bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of the Interval Between Preoperative Radiation Therapy and Surgery on Downstaging and on the Rate of Sphincter-Sparing Surgery for Rectal Cancer: The Lyon R90-01 Randomized Trial
Authors: Francois Yves , Nemoz Chantal J. , Baulieux Jacques , Vignal Jacques , Grandjean Jean-Paul , Partensky Christian , Souquet Jean Christophe , Adeleine Patrice , Gerard Jean-Pierre
Published: February 2017

PURPOSE: The optimal timing of surgery after preoperative radiotherapy in rectal cancer is unknown. The aim of this trial was to evaluate the role of the interval between preoperative radiotherapy and surgery.

PATIENTS AND METHODS: Patients with rectal carcinoma accessible to rectal digital examination, staged T2 to T3, NX, M0, were randomized before radiotherapy (39 Gy in 13 fractions) into two groups: in the short interval (SI) group, surgery had to be performed within 2 weeks after completion of radiation therapy, compared with 6 to 8 weeks in the long interval (LI) group. Between 1991 and 1995, 201 patients were enrolled onto the study.

RESULTS: A long interval between preoperative radiotherapy and surgery was associated with a significantly better clinical tumor response (53.1% in the SI group v 71.7% in the LI group, P = .007) and pathologic downstaging (10.3% in the SI group v 26% in the LI group, P = .005). At a median follow-up of 33 months, there were no differences in morbidity, local relapse, and short-term survival between the two groups. Sphincter-preserving surgery was performed in 76% of cases in the LI group versus 68% in the SI group (P = 0.27).

CONCLUSION: A long interval between preoperative irradiation and surgery provides increased tumor downstaging with no detrimental effect on toxicity and early clinical results. When sphincter preservation is questionable, a long interval may increase the chance of a successful sphincter-saving surgery.
Medullary-Type Poorly Differentiated Adenocarcinoma of the Large Bowel: A Distinct Clinicopathologic Entity Characterized by Microsatellite Instability and Improved Survival
Authors: Lanza Giovanni , Gafà Roberta , Matteuzzi Maurizio , Santini Alessandra
Published: February 2017

PURPOSE: Recent studies suggest the existence of a distinct class of poorly differentiated large bowel adenocarcinomas, usually termed medullary-type adenocarcinomas (MTAs). The aim of the present study was to accurately define the clinical, histopathologic, biologic, and genetic features of this tumor type.

MATERIALS AND METHODS: Among 1,265 surgically resected sporadic colorectal carcinomas, 45 MTAs were identified on the basis of the following criteria: predominantly solid growth pattern (at least 70% of the tumor area) and lack of marked nuclear pleomorphism. The clinicopathologic, biologic, and genetic characteristics of MTAs were compared with those of a series of 457 common glandular colorectal adenocarcinomas.

RESULTS: The significantly different clinicopathologic features of MTAs were proximal location, large size, invasion into adjacent organs, expanding pattern of growth, low incidence of distant metastases, more frequent conspicuous peritumoral lymphocytic infiltration, and Crohn's-like lymphoid reaction. Furthermore, young patients with MTAs often demonstrated a family history highly suggestive of a hereditary background. Unlike glandular adenocarcinomas, the large majority of MTAs were DNA diploid by flow cytometric analysis (21 of 25, 84%) and p53 negative by immunohistochemistry (36 of 41, 87.8%). In addition, 18 of the 20 MTAs examined by DNA microsatellite analysis demonstrated widespread microsatellite instability (90% of cases). Patients with MTAs showed a better clinical outcome with respect to patients with common poorly differentiated adenocarcinomas (PDAs) (P < .0001) and well- or moderately differentiated adenocarcinomas (WMDAs) (P = .133). In particular, none of the 33 patients with completely resectable stage II and III MTAs developed tumor recurrence during the observation period. Conversely, 24.7% of patients with stage II and III WMDAs and 48.9% of patients with stage II and III PDAs, who had undergone curative surgical resection, died of recurrent disease (P = .01 and P < .0001, respectively).

CONCLUSION: All these data strongly indicate that MTAs represent a distinct pathologic entity, with specific histologic appearance and peculiar clinical and genetic features. These tumors need to be classified separately from other poorly differentiated colorectal carcinomas.
Multicenter, Randomized, Phase III Trial of CD8+ Tumor-Infiltrating Lymphocytes in Combination With Recombinant Interleukin-2 in Metastatic Renal Cell Carcinoma
Authors: Figlin Robert A. , Thompson John A. , Bukowski Ronald M. , Vogelzang Nicholas J. , Novick Andrew C. , Lange Paul , Steinberg Gary D. , Belldegrun Arie S.
Published: February 2017

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8+ tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients.

PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8+ TILs (5 × 107 to 3 × 1010 cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 × 106 IU/m2 by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs.

RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board.

CONCLUSION: Treatment with CD8+ TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.
Outcome of Postchemotherapy Surgery After Treatment With Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients With Unresectable or Metastatic Transitional Cell Carcinoma
Authors: Dodd Paul M. , McCaffrey John A. , Herr Harry , Mazumdar Madhu , Bacik Jennifer , Higgins Geralyn , Boyle Mary G. , Scher Howard I. , Bajorin Dean F.
Published: February 2017

PURPOSE: The role of postchemotherapy surgery for patients with metastatic transitional cell carcinoma (TCC) is controversial. We retrospectively analyzed our experience with patients who underwent postchemotherapy surgery after methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy to assess an impact on long-term survival.

PATIENTS AND METHODS: This report is based on the retrospective analysis of 203 patients with unresectable primary tumors or metastatic TCC, previously reported in five trials of M-VAC chemotherapy. Fifty patients underwent postchemotherapy surgery for suspected or known residual disease. Characteristics of patients selected for surgery, results of surgery, and the impact of surgery on survival were assessed.

RESULTS: In 17 patients, no viable tumor was found at postchemotherapy surgery, pathologically confirming a complete response to chemotherapy. Three patients had unresectable residual TCC. In 30 patients, residual, viable TCC was completely resected, which resulted in a complete response to chemotherapy plus surgery. Ten (33%) of these 30 patients remained alive at 5 years, similar to results observed for patients who attained a complete response to chemotherapy alone (41%). Analysis by baseline extent of disease suggested that patients with unresectable primary tumors or with metastases restricted to lymph node sites were most likely to survive for 5 years.

CONCLUSION: Postchemotherapy surgical resection of residual cancer may result in 5-year disease-free survival in some patients who would otherwise succumb to disease. Optimal candidates include patients whose prechemotherapy sites of disease are restricted to the primary or lymph node sites and who have a major response to chemotherapy.
Proposed Agenda for the Measurement of Quality-of-Care Outcomes in Oncology Practice
Authors: Mandelblatt Jeanne S. , Ganz Patricia A. , Kahn Katherine L.
Published: February 2017

ABSTRACT: Cancer is an important disease, and health care services have the potential to improve the quality and quantity of life for cancer patients. The delivery of these services also has recently been well codified. Given this framework, cancer care presents a unique opportunity for clinicians to develop and test outcome measures across diverse practice settings. Recently, the Institute of Medicine released a report reviewing the quality of cancer care in the United States and called for further development and monitoring of quality indicators. Thus, as we move into the 21st century, professional and regulatory agencies will be seeking to expand process measures and develop and validate outcomes-oriented measures for cancer and other diseases. For such measures to be clinically relevant and feasible, it is key that the oncology community take an active leadership role in this process. To set the stage for such activities, this article first reviews broad methodologic concerns involved in selecting measures of the quality of care, using breast cancer to exemplify key issues. We then use the case of breast cancer to review the different phases of cancer care and provide examples of phase-specific measures that, after careful operationalization, testing, and validation, could be used as the basis of an agenda for measuring the quality of breast cancer care in oncology practice. The diffusion of process and outcome measures into practice; the practicality, reliability, and validity of these measures; and the impact that these indicators have on practice patterns and the health of populations will be key to evaluating the success of such quality-of-care paradigms. Ultimately, improved quality of care should translate into morbidity and mortality reductions.
Effect of Blood Tamoxifen Concentrations on Surrogate Biomarkers in a Trial of Dose Reduction in Healthy Women
Authors: Decensi Andrea , Gandini Sara , Guerrieri-Gonzaga Aliana , Johansson Harriet , Manetti Lapo , Bonanni Bernardo , Sandri Maria Teresa , Barreca Antonella , Costa Alberto , Robertson Chris , Lien Ernst A.
Published: February 2017

PURPOSE: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction.

PATIENTS AND METHODS: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, blood cell count, fibrinogen, antithrombin III, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer.

RESULTS: The means (± SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mL) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 ± 15.1 and 43.7 ± 22.5 with 10 mg every other day, 51.2 ± 24.1 and 90.7 ± 48.0 with 10 mg/d, and 136.0 ± 52.7 and 230.6 ± 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations.

CONCLUSION: An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent.
Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease
Authors: Cobleigh Melody A. , Vogel Charles L. , Tripathy Debu , Robert Nicholas J. , Scholl Susy , Fehrenbacher Louis , Wolter Janet M. , Paton Virginia , Shak Steven , Lieberman Gracie , Slamon Dennis J.
Published: February 2017

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease.

PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals.

RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events.

CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.
Multicenter Phase II Trial of Temozolomide in Patients With Anaplastic Astrocytoma or Anaplastic Oligoastrocytoma at First Relapse
Authors: Yung W.K. Alfred , Prados Michael D. , Yaya-Tur Ricardo , Rosenfeld Steven S. , Brada Michael , Friedman Henry S. , Albright Robert , Olson Jeffrey , Chang Susan M. , O'Neill Alison M. , Friedman Allan H. , Bruner Janet , Yue Nancy , Dugan Margaret , Zaknoen Sara , Levin Victor A.
Published: February 2017

PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse.

PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m2/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m2/d; the dose could be increased to 200 mg/m2/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle.

RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients.

CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.
Topotecan and Cytarabine Is an Active Combination Regimen in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia
Authors: Beran Miloslav , Estey Elihu , O'Brien Susan , Cortes Jorge , Koller Charles A. , Giles Francis J. , Kornblau Steven , Andreeff Michael , Vey Norbert , Pierce Sherry R. , Hayes Kimberly , Wong Gee Chuan , Keating Michael , Kantarjian Hagop
Published: February 2017

PURPOSE: To evaluate the efficacy and safety of the combination of topotecan and cytarabine in patients with myelodysplastic syndromes (MDSs) and chronic myelomonocytic leukemia (CMML).

PATIENTS AND METHODS: Fifty-nine patients with MDSs and 27 with CMML were enrolled. They were either previously untreated (66%) or had received only biologic agents (14%) or chemotherapy with or without biologic agents (20%). Treatment consisted of topotecan 1.25 mg/m2 by continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 hours daily for 5 days. Prophylaxis included antibacterial, antifungal, and antiviral agents. At a median follow-up of 7 months, all 86 patients were assessable for response and toxicity.

RESULTS: Complete remission (CR) was observed in 48 patients (56%; 61% with MDSs, 44% with CMML; P = .15). Similar CR rates were observed for patients with good-risk and poor-risk MDS (70% and 56%, respectively). The treatment effectively induced CR in patients with a poor-prognosis karyotype involving chromosomes 5 and 7 (CR, 71%) and secondary MDSs (CR, 72%). Fifty-four patients received one induction course, 25 patients received two, and the rest received more than two. The median number of continuation courses was two. The median overall duration of CR was 34 weeks (50 weeks for MDSs and 33 weeks for CMML). The median survival was 60 weeks for MDS and 44 weeks for CMML patients. CR and survival durations were longer in patients with refractory anemia with excess blasts (RAEB). Grade 3 or 4 mucositis or diarrhea was observed in three patients each. Fever was observed in 63%, and infections in 49% of patients. Six patients (7%) died during induction therapy.

CONCLUSION: Topotecan and cytarabine induced high CR rates in unselected patients with MDSs and CMML, particularly among patients with poor-prognosis cytogenetics and secondary MDSs. Topotecan-cytarabine is an active induction regimen in MDS and CMML patients, is well tolerated, and is associated with a low mortality rate.
Comparison of Two Quality-of-Life Instruments for Cancer Patients: The Functional Assessment of Cancer Therapy-General and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30
Authors: Kemmler Georg , Holzner Bernhard , Kopp Martin , Dünser Martina , Margreiter Raimund , Greil Richard , Sperner-Unterweger Barbara
Published: February 2017

PURPOSE: To compare two quality-of-life (QOL) questionnaires for cancer patients, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-General (Fact-G), on the basis of empirical data.

PATIENTS AND METHODS: Two hundred forty-four patients with a diagnosis of breast cancer or Hodgkin's disease completed both the EORTC QLQ-C30 and the FACT-G (German language version) during the same session. Questionnaire data were analyzed on a subscale basis using correlation analysis, canonical correlation, and multiple linear regression.

RESULTS: Correlations between corresponding subscales of the FACT-G and the EORTC QLQ-C30 ranged from r = .14 for the social domain (very poor agreement) to r = .66 for the physical domain (good agreement), with r values for the other domains lying between these extremes. Canonical correlation analysis for the two sets of subscales revealed that overall agreement between the two instruments was only moderate (first canonical correlation coefficient r = .85, but overall redundancy less than 40%). Of the five FACT-G subscales, only one, physical well-being, was well represented by the EORTC QLQ-C30 subscales (multiple linear regression, R2 = .67). Only three of eight EORTC QLQ-C30 subscales (physical functioning, global QOL, general symptoms) were represented fairly well by FACT-G subscales (R2 = .43 to .60). The lowest R2 values (< .15; ie, virtually no representation by the other instrument) were found for the FACT-G social well-being and relation with doctors and EORTC QLQ-C30 cognitive functioning subscales.

CONCLUSION: For the sample investigated, the EORTC QLQ-C30 and the FACT-G were found to measure markedly different aspects of QOL, despite considerable overlap. Replicability provided, this implies that neither of the two QOL instruments can be replaced by the other and that a direct comparison of results obtained with the two instruments is not possible.
Activity of Docetaxel in Platinum-Treated Non–Small-Cell Lung Cancer: Results of a Phase II Multicenter Trial
Authors: Gandara David R. , Vokes Everett , Green Mark , Bonomi Phillip , Devore Russell , Comis Robert , Carbone David , Karp Daniel , Belani Chandra
Published: February 2017

PURPOSE: Although several new chemotherapeutic agents are promising as primary therapy in non-small–cell lung cancer (NSCLC), few have demonstrated activity in platinum-refractory disease. Based on encouraging results reported in two single-institution studies of docetaxel in this setting, we performed a multicenter phase II trial evaluating this novel taxane in previously treated NSCLC patients prospectively categorized by platinum response status.

PATIENTS AND METHODS: Eighty patients with NSCLC previously treated with platinum-based chemotherapy received docetaxel at a dose of 100 mg/m2 intravenously over 1 hour, repeated every 21 days, accompanied by dexamethasone 8 mg orally twice daily for 5 days. Forty-seven patients (59%) were defined as platinum-refractory based on response status to prior therapy.

RESULTS: The median number of cycles delivered per patient was four (range, one to 21 cycles). Partial response was observed in 13 (16%) of 80 of patients, with similar response rates in platinum-sensitive and platinum-refractory patients. The median survival time was 7 months, and the 1-year survival rate was 25%. Docetaxel was relatively well tolerated in this previously treated population. Grade IV neutropenia was common in patients (77%) but typically of brief duration. Febrile neutropenia was observed in 11 patients (14%), with no fatal infections. Severe fluid retention was rare (4% of patients).

CONCLUSIONS: This multicenter phase II trial confirms antitumor activity and encouraging survival with docetaxel therapy in platinum-treated and platinum-refractory NSCLC. To validate these results, a phase III trial randomizing platinum-treated patients to docetaxel or best supportive care is underway.
Pharmacokinetic, Metabolic, and Pharmacodynamic Profiles in a Dose-Escalating Study of Irinotecan and Cisplatin
Authors: de Jonge Maja J. A. , Verweij Jaap , de Bruijn Peter , Brouwer Eric , Mathijssen Ron H. J. , van Alphen Robbert J. , de Boer-Dennert Maureen M. , Vernillet Laurent , Jacques Christian , Sparreboom Alex
Published: February 2017

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of irinotecan and cisplatin administered once every 3 weeks in a dose-escalating study in patients with solid tumors.

PATIENTS AND METHODS: Fifty-two cancer patients were treated with irinotecan administered as a 90-minute infusion at doses ranging from 175 to 300 mg/m2 followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m2. After reaching the maximum-tolerated dose, the sequence of drug administration was revised. For pharmacokinetic analysis, serial plasma samples were obtained on days 1 through 3 of the first cycle. Forty-five patients were assessable for irinotecan pharmacokinetics, and 46 were assessable for cisplatin pharmacokinetics.

RESULTS: Irinotecan and cisplatin demonstrated linear pharmacokinetics comparable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasma metabolite of irinotecan, whereas 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possibly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compared with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. The percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinotecan (P = .0245) and SN-38 (P = .0123). The severity of diarrhea was not significantly related to the AUCs of irinotecan and SN-38, nor to the systemic glucuronidation rate of SN-38.

CONCLUSION: There was no apparent pharmacokinetic interaction between irinotecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. The incidence and severity of delayed-type diarrhea was not related to any of the studied parameters.
Molecular Biology of the Ewing’s Sarcoma/Primitive Neuroectodermal Tumor Family
Authors: de Alava Enrique , Gerald William L.
Published: February 2017

ABSTRACT: Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET) are members of a tumor family consistently associated with chromosomal translocation and functional fusion of the EWS gene to any of several structurally related transcription factor genes. Similar gene fusion events occur in other mesenchymal and hematopoietic tumors and are tumor-specific. The resulting novel transcription factor–like chimeric proteins are believed to contribute to tumor biology by aberrant regulation of gene expression altering critical controls of cell proliferation and differentiation. These tumor-specific molecular rearrangements are useful for primary diagnosis, may provide prognostic information, and present potential therapeutic targets. The recent advances in our understanding of the molecular biology of ES and PNET represent a paradigm for the application of the basic biology of neoplasia to clinical management of patients.
Is Radiation Therapy a Preferred Alternative to Surgery for Squamous Cell Carcinoma of the Base of Tongue?
Authors: Mendenhall William M. , Stringer Scott P. , Amdur Robert J. , Hinerman Russell W. , Moore-Higgs Giselle J. , Cassisi Nicholas J.
Published: February 2017

PURPOSE: To evaluate irradiation alone for treatment of base-of-tongue cancer.

PATIENTS AND METHODS: Two hundred seventeen patients with squamous cell carcinoma of the base of tongue were treated with radiation alone and had follow-up for ≥ 2 years.

RESULTS: Local control rates at 5 years were as follows: T1, 96%; T2, 91%; T3, 81%; and T4, 38%. Multivariate analysis revealed that T stage (P = .0001) and overall treatment time (P = .0006) significantly influenced local control. The 5-year rates of local-regional control were as follows: I, 100%; II, 100%; III, 83%; IVA, 64%; and IVB, 65%. Multivariate analysis revealed that the following parameters significantly affect the probability of this end point: T stage (P = .0001), overall treatment time (P = .0001), overall stage (P = .0131), and addition of a neck dissection (P = .0021). The rates of absolute and cause-specific survival at 5 years were as follows: I, 50% and 100%; II, 81% and 100%; III, 65% and 76%; IVA, 42% and 56%; and IVB, 44% and 52%. Severe radiation complications developed in eight patients (4%).

CONCLUSION: The likelihood of cure after external-beam irradiation was related to stage, overall treatment time, and addition of a planned neck dissection. The local-regional control rates and survival rates after radiation therapy were comparable to those after surgery, and the morbidity associated with irradiation was less.
Angiocentric Lymphoma of the Head and Neck: Patterns of Systemic Failure After Radiation Treatment
Authors: Kim Gwi Eon , Cho Jae Ho , Yang Woo Ick , Chung Eun Ji , Suh Chang Ok , Park Kyung Ran , Hong Won Pyo , Park In Yong , Hahn Jee Sook , Roh Jae Kyung , Kim Byung Soo
Published: February 2017

PURPOSE: To investigate the patterns of systemic failure and the clinical outcome in patients with angiocentric lymphoma of the head and neck who were treated with radiation alone, and to discuss the optimal mode of treatment for these patients.

PATIENTS AND METHODS: We reviewed the records of 92 patients with stage I or II angiocentric lymphoma who were treated at Yonsei Cancer Center between 1976 and 1994. All patients were treated with involved-field irradiation. Radiation doses ranged from 40 to 60 Gy (median dose, 50.4 Gy). Treatment response, patterns of treatment failure including systemic failure, and clinical outcome after radiation treatment were analyzed.

RESULTS: The most frequently involved site was the nasal cavity, either alone or in conjunction with other sites. In 16 patients (17.4%), angiocentric lymphoma was accompanied by cervical lymphadenopathy. Disease was classified as stage I in 62 patients (67.4%) and stage II in 30 patients (32.6%). After completion of radiation treatment, 61 patients (66.3%) achieved a complete response and 16 (17.4%) a partial response. Half of the patients (50.0%) ultimately experienced local recurrence with or without other components of failure, whereas regional failure was relatively uncommon (10.9%). Systemic failure occurred in 25.0% of patients during follow-up. Six patients had histologic findings identical to those at the time of the original disease (group I), whereas four patients exhibited morphologic features of frank lymphomas (group II). The majority of patients with systemic relapse had the predilection sites for widespread extranodal involvement, such as the skin, brain, lung, gastrointestinal tract, or testes. In addition, seven patients died from various medical illnesses or immunologic disorders, including hemophagocytic syndrome and second primary cancers (group III). After a median follow-up of 56 months, the overall survival and disease-free survival rates for all patients were 40.1% and 37.8%, respectively. All patients except one with systemic failure died within 1 year.

CONCLUSION: Treatment with radiation alone had suboptimal results, partly because of the occurrence of a variety of systemic failure with diverse clinicopathologic features. Given the frequent occurrence of systemic failure after radiation treatment, we believe that the multimodality treatment approach containing more effective chemotherapeutic agents should be incorporated in the treatment of angiocentric lymphoma confined to the head and neck.
Prognostic Significance of Vascular Endothelial Growth Factor Protein Levels in Oral and Oropharyngeal Squamous Cell Carcinoma
Authors: Smith Benjamin D. , Smith Grace L. , Carter Darryl , Sasaki Clarence T. , Haffty Bruce G.
Published: February 2017

PURPOSE: Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis in many different tumor types. VEGF levels may affect tumor growth, metastatic potential, and response to radiotherapy. This study assesses the prognostic value of VEGF protein levels in a cohort of patients with oral and oropharyngeal squamous cell carcinomas. The relationships between clinical outcome and the covariables of tumor-node-metastasis stage, disease stage (I to IV), grade, margin status, race, sex, and age were also determined.

PATIENTS AND METHODS: Chart review identified 77 patients with oral or oropharyngeal squamous cell carcinoma treated with gross total surgical resection and postoperative radiation between 1981 and 1992. Sufficient follow-up data and tumor tissue were available in 56 patients (73%). VEGF protein levels were determined using immunohistochemistry. The association between VEGF status, covariables, and outcome was assessed in a bivariate and multivariate model using two-sided statistical tests.

RESULTS: Twenty-three tumors (41%) were positive for VEGF expression. VEGF-positive tumors were more likely to recur locally (relative risk [RR] = 3.08; 95% confidence interval [CI], 1.03 to 9.24) and distantly (RR = 4.62; 95% CI, 1.41 to 15.10). In bivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.66; 95% CI, 1.27 to 5.56) and overall survival (RR = 3.21; 95% CI, 1.63 to 6.32). In multivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.75; 95% CI, 1.30 to 5.79) and overall survival (RR = 3.53; 95% CI, 1.75 to 7.13).

CONCLUSION: In this cohort, VEGF positivity was the most significant predictor of poor prognosis. VEGF status may prove to be an important prognostic factor in head and neck cancer.
Activity of Exemestane in Metastatic Breast Cancer After Failure of Nonsteroidal Aromatase Inhibitors: A Phase II Trial
Authors: Lønning Per Eystein , Bajetta Emilio , Murray Robin , Tubiana-Hulin Michèle , Eisenberg Peter D. , Mickiewicz Elizabeth , Celio Luigi , Pitt Paula , Mita Monica , Aaronson Neil K. , Fowst Camilla , Arkhipov Alexei , di Salle Enrico , Polli Anna , Massimini Giorgio
Published: February 2017

PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor.

PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58).

RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients.

CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.
Phase II Trial of Weekly Intravenous Gemcitabine With Continuous Infusion Fluorouracil in Patients With Metastatic Renal Cell Cancer
Authors: Rini Brian I. , Vogelzang Nicholas J. , Dumas Mary C. , Wade James L. , Taber David A. , Stadler Walter M.
Published: February 2017

PURPOSE: To determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC).

PATIENTS AND METHODS: Between June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m2 over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m2/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle. Patients had a Cancer and Leukemia Group B performance status of 0 or 1, with a median time since diagnosis of metastatic disease of 10 months (range, 0 to 129 months). Thirty-three patients (80%) had multiple metastatic sites, and 34 patients (83%) had prior chemotherapy or immunotherapy.

RESULTS: Of the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. The duration of response for the seven partial responders was 2, 3, 7, 8, 10, 11, and 14 months. Median progression-free survival for the gemcitabine/5-FU group was 28.7 weeks versus 8 weeks for a similar cohort of patients treated on previous phase II studies at the University of Chicago (P = .008). The regimen was well tolerated, with fatigue, mucositis, nausea/vomiting, and grade 2 hematologic toxicities being most common.

CONCLUSION: Weekly gemcitabine with continuous infusion 5-FU is an active combination in patients with metastatic RCC. Therapy was well tolerated and produced an improvement in progression-free survival over historical controls.
Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials
Authors: Gallo James M. , Laub Paul B. , Rowinsky Eric K. , Grochow Louise B. , Baker Sharyn D.
Published: February 2017

PURPOSE: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition.

PATIENTS AND METHODS: All data were collected from 82 patients entered in four different phase I trials that were previously reported as separate studies from 1992 to 1996. All patients received topotecan as a 30-minute constant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m2. Among the 82 patients were 30 patients classified as having renal insufficiency and 13 patients with hepatic dysfunction. The population pharmacokinetic model was built in sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalized additive modeling.

RESULTS: A linear two-compartment model characterized total topotecan plasma concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment) were related to various combinations of covariates. The relationship for total clearance (TVCL [L/h] = 32.0 + [0.356(WT − 71) + 0.308(HT − 168.5) − 8.42(SCR − 1.1)] × [1 + 0.671 sex]) was dependent on the patients’ weight (WT), height (HT), serum creatinine (SCR), and sex and had a moderate ability to predict (r2 = 0.64) each patient’s individual clearance value. The addition of covariates to the population model improved the prediction errors, particularly for clearance. Removal of 10 outlying patients from the analysis improved the ability of the model to predict individual clearance values (r2 = 0.77).

CONCLUSION: A population pharmacokinetic model for total topotecan has been developed that incorporates measures of body size and renal function to predict total clearance. The model can be used prospectively to obtain a revised and validated model that can then be used to design individualized dosing regimens.
Pharmacoeconomic Analysis of Liposomal Amphotericin B Versus Conventional Amphotericin B in the Empirical Treatment of Persistently Febrile Neutropenic Patients
Authors: Cagnoni Pablo J. , Walsh Thomas J. , Prendergast Mary M. , Bodensteiner David , Hiemenz Sharon , Greenberg Richard N. , Arndt Carola A. S. , Schuster Mindy , Seibel Nita , Yeldandi Vijay , Tong Kuo B.
Published: February 2017

PURPOSE: In a randomized, double-blind, comparative, multicenter trial, liposomal amphotericin B was equivalent to conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients, using a composite end point, but was more effective in reducing proven emergent fungal infections, infusion-related toxicities, and nephrotoxicity. The purpose of this study was to compare the pharmacoeconomics of liposomal versus conventional therapy.

PATIENTS AND METHODS: Itemized hospital billing data were collected on 414 patients from 19 of the 32 centers that participated in the trial. Hospital length of stay and costs from the first dose of study medication to the time of hospital discharge were assessed.

RESULTS: Hospital costs from the time of first dose to discharge were significantly higher for all patients who received liposomal amphotericin B ($48,962 v $43,183; P = .022). However, hospital costs were highly sensitive to the cost of study medication ($39,648 v $43,048 when drug costs were not included; P = .416). Using decision analysis models and sensitivity analyses to vary the cost of study medications and the risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients.

CONCLUSION: The cost of liposomal amphotericin B and patient risk for developing nephrotoxicity play large roles in determining whether liposomal amphotericin B is cost-effective as first-line empirical therapy in persistently febrile neutropenic patients.
Leukocytosis and the Retinoic Acid Syndrome in Patients With Acute Promyelocytic Leukemia Treated With Arsenic Trioxide
Authors: Camacho Luis H. , Soignet Steven L. , Chanel Suzanne , Ho Raymond , Heller Glenn , Scheinberg David A. , Ellison Ralph , Warrell Raymond P.
Published: February 2017

PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena.

PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg.

RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/μL (range, 1,200 to 72,300 cells/μL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/μL; range, 500 to 5,400 cells/μL; P = .01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P < .001), and no patient without a peak leukocyte count greater than 10,000 cells/μL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P = .37).

CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.
Time-Dependent Relevance of Steroid Receptors in Breast Cancer
Authors: Coradini Danila , Daidone Maria Grazia , Boracchi Patrizia , Biganzoli Elia , Oriana Saro , Bresciani Gianluigi , Pellizzaro Cinzia , Tomasic Gorana , Di Fronzo Giovanni , Marubini Ettore
Published: February 2017

PURPOSE: To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation.

PATIENTS AND METHODS: We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node–negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered.

RESULTS: ER content and tumor size (adjusted for all the other covariates) showed a time-dependent relationship with the risk of new disease manifestations. In particular, ER content failed to show a prognostic effect within the first years of follow-up; thereafter, a positive association with risk of relapse was observed. For tumor size, within the first years of follow-up, the risk of relapse was directly related to size for only tumors up to 2.5 cm in diameter; thereafter, the impact on prognosis progressively decreased.

CONCLUSION: The availability of a long follow-up on a large breast cancer series, as well as the use of innovative statistical approaches, allowed us to explore the functional relation between steroid receptors and clinical outcome and to generate a hypothesis on the involvement of ER in favoring long-term metastasis development.
Occult Ovarian Tumors in Women With BRCA1 or BRCA2 Mutations Undergoing Prophylactic Oophorectomy
Authors: Lu Karen H. , Garber Judy E. , Cramer Daniel W. , Welch William R. , Niloff Jonathan , Schrag Deborah , Berkowitz Ross S. , Muto Michael G.
Published: February 2017

PURPOSE: To review the findings at prophylactic oophorectomy of a series of women who presented to a familial breast and ovarian cancer clinic.

MATERIALS AND METHODS: Data from medical charts, operative notes, and pathology reports were collected on women who had undergone prophylactic oophorectomies because of the elevated risk of ovarian cancer. Because only a subset of patients underwent BRCA1 and BRCA2 testing, each patient’s risk of hereditary predisposition was calculated using the Berry-Parmigiani model and family history data.

RESULTS: From June 1989 to December 1998, 50 women seen at our clinic underwent prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%. Among this group, four incidental tumors were found (four of 33, or 12%); one tumor was noted at the time of surgery and three were noted only in the final pathology. Two patients had microscopic, poorly differentiated serous adenocarcinomas in multiple sites on both ovaries. A third patient had a bilateral serous borderline tumor with micropapillary features. The fourth patient had a microscopic serous borderline ovarian tumor. All four patients had germline BRCA1 or BRCA2 mutations, and three had unremarkable transvaginal ultrasonography examinations within 6 months before prophylactic surgery.

CONCLUSION: Foci of malignant tumor are not uncommon in prophylactic oophorectomies performed in women at very high risk for ovarian cancer and may not be detected on ultrasonograms. Surgeons should have a high suspicion of finding cancer in these women at the time of prophylactic surgery, and careful pathologic assessment of the specimens should be conducted.