[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. DOI:10.1371/journal.pone.0070191 · 3.23 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). DOI:10.1007/s00280-013-2171-4 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction.
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.
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 area under the curve [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 maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites.
In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (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; 19(13). DOI:10.1158/1078-0432.CCR-12-3214 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Preclinical studies have demonstrated that low-dose hydroxyurea (HU) enhances the cytotoxic effects of gemcitabine on human cancer cells; however, the combination has not been well studied on patients with recurrent, locally persistent head and neck squamous cell carcinomas (HNSCC). Additionally, the potential biomarkers to predict the response of HNSCC to the regimen remain largely unknown.
Twenty-two HNSCC patients underwent two-day HU (500 mg/m2, day 1 and 8) and gemcitabine (500 mg/m2, day 2 and 9) infusions every 21 days for a median of two (1–12) cycles until disease progression or adverse effects prohibited further therapy. RNA from pre-therapy tissues was subjected to cDNA microarray analysis to identify differentially expressed genes between stable and progressive disease. Validation of selected genes was performed by quantitative RT-PCR and immunohistochemistry.To further investigate the impact of growth arrest and DNA-damage-inducible protein alpha (GADD45α)on cellular sensitivity to the combination of HU and gemcitabine, GADD45α was over expressed in human oropharyngeal carcinoma KB cells.
Ten patients displayed partial remission and/or stable disease, while nine patients displayed progressive disease. The progression free survival for stable disease was 5.88 months and the median overall survival was 12.4 months, while the progression free survival and the median overall survival for all patients were 1.71 and 7.23 months, respectively. A set of 112 genes was differentially expressed between stable and progressive disease. mRNA expression of c-Fos, BCL2/adenovirus E1B 19 kDa-interacting protein 3, paired-like homeodomain 1 and phosphoglycerate kinase 1 was more highly expressed in progressive disease, while mRNA and protein expressin of GADD45α and GADD45γ were significantly decreased in progressive disease in stable disease. Moreover, over expression of GADD45α sensitized KB cells to the combination of HU and gemcitabine.
The combination of HU and gemcitabine may be useful in HNSCC control with reasonable tolerance and toxicity. Based on gene expression profiles, a subset of patients may be potentially identified to gain increased treatment benefits.
Head & Neck Oncology 02/2013; 5(3):25. · 3.14 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.
Journal of Oncology Pharmacy Practice 01/2013; 20(2). DOI:10.1177/1078155212474048
[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. DOI:10.1158/1078-0432.CCR-11-2873 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2012; 18(8):1273-80. DOI:10.1016/j.bbmt.2012.01.021 · 3.40 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 12/2011; 117(24):5493-9. DOI:10.1002/cncr.26245 · 4.89 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. DOI:10.1007/s00280-011-1779-5 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs).
Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not.
Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04).
The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.
Cancer Chemotherapy and Pharmacology 08/2011; 69(2):505-14. DOI:10.1007/s00280-011-1721-x · 2.77 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. DOI:10.1007/s00280-011-1637-5 · 2.77 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.
[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.
[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. DOI:10.1007/s00280-010-1242-z · 2.77 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.
Journal of Thoracic Disease 12/2009; 1(1):11-6. · 1.78 Impact Factor
[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. · 1.83 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. DOI:10.1177/1078155209104383