Eric X Chen

Austin Health, Melbourne, Victoria, Australia

Are you Eric X Chen?

Claim your profile

Publications (47)383.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background In preclinical models, the proton pump inhibitor pantoprazole enhances the antitumor activity of chemotherapeutic agents by improving drug distribution and by inhibiting autophagy. Methods Patients with advanced solid tumors (n = 24) received doxorubicin 60 mg/m(2) and escalating doses of pantoprazole (80, 160, 240 and 360 mg) administered intravenously prior to doxorubicin. Blood samples were collected for pharmacokinetic studies. An optional biopsy was performed to evaluate doxorubicin concentration and pharmacodynamic markers of drug activity. Results Twenty-four patients participated in the study (17 in the dose escalation phase and 7 in the dose expansion). Three patients experienced a dose limiting toxicity (grade 3 fatigue in the three cases), one patient at dose level 3 (pantoprazole 240 mg) and two patients at dose level 4 (pantoprazole 360 mg). Dose level 4 was considered to exceed the maximum tolerated dose. The recommended phase II dose was pantoprazole 240 mg and doxorubicin 60 mg/m(2). The most commonly observed toxicities included fatigue, neutropenia and leukopenia. Two patients achieved a confirmed partial response. Median maximum serum concentration of pantoprazole was 84.3 μM at 1-2 h after injection of pantoprazole 240 mg. No drug-drug interaction was observed. A single on-treatment tumor biopsy showed a sharply decreasing gradient in doxorubicin concentration and associated activity markers with increasing distance from tumor blood vessels. Conclusion Administration of high doses of pantoprazole in combination with doxorubicin is feasible. The recommended phase II dose of pantoprazole, 240 mg, will be evaluated in combination with docetaxel as first line in patients with castration-resistant prostate cancer.
    Investigational New Drugs 09/2014; · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose A prospective cohort study was conducted to evaluate toxicity, quality of life (QOL), and clinical outcomes in patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for anal and perianal cancer. Methods and Materials From June 2008 to November 2010, patients with anal or perianal cancer treated with IMRT were eligible. Radiation dose was 27 Gy in 15 fractions to 36 Gy in 20 fractions for elective targets and 45 Gy in 25 fractions to 63 Gy in 35 fractions for gross targets using standardized, institutional guidelines, with no planned treatment breaks. The chemotherapy regimen was 5-fluorouracil and mitomycin C. Toxicity was graded with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Correlations between dosimetric parameters and both physician-graded toxicities and patient-reported outcomes were evaluated by polyserial correlation. Results Fifty-eight patients were enrolled. The median follow-up time was 34 months; the median age was 56 years; 52% of patients were female; and 19% were human immunodeficiency virus—positive. Stage I, II, III, and IV disease was found in 9%, 57%, 26%, and 9% of patients, respectively. Twenty-six patients (45%) required a treatment break because of acute toxicity, mainly dermatitis (23/26). Acute grade 3 + toxicities included skin 46%, hematologic 38%, gastrointestinal 9%, and genitourinary 0. The 2-year overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS), and cumulative locoregional failure (LRF) rates were 90%, 77%, 84%, and 16%, respectively. The global QOL/health status, skin, defecation, and pain scores were significantly worse at the end of treatment than at baseline, but they returned to baseline 3 months after treatment. Social functioning and appetite scores were significantly better at 12 months than at baseline. Multiple dose-volume parameters correlated moderately with diarrhea, skin, and hematologic toxicity scores. Conclusion IMRT reduces acute grade 3 + hematologic and gastrointestinal toxicities compared with reports from non-IMRT series, without compromising locoregional control. The reported QOL scores most relevant to acute toxicities returned to baseline by 3 months after treatment.
    International journal of radiation oncology, biology, physics 01/2014; · 4.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2004 to provide a set of 10 specific and comprehensive guidelines regarding adverse event (AE) reporting in randomized clinical trials (RCTs). Limited data exist regarding adherence to these guidelines in publications of oncology RCTs. All phase III RCTs published between 2007 and 2011 were reviewed using a 16-point AE reporting quality score (AERQS) based on the 2004 CONSORT extension. Multivariable linear regression was used to identify features associated with improved reporting quality. A total of 325 RCTs were reviewed. The mean AERQS was 10.1 on a 16-point scale. The most common items that were poorly reported were the methodology of AE collection (adequately reported in only 10% of studies), the description of AE characteristics leading to withdrawals (15%), and whether AEs are attributed to trial interventions (38%). Even when reported, the methods of AE collection and analysis were highly heterogeneous. The multivariable regression model revealed that industry funding, intercontinental trials, and trials in the metastatic setting were predictors of higher AERQS. The quality of AE reporting did not improve significantly over time and was not better among articles published in journals with a high impact factor. Our findings show that some methodologic aspects of AE collection and analysis were poorly reported. Given the importance of AEs in evaluating new treatments, authors should be encouraged to adhere to the 2004 CONSORT guidelines regarding AE reporting.
    Journal of Clinical Oncology 09/2013; · 18.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus. Methods Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations. Results Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted. Conclusions RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.
    Investigational New Drugs 07/2013; · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. Methods Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) ≥ 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. Results Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44-83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23-55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69-94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1-12.9); and median OS was 28.6 months (95 % CI: 18.2-37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. Conclusions Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted.
    Investigational New Drugs 01/2013; · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ideally, statisticians should be involved in the design, analysis, and reporting of randomized clinical trials (RCTs). This study assessed the impact of a statistician involvement in published medical oncology RCTs between 2005 and 2009. The reporting quality of each publication was rated using the Overall Reporting Quality Score on the basis of either 2001 or 2010 Consolidated Standards of Reporting Trials criteria. A four-question email survey on the statistical design and analysis was sent to the corresponding authors of each trial. Nonresponders were approached a maximum of three times. Overall, 107 responses were received from 357 solicited authors (30%). Corresponding authors from industry-funded RCTs were less likely to respond (51 vs. 65%, P=0.013). The same person was responsible for statistical design and analyses in 47% of cases. Overall, the statistician involved held a PhD (or equivalent) in statistics in most cases. The statisticians responsible for the statistical design and analysis were listed as coauthors in 68 and 81% of RCT manuscripts. There was no statistically significant impact on manuscript reporting quality of the degree of statistician involvement in manuscript preparation. Fewer trials were reported as positive when the responsible statistician was listed as a coauthor. It is possible that RCTs included in this review are in general of higher quality or were more likely to have a greater level of statistician involvement than smaller, single-arm, or unpublished studies. This imbalance could explain the lack of significant difference observed in the Overall Reporting Quality Score between trials where statisticians were listed as coauthors or not.
    Anti-cancer drugs 12/2012; · 2.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary endpoint (PEP) analysis were established. The objectives of this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess the intrapublication consistency in PEP reporting. All adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries. A total 366 RCTs were identified. Trial registration was found for 215 trials and the rate increased from 43% in 2005 to 82% in 2009 (P < 0.001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15 to 67% (P < 0.001). PEP differs between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% RCTs, mainly due to inadequate reporting of PEP or of sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly due to negative superiority studies being interpreted as showing equivalence. The rates of trial registration and of trials with clearly defined PEP have improved over time, however 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers and readers for increased awareness and scrutiny of reporting outcomes of oncology RCTs.
    Bulletin du cancer 10/2012; 99(10):943-952. · 0.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in the mid-1990s for the explicit purpose of improving clinical trial reporting. However, there is little information regarding the adherence to CONSORT guidelines of recent publications of randomized controlled trials (RCTs) in oncology. All phase III RCTs published between 2005 and 2009 were reviewed using an 18-point overall quality score for reporting based on the 2001 CONSORT statement. Multivariable linear regression was used to identify features associated with improved reporting quality. To provide baseline data for future evaluations of reporting quality, RCTs were also assessed according to the 2010 revised CONSORT statement. All statistical tests were two-sided. A total of 357 RCTs were reviewed. The mean 2001 overall quality score was 13.4 on a scale of 0-18, whereas the mean 2010 overall quality score was 19.3 on a scale of 0-27. The overall RCT reporting quality score improved by 0.21 points per year from 2005 to 2009. Poorly reported items included method used to generate the random allocation (adequately reported in 29% of trials), whether and how blinding was applied (41%), method of allocation concealment (51%), and participant flow (59%). High impact factor (IF, P = .003), recent publication date (P = .008), and geographic origin of RCTs (P = .003) were independent factors statistically significantly associated with higher reporting quality in a multivariable regression model. Sample size, tumor type, and positivity of trial results were not associated with higher reporting quality, whereas funding source and treatment type had a borderline statistically significant impact. The results show that numerous items remained unreported for many trials. Thus, given the potential impact of poorly reported trials, oncology journals should require even stricter adherence to the CONSORT guidelines.
    CancerSpectrum Knowledge Environment 07/2012; 104(13):982-9. · 14.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In designing phase III randomized clinical trials (RCTs), the expected magnitude of the benefit of the experimental therapy (δ) determines the number of patients required and the number of person-years of follow-up. We conducted a systematic review to evaluate how reliably δ approximates the observed benefit (B) in RCTs that evaluated cancer treatment. RCTs evaluating systemic therapy in adult cancer patients published in 10 journals from January 1, 2005, through December 31, 2009, were identified. Data were extracted from each publication independently by two investigators. The related-samples Sign test was used to determine whether the median difference between δ and B was statistically significant in different study subsets and was two-sided. A total of 253 RCTs met the eligibility criteria and were included in the analysis. Regardless of whether benefit was defined as proportional change (median difference between δ and B = -13.0%, 95% confidence interval [CI] = -21.0% to -8.0%), absolute change (median difference between δ and B = -8.0%, 95% CI = -9.9% to -5.1%), or median increase in a time-to-event endpoint (median difference between δ and B = -1.4 months, 95% CI = -2.1 to -0.8 months), δ was consistently and statistically significantly larger than B (P < .001, for each, respectively). This relationship between δ and B was independent of year of publication, industry funding, management by cooperative trial groups, type of control arm, type of experimental arm, disease site, adjuvant treatment, or treatment for advanced disease, and likely contributed to the high proportion of negative RCTs (158 [62.5%] of 253 studies). Investigators consistently make overly optimistic assumptions regarding treatment benefits when designing RCTs. Attempts to reduce the number of negative RCTs should focus on more realistic estimations of δ. Increased use of interim analyses, certain adaptive trial designs, and better biological characterization of patients are potential ways of mitigating this problem.
    CancerSpectrum Knowledge Environment 04/2012; 104(8):590-8. · 14.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.
    Journal of Clinical Oncology 03/2012; 30(13):1527-33. · 18.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary end point (PEP) analysis were established. The objectives of this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess intrapublication consistency in PEP reporting. All adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries. A total 366 RCTs were identified. Trial registration was found for 215 trials, and the rate increased from 43% in 2005 to 82% in 2009 (P < .001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15% to 67% (P < .001). PEP differed between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% of RCTs, mainly because of inadequate reporting of PEP or sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly resulting from negative superiority studies being interpreted as showing equivalence. The rates of trial registration and of trials with clearly defined PEPs have improved over time; however, 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers, and readers to exercise increased awareness and scrutiny of reporting outcomes of oncology RCTs.
    Journal of Clinical Oncology 12/2011; 30(2):210-6. · 18.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To perform a comprehensive cognitive function (CF) assessment in patients who were relapse free after curative intent radiotherapy (RT) or chemoradiotherapy for squamous cell carcinoma of the head and neck. Patients underwent neuropsychological tests to assess their objective CF; completed questionnaires to assess subjective CF, quality of life, and affect; and underwent blood tests to assess hematologic, biochemical, endocrine, and cytokine status. Retrospectively, the dosimetry of incidental radiation to the brain was determined for all patients, and the dose intensity of cisplatin was determined in those who had undergone chemoradiotherapy. A total of 10 patients were enrolled (5 treated with radiotherapy only and 5 with radiotherapy and cisplatin). The mean time from the end of treatment was 20 months (range, 9-41). All patients were able to complete the assessment protocol. Of the 10 patients, 9 had impaired objective CF, with memory the most severely affected. The severity of memory impairment correlated significantly with the radiation dose to the temporal lobes, and impaired dexterity correlated significantly with the radiation dose to the cerebellum, suggesting that these deficits might be treatment related. Patients receiving cisplatin appeared to have poorer objective CF than patients receiving only RT, although this difference did not achieve statistical significance, likely owing to the small sample size. Consistent with the published data, objective CF did not correlate with subjective CF or quality of life. No association was found between objective CF and patients' affect, hematologic, biochemical, endocrine, and cytokine status. Neuropsychological testing is feasible in squamous cell carcinoma of the head-and-neck survivors. The findings were suggestive of treatment-related cognitive dysfunction. These results warrant additional investigation.
    International journal of radiation oncology, biology, physics 09/2011; 81(1):126-34. · 4.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Decision making in advanced cancer is increasingly complex. We developed a decision aid (DA) for patients with advanced colorectal cancer who are considering first-line chemotherapy and reviewing treatment options, prognostic information, and toxicities. We examined its impact on patient understanding, treatment decisions, decisional conflict, decision making, consultation satisfaction, anxiety, and quality of life by using a randomized trial design. In all, 207 patients with colorectal cancer who were considering first-line chemotherapy for metastatic disease were randomly assigned to receive a standard medical oncology consultation or a consultation in which the DA (take-home booklet with audio recording, reviewed by an oncologist) was used. Participants completed questionnaires postconsultation, postdecision, and 1 month later. In this study, 100 patients were randomly assigned to the control arm, and 107 received the DA. Median age of the sample was 62 years, 58% were male, 89% had a performance status of 0 or 1, and 36% had received prior adjuvant chemotherapy. Patients receiving the DA demonstrated a greater increase in understanding of prognosis, options, and benefits, with higher overall understanding (P < .001). Decisional conflict, treatment decisions, and achievement of involvement preferences were similar between the groups. Anxiety was similar across groups and decreased over time. Most patients were confident in a decision during the first consultation; 74% chose chemotherapy, 7% supportive care alone, and 10% observation. This randomized trial of a decision aid in advanced cancer showed that its use in advanced colorectal cancer improved patient understanding of prognosis, treatment options, risks, and benefits without increasing anxiety. DAs can improve informed consent and can be tested through randomized trials even in the advanced cancer setting.
    Journal of Clinical Oncology 05/2011; 29(15):2077-84. · 18.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GTI-2040 is a novel antisense oligonucleotide to the R2 subunit of ribonucleotide reductase. This phase II trial was conducted to determine the efficacy and tolerability of GTI-2040 when combined with docetaxel and prednisone for the treatment of patients with castration-resistant prostate cancer (CRPC). Chemo-naïve CRPC patients with adequate performance status and organ function were treated with docetaxel 75 mg/m(2) IV on day 1 plus GTI-2040 5 mg/kg/day by continuous intravenous infusion day 1-14 on a 21 day cycle, with prednisone 5 mg orally twice daily. The primary endpoint was PSA response rate. Pharmacokinetic studies of GTI-2040 and pharmacodynamic studies on peripheral blood mononuclear cells (PBMC) were also performed. Twenty-two patients in total (19 from this study and 3 from a prior phase I/II study at this institution) were treated at the recommended phase II dose. A confirmed PSA response was seen in 9/22 patients (41%). Of 16 patients with measurable disease, there was 1 partial response (PR) and 12 stable disease (SD) lasting 3.6 months (median), as best response. The most common toxicities were anemia, fatigue, lymphopenia, leucopenia and neutropenia. Grade 3+ toxicities included neutropenia, lymphopenia, leucopenia, fatigue, febrile neutropenia and hypophosphatemia. The PSA response rate of GTI-2040 in combination with docetaxel and prednisone just met the minimum phase II criteria for further enrollment. However, after evaluation of all the clinical data, further study of this dose and schedule of GTI-2040 in CRPC was not recommended.
    Cancer Chemotherapy and Pharmacology 04/2011; 67(4):927-33. · 2.80 Impact Factor
  • Benoit You, Eric X Chen
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the last decade, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have been firmly established as essential drugs for the treatment of metastatic colorectal cancer (CRC). Cetuximab and panitumumab have been approved by American and European drug agencies. This review aims at exploring the main outcomes of clinical studies performed during their clinical development, from phase I to III trials, and hence at giving a comprehensive review of the scientific rational and up-to-date evidence sustaining the use of these drugs. Many areas are still under active investigation such as administration schedules, their efficacy in comparison with bevacizumab, their role in adjuvant therapy, molecular predictors, and management of side effects.
    The Journal of Clinical Pharmacology 03/2011; · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the efficacy of gemcitabine-platinum regimen, the outcome of patients with recurrent and/or metastatic nasopharyngeal carcinoma (RM NPC) is poor. A phase II trial was conducted to determine the efficacy of erlotinib, given as maintenance therapy after gemcitabine-platinum chemotherapy in patients with RM NPC. Patients were treated with gemcitabine 1000 mg/m on days 1 and 8 as well as cisplatin 70 mg/m on day 1 (or carboplatin area under curve 5 on day 1, if contraindication to cisplatin) 3 weeks. After 6 chemotherapy cycles (or before in case of progression), patients were switched to erlotinib 150 mg/d 4 weeks. Primary end point was time to progression in patients without progressive disease after 6 chemotherapy cycles and treated with maintenance erlotinib. Epstein-Barr virus DNA plasma levels, measured using quantitative real-time polymerase chain reaction, were correlated with outcome. Of 20 enrolled patients, 19 patients received 96 chemotherapy cycles. Fifteen patients were switched to erlotinib and received 36 cycles (range: 1 to 6 cycles). Safety profiles observed with the chemotherapy combination and erlotinib were those expected. Of 12 patients evaluable for response to erlotinib, all progressed except 3 patients (25%) who had stable disease for 3, 4, and 7 months, respectively. Median time to progression was 6.9 months for 13 patients without progressive disease after 6 chemotherapy cycles and treated with erlotinib. No correlation was identified between Epstein-Barr virus DNA plasma levels and clinical outcome. Maintenance or second-line therapy with erlotinib after chemotherapy was not effective in RM NPC. Historical comparison with patients treated with the same chemotherapy alone until progression suggests that it may be detrimental to stop chemotherapy after 6 cycles if disease did not progress.
    American journal of clinical oncology 02/2011; 35(3):255-60. · 2.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We examine the potential prognostic and predictive roles of EGFR variant III mutation, EGFR gene copy number (GCN), human papillomavirus (HPV) infection, c-MET and p16INK4A protein expression in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We analyzed the archival tumor specimens of 53 patients who were treated in 4 phase II trials for R/M SCCHN. Two trials involved the EGFR inhibitor erlotinib, and 2 trials involved non-EGFR targeted agents. EGFRvIII mutation was determined by quantitative RT-PCR, HPV DNA by Linear Array Genotyping, p16 and c-MET protein expression by immunohistochemistry, and EGFR GCN by FISH. EGFRvIII mutation, detected in 22 patients (42%), was associated with better disease control, but no difference was seen between erlotinib-treated versus non-erlotinib treated patients. EGFRvIII was not associated with TTP or OS. The presence of HPV DNA (38%), p16 immunostaining (32%), c-MET high expression (58%) and EGFR amplification (27%), were not associated with response, TTP or OS. EGFRvIII mutation, present in about 40% of SCCHN, appears to be an unexpected prognostic biomarker associated with better disease control in R/M SCCHN regardless of treatment with erlotinib. Larger prospective studies are required to validate its significance.
    Head & Neck Oncology 02/2011; 3:11. · 3.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To compare the patterns of care for elderly head-and-neck cancer patients with those of younger patients. A retrospective review was conducted of all new mucosal head-and-neck cancer referrals to radiation oncology between July 1, 2003 and December 31, 2007 at our institution. The clinical characteristics, treatment pattern, tolerance, and outcomes were compared between the elderly (aged ≥75 years) and younger (aged <75 years) cohorts. A total of 2,312 patients, including 452 (20%) elderly and 1,860 (80%) younger patients, were studied. The elderly patients were more likely to be women (36% vs. 27%, p <.01) and to have other malignancies (23% vs. 13%, p <.01), Stage I or II disease (38% vs. 32%, p <.01), and N0 status (56% vs. 42%, p <.01). Treatment was less often curative in intent (79% vs. 93%, p <.01). For the 1,487 patients who received definitive radiotherapy (RT), no differences were found between the elderly (n = 238) and younger (n = 1,249) patients in treatment interruption, completion, or treatment-related death. Within the subset of 760 patients who received intensified treatment (concurrent chemoradiotherapy or hyperfractionated accelerated RT), no difference was seen between the elderly (n = 46) and younger (n = 714) patients in treatment interruption, completion, or treatment-related death. After a median follow-up of 2.5 years, the 2-year cause-specific survival rate after definitive RT was 72% (range, 65-78%) for the elderly vs. 86% (range, 84-88%) for the younger patients (p <.01). Elderly head-and-neck cancer patients exhibited different clinical characteristics and experienced different patterns of care from younger patients. Although age itself was an adverse predictor of cause-specific survival, its effect was modest. Elderly patients selected for definitive RT or intensified RT showed no evidence of impaired treatment tolerance.
    International journal of radiation oncology, biology, physics 01/2011; 79(1):46-51. · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patient selection for phase I trials (PIT) in oncology is challenging. A typical inclusion criterion for PIT is 'life expectancy > 3 months', however the 90 day mortality (90DM) and overall survival (OS) of patients with advanced solid malignancies are difficult to predict. We analyzed 233 patients who were enrolled in PIT at Princess Margaret Hospital. We assessed the relationship between 17 clinical characteristics and 90DM using univariate and multivariate logistic regression analyses to create a risk score (PMHI). We also applied the Royal Marsden Hospital risk score (RMI), which consists of 3 markers (albumin < 35g/L, > 2 metastatic sites, LDH > ULN). Median age was 57 years (range 21-88). The 90DM rate was 14%; median OS was 320 days. Predictors of 90DM were albumin < 35g/L (OR = 8.2, p = 0.01), > 2 metastatic sites (OR = 2.6, p = 0.02), and ECOG > 0 (OR = 6.3, p = 0.001); all 3 factors constitute the PMHI. To predict 90DM, the PMHI performed better than the RMI (AUC = 0.78 vs 0.69). To predict OS, the RMI performed slightly better (RMI ≥ 2, HR = 2.2, p = 0.002 vs PMHI ≥ 2, HR = 1.6, p = 0.05). To predict 90DM, the PMHI is helpful. To predict OS, risk models should include ECOG > 0, > 2 metastatic sites, and LDH > ULN. Prospective validation of the PMHI is warranted.
    BMC Cancer 01/2011; 11:426. · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. Patients and Methods: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.
    Clinical Cancer Research 01/2011; 17(6):1582-90. · 7.84 Impact Factor

Publication Stats

1k Citations
383.57 Total Impact Points

Institutions

  • 2012
    • Austin Health
      Melbourne, Victoria, Australia
    • Sarah Cannon Research Institute
      Nashville, Tennessee, United States
  • 2006–2011
    • University Health Network
      • Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2010
    • McMaster University
      • Department of Clinical Epidemiology and Biostatistics
      Hamilton, Ontario, Canada
  • 2006–2010
    • University of Toronto
      Toronto, Ontario, Canada
  • 2005–2009
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
    • National Cancer Institute (USA)
      Maryland, United States
    • Hamilton Health Sciences
      Hamilton, Ontario, Canada
  • 2005–2008
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada