade surface osteosarcoma and one of periosteal osteosarcoma. The sites of involvement were the craniofacial bones in six cases, the first cervical vertebra in one, the girdle bones in seven, and the extremities of long bones in nine. Three patients had metastatic disease at the diagnosis of osteosarcoma. Palliative therapy was administered to seven patients. The aim of treatment was curative for 16 patients, two of whom underwent amputation without further therapy. Intensive chemotherapy regimens were administered to 14 patients before and/or after surgery. Fifteen patients achieved complete surgical remission. Twelve patients were alive and disease-free at a median follow-up duration of 7.5 years. Overall and event-free survivals at 8 years were 50% and 41%, respectively.

CONCLUSION: Patients with radiation-related osteosarcoma and resectable lesions can be cured with surgery and intensive preoperative and postoperative chemotherapy.
Diffuse Large-Cell Lymphoma of the Testis
Authors: Tondini Carlo , Ferreri Andrés J.M. , Siracusano Licia , Valagussa Pinuccia , Giardini Roberto , Rampinelli Irene , Bonadonna Gianni
Published: February 2017

PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy.

PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index.

RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites.

CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning.
Efficacy of Nephron-Sparing Surgery for Renal Cell Carcinoma: Analysis Based on the New 1997 Tumor-Node-Metastasis Staging System
Authors: Belldegrun Arie , Tsui Ke-Hung , deKernion Jean B. , Smith Robert B.
Published: February 2017

PURPOSE: To analyze the experience with nephron-sparing surgery as a treatment modality for renal cell carcinoma (RCC).

PATIENTS AND METHODS: Between 1980 and 1997, 146 patients underwent partial nephrectomy at the University of California–Los Angeles Medical Center. A matched group of 125 patients who underwent radical nephrectomy at the same institution between 1986 and 1997 were selected for comparison. Patients were monitored for an average period of 57 months. Patients were staged according to both the 1997 and 1987 tumor-node-metastasis (TNM) staging criteria. Survival data were calculated in terms of both staging criteria.

RESULTS: When comparing cancer-specific survival rates for patients with T1 lesions under both the 1987 and 1997 TNM staging criteria, no statistically significant difference in survival was noted (P = .53), although most of the tumors in our series measured ≤ 4 cm. Patients with T2 lesions (1997 TNM) demonstrated a significant decrease in survival (66%) when compared with patients with T1 lesions (100%; P < .001). No statistically significant difference in survival for patients with T1 RCC treated with either radical or partial nephrectomy was noted (P = .219). Survival rates of partial and radical nephrectomies for patients with unilateral T1 RCC and a normal contralateral kidney also were not significantly different (P = .53). In contrast, for patients with lesions greater than T1, survival rates were significantly higher with radical versus partial nephrectomy (P = .001).

CONCLUSION: Partial nephrectomy has become an effective method of treating T1 RCC lesions as categorized by both the 1987 and the revised 1997 TNM staging criteria. Selected patients with localized unilateral RCC lesions less than 7 cm (ideally, < 4 cm) and a normal contralateral kidney will benefit from partial nephrectomy.
Number of Nodes Examined and Staging Accuracy in Colorectal Carcinoma
Authors: Wong Jan H. , Severino Richard , Honnebier M. Barbera , Tom Paul , Namiki Thomas S.
Published: February 2017

PURPOSE: The objective of this study was to determine the number of nodes that need to be examined to accurately reflect the histology of the regional lymphatics in colorectal carcinoma.

PATIENTS AND METHODS: Patients undergoing curative resection for T2 and T3 colorectal cancer between 1992 and 1996 were reviewed. Pathologic data from these patients were entered into a computerized database for storage, retrieval, and analysis. The major outcome measured was the number of nodes that need to be examined to achieve a node-positive rate consistent with that reported in the National Cancer Data Base (NCDB) report.

RESULTS: The number of nodes examined ranged from 0 to 78 (mean, 17 nodes). Node-negative patients had fewer nodes examined (mean, 14 nodes) than node-positive patients (mean, 20 nodes; P = .003). The entire sample had a node-positive rate of 38.8% (95% confidence interval [CI], 32% to 45.5%), not statistically different from that in the NCDB report. When at least 14 nodes were examined, the percent of patients with at least one positive node was 33.3% (95% CI, 24.6% to 42.3%), not statistically different from the NCDB report.

CONCLUSION: In a sample of patients statistically similar to the sample in the NCDB report, the examination of at least 14 nodes after resection of T2 or T3 carcinoma of the colon and rectum will accurately stage the lymphatic basin.
Analysis of Surgical Margins With the Molecular Marker eIF4E: A Prognostic Factor in Patients With Head and Neck Cancer
Authors: Nathan Cherie-Ann O. , Franklin Scott , Abreo Fleurette W. , Nassar Raja , De Benedetti Arrigo , Glass Jonathan
Published: February 2017

PURPOSE: Complete excision of cancer is guided by histologic assessment of surgical margins. Molecular markers may be more sensitive in identifying malignant cells. eIF4E, a eukaryotic protein synthesis initiation factor, is found elevated in all head and neck squamous cell cancers (HNSCC). In a preliminary study using Western blots and a retrospective study using immunohistochemistry, eIF4E elevation in histologically tumor-free surgical margins correlated with a higher local-regional recurrence. We wanted to confirm this hypothesis in a prospective study.

PATIENTS AND METHODS: Immunohistochemical analysis of surgical margins and tumors with an antibody to eIF4E was performed on all newly diagnosed HNSCC patients who underwent surgical resection for their disease between January 1996 and December 1997.

RESULTS: All 65 patients had elevated levels of eIF4E in the tumors. Thirty-six patients (55%) had elevated eIF4E in histologically tumor-free margins, and 20 of these patients (56%) have had local-regional recur- rrences. Twenty-nine patients (45%) had no elevation of eIF4E in the margins, and only two of these patients (6.9%) have had recurrences. Cox regression analysis showed that elevated eIF4E in the margins was an independent prognostic factor (P = .009) for recurrence. The Kaplan-Meier curves for the probability of nonrecurrence were significantly different for positive and negative eIF4E margins (P = .0001, log-rank test).

CONCLUSION: In histologically tumor-free surgical margins, elevated levels of eIF4E predict a significantly increased risk of recurrence. Elevated levels of eIF4E in tumor margins may identify patients who could benefit from additional therapy.