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ABSTRACT: To determine the impact of each comprehensive geriatric assessment (CGA) domain on overall survival (OS) and develop a prognostic scoring system for elderly patients with cancer.
A retrospective analysis of CGA data collected from 249 consecutive patients with cancer who attended the outpatient geriatric oncology clinic at the National Cancer Center Singapore age 70 years or older was performed. Univariate and multivariate analyses were performed using Cox proportional hazards method to identify significant prognostic factors within the CGA. A simple nomogram to predict OS was developed using regression coefficients from the multivariate model. Concordance between predicted and observed response of the individual patient score was evaluated by means of Harrell's c-index. Calibration was performed using simulated data via bootstrap.
Median age of the patients was 77 years (range, 70 to 94 years). In our model, age (hazard ratio [HR], 1.04; 95% CI, 1.01 to 1.07), abnormal albumin level (HR, 1.97; 95% CI, 1.23 to 3.15), poor Eastern Cooperative Oncology Group performance status (≥ 2 v < 2: HR, 1.77; 95% CI, 1.15 to 2.72), abnormal geriatric depression scale status (HR, 1.81; 95% CI, 1.29 to 2.56), high malnutrition risk (high v low risk: HR, 1.84; 95% CI, 1.17 to 2.87), and advanced disease stage (late v early: HR, 1.71; 95% CI, 0.98 to 2.95) were independent predictors of survival.
Results confirm the importance of the CGA in assessment of elderly patients with cancer. The development of this nomogram incorporating these prognostic factors helps predict OS of patients, for further intervention.
Journal of Clinical Oncology 08/2011; 29(27):3620-7. · 18.37 Impact Factor
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ABSTRACT: An understanding of the mutations of the proto-oncogenes and tumor suppressor genes that occur in thyroid cancers should eventually explain the diverse clinical characteristics of these tumors and also direct therapy. Some insights have already emerged in the last decade; some abnormalities in tumor genes are consistently associated with specific clinical and pathologic findings. These genetic abnormalities usually represent somatic mutations in tumors of follicular epithelial origin, as opposed to inherited mutations in medullary thyroid cancers of parafollicular C cells origin because most thyroid tumors are sporadic and not familial. This is different from the multiple endocrine neoplasia syndromes in which the primary tumorigenic gene mutations are inherited. This improved understanding of the molecular basis of these diseases has led to the development of novel targeted therapeutic approaches which will be discussed in this paper.
Journal of Oncology 01/2010; 2010.
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ABSTRACT: We evaluated the effect of comorbidities on clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) who have poor performance status (PS 2/3) and/or are elderly (≥70 years old). SUMMARIZED DESCRIPTION: The impact of age (<70 versus >70), PS, and comorbidity score - Cumulative Illness Rating Scale for Geriatrics (CIRS-G) on treatment response, toxicities, QOL and overall survival (OS) was analyzed using data from a completed phase II trial that randomly assigned patients with advanced NSCLC who had PS 2/3 and/or were aged ≥70 to receive gemcitabine (GEM), vinorelbine (VIN) or docetaxel (DOC).
Data from records of 134 patients accrued during the trial were available for analysis. Eighty-eight patients (66%) were aged ≥70 years. 59 patients (67%) had PS of ECOG 0-2 and 29 patients (33%) had ECOG 3. In those aged ≥70, 53 (60%) had at least one comorbidity rated CIRS-G category 3/4 while those aged <70, 12 (26%) had at least one CIRS-G 3/4 comorbidity. Age, PS, and comorbidity scores had no significant association with PFS and QOL scores changes, although PS had marginal influence on OS (0.05<p<0.10). There was significantly greater hematological toxicities and fatigue in patients who had comorbidities of a severe nature. The presence of comorbidity rated CIRS-G category 4 was significantly associated with lower dose intensity of drugs received with no overall impact on response nor survival. In the multivariate analysis, only older patients retained significance with favorable hazard ratio (HR) of 0.5 for overall survival.
Presence of comorbidities alone should not deter the oncologist from treating elderly cancer patients with cytotoxics. Patients with severe comorbidities may experience more toxicity and receive less cycles of chemotherapy and early medical intervention to control these comorbidities may mitigate risk of treatment using cytotoxics.
Critical reviews in oncology/hematology 11/2009; 76(1):53-60. · 5.27 Impact Factor
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Donald Poon,
Benjamin O Anderson,
Li-Tzong Chen,
Koichi Tanaka,
Wan Yee Lau,
Eric Van Cutsem,
Harjit Singh,
Wan Cheng Chow,
London Lucien Ooi,
Pierce Chow,
Maung Win Khin,
Wen Hsin Koo
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ABSTRACT: Asia has a disproportionately large share of the world's hepatocellular carcinoma (HCC), mainly because of the endemic status of chronic hepatitis B and C viruses, which leads to liver cirrhosis and an increased risk of HCC. This etiological factor presents important opportunities for prevention, early detection, diagnosis, and treatment of HCC. This consensus statement reviews the available medical evidence for management of HCC in Asia, and gives treatment recommendations that are adapted to resource availability in this diverse region with disparate health-care delivery systems.
The lancet oncology 11/2009; 10(11):1111-8. · 14.47 Impact Factor
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Hung Huynh,
Van Chanh Ngo,
Heng Nung Koong, Donald Poon,
Su Pin Choo,
Han Chong Toh,
Choon Hua Thng,
Pierce Chow,
Hock Soo Ong,
Alexander Chung,
Boon Cher Goh,
Paul D Smith,
Khee Chee Soo
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ABSTRACT: Hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor where the Raf/MEK/ERK pathway is activated; suggesting that inhibition of this pathway may have therapeutic potential.
We treated patient-derived HCC xenografts with (i) sorafenib, (ii) AZD6244 (ARRY-142886), and (iii) sorafenib plus AZD6244. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to both angiogenesis and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry.
We report here that sorafenib treatment resulted in suppression of tumor growth, reduction in cell proliferation, induction of apoptosis and inhibition of mTOR targets. Sorafenib-induced elevation of the insulin-like growth factor receptor 1 (IGF-1R), phospho-c-Raf Ser338, phospho-MEK Ser217/221 and phospho-ERK Thr202/Tyr204 was attenuated by co-treating cells with anti-human IGF-1R antibody or over-expression of activated mutant p70S6K. Pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. Such inhibition led to a further increase in pro-apoptotic Bim, apoptosis and a profound inhibition of cell proliferation.
Our findings underscore the potential of a combined therapeutic approach with sorafenib and MEK inhibitors in the treatment of HCC.
Journal of Hepatology 10/2009; 52(1):79-87. · 9.26 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor beta Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1Rbeta and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10-0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10-0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10-0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC.
Journal of Cellular and Molecular Medicine 03/2009; 13(8B):2673-83. · 4.13 Impact Factor
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ABSTRACT: Nasopharyngeal carcinoma (NPC) is a disease that is highly responsive to various chemotherapeutic agents. In the metastatic setting, 2-drug combination chemotherapy generally provides a response rate of 55% to 75%, and median survival of 10 to 12 months. The objective of the current study was to assess the efficacy of a 3-drug combination followed by maintenance treatment in patients with metastatic NPC.
Patients with metastatic NPC were treated with a combination of gemcitabine at a dose of 1,000 mg/m(2), paclitaxel at a dose of 70 mg/m(2), and carboplatin at an area under the concentration-time-curve (AUC) of 2.5 on Days 1 and 8 every 21 days. Patients who achieved partial or complete response continued to receive weekly 5-fluorouracil at a dose of 450 mg/m(2) and leucovorin at a dose of 30 mg/m(2) for 48 weeks.
Twenty-eight patients were recruited. Twenty-two (79%) patients had >or=2 sites of disease. Toxicities were mainly from bone marrow suppression, with 79% grade 3/4 neutropenia, 32% grade 3/4 anemia, and 29% grade 3/4 thrombocytopenia (according to the National Cancer Institute Common Toxicity Criteria). The overall response rate to the 3-drug regimen was 86%, with a complete response rate of 11%. The median duration of response was 8 months and the median overall survival was 22 months.
This regimen of a 3-drug combination followed by maintenance is feasible and has demonstrated an encouraging response rate and overall survival.
Cancer 07/2008; 113(6):1332-7. · 4.77 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.
Journal of Cellular and Molecular Medicine 06/2008; 13(7):1371-80. · 4.13 Impact Factor
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ABSTRACT: Patients with poor performance status and/or are elderly are frequently considered a compromised group at high risk of chemotherapy-related morbidities and less likely to benefit from treatment. We aimed to evaluate tolerability and efficacy of three single-agent regimens in these patients.
Patients with advanced non-small cell lung cancer who had performance status 2/3 and/or were aged 70 and older were randomly assigned to receive gemcitabine, vinorelbine, or docetaxel. Objective response, toxicities, and quality of life were evaluated.
One hundred thirty-five patients were registered, of whom one was ineligible. Of the 134 patients, 43 received gemcitabine, 45 vinorelbine, and 46 docetaxel. The response rate was 16%, 20%, 22% for gemcitabine, vinorelbine, and docetaxel, respectively. The main grade 3/4 toxicities were fatigue (18%) and neutropenia (16%). There was improvement in global health scores, cough, and dyspnea for all treatment groups. The improvement in dyspnea was most marked in patients with performance status 3.
There was no significant advantage of any of the treatment arms over the rest. There was benefit seen with improvement of quality of life in patients who were able to receive more cycles of chemotherapy.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2007; 2(3):230-6. · 4.55 Impact Factor
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ABSTRACT: Corticosteroids are used in the management of intestinal obstruction (IO) in carcinomatosis peritonei. There is considerable overlap in the symptoms experienced in IO and functional adrenal insufficiency (AI). The success of symptom palliation in IO may be related to the presence of AI. The aim of this preliminary study was to evaluate the incidence of functional adrenal insufficiency in patients with IO and its relation to clinical outcome and symptom control. Twenty-nine consecutive patients with IO and carcinomatosis peritonei from gastrointestinal cancers admitted to our inpatient service between January and October 2002 were analyzed. They were screened for AI using the short corticotropin stimulation test. Thirteen patients (45%) had functional AI. Differences in characteristics of patients with normal adrenal function (Group 1) and adrenal insufficiency (Group 2) were not statistically significant. Time taken to control symptoms in Group 2 was longer. Mean duration of hospitalization per month of survival was two times longer in Group 2 relative to Group 1 (7.9 versus 4.0 days, P=0.011). Functional AI may be caused by cytokines produced in advanced cancer mediating direct adrenal suppression. Prompt corticosteroid therapy in the presence of AI may facilitate IO symptom palliation.
Journal of Pain and Symptom Management 05/2005; 29(4):411-8. · 2.50 Impact Factor
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ABSTRACT: The aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transporters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer.
Irinotecan was administered at 100 mg m(-2) over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was performed during the first cycle. All patients were genotyped for allelic variants in genes encoding drug metabolizing enzymes (CYP3A4, CYP3A5, UGT1A1) and drug transporters (ABCB1, ABCC2 and ABCG2) that are involved in irinotecan disposition.
Of the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic-phenotypic associations were apparent only for transporter genes. The C(max) of irinotecan was significantly lower in patients carrying the CC genotype at exon 26 of the ABCB1 gene compared with those harbouring at least one variant allele (P = 0.047). Patients harbouring the wild type ABCG2 CTCA genotype were associated with significantly higher values for relative extent of conversion (REC) of irinotecan to SN-38 compared with patients carrying at least one deletion CTCA allele (P = 0.019).
The present exploratory study shows that genetic polymorphisms in drug transporter genes, particularly in ABCB1 and ABCG2 genes, may be important in influencing the pharmacokinetics of irinotecan and its metabolites. The predictive value of the identified allelic variants in the ABCG2 and ABCB1 genes on irinotecan disposition should be further investigated in a larger patient population as well as in other ethnic populations.
British Journal of Clinical Pharmacology 05/2005; 59(4):415-24. · 2.96 Impact Factor
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ABSTRACT: This Phase II study was designed to evaluate the efficacy and safety of irinotecan in patients with advanced nasopharyngeal carcinoma (NPC).
Patients with disseminated, undifferentiated NPC that progressed during or within 3 months of platinum-based and/or taxane-based regimen were eligible. Irinotecan at a dose of 100 mg/m(2) was administered on Days 1, 8, and 15 every 28 days, up to a maximum of 6 cycles, until disease progression or the appearance of intolerable toxicity.
Twenty-eight patients were evaluable for toxicity and response. Patient characteristics were as follows: The median age was 46.5 years (range, 40.3-71.6 years), the median number of prior lines of chemotherapy was 2 (range, 1-9), the majority of patients (89%) had good Eastern Cooperative Oncology Group performance status (0-1), and the majority of patients (82.1%) had >/= 2 sites of distant metastases. A total of 79 cycles of irinotecan with a median of 3 cycles per patient were administered. Toxicity > Grade 3 included neutropenia in 5 patients (17%), anemia in 5 patients (17%), and diarrhea in 4 patients (14%). The best response outcomes were 4 patients (14%) who achieved partial responses and 1 patient (4%) who achieved stable disease. Global quality-of-life scores were stable during treatment. Using the Kaplan-Meier method, the median progression-free survival was 3.9 months, and the median overall survival was 11.4 months. The partial responders had a durable response (range, 5.7-12.2 months).
Results from this trial suggest that irinotecan is an active salvage agent with modest toxicity in patients with advanced NPC who are refractory to platinum/taxane-based chemotherapy. Studies combining irinotecan with other active agents in the first-line setting are warranted.
Cancer 02/2005; 103(3):576-81. · 4.77 Impact Factor
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The Lancet Oncology 09/2004; 5(8):509-10. · 22.59 Impact Factor
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ABSTRACT: To analyze the results of concurrent chemoradiotherapy in patients with locoregional recurrent nasopharyngeal carcinoma.
We performed a retrospective analysis of 35 patients with locoregional recurrent nasopharyngeal carcinoma referred to our department between March 1994 and November 2002. Most patients were male (77%), Chinese (97%), and had undifferentiated carcinoma (89%). Most had extensive locally recurrent Stage rT3-T4 disease (66%) with a median age at recurrence of 49 years (range, 35-69 years). A repeat course of radiotherapy was given concurrently with cisplatin, with cisplatin/5-fluorouracil as consolidation treatment. Significant morbidities were present, including cranial nerve palsies due to extensive recurrent local disease before treatment of the recurrence.
The response rate to concurrent chemoradiotherapy was 58% (29% complete response and 29% partial response). The 5-year progression-free and overall survival rate, calculated using the Kaplan-Meier method, was 15% and 26%, respectively. Only 3 patients developed systemic metastases. Grade 3-4 acute toxicities included emesis (9%) and neutropenia (14%), and Grade 3-4 late toxicities consisted of temporal lobe necrosis (3%), cranial neuropathy (6%), and endocrine abnormalities (14%).
Concurrent chemoradiotherapy is feasible in a selected group of patients with locoregional recurrent NPC, but the risk of major late toxicities is significant.
International Journal of Radiation OncologyBiologyPhysics 09/2004; 59(5):1312-8. · 4.11 Impact Factor
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ABSTRACT: The purpose of this study was to confirm our hypothesis that the development of functional intestinal obstruction in carcinomatosis peritonei (CP) is related to cytokine-mediated inhibition of the Akt pathway and to investigate the phenomenon of relative adrenal insufficiency in CP.
Human adrenocortical cells (NCI-H295R) were treated with serum derived from eight cancer patients who had intestinal obstruction and functional adrenal insufficiency. Serum from three normal healthy subjects and three who had CP but without intestinal obstruction or adrenal insufficiency were used as controls. The differential effects of serum on the treated cells were studied using Western blot analysis. Cortisol production of these treated cells was assayed with cortisol ELISA kits.
Phosphorylation of Akt at Ser473 and Ser308 in cells was significantly reduced when treated with serum from patients with intestinal obstruction but not controls. Phosphorylation of PDK1 at Ser241, mTOR downstream targets like p70S6 at Thr421/Ser424 and Thr389, and lastly 4EBP-1 at Ser70 a downstream target of p70S6 was reduced by approximately 50%, 40%, and 70%, respectively. There was enhanced phosphorylation of elF4E an initiating factor in protein translation in cells treated with patient serum compared to controls. Cortisol synthesis was stimulated upon treatment with patient serum but not with control serum.
Inhibition of Akt phosphorylation is a mechanism that could play a major role in the development of intestinal obstruction in carcinomatosis peritonei. The identification of the mediating cytokines will lead to the development of cogent targeted therapeutic strategies.
Hematology/ Oncology and Stem Cell Therapy 1(2):73-9.
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ABSTRACT: Chemotherapeutic treatment options for advanced unresectable and/or metastatic hepatocellular carcinoma (HCC) are limited. Currently available treatments are associated with low response rates and little evidence of improved survival, so we evaluated a new chemoimmunotherapy regimen.
Seven patients with unresectable and/or metastatic HCC were treated with intravenous oxaliplatin (30mg/m2) and doxorubicin (20mg/m2) given on days 1, 8 and 15 in a 28-day cycle, a daily continuous infusion of fluorouracil (200mg/m2) and subcutaneous interferon alfa-2b 5 MU administered thrice weekly (OXAFI). Treatment was administered to a maximum of six cycles. Data on the response to treatment, toxicity, surgical procedures and survival outcome was reviewed.
The best response was three partial responses, three stable disease responses and one progressive disease response. Two patients underwent interval hepatic resection, and histological analysis in one patient showed a complete pathological response. Another patient underwent a liver transplant after four cycles of treatment. These three patients were alive with no evidence of disease at 23, 21 and 18 months follow-up, respectively. At a median follow-up of 14 months (range 2-23 months), one patient died 2 months after diagnosis due to progressive disease, while all six other patients were alive. Neutropenia was the predominant toxicity, but there were no episodes of febrile neutropenia, hospital admissions or deaths. There were no cases of hepatitis B virus re-activation.
OXAFI shows activity in HCC and has manageable toxicity. Complete pathological remission is possible with this regimen.
Hematology/ Oncology and Stem Cell Therapy 1(3):159-65.
