bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Endocrine-Related Factors on Response to Perioperative Chemotherapy for Patients With Node-Negative Breast Cancer
Authors: Colleoni Marco , Gelber Shari , Coates Alan S. , Castiglione-Gertsch Monica , Gelber Richard D. , Price Karen , Rudenstam Carl-Magnus , Lindtner Jurij , Collins John , Thürlimann Beat , Holmberg Stig B. , Cortes-Funes H. , Simoncini Edda , Murray Elizabeth , Fey Martin , Goldhirsch Aron
Published: February 2017

PURPOSE: We investigated tumor- and patient-related features that might influence the response to perioperative chemotherapy (PeCT) compared with no adjuvant therapy for patients with node-negative breast cancer.

PATIENTS AND METHODS: A total of 1,275 patients were randomized to either no adjuvant treatment (427 patients) or PeCT (848 patients). The following variables thought to have prognostic significance were evaluated: grade, tumor size, estrogen (ER) and progesterone receptor (PgR) content (absent; low, 1 to 9 fmol/mg cytosol protein; or positive, ≥ 10 fmol/mg cytosol protein), c-erbB-2 overexpression, menopausal status, and age. Cox proportional hazards regression models were used to assess the relative influence of these factors to predict the effect of PeCT on disease-free survival (DFS). Median follow-up was 13.5 years.

RESULTS: The 10-year DFS percentage for 692 premenopausal patients did not significantly differ between the PeCT and no-adjuvant-treatment groups: 61% and 59%, respectively (relative risk [RR], 0.95; 95% confidence interval [CI], 0.75 to 1.20; P = .70). No predictive factors were identified. For 583 postmenopausal patients, 10-year DFS percentages for the groups were 63% and 58%, respectively (RR, 0.75; 95% CI, 0.58 to 0.93; P = .03). The absence of expression of ER, PgR, or both ER and PgR was the most important factor predicting improved outcome with PeCT among postmenopausal patients. The 10-year DFS percentages were 85% and 53% for the steroid hormone receptor–absent cohort of treated and untreated patients, respectively (RR, 0.18; 95% CI, 0.06 to 0.49; P = .0009).

CONCLUSION: The role of PeCT should be explored for patients whose primary tumors do not express steroid hormone receptors, because it is likely that early initiation of treatment is exclusively relevant for such patients.
Multicenter Phase II Trial of Weekly Paclitaxel in Women With Metastatic Breast Cancer
Authors: Perez Edith A. , Vogel Charles L. , Irwin David H. , Kirshner Jeffrey J. , Patel Ravi
Published: February 2017

PURPOSE: We evaluated the safety and efficacy of weekly paclitaxel therapy in women with metastatic breast cancer in a phase II multicenter trial. Entry criteria were relatively liberal to reflect the heterogeneity of metastatic breast cancer in clinical practice.

PATIENTS AND METHODS: Patients had histologically confirmed and measurable metastatic breast cancer. Up to two prior chemotherapy regimens for metastatic disease, including prior therapy with anthracyclines and taxanes and prior high-dose therapy, were allowed. Paclitaxel 80 mg/m2 was administered weekly for 4 weeks per 4-week cycle.

RESULTS: We enrolled 212 patients; 211 were assessable for toxicity and 177 were assessable for response. Ninety percent of patients had received prior chemotherapy (adjuvant, metastatic, or both), 46% of patients had three or more involved metastatic sites, and 60% of patients had visceral-dominant disease. Responses were documented on two occasions and were independently reviewed. The overall response rate (complete plus partial response) was 21.5% (95% confidence interval, 15.4% to 27.5%), with 41.8% of patients having disease stabilization. Median time to progression was 4.7 months, and overall survival in all 212 patients enrolled was 12.8 months. Therapy was well tolerated, with a 15% incidence of grade 3/4 hematologic toxicity and a 9% incidence of grade 3 neurotoxicity; other serious toxicities were rare. The response rate and toxicity profile in the 34% of patients ≥ 65 years of age were similar to that of younger patients.

CONCLUSION: Weekly paclitaxel therapy was well tolerated and demonstrated reasonable activity in this relatively heavily pretreated population with advanced disease. Further study of weekly paclitaxel in combination therapy is warranted.
Impact of the Media and the Internet on Oncology: Survey of Cancer Patients and Oncologists in Canada
Authors: Chen Xueyu , Siu Lillian L.
Published: February 2017

PURPOSE: To evaluate the use of the news media and the Internet as sources of medical information by patients and oncologists in Canada and to investigate the impact on patients’ treatment decisions and the patient-doctor relationship.

PATIENTS AND METHODS: During a 2-week period, 191 ambulatory patients participated in the survey. Questionnaires were also mailed to Canadian oncologists: 410 of 686 questionnaires were returned (response rate = 60%).

RESULTS: Of the 191 patients, 86% wanted as much information as possible about their illness, 54% reported receiving insufficient information, 83% cited physicians as their primary information source, and 7% cited the Internet. Seventy-one percent of patients actively searched for information, and 50% used the Internet. Patients’ opinions about the balance, accuracy, and relevance of news media reports were evenly split. English as the first language, access to the Internet, and use of alternative treatments predicted a higher rate of information seeking. Most oncologists routinely pay some attention to medical news and believe that it is difficult for patients to interpret medical information in the media and on the Internet accurately. Both patients and oncologists agree that information seeking does not affect the patient-physician relationship.

CONCLUSION: Information searching is common among cancer patients in Canada. It does not affect the patient-doctor relationship. The media and the Internet are powerful means of medical information dissemination. Strategic efforts are needed to improve the quality of medical news reporting by the media, and to provide guidance for patients to understand their disease and interpret such information better.
ERCC1 and Thymidylate Synthase mRNA Levels Predict Survival for Colorectal Cancer Patients Receiving Combination Oxaliplatin and Fluorouracil Chemotherapy
Authors: Shirota Yoshinori , Stoehlmacher Jan , Brabender Jan , Xiong Yi-Ping , Uetake Hiroyuki , Danenberg Kathleen D. , Groshen Susan , Tsao-Wei Denise D. , Danenberg Peter V. , Lenz Heinz-Josef
Published: February 2017

PURPOSE: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ERCC1) gene are associated with response to and survival of fluorouracil (5-FU)/oxaliplatin chemotherapy in metastatic colorectal cancer.

PATIENTS AND METHODS: Patients had progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy. All patients were evaluated for eligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction.

RESULTS: The median TS gene expression level from 50 metastasized tumors was 3.4 × 10−3 (minimum expression, 0.18 × 10−3;maximum expression, 11.5 × 10−3), and the median ERCC1 gene expression level was 2.53 × 10−3 (minimum, 0.0; maximum, 14.61 × 10−3). The gene expression cutoff values for chemotherapy nonresponse were 7.5 × 10−3 for TS and 4.9 × 10−3 for ERCC1. The median survival time for patients with TS ≤ 7.5 × 10−3 (43 of 50 patients) was 10.2 months, compared with 1.5 months for patients with TS greater than 7.5 × 10−3 (P < .001). Patients with ERCC1 expression ≤ 4.9 × 10−3 (40 of 50 patients) had a median survival time of 10.2 months, compared with 1.9 months for patients with ERCC1 expression greater than 4.9 × 10−3 (P < .001). A TS of 7.5 × 10−3 segregated significantly into response, stable disease, and progression (P = .02), whereas the association between ERCC1 and response did not reach statistical significance (P = .29).

CONCLUSION: These data suggest that intratumoral ERCC1 mRNA and TS mRNA expression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU–resistant metastatic colorectal cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study.
Long-Term Results of Blood and Marrow Transplantation for Hodgkin’s Lymphoma
Authors: Akpek Görgün , Ambinder Richard F. , Piantadosi Steven , Abrams Ross A. , Brodsky Robert A. , Vogelsang Georgia B. , Zahurak Marianna L. , Fuller Donald , Miller Carole B. , Noga Stephen J. , Fuchs Ephraim , Flinn Ian W. , O’Donnell Paul , Seifter Eric J. , Mann Risa B. , Jones Richard J.
Published: February 2017

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin’s lymphoma (HL).

PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients ≤ age 55 with HLA-matched siblings were prioritized toward allo BMT. The median age was 28 years (range, 13 to 52 years) for the 53 allo patients and 30.5 years (range, 11 to 62 years) for the 104 auto patients.

RESULTS: The median follow-up after BMT for surviving patients was 5.1 years (range, 1 to 13.8 years). For the entire group, the probabilities of event-free survival (EFS) and relapse at 10 years were 26% (95% confidence interval [CI], 18% to 33%) and 58% (95% CI, 48% to 69%), respectively. According to multivariate analysis, disease status before BMT (sensitive relapse if responding to conventional-dose therapy or resistant disease if not) (hazard ratio [HR] = 0.39, P < .0001) and date of BMT (HR = 0.93, P = .004) were independent predictors of EFS, whereas only disease status (HR = 0.35, P < .0001) influenced relapse. There was a trend for probability of relapse in sensitive patients to be less after allo BMT at 34% (range, 8% to 59%) versus 51% (range, 36% to 67%) for the auto patients (HR = 0.51, P = .17). There was a continuing risk of relapse or secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) for 12 years after auto BMT, whereas there were no cases of secondary AML/MDS or relapses beyond 3 years after allo BMT.

CONCLUSION: There seems to be a clinical graft-versus-HL effect associated with allo BMT. Allo BMT for HL also seems to have a lower risk of secondary AML/MDS than auto BMT. Thus, allo BMT warrants continued study in HL.
Pilot Trial of Interleukin-2 With Granulocyte Colony-Stimulating Factor for the Mobilization of Progenitor Cells in Advanced Breast Cancer Patients Undergoing High-Dose Chemotherapy: Expansion of Immune Effectors Within the Stem-Cell Graft and Post–Stem-Cell Infusion
Authors: Sosman J.A. , Stiff P. , Moss S.M. , Sorokin P. , Martone B. , Bayer R. , van Besien K. , Devine S. , Stock W. , Peace D. , Chen Y. , Long C. , Gustin D. , Viana M. , Hoffman R.
Published: February 2017

PURPOSE: To evaluate whether administration of interleukin-2 (IL-2) with granulocyte colony-stimulating factor (G-CSF) improves mobilization of immune effector cells into the stem-cell graft of patients undergoing high-dose chemotherapy and autografting.

PATIENTS AND METHODS: We performed a trial of stem-cell mobilization with IL-2 and G-CSF in advanced breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem cells followed by IL-2. The trial defined immune, hematologic, and clinical effects of IL-2 in this setting.

RESULTS: Of 32 patients enrolled, nine received G-CSF alone for mobilization. Twenty-one of 23 patients mobilized with IL-2 plus G-CSF had stem cells collected with more mononuclear cells than those receiving G-CSF (19.3 v 10.4 × 108/kg; P = .006), but fewer CD34+progenitor cells (6.9 v 22.0 × 106/kg; P = .049). The IL-2 plus G-CSF–mobilized patients had greater numbers of activated T (CD3+/CD25+) cells (P = .009), natural killer (NK; CD56+) cells (P = .007), and activated NK (CD56 bright+) cells (P = .039) than those patients mobilized with G-CSF. NK (P = .042) and lymphokine-activated killer (LAK) (P = .016) activity was increased in those mobilized with IL-2 + G-CSF, whereas G-CSF–mobilized patients had a decline in cytolytic activity. In the third week posttransplantation, immune reconstitution was superior in those mobilized with IL-2 plus G-CSF based on greater numbers of activated T cells (P = .003), activated NK cells (P = .04), and greater LAK activity (P = .003). The 16 of 21 IL-2 + G-CSF–mobilized patients with adequate numbers of stem cells (> 1.5 × 106CD34+cells/kg) collected engrafted rapidly posttransplantation.

CONCLUSION: The results demonstrate that G-CSF + IL-2 can enhance the number and function of antitumor effector cells in a mobilized autograft without impairing the hematologic engraftment, provided that CD34 cell counts are more than 1.5 × 106cells/kg. Mobilization of CD34+stem cells does seem to be adversely affected. In those mobilized with IL-2 and G-CSF, post–stem-cell immune reconstitution of antitumor immune effector cells was enhanced.
Expression of the Neurotrophin Receptor TrkB Is Associated With Unfavorable Outcome in Wilms’ Tumor
Authors: Eggert Angelika , Grotzer Michael A. , Ikegaki Naohiko , Zhao Huaqing , Cnaan Avital , Brodeur Garrett M. , Evans Audrey E.
Published: February 2017

PURPOSE: Neurotrophins and their receptors regulate the proliferation, differentiation, and death of neuronal cells, and they have been implicated in the pathogenesis and prognosis of neuroblastomas and medulloblastomas. Tyrosine kinase (Trk) receptors also are expressed in extraneural tissues.

PATIENTS AND METHODS: To study the role of neurotrophin receptors and ligands in Wilms’ tumor (WT), we determined their expression by semiquantitative duplex reverse transcriptase polymerase chain reaction in 39 patients with primary WT. Comparison of mRNA expression levels with clinical variables was performed by use of Cox regression analysis.

RESULTS: Children with WT that expressed high levels of full-length TrkB mRNA (TrkBfull) had a significantly greater risk of death than children whose tumors had little or no TrkBfull expression (hazard ratio, 9.7; P = .02). The 5-year relapse-free survival was 100% versus 65% for patients with low versus high tumor expression of TrkBfull (P < .003). Conversely, children with tumors that expressed high mRNA levels of a functionally inactive truncated TrkB receptor (TrkBtrunc) had a greater chance of survival than children with low levels of TrkBtrunc (hazard ratio, 0.08; P = .005). The 5-year relapse-free survival was 95% versus 68% for patients with high versus low levels of TrkBtrunc (P = .01). The hazard ratios for TrkBfull and TrkBtrunc remained significant after they were adjusted for tumor stage (P = .01 and P = .017, respectively). All WTs with high levels of TrkB expression also expressed the brain-derived nerve growth factor ligand.

CONCLUSION: Expression of TrkBfull in WT is associated with worse outcome, perhaps because it provides an autocrine survival pathway. Conversely, TrkBtrunc expression is associated with excellent outcome, perhaps as a result of a dominant negative effect.
Recombinant Urate Oxidase for the Prophylaxis or Treatment of Hyperuricemia in Patients With Leukemia or Lymphoma
Authors: Pui Ching-Hon , Mahmoud Hazem H. , Wiley Joseph M. , Woods Gerald M. , Leverger Guy , Camitta Bruce , Hastings Caroline , Blaney Susan M. , Relling Mary V. , Reaman Gregory H.
Published: February 2017

PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys.

PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied.

RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P = .0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P = .0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P = .0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P = .0003 and P = .02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 ± 6.3 (SD) hours and 21.1 ± 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme.

CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.
High-Dose Therapy and Autologous Stem-Cell Support for Chemosensitive Transformed Low-Grade Follicular Non-Hodgkin’s Lymphoma: A Case-Matched Study From the European Bone Marrow Transplant Registry
Authors: Williams C. D. , Harrison C. N. , Lister T. A. , Norton A. J. , Blystad A. K. , Coiffier B. , Taghipour G. , Schmitz N. , Goldstone A. H. ,   for the European Bone Marrow Transplant Lymphoma Working Party
Published: February 2017

PURPOSE: To assess the outcome of high-dose therapy with autologous stem-cell support in patients with histologic transformation of low-grade follicular non-Hodgkin’s lymphoma (NHL) and identify significant prognostic factors, as well as to compare survival of these patients with that of patients with matched low-grade and de novo high- or intermediate-grade NHL undergoing the same procedure.

PATIENTS AND METHODS: Fifty patients with transformed low-grade NHL have been reported to the European Bone Marrow Transplant registry. Outcome from high-dose therapy and significant prognostic factors were analyzed. Their survival was also compared with that of 200 patients with matched low-grade NHL and 200 patients with matched de novo high- or intermediate-grade NHL by a case-matched analysis.

RESULTS: The procedure-related death rate among the 50 transformed NHL patients was 18%. Overall survival (OS) and progression-free survival (PFS) rates were 51% and 30% at 5 years, respectively. Median PFS time was 13 months. Raised lactate dehydrogenase levels at transformation (P = .0031) was identified as the only adverse significant predictor of PFS on multivariate analysis. A subgroup of patients with residual chemosensitive disease who attained complete remission after high-dose therapy had the best outcome, with an OS at 5 years of 69%. A comparison with matched patients with low-grade disease and with de novo high- or intermediate-grade lymphoma showed no significant difference in OS (P = .939 and P = .438, respectively).

CONCLUSION: Patients with chemosensitive transformed lymphoma should be seriously considered for high-dose therapy and autologous stem-cell support.
Infusional CHOP Chemotherapy (CVAD) With or Without Chemosensitizers Offers No Advantage Over Standard CHOP Therapy in the Treatment of Lymphoma: A Southwest Oncology Group Study
Authors: Gaynor Ellen R. , Unger Joseph M. , Miller Thomas P. , Grogan Thomas M. , White Leonard A. , Mills Glenn M. , Balcerzak Stanley P. , Varterasian Mary , LeBlanc Michael , Fisher Richard I.
Published: February 2017

PURPOSE: Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkin’s lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516).

PATIENTS AND METHODS: All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m2 by intravenous bolus day 1, doxorubicin 12.5 mg/m2/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days.

RESULTS: Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516).

CONCLUSION: CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.
Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833
Authors: Chico Isagani , Kang Min H. , Bergan Raymond , Abraham Jame , Bakke Susan , Meadows Beverly , Rutt Ann , Robey Rob , Choyke Peter , Merino Maria , Goldspiel Barry , Smith Tom , Steinberg Seth , Figg William D. , Fojo Tito , Bates Susan
Published: February 2017

PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion.

PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833.

RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m2/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m2/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (Cpss) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m2/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m2/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non–small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma.

CONCLUSION: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.
Phase I and Pharmacokinetic Study of LU79553, a DNA Intercalating Bisnaphthalimide, in Patients With Solid Malignancies
Authors: Villalona-Calero Miguel A. , Eder Joseph P. , Toppmeyer Deborah L. , Allen Lee F. , Fram Robert , Velagapudi Raja , Myers Michael , Amato Anthony , Kagen-Hallet Kathleen , Razvillas Betty , Kufe Donald W. , Von Hoff Daniel D. , Rowinsky Eric K.
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks.

PATIENTS AND METHODS: Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course.

RESULTS: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m2/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m2/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m2/d dose level. At the 18-mg/m2/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment.

CONCLUSION: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m2/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.
Phase III Trial of Standard-Dose Intravenous Cisplatin Plus Paclitaxel Versus Moderately High-Dose Carboplatin Followed by Intravenous Paclitaxel and Intraperitoneal Cisplatin in Small-Volume Stage III Ovarian Carcinoma: An Intergroup Study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group
Authors: Markman Maurie , Bundy Brian N. , Alberts David S. , Fowler Jeffrey M. , Clark-Pearson Daniel L. , Carson Linda F. , Wadler Scott , Sickel Joshua
Published: February 2017

PURPOSE: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin.

PATIENTS AND METHODS: Patients were randomized to receive either IV paclitaxel 135 mg/m2 over 24 hours followed by IV cisplatin 75 mg/m2 every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m2 over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m2 every 3 weeks for six courses.

RESULTS: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received ≤ two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P = .01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P = .05, one-tail).

CONCLUSION: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.
Microsatellite Instability Is an Independent Indicator of Recurrence in Sporadic Stage I-II Endometrial Adenocarcinoma
Authors: Fiumicino Silvia , Ercoli Alfredo , Ferrandina Gabriella , Hess Patricia , Raspaglio Giuseppina , Genuardi Maurizio , Rovella Valentina , Bellacosa Alfonso , Cicchillitti Lucia , Mancuso Salvatore , Bignami Margherita , Scambia Giovanni
Published: February 2017

PURPOSE: The aim of this study was to define the prognostic role of microsatellite status in 65 stage I-II primary sporadic endometrioid endometrial adenocarcinoma (EEA) patients.

PATIENTS AND METHODS: Familiarity for neoplasia was ascertained in all patients on the basis of a questionnaire. Microsatellite status was assessed by matching normal and tumoral DNA probed for five dinucleotide repeats and one mononucleotide repeat marker. Microsatellite status was analyzed in relation to clinicopathologic characteristics of the patients and length of disease-free survival (DFS).

RESULTS: Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or microsatellite instability (MI). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). The percentage of MI was significantly higher in poorly than in well to moderately differentiated tumors (50% v 9%; P = .003). The 5-year DFS rate of MI patients was 63% (95% confidence interval [CI], 35% to 91%) versus 96% (95% CI, 91% to 101%) of MS patients (P = .0004). In multivariate analysis, only the presence of MI, stage II of disease, and depth of myometrial invasion greater than 50% retained independent prognostic roles.

CONCLUSION: The assessment of microsatellite status may provide useful information for preoperative prognostic characterization of stage I-II primary sporadic EEA patients in which more individualized treatment options can be attempted.
Improved Response With Higher Corticosteroid Dose in Children With Acute Lymphoblastic Leukemia
Authors: Schwartz Cindy L. , Thompson E. Brad , Gelber Richard D. , Young Mary L. , Chilton David , Cohen Harvey J. , Sallan Stephen E.
Published: February 2017

PURPOSE: We investigated whether there was a dose-response relationship for the use of corticosteroids in childhood acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS: Three hundred sixty-nine patients, ages 1 to 18 years with ALL, were randomly assigned to receive one of four different doses of corticosteroid (prednisolone 40 mg/m2/d or dexamethasone 6, 18, or 150 mg/m2/d) administered as a 3-day, single-drug window before initiation of standard, multidrug induction chemotherapy. Corticosteroid drug response was measured by reduction in bone marrow blast counts and absolute peripheral blast counts after 3 days. Glucocorticoid receptor (GCR) number and the effective concentration of dexamethasone resulting in a 50% reduction of leukemic cell viability in vitro (EC-50) were evaluated at days 0 and 3.

RESULTS: Increasing dexamethasone doses resulted in greater marrow blast response (P = .007), with a similar trend in peripheral-blood blast response. High-dose corticosteroid regimens (dexamethasone 18 or 150 mg/m2/d) elicited better responses than standard doses of dexamethasone or prednisone (bone marrow, P = .002; peripheral blasts, P = .05). Among patients treated with standard-dose corticosteroids, 38% with resistant (EC-50 > 10-7) peripheral blasts had a good response compared with 92% with sensitive (EC-50 < 10-7) peripheral blasts (P = .01). In contrast, there was no differential response according to EC-50 group after high-dose corticosteroids. Similarly, an association between response and GCR on peripheral-blood blasts was noted after standard-dose corticosteroid regimens but not after high-dose corticosteroid regimens.

CONCLUSION: Response of ALL to glucocorticoid therapy increased with dose. Higher-dose corticosteroid treatment abrogated the effect of relative drug insensitivity and of low GCR on peripheral blasts.
Treatment and Outcome of 83 Children With Intraspinal Neuroblastoma: The Pediatric Oncology Group Experience
Authors: Katzenstein Howard M. , Kent Paul M. , London Wendy B. , Cohn Susan L.
Published: February 2017

PURPOSE: To investigate whether the rate of neurologic recovery or the incidence of long-term sequelae differed for children with neuroblastoma (NB) initially treated with chemotherapy versus surgical decompression with laminectomy, we reviewed the Pediatric Oncology Group (POG) experience.

PATIENTS AND METHODS: A retrospective review of children diagnosed with intraspinal NB registered on POG NB Biology Protocol 9047 was performed. Survival, neurologic outcome, and orthopedic sequelae were evaluated according to age of the patient at diagnosis, stage of disease, duration and severity of neurologic symptoms, and therapeutic intervention.

RESULTS: Between May 1990 and January 1998, 83 children with intraspinal NB were entered onto the study. Five-year survival for this cohort of patients was 71% ± 9%. Forty-three (52%) of the patients had neurologic symptoms at diagnosis. After treatment, six of 15 severely affected patients, who presented with paralysis, completely recovered neurologic function. Two of five patients with moderate deficits, consisting of paresis and bowel/bladder dysfunction, completely recovered neurologic function. Seventeen of 22 assessable children, who had mild symptoms comprised of paresis alone, fully recovered. Seven of 24 assessable patients who had undergone laminectomy developed scoliosis, whereas spinal deformities were only detected in one of 49 assessable patients managed without laminectomy (P = .001).

CONCLUSION: The frequency of complete neurologic recovery in children with intraspinal NB inversely correlated with the severity of the presenting neurologic deficits. The rate of neurologic recovery was similar for patients treated with chemotherapy compared to those managed with laminectomy. Fewer orthopedic sequelae were observed in the children managed with chemotherapy than were seen in children managed with laminectomy.
Multicenter Phase I-II Trial of Docetaxel, Cisplatin, and Fluorouracil Induction Chemotherapy for Patients With Locally Advanced Squamous Cell Cancer of the Head and Neck
Authors: Posner Marshall R. , Glisson Bonnie , Frenette Gary , Al-Sarraf Muhyi , Colevas A. Dimitrios , Norris Charles M. , Seroskie Jeffery D. , Shin Dong M. , Olivares Robert , Garay Carlos A.
Published: February 2017

PURPOSE: We conducted a phase I-II, multi-institutional trial to determine the maximum-tolerated dose (MTD) of cisplatin in an induction chemotherapy regimen of docetaxel, cisplatin, and fluorouracil for squamous cell cancer of the head and neck (SCCHN) and to determine the safety, tolerability, and efficacy of the regimen at MTD.

PATIENTS AND METHODS: A total of 43 patients with previously untreated, locally advanced, curable SCCHN were entered. Overall, 29 patients (67%) had N2 or N3 nodal disease and nine (21%) had T4 primary tumors. All patients received docetaxel 75 mg/m2 on day 1; cisplatin at 75 (level I) or 100 (level II) mg/m2 on day 1; and a continuous fluorouracil infusion at 1,000 mg/m2/d on days 1 through 4. Patients were treated with prophylactic antibiotics on days 5 through 15. Cycles were repeated every 21 days for a total of three cycles. Patients then received definitive therapy based on institutional preferences.

RESULTS: Thirteen patients were treated at level I, and 30 patients were treated at level II. All 43 patients were assessable for toxicity. There were no major differences in toxicity between level I and level II. Cisplatin-associated grade 3 or 4 hypomagnesemia or hypocalcemia occurred in 13 (30%) and hearing loss in two patients (5%). Grade 3 or 4 neutropenia was observed in 41 patients (95%) and febrile neutropenia occurred in eight (19%). There was one serious infection (2%). There were 17 (40% [95% confidence interval [CI], 25% to 56%]) clinical complete responders (CR), 23 (54% [95% CI, 39% to 69%]) partial responders (PR), one (2%) with no change, and two (5%) unassessable patients. Major responses (CR, PR) were observed in 40 (93% [95% CI, 81% to 99%]) patients. Primary site CR was documented in 24 (54%) of patients. Postchemotherapy primary site biopsies were performed in 25 patients (58%) and pathologically negative biopsy was obtained in 11 (92%) of 12 primary site clinical CRs and seven (54%) of 13 with PR or no change. Overall, negative biopsies were obtained in 18 patients (72%).

CONCLUSION: TPF induction chemotherapy can be delivered safely with a cisplatin dose of 100 mg/m2 in previously untreated patients with SCCHN. The regimen is associated with a high rate of primary site clinical and pathologic CRs. Phase III comparison with cisplatinum and fluorouracil chemotherapy is warranted.
Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Human Pancreatic Adenocarcinomas: Clinicopathologic and Prognostic Significance of Matrilysin Expression
Authors: Yamamoto Hiroyuki , Itoh Fumio , Iku Shouhei , Adachi Yasushi , Fukushima Hiroshi , Sasaki Shigeru , Mukaiya Mitsuhiro , Hirata Koichi , Imai Kohzoh
Published: February 2017

PURPOSE: A disruption in the balance between the matrix metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been implicated in the progression of many types of cancer. The aim of this study was to determine whether a specific MMP or TIMP has clinicopathologic and prognostic significance in pancreatic carcinoma.

PATIENTS AND METHODS: Using immunohistochemistry, we analyzed 70 pancreatic ductal adenocarcinoma tissues for expression of MMP-1, MMP-2, MMP-3, MMP-7 (matrilysin), MMP-9, MT1-MMP, TIMP-1, and TIMP-2. The results were matched with clinicopathologic characteristics and patients’ survival. The effects of the suppression of a specific MMP on in vitro invasiveness of pancreatic carcinoma cells were also examined.

RESULTS: Expression of MMP-1, MMP-2, MMP-3, matrilysin, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was detected in either tumor cells or tumor stromal cells, or in both components, at varying frequencies. Among MMPs, matrilysin showed a unique distribution in the tumor nests; its expression was usually most pronounced at the invasive front of the tumors. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 40 cases (57%), were judged to be positive for matrilysin. Matrilysin positivity was significantly correlated with pT, pN, and pM categories and with more advanced pathologic tumor-node-metastasis stages. Patients with matrilysin-positive carcinoma had a significantly shorter overall survival time than did those with matrilysin-negative carcinoma. Matrilysin was a significant independent prognostic factor for overall survival in multivariate analysis. In contrast, there was no correlation between the presence of other MMPs or TIMPs and clinicopathologic characteristics, nor was the presence of individual MMPs or TIMPs related to survival. Antisense matrilysin-transfected CFPAC-1 cells expressed reduced levels of matrilysin and demonstrated a similar growth potential but were less invasive in vitro compared with neotransfected CFPAC-1 cells.

CONCLUSION: Our results suggest that matrilysin may play a key role in progression of pancreatic carcinoma and thereby contribute to a poor prognosis. Because different synthetic MMP inhibitors affect different types of MMPs to a different degree, examination of the expression of MMPs, especially that of matrilysin, may serve as an indicator for selecting the most effective MMP inhibitor.
Molecular Staging of Early Colon Cancer on the Basis of Sentinel Node Analysis: A Multicenter Phase II Trial
Authors: Bilchik Anton J. , Saha Sukamal , Wiese David , Stonecypher James A. , Wood Thomas F. , Sostrin Stuart , Turner Roderick R. , Wang He-Jing , Morton Donald L. , Hoon Dave S.B.
Published: February 2017

PURPOSE: Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis.

PATIENTS AND METHODS: In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: β-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10−3to 10−4μg of RNA and one to five tumor cells in 107lymphocytes of healthy donors.

RESULTS: One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P < .04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs.

CONCLUSION: Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.
Clinical Implications of Circulating Angiogenic Factors in Cancer Patients
Authors: Poon Ronnie Tung-Ping , Fan Sheung-Tat , Wong John
Published: February 2017

PURPOSE: Angiogenesis, a process fundamental to tumor growth, is regulated by angiogenic factors. This article reviews prognostic and other clinical implications of circulating angiogenic factors in cancer patients.

METHODS: A MEDLINE search of literature was performed using the names of various angiogenic factors as the key words. Studies pertaining to circulating angiogenic factors in cancer patients were reviewed. Pertinent literature regarding tumor expression of common angiogenic factors and their prognostic relevance in human cancers were also examined.

RESULTS: A substantial number of studies have demonstrated a strong association between elevated tumor expression of vascular endothelial growth factor (VEGF) and advanced disease or poor prognosis in various cancers. This supports the pivotal role of VEGF in regulating tumor angiogenesis. More recently, there is mounting evidence that the level of circulating VEGF in patients with different types of cancer may be predictive of tumor status and prognosis. Preliminary data also suggest that circulating VEGF may be useful in predicting and monitoring tumor response to anticancer therapies and in follow-up surveillance for tumor relapse. There are reports supporting the prognostic value of other circulating angiogenic factors such as basic fibroblast growth factor, platelet-derived endothelial cell growth factor, transforming growth factor-beta, and angiogenin, but their clinical significance is less conclusive because of limited data.

CONCLUSION: Circulating VEGF seems to be a reliable surrogate marker of angiogenic activity and tumor progression in cancer patients. Evaluation of circulating angiogenic factors is a promising novel approach of prognostication in cancer patients that has the advantages of being convenient and noninvasive, and it may provide new prognostic information that is not afforded by conventional clinicopathologic prognostic indicators.