bluuebunny/crossref_metadata_2025 huggingface dataset:
Locoregional Recurrence Patterns After Mastectomy and Doxorubicin-Based Chemotherapy: Implications for Postoperative Irradiation
Authors: Katz Angela , Strom Eric A. , Buchholz Thomas A. , Thames Howard D. , Smith Cynthia D. , Jhingran Anuja , Hortobagyi Gabriel , Buzdar Aman U. , Theriault Richard , Singletary S. Eva , McNeese Marsha D.
Published: February 2017

PURPOSE: The objective of this study was to determine locoregional recurrence (LRR) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation.

PATIENTS AND METHODS: A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospective trials. Median follow-up time was 116 months. Rates of isolated and total LRR (± distant metastasis) were calculated by Kaplan-Meier analysis.

RESULTS: The 10-year actuarial rates of isolated LRR were 4%, 10%, 21%, and 22% for patients with zero, one to three, four to nine, or ≥ 10 involved nodes, respectively (P < .0001). Chest wall (68%) and supraclavicular nodes (41%) were the most common sites of LRR. T stage (P < .001), tumor size (P < .001), and ≥ 2-mm extranodal extension (P < .001) were also predictive of LRR. Separate analysis was performed for patients with T1 or T2 primary disease and one to three involved nodes (n = 404). Those with fewer than 10 nodes examined were at increased risk of LRR compared with those with ≥ 10 nodes examined (24% v 11%; P = .02). Patients with tumor size greater than 4.0 cm or extranodal extension ≥ 2 mm experienced rates of isolated LRR in excess of 20%. Each of these factors continued to significantly predict for LRR in multivariate analysis by Cox logistic regression.

CONCLUSION: Patients with tumors ≥ 4 cm or at least four involved nodes experience LRR rates in excess of 20% and should be offered adjuvant irradiation. Additionally, patients with one to three involved nodes and large tumors, extranodal extension ≥ 2 mm, or inadequate axillary dissections experience high rates of LRR and may benefit from postmastectomy irradiation.
Relationship Between Tumor Location and Relapse in 6,781 Women With Early Invasive Breast Cancer
Authors: Lohrisch Caroline , Jackson Jeremy , Jones Amanda , Mates Donna , Olivotto Ivo A.
Published: February 2017

PURPOSE: To explore the independent prognostic impact of medial hemisphere tumor location in early breast cancer.

PATIENTS AND METHODS: A comprehensive database was used to review patients referred to the British Columbia Cancer Agency from 1989 to 1995 with early breast cancer. Patients were grouped according to relapse risk (high or nonhigh) and adjuvant systemic therapy received. Multiple regression analysis was used to determine whether the significance of primary tumor location (medial v lateral hemisphere) was independent of known prognostic factors and treatment.

RESULTS: In the adjuvant systemic therapy groups, medial location was associated with a 50% excess risk of systemic relapse and breast cancer death compared with lateral location. Five-year systemic disease-free survival rates were 66.3% and 74.2% for high-risk medial and lateral lesions, respectively (P < .005). Corresponding 5-year disease-specific survival rates were 75.7% and 80.8%, respectively (P < .03). No significant differences were observed between medial and lateral location for low-risk disease regardless of adjuvant therapy or for high-risk disease with no adjuvant therapy. Local recurrence rates were similar for all risk and therapy groups.

CONCLUSION: The two-fold risk of relapse and breast cancer death associated with high-risk medial breast tumors may be due to occult spread to internal mammary nodes (IMNs). Enhanced local control, such as with irradiation of the IMN chain, may be one way to reduce the excess risk. Ongoing randomized controlled trials may provide prospective answers to the question of the optimal volume of radiotherapy.
High-Producer Haplotypes of Tumor Necrosis Factor Alpha and Lymphotoxin Alpha Are Associated With an Increased Risk of Myeloma and Have an Improved Progression-Free Survival After Treatment
Authors: Davies Faith E. , Rollinson Sara J. , Rawstron Andrew C. , Roman Eve , Richards Stephen , Drayson Mark , Child J. Anthony , Morgan Gareth J.
Published: February 2017

PURPOSE: To determine the effect of polymorphic variations in the tumor necrosis factor alpha (TNFα) and lymphotoxin alpha (LTα) genes on the predisposition to myeloma and the effect of these polymorphisms on response to treatment and overall survival.

PATIENTS AND METHODS: Genotype distribution was determined in 63 patients with monoclonal gammopathy of uncertain significance (MGUS) and 198 patients with myeloma and compared with that in 250 age- and sex-matched population-based controls. The effect on treatment response and survival was determined in 171 myeloma patients treated with either conventional or high-dose chemotherapy.

RESULTS: Comparison of the extended TNFα/LTα haplotype in the myeloma cases and controls showed a significant excess of high-producer alleles in the cases. The double heterozygotes TNF1/2 and LT10.5/5.5 were present in 35.8% of cases but in only 18% of the controls; this presence was associated with a significant increased risk of myeloma (odds ratio, 2.05; 95% confidence interval, 1.26 to 3.35). A similar odds ratio was seen in the MGUS cases, suggesting that this genotype is associated with the initiation of plasma-cell disorders rather than the progression of MGUS to myeloma. The median overall survival time of myeloma patients was 53.8 months and showed no difference with regard to TNFα/LTα polymorphic status. A trend toward an improved progression-free survival was apparent in cases with a high-producer haplotype, although this effect was seen only in patients receiving high-dose chemotherapy.

CONCLUSION: Individuals with polymorphisms associated with a high production of TNFα/LTα are at a significantly increased risk of developing MGUS and myeloma. The impact of polymorphic status on overall survival is minimal, although there is a trend toward an increased progression-free survival in the high-producer group.
Communication Between Primary Care Physicians and Radiation Oncologists Regarding Patients With Cancer Treated With Palliative Radiotherapy
Authors: Barnes Elizabeth A. , Hanson John , Neumann Catherine M. , Nekolaichuk Cheryl L. , Bruera Eduardo
Published: February 2017

PURPOSE: The purpose of this study was to assess the satisfaction and information needs of primary care physicians (PCPs) regarding communication with radiation oncologists (ROs), with respect to patients who receive palliative radiotherapy (RT). A selected objective was to evaluate the agreement between PCPs’ expectations and the content of the RO letter sent after completion of RT. PCPs’ knowledge of the role of palliative RT and their awareness of available patient support services were also determined.

METHODS: The PCPs of patients discharged from the Cross Cancer Institute after receiving palliative RT were surveyed using a mail-out questionnaire. Questions regarding communication, RT knowledge, and awareness of support services were asked. The corresponding RO letter was reviewed.

RESULTS: A total of 148 PCPs were identified and were mailed questionnaires, with 114 (77%) responding. Overall, 80% (87 of 109) of PCPs found the RO letter to be useful in patient management. However, there was poor (< 53%) agreement between PCPs’ expectations and the actual content of the RO letter. Knowledge of the indications and effectiveness of palliative RT was limited, with PCPs obtaining a median score of 4 of a possible 8. Only 27% (31 of 114) of PCPs were aware of all five of the patient support services listed.

CONCLUSION: Results show that although the majority of PCPs found the RO letter useful, they believed that the letter lacked important information while containing unnecessary details. Communication between PCPs and ROs needs improvement, especially considering that PCPs seem to have limited knowledge of palliative RT.
Oncogenes and Male Breast Carcinoma: c-erbB-2 and p53 Coexpression Predicts a Poor Survival
Authors: Pich Achille , Margaria Elena , Chiusa Luigi
Published: February 2017

PURPOSE: To investigate the prognostic value of biomarkers in male breast carcinoma (MBC).

PATIENTS AND METHODS: Fifty patients (mean age, 62.2 years) with invasive ductal carcinoma were retrospectively studied. All patients received surgery; 35 had adjuvant postoperative therapy. The median follow-up was 59 months (range, 1 to 230 months). c-myc, c-erbB-2, p53, and bcl-2 proteins were immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using 9E11, CB11, DO7, and bcl-2 124 monoclonal antibodies (mAbs). Estrogen, progesterone, and androgen receptors were detected using specific mAbs. Cell proliferation was assessed by MIB-1 mAb.

RESULTS: In univariate analysis, c-myc, c-erbB-2, and p53 protein overexpression was significantly correlated with prognosis. The median survival was 107 months for c-myc–negative and 52 months for c-myc–positive patients (P = .01), 96 months for c-erbB-2–negative and 39 months for c-erbB-2–positive patients (P = .02), and 100 months for p53-negative and 33 months for p53-positive patients (P = .0008). Tumor histologic grade (P = .01), tumor size (P = .02), patient age at diagnosis (P = .03), and MIB-1 scores (P = .0004) also had prognostic value. In multivariate analysis, only c-erbB-2 and p53 immunoreactivity retained independent prognostic significance. All nine patients who did not express c-erbB-2 and p53 proteins were alive after 58 months, whereas none of the 14 patients expressing both proteins survived at 61 months follow-up (P = .0002).

CONCLUSION: Overexpression of c-myc, c-erbB-2, and p53 proteins may be regarded as an additional prognostic factor in MBC. The combination of c-erbB-2 and p53 immunoreactivity can stratify patients into different risk groups.
Effect of Providing Cancer Patients With the Audiotaped Initial Consultation on Satisfaction, Recall, and Quality of Life: A Randomized, Double-Blind Study
Authors: Ong L.M.L. , Visser M.R.M. , Lammes F.B. , van der Velden J. , Kuenen B.C. , de Haes J.C.J.M.
Published: February 2017

PURPOSE: By means of a randomized double-blind study, the effect of providing taped initial consultations on cancer patients’ satisfaction, recall, and quality of life was investigated.

PATIENTS AND METHODS: Consecutive cancer patients referred to either the gynecology or medical oncology outpatient clinic were eligible. Initial consultations were audiotaped. Patients were either provided with the tape (experimental group) or not (control group). Baseline variables included sociodemographics, preferences for information, coping styles, and clinical characteristics. Follow-up (after 1 week and 3 months) variables included attitudes toward the intervention, satisfaction, recall, and quality of life. Assessments took place through mailed questionnaires and telephone interviews.

RESULTS: Two hundred one patients were included (response, 71%), 105 in the experimental group and 96 in the control group. Most patients (75%) listened to the tape, the majority of which (73%) listened with others. Almost all patients, both in the experimental group (96%) and control group (98%) were positive about the intervention. Expectations were confirmed; patients provided with the tape were more satisfied (P < .05) and recalled more information (P < .01) than patients without the tape. The intervention did not have an effect on quality of life. An interaction effect was found between the intervention and patients’ age on satisfaction with the taped consultation (P < .01) and recall of diagnostic information (P < .01); access to tapes seems more helpful in enhancing satisfaction in younger patients and recall of diagnostic information in older patients.

CONCLUSION: Cancer patients and their families value the taped initial consultation. This intervention enhances their satisfaction and improves their recall of information. Tapes seem more helpful in enhancing satisfaction in younger patients and recall of diagnostic information in older patients.
Phase I and Pharmacokinetic Study of a New Taxoid, RPR 109881A, Given as a 1-Hour Intravenous Infusion in Patients With Advanced Solid Tumors
Authors: Kurata Takayasu , Shimada Yasuhiro , Tamura Tomohide , Yamamoto Noboru , Hyodo Ichinosuke , Saeki Toshiaki , Takashima Shigemitsu , Fujiwara Keiichi , Wakasugi Hideyuki , Kashimura Masaki
Published: February 2017

PURPOSE: RPR 109881A is a new semisynthetic taxoid compound that has a similar mechanism of action to docetaxel. The purpose of this phase I study was to characterize the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetic profile, and antitumor effects of this agent.

PATIENTS AND METHODS: Nineteen eligible patients with advanced solid tumors were enrolled. RPR 109881A was administered as a 1-hour intravenous infusion every 3 weeks at doses ranging from 15 to 75 mg/m2. Pharmacokinetic evaluation was performed at the first cycle.

RESULTS: Neutropenia (febrile neutropenia) and fatigue were dose-limiting toxicities at doses of 60 and 75 mg/m2and seemed to be dose-related. Both thrombocytopenia and anemia were infrequent. Nonhematologic toxicities were generally mild. Pharmacokinetic studies indicated that RPR 109881A plasma disposition was bi- or triphasic, with a high total plasma clearance, a large volume of distribution, and a long terminal half-life. The area under the concentration-time curve (AUC) and the peak concentration of RPR 109881A seemed to increase with increasing dose proportionally, suggesting linear pharmacokinetics. Urinary excretion over 48 hours was low, with a mean of 0.8 ± 0.36% of the administered dose. A significant relationship existed between the percentage decrease of neutrophil counts and the AUC of RPR 109881A. Among 18 assessable patients, two partial and two minor responses were documented.

CONCLUSION: RPR 109881A was found to be a well-tolerated and promising taxoid agent. The MTD was 75 mg/m2, and the recommended dose for phase II study was 60 mg/m2as a 1-hour infusion every 3 weeks.
High Survival Rate in Infant Acute Leukemia Treated With Early High-Dose Chemotherapy and Stem-Cell Support
Authors: Marco Fernando , Bureo Encarna , Ortega Juan J. , Badell Isabel , Verdaguer Amparo , Martínez Ana , Muñoz Arturo , Madero Luis , Olivé Teresa , Cubells Josep , Castel Victoria , Sastre Ana , Maldonado M. Soledad , Díaz Miguel A. ,   from the Grupo Español de Trasplante de Médula Ósea en Niños
Published: February 2017

PURPOSE: Infants with acute leukemia have a poor prognosis when treated with conventional chemotherapy. It is still unknown if stem-cell transplantation (SCT) can improve the outcome of these patients. In the present study, we review our experience with SCT in infant acute leukemia to clarify this issue.

PATIENTS AND METHODS: We report the results of 26 infants who were submitted to a SCT for acute leukemia. There were 15 cases of acute myeloid leukemia and 10 cases of acute lymphoid leukemia. One patient had a bilineal leukemia. Twenty-two patients were in their first complete response (CR1), three were in their second CR, and one was in relapse. Eight patients were submitted to allogeneic SCT, and 18 underwent autologous SCT.

RESULTS: With a median follow-up of 67 months, the 5-year overall survival and disease-free survival (DFS) are 64% (SE = 9%) and 63% (SE = 10%), respectively. Autologous and allogeneic SCT offered similar outcome. There was not any transplant-related mortality, and all deaths were caused by relapse in the first 6 months after SCT. In multivariate analysis, the single factor associated with better DFS was an interval between CR1 and SCT of less than 4 months (P < .025).

CONCLUSION: SCT is a valid option in the treatment of infant acute leukemia, and it may overcome the high risk of relapse with conventional chemotherapy showing very reduced toxicity. This study suggests that SCT should be performed in CR1 in the early phase of the disease.
Epstein-Barr Virus Infection Is Predictive of CNS Involvement in Systemic AIDS-Related Non-Hodgkin’s Lymphomas
Authors: Cingolani Antonella , Gastaldi Roberta , Fassone Lucia , Pierconti Francesco , Giancola Maria Letizia , Martini Maurizio , De Luca Andrea , Ammassari Adriana , Mazzone Carla , Pescarmona Edoardo , Gaidano Gianluca , Larocca Luigi Maria , Antinori Andrea
Published: February 2017

PURPOSE: This study aimed at correlating Epstein-Barr virus (EBV) infection of systemic AIDS-related non-Hodgkin lymphomas (AIDS-NHL) with the development of a CNS localization of the tumor.

PATIENTS AND METHODS: Demographic, epidemiologic, clinical, histologic, and virologic features were collected for all systemic AIDS-NHL patients included in the study (n = 50). Pathologic specimens were classified according to the working formulation for NHL and the Revised European-American Lymphoma classification. EBV infection in tumor tissue samples was studied by EBV small encoded RNA in situ hybridization; EBV-DNA detection in CSF was carried out by nested polymerase chain reaction using Epstein-Barr nuclear antigen-1–specific primers. In addition, selected EBV-positive lymphomas were subjected to a detailed characterization of EBV molecular heterogeneity.

RESULTS: Eleven patients had a CNS involvement at some point during their clinical history (four at diagnosis and seven at relapse). Thirty patients (11 with CNS involvement and 19 without) harbored EBV infection of the tumor. Sensitivity, specificity, and positive and negative predictive values of EBV-DNA detection in CSF for CNS involvement by lymphoma were 90%, 100%, 100%, and 97.6%, respectively. Factors significantly predictive of CNS involvement were EBV infection of the tumor (P = .003), an extranodal disease at diagnosis other than CNS (P = .006), and a non-CNS relapse (P = .01). In four cases of CNS involvement, EBV-DNA in CSF preceded any other sign of disease by a mean of 35 days.

CONCLUSION: These results show that EBV infection of the tumor clone significantly increases the risk of CNS involvement by systemic AIDS-NHL, without regard of specific molecular features. The detection of EBV-DNA in the CSF of AIDS-NHL patients may select cases with higher risk of CNS involvement and, therefore, may prove useful in the therapeutic stratification of these tumors.
Effect of Radiotherapy After Breast-Conserving Treatment in Women With Breast Cancer and Germline BRCA1/2 Mutations
Authors: Pierce Lori J. , Strawderman Myla , Narod Steven A. , Oliviotto Ivo , Eisen Andrea , Dawson Laura , Gaffney David , Solin Lawrence J. , Nixon Asa , Garber Judy , Berg Christine , Isaacs Claudine , Heimann Ruth , Olopade Olufunmilayo I. , Haffty Bruce , Weber Barbara L.
Published: February 2017

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease.

PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence.

RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P = .0004) and nuclear (P = .009) grade and negative estrogen (P = .0001) and progesterone (P = .002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant).

CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.
Comparison of Young Clinical Investigators’ Accuracy and Reproducibility When Measuring Pulmonary and Skin Surface Nodules Using a Circumferential Measurement Versus a Standard Caliper Measurement: American Association for Cancer Research/American Society of Clinical Oncology Clinical Trials Workshop
Authors: Monsky Wayne L. , Heddens David K. , Clark Gary M. , Von Hoff Daniel D. , Coltman Charles A. , Dorr Robert T. , Alberts David S.
Published: February 2017

PURPOSE: The clinical investigator must understand that errors in measuring tumors can greatly affect such clinical-trial end points as tumor response. We performed a prospective, controlled study of tumor measurements that compared circumferential measurements made with a loop planimeter with linear measurements made with a standard caliper.

METHODS: Using a cross-over design, 76 clinical oncology fellows/junior oncology faculty members attending a Methods in Clinical Cancer Research Workshop sponsored by the American Association for Cancer Research and the American Society of Clinical Oncology measured five pulmonary nodule phantoms that ranged in size from 1.76 to 13.21 cm2 and five surface nodule phantoms with sizes ranging from 2.3 to 12.9 cm2. To perform these measurements, they used both a loop planimeter and a caliper. Forty-two and 40 participants repeated measurements 3 days later on pulmonary and surface nodules. Accuracy, reproducibility, and time efficiency were evaluated.

RESULTS: The linear caliper measurements overestimated pulmonary nodule and surface nodule size by a median of 37% and 23%, respectively. Circumferential loop planimeter measurements overestimated pulmonary nodule size and surface nodule size by a median of 8% and 17%, respectively. Interobserver reproducibility for the planimeter was greater than that for the caliper, as evidenced by thinner measurement interquartile ranges. Furthermore, intraobserver reproducibility was higher for the planimeter, with its variability being only 31.4% and 25.5% as large as that of the caliper when measuring the pulmonary and surface nodules, respectively.

CONCLUSION: Circumferential measurements provide better accuracy, reproducibility, and speed in measuring both pulmonary and surface nodules than do perpendicular diameters.
Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors
Authors: Couteau Corinne , Risse Marie-Laure , Ducreux Michel , Lefresne-Soulas Florence , Riva Alessandro , Lebecq Anne , Ruffié Pierre , Rougier Philippe , Lokiec François , Bruno René , Armand Jean-Pierre
Published: February 2017

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed.

RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study.

CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.
Second-Line Chemotherapy in Relapsing or Refractory Non–Small-Cell Lung Cancer: A Review
Authors: Huisman C. , Smit E.F. , Giaccone G. , Postmus P.E.
Published: February 2017

PURPOSE: Since the increased use of first-line chemotherapy for non–small-cell lung cancer (NSCLC), second-line chemotherapy may nowadays be considered for a growing group of patients. Guidelines for second-line treatment have to be developed yet.

METHODS: We reviewed the published literature on second-line chemotherapy for NSCLC with emphasis on the role of factors such as pretreatment, response to first-line treatment, and length of disease-free-interval.

RESULTS: Thirty-four single-agent-studies and 24 multidrug-studies on second-line treatment were identified. Docetaxel has been studied most extensively and is the only agent that has been studied in randomized phase III trials. Different definitions of sensitivity applied by different authors and conflicting results have been reported about the influence of response to prior chemotherapy.

CONCLUSION: Since most patients are treated with a platinum-based regimen in the first line, platinum resistance usually is a major consideration for the use of second-line agents. We argue, however, that a more general definition of drug resistance is more appropriate than resistance to platinum only. Criteria to select NSCLC patients for second-line treatment have not been defined yet. This is also important in light of the upcoming necessity to test new drugs in pretreated instead of treated patients. Guidelines for second-line treatment of NSCLC based on clinical information on drug sensitivity to first-line therapy need to be developed.
Human Immunodeficiency Virus–Related Cancer in Children: Incidence and Treatment Outcome—Report of the Italian Register
Authors: Caselli D. , Klersy C. , de Martino M. , Gabiano C. , Galli L. , Tovo P.A. , Aricò M. ,   for the Italian Register for HIV Infection in Children
Published: February 2017

PURPOSE: To outline the incidence, presenting features, treatment response, and outcome of human immunodeficiency virus (HIV)–associated malignancies in infancy and childhood, together with the estimated risk of HIV-associated cancer in children born to mothers infected with HIV.

PATIENTS AND METHODS: The Italian Register for HIV Infection in Children collected data by specific registration and follow-up forms. By March 1999, 5,060 children were recruited, including 4,889 with perinatal exposure to HIV-1. Overall, 1,331 infected children were enrolled onto the Register and classified according to current Centers for Disease Control criteria; of them, 1,163 were vertically infected (24% of those with perinatal exposure). Of these 1,163, 569 (49%) were considered to have been prospectively followed-up since they had been registered at birth or within the first 3 months of age.

RESULTS: Of the 1,331 children observed for a median time of 6.5 years, 35 developed 36 malignancies, four of which occurred in patients with blood-borne risk. For the 1,163 vertically infected children, the cumulative number of years of observation was 7,178 child-years and the cumulative incidence of HIV-associated tumors was 4.18 per 1,000 children/yr (95% confidence interval [CI], 2.92 to 5.98). When only the 569 vertically infected children prospectively followed up since birth were considered, the cumulative number of years of observation was 2,803 child-years. In this group, 10 tumors were observed, with a cumulative incidence of HIV-associated tumors of 3.57 per 1,000 children per year (95% CI, 1.92 to 6.63).

CONCLUSION: The risk of cancer was significantly higher but not restricted to symptomatic and/or immune-compromised children. Cancer-directed treatment should be given promptly to these patients, who have a fair chance to survive their tumor in view of potential highly aggressive antiretroviral therapy–associated improvement in survival and quality of life.
Preoperative Mobilization of Circulating Dendritic Cells by Flt3 Ligand Administration to Patients With Metastatic Colon Cancer
Authors: Morse Michael A. , Nair Smita , Fernandez-Casal Monica , Deng Yuping , St Peter Michelle , Williams Rhonda , Hobeika Amy , Mosca Paul , Clay Tim , Cumming R. Ian , Fisher Eva , Clavien Pierre , Proia Alan D. , Niedzwiecki Donna , Caron Dania , Lyerly H. Kim
Published: February 2017

PURPOSE: To evaluate preoperative dendritic cell (DC) mobilization and tumor infiltration after administration of Flt3 ligand (Flt3L) to patients with metastatic colon cancer.

PATIENTS AND METHODS: Twelve patients with colon cancer metastatic to the liver or lung received Flt3L (20 μg/kg/d subcutaneously for 14 days for one to three cycles at monthly intervals) before attempted metastasectomy. The number and phenotype of DCs mobilized into peripheral-blood mononuclear cells (PBMCs) were evaluated by flow cytometry. After surgical resection, metastatic tumor tissue was evaluated for DC infiltration. In vivo immune responses to recall antigens were measured.

RESULTS: After Flt3L administration, on average, the total number of leukocytes in the peripheral blood increased from 5.9 ± 1.0 × 103/mm3to 11.2 ± 3.8 × 103/mm3(mean ± SD, P = .0001). The percentage of CD11c+CD14−DCs in PBMCs increased from 2.4% ± 1.8% to 8.8% ± 4.7% (P = .004). Delayed-type hypersensitivity (DTH) responses to recall antigens (Candida, mumps, and tetanus) showed marginally significant increases in reactivity after Flt3L administration (P = .06, P = .03, and P = .08, respectively). An increase in the number of DCs was observed at the periphery of the tumors of patients who received Flt3L compared with those of patients who had not.

CONCLUSION: Flt3L is capable of mobilizing DCs into the peripheral blood of patients with metastatic colon cancer and may be associated with increases in DC infiltration in the peritumoral regions. Flt3L mobilization is associated with a trend toward increased DTH responses to recall antigens in vivo. The use of Flt3L to increase circulating DCs for cancer immunotherapy should be considered.
Phase I and Pharmacokinetic Study of Irofulven, a Novel Mushroom-Derived Cytotoxin, Administered for Five Consecutive Days Every Four Weeks in Patients With Advanced Solid Malignancies
Authors: Eckhardt S. Gail , Baker Sharyn D. , Britten Carolyn D. , Hidalgo Manuel , Siu Lillian , Hammond Lisa A. , Villalona-Calero Miguel A. , Felton Sally , Drengler Ronald , Kuhn John G. , Clark Gary M. , Smith Sheri L. , MacDonald John R. , Smith Charlotte , Moczygemba Judy , Weitman Steve , Von Hoff Daniel D. , Rowinsky Eric K.
Published: February 2017

PURPOSE: To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies.

PATIENTS AND METHODS: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m2 as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven.

RESULTS: Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m2 dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m2 dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m2 dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes.

CONCLUSION: Given the results of this study, the recommended dose of irofulven is 10.64 mg/m2 as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.
Favorable Biology and Outcome of Stage IV-S Neuroblastoma With Supportive Care or Minimal Therapy: A Children’s Cancer Group Study
Authors: Nickerson H. James , Matthay Katherine K. , Seeger Robert C. , Brodeur Garret M. , Shimada Hiroyuki , Perez Carlos , Atkinson James B. , Selch Michael , Gerbing Robert B. , Stram Daniel O. , Lukens John
Published: February 2017

PURPOSE: Stage IV-S neuroblastoma is a metastatic disease associated with spontaneous regression and good survival, but 10% to 20% of infants die from early complications. The purpose of this study was to evaluate outcome and prognostic factors in infants with stage IV-S neuroblastoma treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy.

PATIENTS AND METHODS: Eighty eligible infants were studied for response and survival with supportive care or, for symptomatic patients, cyclophosphamide 5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days. Staging was reviewed centrally, and MYCN gene copy number, Shimada histopathologic classification, serum ferritin levels, and bone marrow immunocytology were determined.

RESULTS: Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P = .005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age ≤ 3 months at diagnosis was significant for EFS (P = .043), it was less significant for survival (P = .077). The only other significant factor predictive for improved survival was favorable Shimada histopathologic classification. Sites of metastatic involvement (liver, skin, or bone marrow) and surgical resection of the primary tumor were not significant for survival.

CONCLUSION: This study confirms the favorable biologic features and excellent survival of infants with stage IV-S neuroblastoma with minimal therapy. Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease may benefit from earlier and more intensive treatment.
Factors Predicting for Efficacy and Safety of Docetaxel in a Compassionate-Use Cohort of 825 Heavily Pretreated Advanced Breast Cancer Patients
Authors: Alexandre J. , Bleuzen P. , Bonneterre J. , Sutherland W. , Misset J.L. , Guastalla J.-P. , Viens P. , Faivre S. , Chahine A. , Spielman M. , Bensmaïne A. , Marty M. , Mahjoubi M. , Cvitkovic E.
Published: February 2017

PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program.

PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m2 every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis.

RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P < .05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction.

CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.
Early Start of Adjuvant Chemotherapy May Improve Treatment Outcome for Premenopausal Breast Cancer Patients With Tumors not Expressing Estrogen Receptors
Authors: Colleoni Marco , Bonetti Marco , Coates Alan S. , Castiglione-Gertsch Monica , Gelber Richard D. , Price Karen , Rudenstam Carl-Magnus , Lindtner Jurij , Collins John , Thürlimann Beat , Holmberg Stig , Veronesi Andrea , Marini Giovanni , Goldhirsch Aron ,   for the International Breast Cancer Study Group
Published: February 2017

PURPOSE: The proper time to commence adjuvant chemotherapy after primary surgery for breast cancer is unknown. An analysis of the International (Ludwig) Breast Cancer Study Group (IBCSG) Trial V at a median follow-up of 11 years suggested that early initiation of adjuvant chemotherapy might improve outcome for premenopausal, node-positive patients whose tumors did not express any estrogen receptor (ER).

PATIENTS AND METHODS: We investigated the relationship between early initiation of adjuvant chemotherapy, ER status, and prognosis in 1,788 premenopausal, node-positive patients treated on IBCSG trials I, II, and VI. The disease-free survival for 599 patients (84 with ER-absent tumors) who commenced adjuvant chemotherapy within 20 days (early initiation) was compared with the disease-free survival for 1,189 patients (142 with ER-absent tumors) who started chemotherapy 21 to 86 days after surgery (conventional initiation). The median follow-up was 7.7 years.

RESULTS: Among patients with ER-absent tumors, the 10-year disease-free survival was 60% for the early initiation group compared with 34% for the conventional initiation group (226 patients; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33 to 0.72; P = .0003). This difference remained statistically significant in a Cox multiple regression analysis controlling for study group, number of positive nodes, tumor size, age, vessel invasion, and institution (HR, 0.60; 95% CI, 0.39 to 0.92; P = .019). Conversely, early initiation of chemotherapy did not significantly improve disease-free survival for patients with tumors expressing ER (1,562 patients; multiple regression HR, 0.93; 95% CI, 0.79 to 1.10; P = .40).

CONCLUSION: In premenopausal patients with ER-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. Further confirmatory studies are required before any widespread modification of current clinical practice. In premenopausal patients with tumors expressing some ER, gains from early initiation are unlikely to be clinically significant.
Randomized Trial of Fludarabine Versus Fludarabine and Idarubicin as Frontline Treatment in Patients With Indolent or Mantle-Cell Lymphoma
Authors: Zinzani Pier Luigi , Magagnoli Massimo , Moretti Luciano , De Renzo Amalia , Battista Raffaele , Zaccaria Alfonso , Guardigni Luciano , Mazza Patrizio , Marra Roberto , Ronconi Fioravante , Lauta Vito Michele , Bendandi Maurizio , Gherlinzoni Filippo , Gentilini Patrizia , Ciccone Fabrizio , Cellini Claudia , Stefoni Vittorio , Ricciuti Francesco , Gobbi Marco , Tura Sante
Published: February 2017

PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas.

PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m2/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m2/d on days 1 through 3 and idarubicin 12 mg/m2 on day 1).

RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P = .021).

CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.
How Do Head and Neck Cancer Patients Prioritize Treatment Outcomes Before Initiating Treatment?
Authors: List Marcy A. , Stracks John , Colangelo Laura , Butler Pamela , Ganzenko Natasha , Lundy Donna , Sullivan Paula , Haraf Daniel , Kies Merrill , Goodwin William , Vokes Everett E.
Published: February 2017

PURPOSE: To determine, pretreatment, how head and neck cancer (HNC) patients prioritize potential treatment effects in relationship to each other and to survival and to ascertain whether patients’ preferences are related to demographic or disease characteristics, performance status, or quality of life (QOL).

PATIENTS AND METHODS: One hundred thirty-one patients were assessed pretreatment using standardized measures of QOL (Functional Assessment of Cancer Therapy-Head and Neck) and performance (Performance Status Scale for Head and Neck Cancer). Patients were also asked to rank a series of 12 potential HNC treatment effects.

RESULTS: Being cured was ranked top priority by 75% of patients; another 18% ranked it second or third. Living as long as possible and having no pain were placed in the top three by 56% and 35% of patients, respectively. Items that were ranked in the top three by 10% to 24% of patients included those related to energy, swallowing, voice, and appearance. Items related to chewing, being understood, tasting, and dry mouth were placed in the top three by less than 10% of patients. Excluding the top three rankings, there was considerable variability in ratings. Rankings were generally unrelated to patient or disease characteristics, with the exception that cure and living were of slightly lower priority and pain of higher priority to older patients compared with younger patients.

CONCLUSION: The data suggest that, at least pretreatment, survival is of primary importance to patients, supporting the development of aggressive treatment strategies. In addition, results highlight individual variability and warn against making assumptions about patients’ attitudes vis-à-vis potential outcomes. Whether patients’ priorities will change as they experience late effects is currently under investigation.
Serum Human Glandular Kallikrein-2 Protease Levels Predict the Presence of Prostate Cancer Among Men With Elevated Prostate-Specific Antigen
Authors: Nam Robert K. , Diamandis Eleftherios P. , Toi Ants , Trachtenberg John , Magklara Angeliki , Scorilas Andreas , Papnastasiou Panayotis A. , Jewett Michael A. S. , Narod Steven A.
Published: February 2017

PURPOSE: We hypothesize that serum human glandular kallikrein-2 (hK2) levels predict the presence of prostate cancer among men prescreened by prostate-specific antigen (PSA).

PATIENTS AND METHODS: We conducted a cross-sectional study of 324 men who had no history of prostate cancer and who were referred for prostate biopsy. PSA and hK2 levels were measured using specific nonisotopic immunometric techniques. Cases were patients who were diagnosed with adenocarcinoma of the prostate from biopsy, and controls were patients who had no evidence of cancer from biopsy. The odds ratio for detection of prostate cancer was determined for hK2 measurements, controlling for age, total-PSA level, digital rectal examination, and symptoms of urinary obstruction.

RESULTS: Of 324 men, 159 (49.1%) had cancer. Mean hK2 levels and hK2:free-PSA ratios were significantly higher in cases than in controls (1.18 v 0.53 ng/mL, respectively, for hK2, P = .0001; 1.17 v 0.62 for hK2:free-PSA ratio, P = .0001). The crude odds ratio for prostate cancer detection for patients in the highest quartile of hK2 level was 5.83 (95% confidence interval [CI], 2.8 to 12.1; P = .0001) compared with patients in the lowest quartile. The adjusted odds ratio was 6.72 (95% CI, 2.9 to 15.6; P = .0001). Similarly, the crude and adjusted odds ratios for prostate cancer detection using the hK2:free-PSA ratio were 7.36 (95% CI, 3.6 to 15.1; P = .0001) and 8.06 (95% CI, 3.7 to 17.4; P = .0001), respectively. These odds ratios were higher than that observed for prostate cancer detection by total-PSA level (2.73; P = .03).

CONCLUSION: Among men prescreened with PSA for prostate cancer, patients with high hK2 measurements have a five- to eight-fold increase in risk for prostate cancer, adjusting for PSA level and other established risk factors. hK2 measurements may be a useful adjunct to PSA in improving patient selection for prostate biopsy.