[Show abstract][Hide abstract] ABSTRACT: We aimed to investigate the prognostic value of RRM1 in GC patients.
A total of assessable 389 GC patients with clinicopathological and survival information were enrolled from City of Hope (COH, n = 67) and Zhejiang University (ZJU, n = 322). RRM1 protein expression was determined by immunohistochemistry on FFPE tissue samples. Kaplan-Meier and Cox analyses were used to measure survival. Ras/Raf activity and invasion assays were used to evaluate the role of RRM1 in GC cell lines.
In vitro experiments demonstrated RRM1 activated Ras/Raf/MAPK signal transduction and promoted GC cell proliferation. Meanwhile, RRM1 expression was significantly associated with lymph node involvement, tumor size, Ki67 expression, histological subtype and histological grade in the GC tissue samples (p<0.05). Kaplan-Meier analysis illustrated that high RRM1 expression predicted poor survival in GC patients in the COH and ZJU cohorts (log-rank p<0.01). In multivariate Cox analysis, the hazard ratios of RRM1 for overall survival were 2.55 (95% CI 1.27-5.15) and 1.51 (95% CI 1.07-2.13) in the COH and ZJU sets, respectively. In particular, RRM1 specifically predicted the outcome of advanced GCs with poor differentiation and high proliferative ability. Furthermore, inhibition of RRM1 by siRNA significantly reduced the dNTP pool, Ras/Raf and MMP-9 activities and the levels of p-MEK, p-ERK and NF-κB, resulting in growth retardation and reduced invasion in AGS and NCI-N87 cells.
RRM1 overexpression predicts poor survival in GC patients with advanced TNM stage. RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs.
PLoS ONE 07/2013; 8(7):e70191. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary objective of this trial was to establish the maximum tolerated dose (MTD) of oxaliplatin 130 mg/m(2) preceded by escalating doses of docetaxel 60 mg/m(2) (75, 90, 100 mg/m(2)) administered every 3 weeks. A total of 11 patients were entered; 10 evaluable for response: 4 stable disease (liver, ovary and esophagus) and 1 partial remission (esophagus). At dose level 1, there was 1 dose-limiting toxicity (DLT) (grade 3 allergic reaction). At dose level 2, there were 3 DLTs (3 grade 4 neutropenia, grade 3 gastritis, diarrhea, hypophosphatemia, neuro-mood). The MTD is docetaxel 60 mg/m(2) with oxaliplatin 130 mg/m(2).
Cancer Chemotherapy and Pharmacology 05/2013; 72(1). · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Pazopanib is a potent, multi-targeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics (PK). The objective of this study was to establish the maximum tolerated dose (MTD) and PK profile of pazopanib in patients with varying degrees of hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. RESULTS: Ninety eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and AUC(0-24) in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower MTD in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. CONCLUSIONS: In patients with mild liver dysfunction, pazopanib is well tolerated at the FDA-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.
Clinical Cancer Research 05/2013; · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite advances in treatment options for metastatic colorectal cancer over the past decade, the number of chemotherapy agents available remains limited. We report here a retrospective review of 11 patients who were treated with panitumumab following documented disease progression on cetuximab. Two patients demonstrated minor radiographic responses, albeit only for a short period of time. We conclude that the use of one epidermal growth factor receptor inhibitor following failure on the other may be of benefit to patients who would otherwise have no other treatment options. However, studies to help identify the subset of patients who might benefit from this strategy are needed.
[Show abstract][Hide abstract] ABSTRACT: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations.
Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements.
Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C(max) compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment.
Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2).
Clinical Cancer Research 03/2012; 18(10):2954-63. · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.
Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated.
Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route.
Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.
Cancer Chemotherapy and Pharmacology 11/2011; 69(3):835-43. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is unclear whether the administration of adjuvant chemotherapy improves survival in patients with American Joint Committee on Cancer (AJCC) stage II colon cancer.
The authors used the State of California Cancer Surveillance Program (CSP) to assess patients ages 18 to 80 years with AJCC stage II colon cancer (ie, T3 or T4 and N0) who underwent surgical resection during 1991 and 2006. Patients who had rectal and rectosigmoid cancers were excluded. The cohort was stratified according to the receipt of adjuvant chemotherapy, and clinical and pathologic characteristics and outcomes were assessed.
From the CSP data, 3716 patients were identified who underwent curative-intent surgical resection for stage II colon cancer. When the 2 treatment groups (surgery plus adjuvant chemotherapy [n = 916] and surgery alone [n = 2800]) were compared, patients who received adjuvant chemotherapy were more likely to be younger and to have left-sided lesions with ≥ 12 lymph nodes examined. There was no difference in sex or tumor differentiation between the 2 groups. According to a Kaplan-Meier analysis, patients who received adjuvant chemotherapy had improved overall survival compared with patients who underwent surgery alone (median survival, 12 years vs 9.2 years, respectively; P < .001). In multivariate analysis, adjuvant chemotherapy was identified as an independent predictor of improved survival (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99; P = .031).
To the authors' knowledge, this is the first population-based analysis to identify a survival advantage for adjuvant chemotherapy in patients with AJCC stage II colon cancer. On the basis of the current findings, the authors concluded that the administration of adjuvant chemotherapy improves survival in select patients with stage II disease.
Cancer 06/2011; 117(24):5493-9. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.
Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (≥ 60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (<20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.
Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl ≥ 20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.
Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.
Cancer Chemotherapy and Pharmacology 04/2011; 68(6):1439-47. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For patients with locally advanced esophageal cancer, prospective randomized clinical trials have reported no added value of surgical resection to chemoradiation alone. Using a large regional cancer registry, our objective was to determine whether curative-intent esophageal resection provided a survival advantage in the multimodality management of esophageal cancer.
Using the Los Angeles County Cancer Surveillance Program (CSP), we identified all patients with local and regional (i.e., AJCC Stages I-III) esophageal cancer during the years 1988-2006. Clinical and pathologic data included patient demographics, tumor information, indication for surgery, lymph node status, and timing of therapy. Overall survival was assessed by the Kaplan-Meier method, and multivariate Cox-regression analysis was performed.
From CSP, 2233 patients with esophageal cancer were identified. Median survival (MS) of the entire cohort was 13.1 months. We stratified this cohort into patients who received chemoradiation alone (n = 645) and patients who received trimodality therapy (n = 286) (i.e., chemoradiation and surgery). Patients had significantly improved survival with trimodality therapy compared with chemoradiation alone (MS 25.2 vs. 12.3 months, respectively; P < 0.001). The survival advantage with trimodality therapy was observed for patients with squamous cell carcinoma (MS 24.5 vs. 12.8 months, respectively; P < 0.001) and adenocarcinoma (MS 25.9 vs. 10.6 months, respectively; P < 0.001). By multivariate analysis, trimodality therapy was a significant prognostic factor for improved survival in patients with esophageal cancer (hazard ratio [HR] 0.66, 95% confidence interval [95% CI]: 0.56-0.77, P < 0.001).
Our data indicate that surgical resection remains an important component of the multimodality management of esophageal cancer.
Annals of Surgical Oncology 02/2011; 18(2):551-8. · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction.
Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally.
Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years.
Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.
Journal of Clinical Oncology 10/2010; 28(29):4507-12. · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.
Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m(2)/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.
Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m(2)/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.
The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m(2)/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.
Cancer Chemotherapy and Pharmacology 10/2010; 66(5):927-33. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Helical tomotherapy is a novel intensity-modulated radiotherapy modality with a helical 360° radiation delivery system and CT imaging ability. The purpose of this report is to review our initial experiences and to assess the toxicity and efficacy of helical tomotherapy for esophageal cancer.
Twenty patients with locally advanced esophageal cancer (T3-4 and/or N+ and/or M1a/b) were treated with helical tomotherapy. Radiotherapy included simultaneous 50 Gy to gross tumorous areas and 45 Gy to areas of suspected subclinical disease. All received combination chemotherapy. Ten patients underwent surgical resection after completion of chemoradiation. Ten patients were ineligible for surgery.
The treatment was well-tolerated. There were no treatment-related deaths or Grade 4 toxicity. Grade 3 toxicities were noted in 9 of 20 patients (45%). Down-staging was noted in 7 of 10 patients (70%) who underwent surgery. The median follow-up time was 24.5 months. Eight patients, including 3 with surgery and 5 without surgery, have died. The 1-year overall survival rates for the entire group, patients with and without surgical resection are 80.0%, 100.0% and 60.0% respectively (log-rank p = 0.244, surgery versus no surgery).
The regimen of combined chemoradiation by helical tomotherapy for locally advanced esophageal cancer is well-tolerated. The toxicity profile compares favorably with that of protocols based on conventional approach and the preliminary indications of efficacy are encouraging.
[Show abstract][Hide abstract] ABSTRACT: A phase II trial of 5-fluorouracil (5-FU) [250450 mg/m2/day × 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m2/day × 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the presence of high-risk HPV-16 in patients with HNSCC, assess the impact of HPV status on treatment response and survival in this select cohort treated with combined modality therapy and to identify the differences in HIF-1alpha and VEGF expression in HPV-positive and -negative tumors.
Patients had resectable, untreated stage III, IV HNSCC of the oral cavity, oropharynx, hyopharynx or larynx, and stage II cancer of the base of tongue, hypopharynx and larynx. HPV status was determined by conventional PCR in fresh frozen biopsy samples and by Taqman PCR assay on formalin-fixed, paraffin-embedded specimens. HIF-1alpha and VEGF expression were assessed by quantitative real-time PCR (RT-PCR). Multivariate Cox proportional hazards regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) based on HPV status.
HPV-16 was detected in 14 of 24 evaluable cases. There were no significant differences in response rates after neoadjuvant chemotherapy (86% vs. 90%) in HPV-positive and HPV-negative patients, respectively. There was a trend toward better progression-free (HR=0.15, 95% CI=0.002-12.54; p=0.06) and overall survival (HR=0.14, 95% CI=0.001-14.12; p=0.10) for HPV-positive patients. In a subset of 13 fresh frozen samples, RT-PCR revealed a significant increase in VEGF mRNA levels in HPV-positive tumors (p<0.01). No difference was seen for HIF-1alpha expression.
HPV presence portended a better prognosis in patients with oropharyngeal SCC treated with a multimodality treatment in a prospective clinical trial. The level of VEGF mRNA was up-regulated in HPV-16-positive tumors possibly through an HIF-1 independent manner.
Anticancer research 06/2009; 29(5):1467-74. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxaliplatin is a unique platinum derivative with anti-tumor activity in a number of malignancies, with neurotoxicity being a frequent side effect. Neurotoxicity can manifest in an acute phase and a chronic phase. The acute phase usually presents as dysesthesias of the hands and feet, jaw tightness, and pharyngolaryngo-dysesthesia, triggered and exacerbated by physical contact with cold temperatures. Although various other symptoms have been reported in the literature, little details are available. We report here, in detail, a case of blepharoptosis which appeared after repeated oxaliplatin infusions, and the disappearance of which seemed to be dependent on the infusion rate.
Journal of Oncology Pharmacy Practice 05/2009; 15(4):255-7.
[Show abstract][Hide abstract] ABSTRACT: GTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors.
Patients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status of > or =60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defined as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level.
The maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m(2) twice daily for 14 days, and oxaliplatin 100 mg/m(2) every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in ribonucleotide reductase expression in peripheral blood mononuclear cells during treatment.
A combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors.
Cancer Chemotherapy and Pharmacology 04/2009; 64(6):1149-55. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the maximum tolerated dose of combined therapy using an yttrium-90-labeled anti-carcinoembryonic antigen (CEA) antibody with gemcitabine in patients with advanced CEA-producing solid tumors.
The chimeric human/murine cT84.66 is an anti-CEA intact IgG1, with high affinity and specificity to CEA. This was given at a fixed yttrium-90-labeled dose of 16.6 mCi/m(2) to subjects who had and an elevated CEA in serum or in tumor by immunohistochemistry. Also required was a tumor that imaged with an (111)In-labeled cT84.66 antibody. Patients were treated with escalating doses of gemcitabine given i.v. over 30 minutes on day 1 and 3 after the infusion of the yttrium-90-labeled antibody. Patients were treated in cohorts of 3. The maximum tolerated dose was determined as the highest level at which no >1 of 6 patients experienced a dose limiting toxicity.
A total of 36 patients were enrolled, and all but one had prior systemic therapy. The maximum tolerated dose of gemcitabine in this combination was 150 mg/m(2). Dose limiting toxicities at a gemcitabine dose of 165 mg/m(2) included a grade 3 rash and grade 4 neutropenia. One partial response was seen in a patient with colorectal cancer, and 4 patients had a >50% decrease in baseline CEA levels associated with stable disease. Human antichimeric antibody responses were the primary reason for stopping treatment in 12 patients.
Feasibility of combining gemcitabine with an yttrium-90-labeled anti-CEA antibody is shown with preliminary evidence of clinical response.
Clinical Cancer Research 04/2009; 15(8):2935-41. · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prolonged survival for patients with unresectable hepatocellular carcinoma (HCC) is consistently reported at lower than 6 months. Oxaliplatin has recently demonstrated activity in HCC. The objective of this study was to determine the response rate, survival, time to progression, and toxicity in patients with poor prognosis HCC when treated with oxaliplatin.
Patients were required to have measurable recurrent, metastatic or unresectable HCC, and to have previously been exposed to no more than 2 prior chemotherapy regimens. Karnofsky performance of 70% or above and adequate organ and hematologic function were required. All patients received treatment with oxaliplatin 100 mg/m on day 1 and 15 as a 2-hour intravenous infusion and were pretreated with antiemetics. Treatment was repeated every 28 days.
Thirty-six patients were enrolled and evaluated, although 6 expired before the first planned evaluation. Karnofsky performance status was 70/80/90/100% in 5/9/9/13 patients, respectively. The median time to progression was 2 months; median survival was 6 months. The 6-month overall survival was 55% (95% confidence interval 41%-74%), and the 6 month event-free survival was 11% (95% confidence interval 4%-28%).
Single agent, oxaliplatin, has produced one partial response of good duration in 36 patients, but failed to meet the a priori criterion for promise in this trial. Sixteen patients were observed to have stable disease with a well tolerated toxicity profile. The combination of oxaliplatin and other agents should be considered to treat HCC in those patients with good functional status.
American journal of clinical oncology 09/2008; 31(4):317-22. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the years, the prognosis following treatment of a primary cancer has significantly improved. However, the growing population of these cancer survivors has led to the realization of multiple longterm complications secondary to their treatment. One of the most devastating long-term complications is the development of a second malignancy.
We report here the case of a 34-year-old man who developed stage IIB node-positive breast cancer almost 15 years following total body irradiation and allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia. To our knowledge, this is only the second report of a male breast cancer following allogeneic bone marrow transplantation (BMT).
Survivors of primary cancer need lifelong monitoring for complications from their initial therapy.
[Show abstract][Hide abstract] ABSTRACT: This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients.
Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long.
The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose.
Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.
Journal of Clinical Oncology 03/2008; 26(4):570-6. · 17.88 Impact Factor