bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Therapy for Locally Advanced Bladder Cancer: Final Report of a Randomized Trial of Cystectomy Plus Adjuvant M-VAC Versus Cystectomy With Both Preoperative and Postoperative M-VAC
Authors: Millikan Randall , Dinney Colin , Swanson David , Sweeney Paul , Ro Jae Y. , Smith Terry L. , Williams Dallas , Logothetis Christopher
Published: February 2017

PURPOSE: We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging.

PATIENTS AND METHODS: A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy.

RESULTS: There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured.

CONCLUSION: These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort.
Brief-Duration High-Intensity Chemotherapy for Patients With Small Noncleaved–Cell Lymphoma or FAB L3 Acute Lymphocytic Leukemia: Results of Cancer and Leukemia Group B Study 9251
Authors: Lee Edward J. , Petroni Gina R. , Schiffer Charles A. , Freter Carl E. , Johnson Jeffrey L. , Barcos Maurice , Frizzera Glauco , Bloomfield Clara D. , Peterson Bruce A.
Published: February 2017

PURPOSE: To define the activity and feasibility of brief-duration high-intensity chemotherapy for adults with small noncleaved, non-Hodgkin’s lymphoma (SNC) and the L3 variant of acute lymphocytic leukemia (L3 ALL).

PATIENTS AND METHODS: Seventy-five adults with either SNC or L3 ALL (median age, 44 years) were treated with an aggressive regimen that consisted of one cycle of cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy with prophylactic CNS irradiation.

RESULTS: All 24 patients with L3 ALL and the 30 of 51 patients with SNC confirmed by central histologic review were included in this analysis. Forty-three of 54 patients achieved complete response (CR) (18 of 24 with ALL and 25 of 30 with SNC), and 28 are alive and in continuous CR with a median follow-up of 5.1 years. Hematologic toxicity was profound, and nonhematologic toxicity was notable, with 10 of 75 patients treated developing significant neurologic toxicity consisting of transverse myelitis in five patients, CNS toxicity in three, and severe peripheral neuropathy in two. All patients who did not achieve CR died of the disease, and all recurrences occurred within 16 months of the end of treatment. Responses and toxicities were similar in the patients with both lymphoma and leukemia.

CONCLUSION: Aggressively delivered chemotherapy is potentially curative in as many as half of patients with SNC and the L3 ALL variant. This treatment regimen had considerable neurologic toxicity and has been modified.
Use of CA-125 to Define Progression of Ovarian Cancer in Patients With Persistently Elevated Levels
Authors: Rustin Gordon J.S. , Marples Maria , Nelstrop Ann E. , Mahmoudi Mohamed , Meyer Tim
Published: February 2017

PURPOSE: To determine an accurate definition for progression of ovarian cancer in patients with a persistently elevated serum CA-125.

PATIENTS AND METHODS: A retrospective analysis was performed on 300 patients with epithelial ovarian carcinoma with at least one measurement of CA-125. The date of progression according to clinical or radiologic criteria was ascertained in the 88 patients with persistently elevated CA-125 levels (> 23 U/mL). This was compared with the date of progression according to CA-125, defined as the date on which the CA-125 level first increased to ≥ twice its nadir level, confirmed by a second sample also ≥ twice the nadir.

RESULTS: Eighty of the 88 patients had evidence of progression by both standard and CA-125 criteria, giving a sensitivity of 94%. In six of these patients, no sample was taken to confirm CA-125 doubling. In 13 patients, CA-125 doubling occurred after the date of clinical progression. Only one patient had a false-positive prediction of progression according to CA-125; the patient died as a result of a myocardial infarct before evidence of clinical progression.

CONCLUSION: In patients whose CA-125 level decreases to normal after chemotherapy, a doubling from the upper limit of normal has been shown to predict progression. In those with persistently elevated levels, doubling of CA-125 from its nadir level has now been shown to accurately define progression. If confirmed, these CA-125 criteria should be used as additional end points in clinical trials.
MSH2 Mutation Carriers Are at Higher Risk of Cancer Than MLH1 Mutation Carriers: A Study of Hereditary Nonpolyposis Colorectal Cancer Families
Authors: Vasen H. F.A. , Stormorken A. , Menko F. H. , Nagengast F. M. , Kleibeuker J. H. , Griffioen G. , Taal B. G. , Moller P. , Wijnen J. T.
Published: February 2017

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations.

PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives.

RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant.

CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.
Surveillance Neuroimaging to Detect Relapse in Childhood Brain Tumors: A Pediatric Oncology Group Study
Authors: Minn A. Yuriko , Pollock Brad H. , Garzarella Linda , Dahl Gary V. , Kun Larry E. , Ducore Jonathan M. , Shibata Atsuko , Kepner James , Fisher Paul G.
Published: February 2017

PURPOSE: To investigate the prognostic significance of surveillance neuroimaging for detection of relapse among children with malignant brain tumors.

PATIENTS AND METHODS: A historical cohort study examined all children who experienced relapse from 1985 to 1999 on one of 10 Pediatric Oncology Group trials for malignant glioma, medulloblastoma, or ependymoma.

RESULTS: For all 291 patients (median age at diagnosis, 8.2 years), median time to first relapse was 8.8 months (range, 0.6 to 115.6 months). Ninety-nine relapses were radiographic, and 192, clinical; median time to relapse was 15.7 versus 6.6 months, respectively (P = .0001). When stratified by pathology, radiographic and clinical groups showed differences in median time to relapse for malignant glioma (7.8 v 4.3 months, respectively; P = .041) and medulloblastoma (23.6 v 8.9 months, respectively; P = .0006) but not ependymoma (19.5 v 13.3 months, respectively; P = .19). When stratified by early (< 8.8 months) or late (≥ 8.8 months) time to relapse, 115 early relapses were clinical, and 32, radiographic; for late relapses, 77 were clinical, and 67, radiographic (P = .001). Overall survival (OS) from relapse was significantly longer for radiographic compared with clinical detection (median, 10.8 months; 1-year OS, 46% v median, 5.5 months; 1-year OS, 33%; P = .002), but this trend did not retain significance when analyzed by pathology subgroups.

CONCLUSION: Surveillance neuroimaging detects a proportion of asymptomatic relapses, particularly late relapses, and may provide lead time for other therapies on investigational trials. During the first year after diagnosis, radiographic detection of asymptomatic relapse was infrequent. A prospective study is needed to formulate a rational surveillance schedule based on the biologic behavior of these tumors.
Prognostic and Predictive Significance of ErbB-2 Breast Tumor Levels Measured by Enzyme Immunoassay
Authors: Eppenberger-Castori Serenella , Kueng Willy , Benz Christopher , Caduff Rosmarie , Varga Zsuzsanna , Bannwart Fridolin , Fink Daniel , Dieterich Holger , Hohl Michael , Müller Heinz , Paris Kaja , Schoumacher Fabrice , Eppenberger Urs
Published: February 2017

PURPOSE: A retrospective analysis to assess the prognostic and predictive clinical value of breast tumor ErbB-2 receptor expression quantified by enzyme immunoassay (EIA), to compare levels measured by EIA with ErbB-2 status determined by immunohistochemistry (IHC), and to correlate receptor content with levels of phosphorylated (Y1248-P) ErbB-2, a measure of functional tyrosine kinase activity.

MATERIALS AND METHODS: EIA quantification of ErbB-2 was performed on membrane extracts from 3,208 well-characterized primary breast cancers. Overall, relapse-free, distant disease-free, and local/regional-free patient survival data were available on 1,123 of these tumors. IHC scoring for ErbB-2 status (HercepTest; DAKO, Glostrup, Denmark) was performed on adjacent sections of 151 cases, and receptor functionality was measured in 230 tumors by an antibody specific for phosphorylated (Y1248-P) ErbB-2.

RESULTS: Unlike nonmalignant breast tissues, breast tumors showed increased ErbB-2 levels in a bimodal distribution, with 12% constituting a distinct set of ErbB-2–overexpressing tumors. The intermodal threshold value for ErbB-2 overexpression distinguished tumors with reduced estrogen and progesterone receptor content, high IHC score for ErbB-2, and significantly increased levels of phosphorylated (Y1248-P) ErbB-2 receptor. By multivariate analysis, EIA-determined ErbB-2 overexpression predicted significantly reduced patient survival that was unaffected by tamoxifen or cyclophosphamide, methotrexate, and fluorouracil adjuvant therapy.

CONCLUSION: Determination of ErbB-2 receptor expression by EIA offers a clinically valuable alternative to semiquantitative IHC assessment of breast tumor ErbB-2 overexpression and affords the opportunity to evaluate ErbB-2 phosphorylation, which may represent an important predictive parameter of receptor functionality.
Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients
Authors: Stein John P. , Lieskovsky Gary , Cote Richard , Groshen Susan , Feng An-Chen , Boyd Stuart , Skinner Eila , Bochner Bernard , Thangathurai Duriayai , Mikhail Maged , Raghavan Derek , Skinner Donald G.
Published: February 2017

PURPOSE: To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes.

PATIENTS AND METHODS: All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients.

RESULTS: A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node–negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node–negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node–negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence.

CONCLUSION: These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.
Increased Temperature of Malignant Urinary Bladder Tumors In Vivo: The Application of a New Method Based on a Catheter Technique
Authors: Stefanadis C. , Chrysochoou C. , Markou D. , Petraki K , Panagiotakos D. B. , Fasoulakis C. , Kyriakidis A. , Papadimitriou C. , Toutouzas P. K.
Published: February 2017

PURPOSE: The aim of this study was to investigate the existence of any thermal difference between malignant tumors and inflammatory benign lesions of the human urinary bladder and to determine whether it correlates with tumor angiogenesis quantification.

PATIENTS AND METHODS: A new method, developed in our institute, is introduced to detect temperature in human urinary bladder, in vivo. This method is based on a thermography catheter. We calculated the differences of the temperature of the solid tumor and of a normal area (ΔT) on 20 subjects (mean age, 72.5 years; 95% confidence interval [CI], 68.5 to 76.4). According to the biopsy histology, Eight (40%) patients had benign tumors, and 12 (60%) had malignant tumors.

RESULTS: We found significant differences of ΔT between patients with benign and malignant tumor (P < .001). Also, differences were found for the mean values of angiogenesis level between malignant and benign tumors (P = .0261), and a moderated positive correlation was estimated between the degree of angiogenesis and ΔT (P = .02). Based on logistic regression analysis, we found that a 1-degree increase of ΔT triples the odds of a patient having a malignant tumor (odds ratio = 2.91; 95% CI, 1.97 to 7.78; P < .001), adjusted for the degree of angiogenesis (P = .0236) and the grade of tumor (P < .001). A threshold point of ΔT = 0.7°C was determined, with sensitivity 83% and specificity 75%.

CONCLUSION: These findings suggest that the calculated difference of temperature between normal tissue and neoplastic area could be a useful criterion in the diagnosis of malignancy in tumors of the human urinary bladder.
Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative Disorders
Authors: Leblond Véronique , Dhedin Nathalie , Bruneel Marie-France Mamzer , Choquet Sylvain , Hermine Olivier , Porcher Raphaël , Quoc Stéphanie Nguyen , Davi Frédéric , Charlotte Frédéric , Dorent Richard , Barrou Benoit , Vernant Jean-Paul , Raphael Martine , Levy Vincent
Published: February 2017

PURPOSE: Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkin’s lymphoma International Prognostic Index (IPI) in 61 patients with PTLD.

PATIENTS AND METHODS: We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates.

RESULTS: In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) ≥ (P = .0001) and nondetection of Epstein-Barr virus (EBV) in the tumor (P = .01). Only a negative link with PS ≥ 2 was observed in multivariate analysis. In univariate analysis, factors predictive of lower survival were PS ≥ 2, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy. The IPI failed to identify a patient subgroup with better survival and was less predictive of the response rate than was a specific index using two risk factors (PS and number of involved sites), which defined three groups of patients: low-risk patients whose median survival time has not yet been reached, intermediate-risk patients with a median survival time of 34 months, and high-risk patients with a median survival time of 1 month.

CONCLUSION: PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.
Effectiveness of Chemotherapy for Advanced Lung Cancer in the Elderly: Instrumental Variable and Propensity Analysis
Authors: Earle Craig C. , Tsai Jerry S. , Gelber Richard D. , Weinstein Milton C. , Neumann Peter J. , Weeks Jane C.
Published: February 2017

PURPOSE: To compare the effectiveness of chemotherapy given to elderly patients in routine practice for stage IV non–small-cell lung cancer (NSCLC) with the efficacy observed in randomized trials.

PATIENTS AND METHODS: We used instrumental variable analysis (IVA) and propensity scores (PS) to simulate the conditions of a randomized trial in a retrospective cohort of patients over age 65 from the Survival, Epidemiology, and End Results (SEER) tumor registry. Geographic variation in chemotherapy use served as the instrument for the IVA analysis, and propensity scores were calculated with a logistic model based on patient disease and sociodemographic characteristics.

RESULTS: Among 6,232 elderly patients, the instrumental variable estimate indicated an increase in median survival of 33 days and an improvement in 1-year survival of 9% attributable to chemotherapy. In a Cox regression model, chemotherapy administration was associated with a hazard ratio of 0.81 (95% confidence interval, 0.76 to 0.85). When survival was analyzed separately within propensity score quintiles, the hazard ratios were all similar, ranging from 0.78 to 0.85. These results are comparable with those of a large meta-analysis, which found a hazard ratio of 0.87 in the subgroup of patients over age 65.

CONCLUSION: Chemotherapy for stage IV NSCLC seems to have effectiveness for elderly patients and those with comorbid conditions that is similar to the efficacy seen in randomized trials containing mostly younger, highly selected patients. All suitable patients should be given the opportunity to consider palliative chemotherapy for metastatic NSCLC.
Phase II Trial of Paclitaxel Plus Gemcitabine in Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer
Authors: Isla Dolores , Rosell Rafael , Sánchez José J. , Carrato Alfredo , Felip Enriqueta , Camps Carlos , Artal Angel , González-Larriba José Luis , Azagra Pilar , Alberola Vicente , Martin Cristina , Massutí Bartomeu
Published: February 2017

PURPOSE: Given the cisplatin-related myelotoxicity and nonhematologic toxicities, we were prompted to undertake a study of the noncisplatin combination of paclitaxel plus gemcitabine to evaluate the efficacy, tolerance, and survival of this combination in patients with locally advanced and metastatic non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients received gemcitabine 2,000 mg/m2 and paclitaxel 150 mg/m2 on days 1 and 15 of a 28-day cycle, for a maximum of eight cycles.

RESULTS: Between December 1997 and June 1998, 89 untreated NSCLC patients were enrolled; 30 (34%) had stage IIIB disease (23 with malignant pleural effusion and seven without), and 59 (66%) had stage IV disease. Eighty-six percent of patients had a performance status of 0 or 1. The median number of cycles administered was four (range, one to eight cycles). The mean dose-intensity for both paclitaxel and gemcitabine was nearly 100%. Hematologic and nonhematologic toxicities were mild. Thirty-eight patients received second-line chemotherapy after completion of the study. The overall intent-to-treat response rate was 32.2%, with a higher response rate for stage IIIB patients (43.3%) than for stage IV patients (26.3%). Overall median survival was 9.9 months, and 1-year survival was 38.8% (14.2 months for stage IIIB and 7.7 months for stage IV; P = .007). Median survival was 10.2 months for patients with a performance status of 0 or 1 and 4.8 months for patients with a performance status of 2 (P = .007).

CONCLUSION: A biweekly paclitaxel/gemcitabine regimen was well tolerated, with an acceptable response rate and a reasonable median survival time, especially in patients with good performance status. It merits further exploration in future studies.
Incidence, Cost, and Outcomes of Bleeding and Chemotherapy Dose Modification Among Solid Tumor Patients With Chemotherapy-Induced Thrombocytopenia
Authors: Elting Linda S. , Rubenstein Edward B. , Martin Charles G. , Kurtin Danna , Rodriguez Saul , Laiho Esa , Kanesan Krishnakumari , Cantor Scott B. , Benjamin Robert S.
Published: February 2017

PURPOSE: To describe the incidence and outcomes of bleeding and chemotherapy dose modifications associated with chemotherapy-induced thrombocytopenia (platelets < 50,000/μL).

PATIENTS AND METHODS: Six hundred nine patients with solid tumors or lymphoma were followed-up during 1,262 chemotherapy cycles complicated by thrombocytopenia for development of bleeding, delay or dose reduction of the subsequent cycle, survival, and resource utilization. The association between survival and bleeding or dose modification was examined using the Cox proportional hazards model. Predisposing factors were identified by logistic regression.

RESULTS: Bleeding occurred during 9% of cycles among patients with previous bleeding episodes (P < .0001), baseline platelets less than 75,000/μL (P < .0001), bone marrow metastases (P = .001), poor performance status (P = .03), and cisplatin, carboplatin, carmustine or lomustine administration (P = .0002). Major bleeding episodes resulted in shorter survival and higher resource utilization (P < .0001). Chemotherapy delays occurred during 6% of cycles among patients with more than five previous cycles (P = .003), radiotherapy (P = .03), and disseminated disease (P = .04). They experienced similar clinical outcomes but used significantly more resources. Dose reductions occurred during 15% of cycles but were not associated with poor clinical outcomes or excess resource utilization. Significantly shorter survival and higher resource utilization were observed among the 20% of patients who failed to achieve an adequate response to platelet transfusion.

CONCLUSION: The incidence of bleeding is low among solid tumor patients overall but exceeds 20% in some subgroups. These subgroups are easily identifiable using routinely available clinical information. A clinical prediction rule is being developed. Poor response to platelet transfusion is a clinically and financially significant downstream effect of thrombocytopenia and warrants further investigation.
Coadministration of Cyclosporine Strongly Enhances the Oral Bioavailability of Docetaxel
Authors: Malingré Mirte M. , Richel Dick J. , Beijnen Jos H. , Rosing Hilde , Koopman Franciska J. , Ten Bokkel Huinink Wim W. , Schot Margaret E. , Schellens Jan H.M.
Published: February 2017

PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4.

PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m2 with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m2.

RESULTS: The mean (± SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m2 without CsA was 0.37 ± 0.33 mg·h/L and 2.71 ± 1.81 mg·h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m2 was 4.41 ± 2.10 mg·h/L. The absolute bioavailability of oral docetaxel was 8% ± 6% without and 90% ± 44% with CsA. The oral combination of docetaxel and CsA was well tolerated.

CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.
Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients—Preliminary Evidence of Activity
Authors: Delaloge S. , Yovine A. , Taamma A. , Riofrio M. , Brain E. , Raymond E. , Cottu P. , Goldwasser F. , Jimeno J. , Misset J. L. , Marty M. , Cvitkovic E.
Published: February 2017

PURPOSE: To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program.

PATIENTS AND METHODS: Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 μg/m2 (six patients), 1,500 μg/m2 (the recommended dose, 22 patients), or 1,800 μg/m2 (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks.

RESULTS: Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing’s sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months.

CONCLUSION: ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.
Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, Administered as a 24-hour Continuous Infusion in Patients With Solid Tumors
Authors: Taamma A. , Misset J. L. , Riofrio M. , Guzman C. , Brain E. , Lopez Lazaro L. , Rosing H. , Jimeno J. M. , Cvitkovic E.
Published: February 2017

PURPOSE: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors.

PATIENTS AND METHODS: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 μg/m2.

RESULTS: The MTD was defined as 1,800 μg/m2 (DL 9), and the phase II RD was 1,500 μg/m2 (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 μg/m2) in 94% and 25% of cycles, respectively. At the RD (1,500 μg/m2), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting ≥ 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood.

CONCLUSION: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 μg/m2, with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.
Phase I Trial of 40-kd Branched Pegylated Interferon Alfa-2a for Patients With Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Rakhit Ashok , Ginsberg Michelle , Rittweger Karen , Vuky Jacqueline , Yu Richard , Fettner Scott , Hooftman Leon
Published: February 2017

PURPOSE: Pegylated (40 kd) interferon alfa-2a (IFNα2a) (PEGASYS, Hoffman-La Roche, Nutley, NJ; PEG-IFN) is a modified form of recombinant human IFNα2a with sustained absorption and prolonged half-life after subcutaneous administration. A phase I study of PEG-IFN with pharmacokinetic and pharmacodynamic evaluations was conducted in previously untreated patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Twenty-seven patients were enrolled onto cohorts of three or six patients. PEG-IFN was administered on a weekly basis by subcutaneous injection. The dose was escalated from 180 μg/wk to a maximum of 540 μg/wk in 90-μg increments. Serial venous blood samples were drawn to assess concentrations of PEG-IFN and two immunologic surrogates, neopterin and 2′-5′ oligoadenylate synthetase (OAS).

RESULTS: The maximum-tolerated dose was determined as 540 μg/wk, because two patients experienced dose-limiting toxicity within 28 days of starting treatment. One developed serum grade 3 ALT elevation, and a second developed grade 3 fatigue. Six patients were treated at 450 μg/wk without dose-limiting toxicity. Over the course of treatment, the side-effect profile was mostly mild to moderate in intensity. Adverse events included fatigue, fever, headache, myalgia, nausea, and decreased appetite. Five patients (19%) achieved a partial response. The mean maximum serum concentration increased from 5.0 to 27 ng/mL, and mean area under the curve increased from 247 to 2,981 ng/h/mL, with dose escalation from 180 μg/wk to 540 μg/wk. Serum concentration of PEG-IFN was sustained at close to peak during the dosing interval, and steady-state was achieved in approximately 5 weeks. The immunologic surrogates, neopterin and OAS, were induced at all doses with a sustained concentration profile similar to PEG-IFN.

CONCLUSION: PEG-IFN is a modified form of IFNα2a with distinct pharmacokinetic advantages and immunomodulatory and antitumor activity for patients with advanced RCC. A dose of 450 μg/wk by subcutaneous administration was determined as a suitable dose for further study. PEG-IFN is more convenient to administer than IFNα and has potential for increased efficacy, less toxicity, or both. The efficacy and toxicity of PEG-IFN will be further assessed in clinical trials and compared with IFNα.
Duration of Chemotherapy in Advanced Non–Small-Cell Lung Cancer: A Randomized Trial of Three Versus Six Courses of Mitomycin, Vinblastine, and Cisplatin
Authors: Smith Ian E. , O’Brien Mary E.R. , Talbot Denis C. , Nicolson Marianne C. , Mansi Janine L. , Hickish Tamas F. , Norton Alison , Ashley Susan
Published: February 2017

PURPOSE: So far there are no published data on optimal duration of chemotherapy for advanced non–small-cell lung cancer (NSCLC); six or more courses are usually recommended. We have carried out a multicenter randomized trial comparing three versus six courses of chemotherapy.

PATIENTS AND METHODS: Patients with stage IIIb or IV NSCLC were randomized at start of treatment to receive either three or six courses of mitomycin 8 mg/m2 (courses 1, 2, 4, and 6), vinblastine 6 mg/m2, and cisplatin 50 mg/m2 (MVP) every 21 days. Treatment was stopped early in both arms for progressive disease or unacceptable toxicity. Key end points were overall survival, duration of symptom relief, and quality-of-life assessment using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 with lung cancer–specific module QLQ-LC13.

RESULTS: Three hundred eight patients were randomized. Seventy-two percent of the 155 patients randomized to three courses completed treatment. In the 153 patients randomized to six courses, 73% completed three courses and 31% six courses. Median survival was 6 versus 7 months, respectively, and 1-year survival 22% versus 25% (P = .2). Median duration of symptom relief was 4.5 months (both arms), and 8% versus 18% had continuing symptom relief (P = .4). Quality-of-life parameters were the same or improved for patients randomized to only three courses, including significantly decreased fatigue (P = .03) and a trend toward decreased nausea and vomiting (P = .06).

CONCLUSION: Our findings show no evidence for additional clinical benefit by continuing MVP chemotherapy beyond three courses. This challenges current orthodoxy of six courses or more. Further trials addressing duration of chemotherapy are now warranted, particularly with newer chemotherapy schedules.
Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase C
Authors: Propper D. J. , McDonald A. C. , Man A. , Thavasu P. , Balkwill F. , Braybrooke J. P. , Caponigro F. , Graf P. , Dutreix C. , Blackie R. , Kaye S. B. , Ganesan T. S. , Talbot D. C. , Harris A. L. , Twelves C.
Published: February 2017

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days.

PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles.

RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P < .02) and monocyte (P < .01) counts in patients receiving doses ≥ 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve0-24 hoursand maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 μmol/L.

CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.
Long-Term Persistence of Monoclonal B Cells After Cure of Helicobacter pylori Infection and Complete Histologic Remission in Gastric Mucosa–Associated Lymphoid Tissue B-Cell Lymphoma
Authors: Thiede Christian , Wündisch Thomas , Alpen Birgit , Neubauer Beatrix , Morgner Andrea , Schmitz Marc , Ehninger Gerhard , Stolte Manfred , Bayerdörffer Ekkehard , Neubauer Andreas
Published: February 2017

PURPOSE: Cure of Helicobacter pylori infection is associated with remission induction in the majority of patients with low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma in localized stages; however, limited data exist as to whether these patients may be cured of their lymphoma. The present study was performed to investigate whether the polymerase chain reaction (PCR) for the rearranged immunoglobulin heavy chain region may be used to define “molecular” remission.

PATIENTS AND METHODS: Ninety-seven patients who suffered from low-grade gastric MALT lymphoma stage IE were observed with central pathology and molecular biology after cure of H pylori infection. PCR was performed with the use of consensus primers for the framework regions 1, 2, and 3 and monoclonality was corroborated by sequence analysis. In selected cases, microdissection was performed to study the origin of the monoclonal B cells.

RESULTS: Of the 97 patients, 77 obtained complete endoscopic and histologic remission (CR). Twenty of 44 patients with PCR monoclonality at diagnosis and with sufficient molecular follow-up displayed monoclonal bands for a median time of 20.5 months after CR (range, 0 to 50.4 months). These B cells were related to the original lymphoma clone by sequence analysis. Microdissection analysis identified basal lymphoid aggregates as the source of these monoclonal B cells. Local relapse occurred in and was observed by PCR in four patients. All four patients displayed monoclonal PCR before relapse, and three of these four showed ongoing PCR monoclonality throughout their course, indicating the persistence of malignant cells.

CONCLUSION: Half of all patients with gastric MALT lymphoma show long-term PCR monoclonality up to several years after cure of H pylori infection and CR. Patients with monoclonal PCR should be observed closely, whereas long-term PCR negativity may indicate cure of the disease.
Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment
Authors: Lara Primo N. , Higdon Roger , Lim Nelson , Kwan Karen , Tanaka Michael , Lau Derick H.M. , Wun Ted , Welborn Jeanna , Meyers Frederick J. , Christensen Scott , O’Donnell Robert , Richman Carol , Scudder Sidney A. , Tuscano Joseph , Gandara David R. , Lam Kit S.
Published: February 2017

PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation.

MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician’s decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual.

RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P = .03; 95% CI, 0.13 to 0.9).

CONCLUSION: Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party–payers is warranted.
Development of Inhalational Agents for Oncologic Use
Authors: Sharma Sunil , White Dorothy , Imondi Anthony R. , Placke Michael E. , Vail David M. , Kris Mark G.
Published: February 2017

ABSTRACT: Because regional chemotherapy has been useful in treatment and palliation of many cancer types, the concept of delivering drugs by inhalation for the treatment of cancers in the lung is attractive. Much higher local drug exposure can be achieved with total doses considerably lower than those required for systemic administration, resulting in lower exposure of nonrespiratory tract tissues to potentially toxic drugs. Regional delivery of chemotherapy to the respiratory tract has been shown to have activity in preclinical and clinical studies. Technical improvements in delivery methods have now made it possible to conduct trials of inhalational agents, both to treat cancers affecting the respiratory tract and to deliver other drugs used in cancer patients. This review discusses the rationale of drug delivery by the inhalational route, its technical challenges, preclinical and clinical experiences, limitations, and promise.
Human Papillomavirus and Prognosis of Invasive Cervical Cancer: A Population-Based Study
Authors: Schwartz Stephen M. , Daling Janet R. , Shera Katherine A. , Madeleine Margaret M. , McKnight Barbara , Galloway Denise A. , Porter Peggy L. , McDougall James K.
Published: February 2017

PURPOSE: To determine the association between human papillomavirus (HPV) type and prognosis of patients with invasive cervical carcinoma.

PATIENTS AND METHODS: Patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB to IV cervical cancer between 1986 and 1997 while residents of three Washington State counties were included (n = 399). HPV typing was performed on paraffin-embedded tumor tissue using polymerase chain reaction methods. Patients were observed for a median of 50.8 months. Total mortality (TM) and cervical cancer–specific mortality (CCSM) were determined. Hazards ratios (HR) adjusted for age, stage, and histologic type were estimated using multivariable models.

RESULTS: Eighty-six patients had HPV 18–related tumors and 210 patients had HPV 16–related tumors. Cumulative TM among patients with HPV 18–related tumors and among patients with HPV 16–related tumors were 33.7% and 27.6%, respectively; cumulative CCSM in these two groups were 26.7% and 18.1%, respectively. Compared with patients with HPV 16–related cancers, patients with HPV 18–related cancers were at increased risk for TM (HRTM, 2.2; 95% confidence interval [CI], 1.3 to 3.6) and CCSM (HRCCSM, 2.5; 95% CI, 1.4 to 4.4). The HPV18 associations were strongest for patients with FIGO stage IB or IIA disease (HRTM, 3.1; 95% CI, 2.3 to 4.2; and HRCCSM, 5.8; 95% CI, 3.9 to 8.7), whereas no associations were observed among patients with FIGO stage IIB to IV disease. Virtually identical associations were found in the subset of patients with squamous cell carcinoma (n = 219).

CONCLUSION: HPV 18–related cervical carcinomas, particularly those diagnosed at an early stage, are associated with a poor prognosis. Elucidating the mechanism or mechanisms underlying this association could lead to new treatment approaches for patients with invasive cervical carcinoma.