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ABSTRACT: Capecitabine is an oral prodrug of flurouracil with broad activity against various malignancies. We explored its tolerance and preliminary efficacy when given together with cisplatin in a phase I/II study preferentially enrolling gastric cancer patients.
The study was a 3+3 dose escalation design and at the recommended phase II dose it included an expanded cohort of patients with upper gastrointestinal cancer. The dose of cisplatin was escalated from 40 to 50 mg/m(2) on day 1, and capecitabine of 2,500 mg/m(2)/day starting on day 2, was escalated from 5 days to 10 and then to 14 days, with the cycle repeated every 21 days. Prolonged maintenance with capecitabine was offered to selected patients completing three to six cycles.
A total of 34 patients were enrolled, and 27 patients were also evaluable for response. Dose limiting toxicities were palmar plantar erythrodyesthesia (PPE) and diarrhea; grade 3 and 4 neutropenia occurred in 8.8% and grade 3 PPE in 5.9%, while the most common grade 1-2 toxicities were anemia, neutropenia, fatigue and PPE (11.7% each). There were no treatment related deaths. With cisplatin at 40-50 mg/m(2) day 1 and capecitabine at 2,500 mg/m(2)/day for 5 -14 days every 21 days, 18 patients with gastric cancer were treated and 7 had partial responses.
A regimen of capecitabine and cisplatin at the doses and schedules explored was safe and active in patients with gastric cancer. Moreover, a 6-month administration of adjuvant capecitabine proved feasible, yielding favorable results after treatment completion and surgery, and should be investigated further.
Anticancer research 03/2012; 32(3):939-45. · 1.73 Impact Factor
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Deirdre J Cohen,
Elliot Newman,
Syma Iqbal,
Richard Y Chang,
Milan Potmesil, Theresa Ryan,
Bernadine Donahue,
Anurag Chandra,
Mengling Liu,
Minerva Utate,
Spiros Hiotis,
Leon H Pachter,
Howard Hochster,
Franco Muggia
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ABSTRACT: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment.
Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival.
Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached.
IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.
Annals of Surgical Oncology 07/2011; 19(2):478-85. · 4.17 Impact Factor
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Jennifer Wu,
Charles Henderson,
Lynn Feun,
Peter Van Veldhuizen,
Philip Gold,
Hui Zheng, Theresa Ryan,
Lawrence S Blaszkowsky,
Haobin Chen,
Max Costa,
Barry Rosenzweig,
MaryLynn Nierodzik,
Howard Hochster,
Franco Muggia,
Giovanni Abbadessa,
Jonathan Lewis,
Andrew X Zhu
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ABSTRACT: Darinaparsin is a novel organic arsenic that reaches higher intracellular concentration with decreased toxicity compared to inorganic arsenic. We conducted a multi-center phase II study with darinaparsin in patients with advanced HCC.
Eligibility criteria included unresectable or metastatic measurable HCC, up to two prior systemic treatments, ECOG performance status < or = 2, Child Pugh Class A or B and adequate organ functions. Darinaparsin was administered at 420 mg/m(2) intravenously, twice weekly at least 72 h apart for 3 weeks in a 4-week cycle. The primary end point was response rate. A Simon two-stage design was used.
Among 15 patients in the first stage, no objective responses were observed. Two patients had stable disease. The median number of cycles on study per patient was 2 (1-6). The median progression free survival and overall survival were 55 days (95% confidence interval: 50-59) and 190 days (95% confidence interval: 93-227), respectively. No treatment related hospitalizations or deaths occurred. Treatment related grade 1-2 toxicities included nausea, vomiting (26.7% each), fatigue (20%), anorexia and diarrhea (13.3% each). Grade 3 anorexia, wheezing, agitation, abdominal pain and SGPT were observed in 1 patient each (6.7%). One patient experienced grade 4 hypoglycemia (6.7%).
Darinaparsin could be safely administered with tolerable toxicity profiles, and no QTc prolongation in patients with advanced HCC. However, at this dose and schedule, it has shown no objective responses in HCC and this trial was terminated as planned after the first stage of efficacy analysis.
Investigational New Drugs 07/2009; 28(5):670-6. · 3.36 Impact Factor
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ABSTRACT: To determine if maintenance rituximab (MR) after standard chemotherapy improves progression-free survival (PFS) in advanced-stage indolent lymphoma.
Patients with stage III-IV indolent lymphoma with responding or stable disease after cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy were stratified by initial tumor burden, residual disease after CVP (minimal or gross), and histology, and randomly assigned to observation (OBS) or MR 375 mg/m(2) once per week for 4 weeks every 6 months for 2 years. PFS was the primary end point.
Three hundred eleven (282 with follicular lymphoma) evaluable patients who received CVP were randomly assigned to OBS (n = 158) or MR (n = 153). Best response improved in 22% MR versus 7% OBS patients (P = .00006). Toxicity was minimal in both study arms. Three-year PFS after random assignment was 68% MR versus 33% OBS (hazard ratio [HR] = 0.4; P = 4.4 x 10(-10) [all patients]) and 64% MR v 33% OBS (HR = 0.4; P = 9.2 x 10(-8) [patients with follicular lymphoma]). There was an advantage for MR regardless of Follicular Lymphoma International Prognostic Index score, tumor burden, residual disease, or histology. In multivariate analysis of MR patients, minimal disease after CVP was a favorable prognostic factor. OS at 3 years was 92% MR versus 86% OBS (HR = 0.6; log-rank one-sided P = .05) and, among patients with follicular lymphoma, OS was 91% MR versus 86% (HR = 0.6; log-rank one-sided P = .08). A trend favoring MR was observed among patients with high tumor burden (log-rank one-sided P = .03).
The E1496 study provides the first phase III data in untreated indolent lymphoma that MR after chemotherapy significantly prolongs PFS.
Journal of Clinical Oncology 05/2009; 27(10):1607-14. · 18.37 Impact Factor
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ABSTRACT: We used a novel combination of induction chemotherapy with gemcitabine (GEM) and cisplatin (CDDP), followed by concurrent chemoradiotherapy (CCRT) with the same agents in patients with locoregionally advanced pancreatic cancer. Surgery or additional chemotherapy followed on the basis of response.
Patients with borderline resectable or locally advanced pancreatic cancer received induction weekly with GEM (1000 mg/m(2)) or CDDP (30 g/m(2)). Patients without progression of disease then underwent surgery or CCRT, including four cohorts of escalating GEM/CDDP doses combined with full-dose radiotherapy. After CCRT, patients deemed resectable underwent surgery; patients with disease that remained unresectable and that did not progress received additional GEM/CDDP for 2 months.
A mean 76% of intended GEM dose and 75% of CDDP dose was delivered during induction (n = 26). There were three incidences of grade 4 toxicity (fever or neutropenia). After induction, five patients progressed and one patient underwent resection. Eighteen patients received CCRT, and three patients underwent resection. After CCRT, disease of 10 patients progressed, and in 5 patients, it remained unresectable without progression, and the patient received additional GEM/CDDP. Dose-limiting toxicity was at dose level IV (thrombocytopenia). Median overall and disease-specific survival was 13 months.
GEM/CDDP induction chemotherapy followed by CCRT is well tolerated and rendered the disease of 4 of 26 patients resectable in this study. The recommended phase II dose for GEM and CDDP in combination with full-dose radiotherapy (5040 cGy) is 300 mg/m(2) and 10 mg/m(2) weekly for 5 weeks. Median survival in this group was 13 months. This neoadjuvant combined modality approach is both feasible and active; further studies are warranted.
Annals of Surgical Oncology 11/2008; 15(12):3521-31. · 4.17 Impact Factor
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ABSTRACT: A phase II trial, using neoadjuvant chemotherapy and intraperitoneal (IP) consolidation, was conducted in patients with locally advanced, potentially resectable gastric cancer or cancer of the gastroesophageal junction, both staged as T3N0, T4N0, or any TN1 or TN2 disease. Preoperative chemotherapy consisted of two cycles of irinotecan 75 mg/m(2) with cisplatin 25 mg/m(2)/week for 4 weeks followed by a 2-week break. Unless disease progression was encountered, surgery was performed and followed by two courses of adjuvant therapy with IP floxuridine 3 g x 3 days plus IP cisplatin 60 mg/m(2) on day 3. Of 32 evaluable patients, 29 (90.6%) underwent surgery, and 25 (86.2%) had R0 on resection. Evidence of primary-tumor downstaging was documented in at least one half of the patients. Toxicity of induction therapy was primarily grade 3/4 neutropenia (38.2%/8.8%), grade 3 diarrhea (20.6%), and grade 3 nausea/vomiting (14.7%). Except for three catheter complications, toxicities with IP therapy were infrequent. After a median follow-up of 28.0 months in 32 patients, 10 patients (31.3%) had no evidence of disease, 4 (12.5%) were alive with disease, 13 (40.6%) had died from disease, and 5 (15.6%) died from unrelated causes. Among 25 patients who underwent R0 resection, there were no local recurrences. Sites of first recurrences were outside the abdominal cavity in seven patients, in the liver in two, and in the abdominal cavity in four patients. Median overall survival for all 32 patients was 36.5 months from the start of treatment after median follow-up of 28 months, whereas median disease-specific survival had not been reached at the time of this analysis. For patients with R0 resection, median overall survival was 48 months after median follow-up of 35 months. The data suggest that an approach consisting of systemic induction therapy, curative surgery with high R0 resection rates, and IP adjuvant therapy has acceptable toxicity and encouraging survival outcomes.
Seminars in Oncology 01/2006; 32(6 Suppl 9):S97-100. · 3.50 Impact Factor
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ABSTRACT: Bacterioplankton productivity in Antarctic waters of the eastern South Pacific Ocean and Drake Passage was estimated by direct counts and frequency of dividing cells (FDC). Total bacterioplankton assemblages were enumerated by epifluorescent microscopy. The experimentally determined relationship between in situ FDC and the potential instantaneous growth rate constant (mu) is best described by the regression equation ln mu = 0.081 FDC - 3.73. In the eastern South Pacific Ocean, bacterioplankton abundance (2 x 10 to 3.5 x 10 cells per ml) and FDC (11%) were highest at the Polar Front (Antarctic Convergence). North of the Subantarctic Front, abundance and FDC were between 1 x 10 to 2 x 10 cells per ml and 3 to 5%, respectively, and were vertically homogeneous to a depth of 600 m. In Drake Passage, abundance (10 x 10 cells per ml) and FDC (16%) were highest in waters south of the Polar Front and near the sea ice. Subantarctic waters in Drake Passage contained 4 x 10 cells per ml with 4 to 5% FDC. Instantaneous growth rate constants ranged between 0.029 and 0.088 h. Using estimates of potential mu and measured standing stocks, we estimated productivity to range from 0.62 mug of C per liter . day in the eastern South Pacific Ocean to 17.1 mug of C per liter . day in the Drake Passage near the sea ice.
Applied and Environmental Microbiology 06/1983; 45(5):1622-32. · 3.83 Impact Factor
