bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraperitoneal Chemotherapy for Ovarian Carcinoma: Results of Long-Term Follow-Up
Authors: Barakat Richard R. , Sabbatini Paul , Bhaskaran Dharmendra , Revzin Margarita , Smith Alex , Venkatraman Ennapadam , Aghajanian Carol , Hensley Martee , Soignet Steven , Brown Carol , Soslow Robert , Markman Maurie , Hoskins William J. , Spriggs David
Published: February 2017

PURPOSE: To determine long-term survival and predictors of recurrence in a retrospective cohort of patients with epithelial ovarian cancer treated with intraperitoneal (IP) chemotherapy.

PATIENTS AND METHODS: Records were reviewed of 433 patients who received IP therapy for ovarian cancer between 1984 and 1998; follow-up data were available for 411 patients. IP therapy was provided as consolidation therapy (n = 89), or for treatment of persistent (n = 310) or recurrent (n = 12) disease after surgery and initial systemic therapy; therapy usually consisted of platinum-based combination therapy. Statistical analysis included tests for associations between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox proportional hazard model.

RESULTS: The mean age of patients was 52 years (range, 25 to 76 years). Distribution by stage and grade was as follows: stage I, 7; II, 24; III, 342; IV, 52; not available (NA), 8; and grade 1, 30; 2, 99; and 3, 289; NA, 15. The median survival from initiation of IP therapy by residual disease was none, 8.7 years; microscopic, 4.8 years; less than 1 cm, 3.3 years; more than 1 cm, 1.2 years. In a multivariate analysis, the only significant predictors of long-term survival were grade and size of residual disease at initiation of IP therapy.

CONCLUSION: Prolonged survival was observed in selected patients receiving IP platinum-based therapy. It is not possible to determine the contribution of IP therapy to survival in this study. A relationship between size of disease at the initiation of IP therapy and long-term survival was demonstrated.
Blinded, Randomized, Multicenter Study to Evaluate Single Administration Pegfilgrastim Once per Cycle Versus Daily Filgrastim as an Adjunct to Chemotherapy in Patients With High-Risk Stage II or Stage III/IV Breast Cancer
Authors: Holmes F.A. , O’Shaughnessy J.A. , Vukelja S. , Jones S.E. , Shogan J. , Savin M. , Glaspy J. , Moore M. , Meza L. , Wiznitzer I. , Neumann T.A. , Hill L.R. , Liang B.C.
Published: February 2017

PURPOSE: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 μg/kg) is as safe and effective as daily filgrastim (5 μg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy.

PATIENTS AND METHODS: Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m2 and doxorubicin 60 mg/m2 on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 μg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 μg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored.

RESULTS: One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar.

CONCLUSION: A single injection of pegfilgrastim 100 μg/kg per cycle was as safe and effective as daily injections of filgrastim 5 μg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m2 and docetaxel 75 mg/m2.
Role of Radiotherapy in the Treatment of Supratentorial Primitive Neuroectodermal Tumors in Childhood: Results of the Prospective German Brain Tumor Trials HIT 88/89 and 91
Authors: Timmermann Beate , Kortmann Rolf-Dieter , Kühl Joachim , Meisner Christoph , Dieckmann Karin , Pietsch Torsten , Bamberg Michael
Published: February 2017

PURPOSE: To evaluate the outcome of children with supratentorial primitive neuroectodermal tumors after surgery, irradiation, and chemotherapy and to identify factors predictive for survival.

PATIENTS AND METHODS: Sixty-three children in the prospective trials HIT 88/89 and HIT 91 were eligible. Complete resection was performed in 21 patients. Patients were randomized for preirradiation chemotherapy, consisting of two cycles of ifosfamide, etoposide, methotrexate, cisplatin, and cytarabine (n = 40), or chemotherapy after irradiation, consisting of eight cycles with cisplatin, vincristine, and lomustine (n = 23). Irradiation volume was recommended to encompass the neuraxis with 35.2-Gy total dose followed by a boost (20.0 Gy) to the primary tumor site (n = 54). Seven patients were irradiated to the tumor region only with a total dose of 54.0 Gy.

RESULTS: Overall survival at 3 years was 48.4%. Progression occurred in 38 children, with local recurrences in 27 patients. The only significant prognostic factor was dose and volume of radiotherapy (progression-free survival after 3 years was 49.3% with correct treatment compared with 6.7% for 15 children with major violations of radiotherapy). Ten early progressions occurred during adjuvant therapy (eight before and two during radiotherapy), nine of them treated with preirradiation chemotherapy. There was a positive trend in outcome for nonmetastatic and pineal tumors.

CONCLUSION: Significant predictive factors were dose and volume of radiotherapy. Volume of irradiation should encompass the whole CNS with additional boost to the tumor region. Local doses of at least 54 Gy and a craniospinal dose of 35 Gy are necessary. Preirradiation chemotherapy seems to increase risk of early progression.
Prospective Evaluation of the Peptide-Bound Collagen Type I Cross-Links N-Telopeptide and C-Telopeptide in Predicting Bone Metastases Status
Authors: Costa Luis , Demers Laurence M. , Gouveia-Oliveira A. , Schaller J. , Costa Eduardo B. , de Moura Miguel C. , Lipton Allan
Published: February 2017

PURPOSE: The objective assessment of bone metastases is currently based on serial changes in skeletal survey. We performed a prospective study to determine whether a correlation exists between the biochemical markers of bone turnover and x-ray evaluation of bone metastases in patients with or without bisphosphonate therapy, and whether bone markers are influenced by extraskeletal disease.

PATIENTS AND METHODS: Patients with either bone or extraskeletal metastases were consecutively enrolled and World Health Organization response criteria were applied for both bone and extraosseous disease every 3 to 4 months. Serum levels of bone-specific alkaline phosphatase (B-AP) and C-telopeptide (ICTP) and urine levels of N-telopeptide (NTX) were measured monthly. The data were analyzed by generalized estimation equation regression.

RESULTS: We studied 97 patients with bone metastases (52 also with extraskeletal metastases) and 26 with extraosseous disease only. Median time on study was 153 days, and 281 objective evaluations (171 in bone) were performed. With bisphosphonates (49 patients receiving pamidronate and three receiving clodronate), percent change from levels without therapy was 47% for NTX (P < .001) and 69% for B-AP (P = .008). With disease progression in bone, percent change from mean levels during stable disease was 152% for NTX (P < .001) and 144% for ICTP (P < .001) regardless of bisphosphonate therapy. NTX had the highest positive predictive value (71%) for the diagnosis of bone metastases progression. Extraskeletal disease had no significant effect on bone markers.

CONCLUSION: Urinary NTX may be a valuable bone marker to assess the antiresorptive effect of bisphosphonate therapy and to evaluate the progression of bone metastases.
Clinical Relevance of Invasion Factors Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 for Individualized Therapy Decisions in Primary Breast Cancer Is Greatest When Used in Combination
Authors: Harbeck Nadia , Kates Ronald E. , Schmitt Manfred
Published: February 2017

PURPOSE: A strong prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor and plasminogen activator inhibitor type 1 (PAI-1) as individual factors is well established in breast cancer. The improvement in clinical risk assessment gained by combining these factors is evaluated here.

PATIENTS AND METHODS: uPA and PAI-1 levels were prospectively measured by enzyme-linked immunosorbent assay in tumor tissue extracts of 761 patients with primary breast cancer.

RESULTS: In the clinically important subgroup of node-negative patients without adjuvant systemic therapy (n = 269; median follow-up, 60 months), the clinical value of testing both uPA and PAI-1 is demonstrated. The criterion either or both high identifies with high sensitivity the patients at high relapse risk while keeping more than half in the low-risk group. uPA/PAI-1 is the strongest predictor of disease-free survival and overall survival; patients with high uPA/PAI-1 have an increased relapse risk (P < .001; relative risk, 4.8; 95% confidence interval [CI], 2.5 to 9.1), in particular for early relapse. Even within risk groups stratified by established criteria (nodal or menopausal status, tumor size, grade, or steroid hormone receptors), uPA/PAI-1 provides significant risk group discrimination. In the whole collective, the significant interaction between uPA/PAI-1 and adjuvant systemic therapy suggests a benefit from adjuvant therapy in high-risk patients as defined by uPA/PAI-1.

CONCLUSION: The clinical relevance of the two tumor-invasion factors uPA and PAI-1 is greatest when they are used in combination. The particular combination of uPA and PAI-1 (both low v either or both high) is superior to either factor alone and supports risk-adapted individualized therapy decisions.
Hodgkin’s Disease in the Elderly: Improved Treatment Outcome With a Doxorubicin-Containing Regimen
Authors: Weekes Colin D. , Vose Julie M. , Lynch Jim C. , Weisenburger Dennis D. , Bierman Philip J. , Greiner Timothy , Bociek Gregory , Enke Charles , Bast Martin , Chan Wing C. , Armitage James O.
Published: February 2017

PURPOSE: Hodgkin’s disease (HD) is a malignancy that displays a bimodal age distribution. Previous reports of treatment in patients ≥ 60 years have found a poor outcome, particularly in patients with advanced disease. Because of an improved side-effect profile, the regimen of chlorambucil, vinblastine, procarbazine, and prednisone (ChlVPP) has been proposed for use in elderly patients.

PATIENTS AND METHODS: From September 1982 to May 1998, 262 patients with previously untreated HD received either ChlVPP (n = 176) or ChlVPP plus doxorubicin/bleomycin/vincristine (ChlVPP/ABV hybrid; n = 86). Fifty-six patients were ≥ 60 years old, and 206 were younger than 60 years.

RESULTS: The 5-year overall survival (OS; 87%
v
39%) and the 5-year event-free survival (EFS; 75%
v
31%) favored patients younger than 60 years of age. Prognostic factors analyzed in patients ≥ 60 years of age, other than type of therapy, included sex, stage, Karnofsky performance score, lactic dehydrogenase, number of extranodal sites, B symptoms, size of largest mass, and histologic subtype. In patients older than 60 years, none of the clinical features was a statistically significant predictor of EFS; however, ChlVPP/ABV hybrid was associated with a decreased risk of an event (relative risk, 0.40; 95% confidence interval, 0.19 to 0.83;
P
= .014) compared with ChlVPP. The 5-year OS for patients ≥ 60 years who received ChlVPP was 30%, compared with 67% for those patients receiving the ChlVPP/ABV regimen (
P
= .0086)

CONCLUSION: Patients ≥ 60 years with HD who require chemotherapy are better treated with ChlVPP/ABV hybrid than with ChlVPP alone.
Aberrant p53 Expression Correlates With Expression of Vascular Endothelial Growth Factor mRNA and Interleukin-8 mRNA and Neoangiogenesis in Non–Small-Cell Lung Cancer
Authors: Yuan Ang , Yu Chong-Jen , Luh Kwen-Tay , Kuo Sow-Hsong , Lee Yung-Chie , Yang Pan-Chyr
Published: February 2017

PURPOSE: To evaluate interactions between expressions of tumor suppressor gene p53 and angiogenic factors vascular endothelial cell growth factor (VEGF) and interleukin-8 (IL-8) and their effect on tumor angiogenesis and patient prognosis in non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: p53, VEGF, IL-8, and the microvessel endothelium were immunostained, and VEGF and IL-8 mRNA expression were quantified using the real-time quantitative reverse-transcription polymerase chain reaction in 65 NSCLC surgical specimens. Aberrant p53 expression was correlated with VEGF and IL-8 mRNA expression, microvessel count (MVC), other clinical-pathologic variables, and patients’ survival.

RESULTS: Tumors with high aberrant p53 expression showed significantly higher VEGF and IL-8 mRNA expression and MVC than those with low aberrant p53 expression (P < .001). When tested as a continuous variable, aberrant p53 expression correlated strongly and positively with VEGF and IL-8 mRNA expression and MVC (P < .0001). Tumors with high aberrant p53 expression were associated with mediastinal or distant lymph node metastasis (P = .006). Survival and postoperative relapse time were significantly shorter in patients with high aberrant p53 expression tumors than in those with low aberrant expression tumors (P < .0001). A significant difference in survival was also seen between patients with high and low tumoral VEGF mRNA expression and between those with high and low tumoral IL-8 mRNA expression (P < .0001).

CONCLUSION: We report here for the first time that aberrant p53 expression is strongly positively correlated with VEGF mRNA and IL-8 mRNA expression in NSCLC. This result indicates that aberrant p53 expression may play a significant role in regulation of VEGF and IL-8 expression and be involved in controlling angiogenesis and explains the adverse prognosis of cancers with high aberrant p53 expression.
Successful Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients With Bladder Cancer by Intravesical Vector Instillation
Authors: Kuball Jürgen , Wen Shu Fen , Leissner Joachim , Atkins Derek , Meinhardt Patricia , Quijano Erlinda , Engler Heidrun , Hutchins Beth , Maneval Daniel C. , Grace Michael J. , Fritz Mary Ann , Störkel Stefan , Thüroff Joachim W. , Huber Christoph , Schuler Martin
Published: February 2017

PURPOSE: To study safety, feasibility, and biologic activity of adenovirus-mediated p53 gene transfer in patients with bladder cancer.

PATIENTS AND METHODS: Twelve patients with histologically confirmed bladder cancer scheduled for cystectomy were treated on day 1 with a single intratumoral injection of SCH 58500 (rAd/p53) at cystoscopy at one dose level (7.5 × 1011 particles) or a single intravesical instillation of SCH 58500 with a transduction-enhancing agent (Big CHAP) at three dose levels (7.5 × 1011 to 7.5 × 1013 particles). Cystectomies were performed in 11 patients on day 3, and transgene expression, vector distribution, and biologic markers of transgene activity were assessed by molecular and immunohistochemical methods in tumors and normal bladder samples.

RESULTS: Specific transgene expression was detected in tissues from seven of eight assessable patients treated with intravesical instillation of SCH 58500 but in none of three assessable patients treated with intratumoral injection of SCH 58500. Induction of RNA and protein expression of the p53 target gene p21/WAF1 was demonstrated in samples from patients treated with SCH 58500 instillation at higher dose levels. Distribution studies after intravesical instillation of SCH 58500 revealed both high transduction efficacy and vector penetration throughout the whole urothelium and into submucosal tumor cells. No dose-limiting toxicity was observed, and side effects were local and of transient nature.

CONCLUSION: Intravesical instillation of SCH 58500 combined with a transduction-enhancing agent is safe, feasible, and biologically active in patients with bladder cancer. Studies to evaluate the clinical efficacy of this treatment in patients with localized high-risk bladder cancer are warranted.
Multicenter Phase II Study of a 28-Day Regimen of Orally Administered Eniluracil and Fluorouracil in the Treatment of Patients With Anthracycline- and Taxane-Resistant Advanced Breast Cancer
Authors: Rivera Edgardo , Sutton Linda , Colwell Bruce , Graham Mark , Frye Debra , Somerville Matt , Conklin Heather S. , McGuirt Chip , Levin Jeremey , Hortobagyi Gabriel N.
Published: February 2017

PURPOSE: Eniluracil (776C85), a potent inactivator of dihydropyrimidine dehydrogenase, allows fluorouracil (5-FU) to be administered orally on a schedule that simulates continuous-infusion 5-FU. The primary objective of this study was to estimate the objective tumor response rate of orally administered eniluracil and 5-FU in the treatment of anthracycline- and taxane-resistant advanced breast cancer.

PATIENTS AND METHODS: Patients with anthracycline- and taxane-resistant advanced breast cancer were enrolled onto this open-label, phase II, multicenter study. Patients received orally administered 5-FU 1.0 mg/m2 with eniluracil given in a 10:1 ratio (eniluracil:5-FU) twice daily for the first 28 days of each 35-day cycle.

RESULTS: Eighty-four patients were enrolled. Eight partial responses were observed in 84 patients (10%; 95% confidence interval [CI], 4.2% to 17.9%), and 20 patients (24%) had stable disease. The median duration of partial response was 20.1 weeks (95% CI, 12 to 26.7 weeks). The median duration of progression-free survival and overall survival for all patients was 9.9 weeks and 40.4 weeks, respectively. Most adverse events were grade 1 or 2 in intensity. Diarrhea, nausea, malaise/fatigue, vomiting, and mucositis were the most common treatment-related nonhematologic adverse events. The most frequently occurring grade 3 or 4 treatment-related adverse events were malaise/fatigue and diarrhea, occurring in 17% and 7% of patients, respectively. The incidence of grade 3 or 4 hematologic toxicity was low. Grade 3 or 4 hyperbilirubinemia occurred in 17% of patients.

CONCLUSION: Eniluracil–5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer. Treatment was convenient, and patient compliance was high.
Irinotecan Plus Gemcitabine Induces Both Radiographic and CA 19-9 Tumor Marker Responses in Patients With Previously Untreated Advanced Pancreatic Cancer
Authors: Rocha Lima Caio Max S. , Savarese Diane , Bruckner Howard , Dudek Arkadiusz , Eckardt John , Hainsworth John , Yunus Furhan , Lester Eric , Miller William , Saville Wayne , Elfring Gary L. , Locker Paula K. , Compton Linda D. , Miller Langdon L. , Green Mark R.
Published: February 2017

PURPOSE: This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer.

PATIENTS AND METHODS: Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m2 over 30 minutes followed immediately by irinotecan 100 mg/m2 over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety.

RESULTS: Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P < .001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r = .67), timing of minimum on-study values (r = .85), and tumor progression (r = .89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%).

CONCLUSION: Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.
Phase I and Pharmacologic Study of Liposomal Lurtotecan, NX 211: Urinary Excretion Predicts Hematologic Toxicity
Authors: Kehrer Diederik F.S. , Bos Annelies M. , Verweij Jaap , Groen Harry J. , Loos Walter J. , Sparreboom Alex , de Jonge Maja J.A. , Hamilton Marta , Cameron Terri , de Vries Elisabeth G.E.
Published: February 2017

PURPOSE: To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase I inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients.

PATIENTS AND METHODS: NX 211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography.

RESULTS: Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m2 (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 ± 0.78 L/h/m2 and 1.15 ± 0.96 L/h/m2, respectively. Urinary recovery (Fu) of lurtotecan was 10.1% ± 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose × Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P < .00001).

CONCLUSION: The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m2 once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211–induced clinical effects.
Randomized Controlled Trial of Single-Agent Paclitaxel Versus Cyclophosphamide, Doxorubicin, and Cisplatin in Patients With Recurrent Ovarian Cancer Who Responded to First-Line Platinum-Based Regimens
Authors: Cantù M. G. , Buda A. , Parma G. , Rossi R. , Floriani I. , Bonazzi C. , Dell’Anna T. , Torri V. , Colombo N.
Published: February 2017

PURPOSE: To assess the activity, efficacy, and tolerability of single-agent paclitaxel and a platinum-containing regimen in previously treated patients with recurrent ovarian cancer.

PATIENTS AND METHODS: Patients who achieved complete remission with platinum-based regimens and whose disease recurred after a progression-free interval of more than 12 months were included in the study. Every 21 days, patients received paclitaxel 175 mg/m2 intravenously (IV) over 3 hours or cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and cisplatin 50 mg/m2 (CAP) IV.

RESULTS: Between June 1992 and May 1995, 97 consecutive patients with assessable or measurable disease were randomized to paclitaxel (n = 50) or CAP (n = 47). The median number of cycles on each arm was six. Toxicities included grade 3/4 leukopenia (4% for paclitaxel v 34% for CAP), grade 3/4 neutropenia (13% v 36%), grade 1/2 myalgia (19% v 4%), allergic reactions (15% v 2%), and grade 2/3 nausea and vomiting (17% v 51%). Complete responses were achieved in 17% and 30% of patients receiving paclitaxel and CAP, respectively, and partial responses were achieved in 28% and 25%, respectively (P = .062). At a median follow-up time of 49 months, median progression-free intervals were 9 months for paclitaxel and 15.7 months for CAP (Cox analysis: hazards ratio [HR], 0.60; 95% confidence interval [CI], 0.37 to 0.97; P = .038); median overall survival times were 25.8 months for paclitaxel and 34.7 months for CAP (Cox analysis: HR, 0.58; 95% CI, 0.34 to 0.98; P = .043).

CONCLUSION: Rechallenge with either single-agent paclitaxel or platinum-based chemotherapy is effective in this patient population. Preliminary results suggest that single-agent paclitaxel may not be as active as platinum-based chemotherapy in recurrent ovarian cancer. Larger randomized trials are needed.
Retrospective Analysis of Carboplatin and Paclitaxel as Initial Second-Line Therapy for Recurrent Epithelial Ovarian Carcinoma: Application Toward a Dynamic Disease State Model of Ovarian Cancer
Authors: Dizon Don S. , Hensley Martee L. , Poynor Elizabeth A. , Sabbatini Paul , Aghajanian Carol , Hummer Amanda , Venkatraman Ennapadam , Spriggs David R.
Published: February 2017

PURPOSE: The majority of patients with epithelial ovarian cancer (EOC) who achieve a complete remission with front-line chemotherapy develop recurrent disease. Carboplatin and paclitaxel are used for patients with platinum-sensitive recurrent disease, although there is little information regarding the response and survival in unselected patients treated with this strategy. We sought to determine the outcomes for patients with EOC treated with carboplatin and paclitaxel at the time of first recurrence. In addition, we sought to define a new paradigm for disease transition in patients with EOC.

PATIENTS AND METHODS: Eighty-nine patients were identified who had a complete response to front-line platinum-based chemotherapy for EOC, relapsed 6 months after completion of front-line chemotherapy, and were treated with carboplatin and paclitaxel as second-line therapy.

RESULTS: Eighty-four cases were available for analysis of survival end points, and 66 were assessable for response. The median follow-up was 27 months. The overall response rate was 70%. The median progression-free interval for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and no deaths from treatment were observed. Using this data, it is possible to construct a disease states model of EOC, which provides risk estimates for transitions between clinically distinct categories.

CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as initial therapy in recurrent EOC. This should form the basis of a randomized trial to determine the best agents for initial treatment of relapse from EOC in potentially platinum-sensitive patients.
Phase III Trial Comparing a Defined Duration of Therapy Versus Continuous Therapy Followed by Second-Line Therapy in Advanced-Stage IIIB/IV Non–Small-Cell Lung Cancer
Authors: Socinski Mark A. , Schell Michael J. , Peterman Amy , Bakri Kamal , Yates Steven , Gitten Robert , Unger Paul , Lee Joanna , Lee Ji-Hyun , Tynan Maureen , Moore Martha , Kies Merrill S.
Published: February 2017

PURPOSE: To compare four cycles of therapy versus continuous therapy to determine the optimal duration of chemotherapy in advanced non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Stage IIIB/IV NSCLC patients were randomized to arm A (four cycles of carboplatin at an area under the curve of 6 and paclitaxel 200 mg/m2 every 21 days) or arm B (continuous treatment with carboplatin/paclitaxel until progression). At progression, all patients on both arms were to receive second-line weekly paclitaxel at 80 mg/m2/wk. The primary end points were survival and quality of life (QOL).

RESULTS: Two hundred thirty patients were randomized. Fifty-seven percent of arm A patients completed four courses of therapy. In the 116 arm B patients, the median number of cycles delivered was four (range, zero to 19 cycles). Forty-two percent received five or more cycles; 18% received eight or more cycles. Overall response rates were 22% and 24% for arms A and B, respectively (P = .80). Median survival time and 1-year survival rates were 6.6 months and 28% for arm A and 8.5 months and 34% for arm B, respectively (log-rank P = .63). Rates of hematologic and nonhematologic toxicity were similar between the two arms, except for neuropathy. The rate of grade 2 to 4 neuropathy increased from 19.9% (95% confidence interval [CI], 13.6% to 26.2%) at cycle 4 to 43% (95% CI, 28.6% to 57.4%) at cycle 8. There were no differences in QOL. Only 45% of patients received second-line therapy (42% in arm A v 47% in arm B, P = .42).

CONCLUSION: This study shows no overall benefit in survival, response rates, or QOL to continuing treatment with carboplatin/paclitaxel beyond four cycles in advanced NSCLC.
Prognostic Significance of Molecular Genetic Aberrations on Chromosome Segment 11p15.5 in Non–Small-Cell Lung Cancer
Authors: Bepler Gerold , Gautam Ashish , McIntyre Lauren M. , Beck Amy F. , Chervinsky David S. , Kim Young-Chul , Pitterle Diana M. , Hyland Andrew
Published: February 2017

PURPOSE: The assessment of prognosis and decisions on treatment for patients with non–small-cell lung cancer (NSCLC) are determined on the basis of disease stage and performance status. NSCLC frequently manifests loss of heterozygosity (LOH) at chromosome segment 11p15.5. Whether LOH at 11p15.5 is an independent prognostic variable has yet to be determined.

PATIENTS AND METHODS: We developed five novel markers, which can be assessed by polymerase chain reaction and restriction enzyme digestion. LOH at 11p15.5 was assessed in 193 patients who underwent surgical resection for pathologic stage I and II of the disease.

RESULTS: LOH at 11p15.5 was associated with poor survival (P = .021). Multivariate logistic regression analysis showed that after disease stage, performance status, weight loss, sex, age at diagnosis, and smoking history were controlled for, patients with LOH were two times more likely to die than those without LOH (relative risk [RR] = 2.01, P = .021). Cox regression analysis with disease stage and LOH revealed that the survival of patients with stage I disease and LOH was similar to the survival of patients with stage II disease, and it was significantly worse than the survival of stage I patients without LOH (RR = 2.38, P = .038).

CONCLUSION: LOH in a 310-kb region on chromosome segment 11p15.5 that includes the gene for the regulatory subunit of the enzyme ribonucleotide reductase is highly predictive of poor survival from NSCLC. The future utility of analysis of the allelic status of this region may involve treatment decisions, such as the use of neoadjuvant and adjuvant chemotherapy for patients with stage I disease.
Mathematical Model to Predict Individual Survival for Patients With Renal Cell Carcinoma
Authors: Zisman Amnon , Pantuck Allan J. , Dorey Fredrick , Chao Debby H. , Gitlitz Barbara J. , Moldawer Nancy , Lazarovici Dana , deKernion Jean B. , Figlin Robert A. , Belldegrun Arie S.
Published: February 2017

PURPOSE: To develop a multivariate model and mathematical formula capable of calculating personalized survival for renal cell carcinoma (RCC) patients with clinically available variables.

PATIENTS AND METHODS: A total of 477 patients out of 661 undergoing nephrectomy at the University of California Los Angeles between 1989 and 1999 were eligible for evaluation and formed the analyzed cohort for this retrospective study. Time to death was the primary end point assessed. Univariate analysis for 14 to 20 variables was conducted, followed by a multivariate Cox analysis. The variables that provided independent information as to the time of death for metastatic and nonmetastatic patients were coded and incorporated into a function based on the Nadas equation principle.

RESULTS: For nonmetastatic patients, the significant variables in the multivariate analysis were Fuhrman’s grade and Eastern Cooperative Oncology Group performance status. For the metastatic patients, Fuhrman’s grade, 1997 classification T stage, number of symptoms, nodal involvement, and immunotherapy were independent predictors for survival. These variables, based on the Cox multivariate regression model, were implanted into an exponential Nadas equation. The expected survival predicted by use of the Nadas equations faithfully describes the actual survival based on Kaplan-Meier curves.

CONCLUSION: We have developed mathematical equations for estimating survival after radical nephrectomy for RCC. The resulting formulas are capable of better tailoring survival estimates for a specific patient and are based on widely accepted clinical prognostic variables. On validation with external data, this type of representation can be used as a tool for the determination of personalized prognosis and may be useful for patient education and counseling.
Maximizing Local Control and Organ Preservation in Stage IV Squamous Cell Head and Neck Cancer With Hyperfractionated Radiation and Concurrent Chemotherapy
Authors: Adelstein David J. , Saxton Jerrold P. , Lavertu Pierre , Rybicki Lisa A. , Esclamado Ramon M. , Wood Benjamin G. , Strome Marshall , Carroll Marjorie A.
Published: February 2017

PURPOSE: Results are reported from an aggressive chemoradiotherapy protocol for advanced squamous cell head and neck cancer.

PATIENTS AND METHODS: Patients with advanced squamous cell head and neck cancer were treated with hyperfractionated radiation therapy (72 Gy at 1.2 Gy twice per day) and two courses of concurrent chemotherapy with fluorouracil (1,000 mg/m2/d) and cisplatin (20 mg/m2/d), both given as 96-hour continuous intravenous infusions during weeks 1 and 4 of radiation therapy. Primary-site resection was reserved for residual or recurrent primary-site disease after chemoradiotherapy. Neck dissection was considered for N2 or greater disease, irrespective of clinical response, and for residual or recurrent neck disease after nonoperative treatment.

RESULTS: Forty-one patients with stage IV disease were treated. Toxicity was significant, with grade 3 to 4 mucositis in 98%, dysphagia in 88%, and skin reaction in 85%. Neutropenic fever requiring hospitalization occurred in 51%. Despite feeding tube placement in 35 patients (85%), the mean weight loss during chemoradiotherapy was 13.3% of initial body weight. One patient died during treatment as a result of a pulmonary embolus. At a median follow-up period of 30 months, the 3-year Kaplan-Meier projected overall survival was 59%, disease-specific survival 69%, likelihood of local control without surgical resection 91%, and local control with surgical resection 97%. The likelihood of distant disease control at 3 years was 74%, and distant metastases were present in eight of 13 patients who died.

CONCLUSION: This chemoradiotherapy schedule produces considerable but manageable toxicity. Survival and organ preservation are excellent for this poor-prognosis patient cohort. Distant metastases are the most common cause of treatment failure.
Effect of Soy Phytoestrogens on Hot Flashes in Postmenopausal Women With Breast Cancer: A Randomized, Controlled Clinical Trial
Authors: Van Patten Cheri L. , Olivotto Ivo A. , Chambers G. Keith , Gelmon Karen A. , Hislop T. Gregory , Templeton Edith , Wattie Angela , Prior Jerilynn C.
Published: February 2017

PURPOSE: Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer.

METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage.

RESULTS: There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 ± 0.43 μmol/L) compared with placebo (0.43 ± 0.37 μmol/L) (P = .02). Overall acceptability and compliance were high and similar in both groups.

CONCLUSION: The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.
Overexpression of c-met as a Prognostic Indicator for Transitional Cell Carcinoma of the Urinary Bladder: A Comparison With p53 Nuclear Accumulation
Authors: Cheng Hong-Lin , Trink Barry , Tzai Tzong-Shin , Liu Hsiao-Sheng , Chan Shih-Huang , Ho Chung-Liang , Sidransky David , Chow Nan-Haw
Published: February 2017

PURPOSE: The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a role in oncogenesis. Given that high titers of hepatocyte growth factor, the specific ligand for Met, are excreted in the urine and tend to reflect disease activity of bladder cancer, we performed this study to examine the clinical significance of Met in human bladder cancer.

MATERIALS AND METHODS: We studied the mRNA expression and genomic alteration of c-met in five bladder cancer cell lines. Significance of Met overexpression was then compared with p53 nuclear accumulation (TP53) in primary bladder cancer (n = 142 patients).

RESULTS: Expression of c-met mRNA tended to positively correlate with differentiation of cancer cell lines in the absence of point mutation. High expression of Met was found in seven cases (4.9%), low expression in 32 cases (22.5%), and negative expression in 103 cases (72.5%). Expression of Met was positively associated with histologic grade, stage classification, tumor size, and nodular tumor growth (P < .05, respectively); however, it was not related to TP53 status. Factors that predicted disease progression were tumor stage, Met status, and TP53 accumulation (P < .05, respectively). Indicators for poor long-term survival were invasive cancer, multiple tumors, and Met overexpression (P = .0006, .01, and .04, respectively).

CONCLUSION: The c-met proto-oncogene plays a more important role in the progression of bladder carcinogenesis than p53. Evaluation of Met expression could identify a subset of bladder cancer patients who may require a more intensive treatment strategy.
Role of P53 and MDM2 in Treatment Response of Human Germ Cell Tumors
Authors: Kersemaekers Anne-Marie F. , Mayer Frank , Molier Michel , van Weeren Pascale C. , Oosterhuis J. Wolter , Bokemeyer Carsten , Looijenga Leendert H.J.
Published: February 2017

PURPOSE: Testicular germ cell tumors (TGCTs) of adolescents and adults are very sensitive to systemic treatment. The exquisite chemosensitivity of these cancers has been attributed to a high level of wild-type P53.

MATERIALS AND METHODS: To clarify the role of P53 in treatment sensitivity and resistance of TGCTs, we performed immunohistochemistry and Western blotting analysis on a series of 39 fresh-frozen primary TGCTs before therapy (unselected series). In a series of formalin-fixed paraffin-embedded TGCTs of patients with fully documented clinical course, including treatment-sensitive (n = 17) and -resistant (n = 18) tumors, P53 status was assessed by immunohistochemistry and mutation analysis. In addition, the involvement of MDM2, a P53 antagonist, was investigated by immunohistochemistry, reverse transcriptase polymerase chain reaction, and in situ hybridization.

RESULTS: Immunohistochemistry demonstrated absence of staining for P53 in 36%, 41%, and 17% of the unselected, responding, and nonresponding TGCTs, respectively. Of the positive TGCTs, most tumors, ie, 49%, 41%, and 33%, showed 1% to 10% positive nuclei. This overall low level of P53 was confirmed by Western blotting. Mutation analysis revealed only one silent P53 mutation in one of the responding patients. All embryonal carcinomas were homogeneously positive for MDM2, encoded by the full length mRNA, while a heterogeneous pattern was found for the other histologic components. Amplification of MDM2 was detected in one out of 12 embryonal carcinomas.

CONCLUSION: Although our results are in line with previous findings of the presence of wild-type P53 in TGCTs, they show that a high level of P53 does not relate directly to treatment sensitivity of these tumors, and inactivation of P53 is not a common event in the development of cisplatin resistance.
Dose-Finding and Pharmacokinetic Study of Cisplatin, Gemcitabine, and SU5416 in Patients With Solid Tumors
Authors: Kuenen Bart C. , Rosen Lee , Smit Egbert F. , Parson Mandy R.N. , Levi Marcel , Ruijter Rita , Huisman Holger , Kedde Marc A. , Noordhuis Paul , van der Vijgh Wim J.F. , Peters Godefridus J. , Cropp Gillian F. , Scigalla Paul , Hoekman Klaus , Pinedo Herbert M. , Giaccone Giuseppe
Published: February 2017

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416.

PATIENTS AND METHODS: Patients received cisplatin 80 mg/m2 on day 1, gemcitabine 1,250 mg/m2 on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m2) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine.

RESULTS: In the first cohort of three patients entered at the 85 mg/m2 dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m2), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m2 developed a thromboembolic event. The dose was then reduced to 85 mg/m2 in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle–dependent manner.

CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.
Comparative Pharmacokinetic Study of Continuous Venous Infusion Fluorouracil and Oral Fluorouracil With Eniluracil in Patients With Advanced Solid Tumors
Authors: Adjei Alex A. , Reid Joel M. , Diasio Robert B , Sloan Jeff A. , Smith Deborah A. , Rubin Joseph , Pitot Henry C. , Alberts Steven R. , Goldberg Richard M. , Hanson Lorelei J. , Atherton Pamela , Ames Matthew M. , Erlichman Charles
Published: February 2017

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU.

PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α–fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity.

RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (CP) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal.

CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state CP and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.