253 research outputs found
Less surgery, improved survival from stage IV colorectal cancer?
No full textLetter to the EditorTimothy J. Price, Niall Tebbutt, Amanda R. Townsen
Fc-gamma receptor polymorphisms, cetuximab therapy, and survival in the NCIC CTG CO.17 trial of colorectal cancer
No full textAbstract not availableGeoffrey Liu, Dongsheng Tu, Marcia Lewis, Dangxiao Cheng, Leslie A. Sullivan, Zhuo Chen, Eric Morgen, John Simes, Timothy J. Price, Niall C. Tebbutt, Jeremy D. Shapiro, G. Mark Jeffery, J. Daniel Mellor, Thomas Mikeska, Shakeel Virk, Lois E. Shepherd, Derek J. Jonker, Christopher J. O'Callaghan, John R. Zalcberg, Christos S. Karapetis, and Alexander Dobrovi
Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer
No full textPurpose: To compare protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin (MMC) in patients with advanced pancreatic cancer in a multicenter, prospectively randomized study.Patients and Methods: Two hundred eight patients were randomized to PVI 5-FU (300 mg/m2/d for a maximum of 24 weeks) or PVI 5-FU plus MMC (7 mg/m2 every 6 weeks for four courses). The major end points were tumor response, survival, toxicity, and quality of life (QOL).Results: The two treatment groups were balanced for baseline demographic factors, and 62% had metastatic disease. The overall response rate was 8.4% (95% confidence interval [CI]) 3.2% to 13.7% for patients treated with PVI 5-FU alone compared with 17.6%; 95% CI 10.3% to 25.1% for PVI 5-FU plus MMC (P = .04). Median failure-free survival was 2.8 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = .14). Median survival was 5.1 months for PVI 5-FU and 6.5 months for PVI 5-FU plus MMC (P = .34). Toxicities in both arms were mild. There was an increased incidence of neutropenia in the 5-FU plus MMC arm (P < .01), although no differences in infection were seen. No patients developed hemolytic uremic syndrome. Global QOL improved significantly after 24 weeks of treatment compared with baseline for patients receiving 5-FU plus MMC, although there was no statistically significant difference in QOL between arms.Conclusion: PVI 5-FU plus MMC resulted in a superior response rate in comparison with PVI 5-FU alone in advanced pancreatic cancer, but this did not translate into a survival advantage. These results emphasize the importance of chemotherapy in this setting and the continuing value of the fluoropyrimidines in pancreatic cancer
Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study
No full textBackground: This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. Methods: Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6). Results: Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. Conclusions: Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.Dusan Kotasek, Niall Tebbutt, Jayesh Desai, Stephen Welch, Lillian L Siu, Sheryl McCoy, Yu-Nien Sun, Jessica Johnson, Adeboye H Adewoye and Timothy Pric
Update on optimal treatment for metastatic colorectal cancer from the ACTG/AGITG expert meeting: ECCO 2015
No full textThe treatment of metastatic CRC (mCRC) has evolved over the last 20 years, from fluoropyrimidines alone to combination chemotherapy and new biologic agents. Median overall survival is now over 24 months for RAS mutated (MT) patients and over 30 months for RAS wild-type (WT) patients. However, there are subgroups of patients with BRAF V600E MT CRC who have a significantly poorer outlook. Newer treatment options are also being explored in select subgroups of patients (anti-HER 2 in HER2 positive mCRC and immunotherapy in patients with defective mismatch repair (dMMR)). The best use of these systemic treatment options, as well as surgery in well-selected patients requires careful consideration of predictive biomarkers and importantly, the optimal sequence in which therapies should be given to derive maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, USA, The Netherlands and Germany met during ECCO 2015 in Vienna to review current practice.Timothy J Price, Subotheni Thavaneswaran, Matthew Burge, Eva Segelov,
Daniel G Haller, Cornelis JA Punt, Dirk Arnold, Christos S Karapetis, Niall C
Tebbutt, Nick Pavlakis, Peter Gibbs and Jeremy D Shapir
Can we accurately report PTEN status in advanced colorectal cancer?
No full textBACKGROUND: Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results. METHODS: We assessed loss of PTEN function in 51 colorectal cancer specimens using Taqman® copy number variation (CNV) and IHC. Two blinded pathologists performed independent IHC assessment on each specimen and inter-observer variability of IHC assessment and concordance of IHC versus Taqman® CNV was assessed. RESULTS: Concordance between pathologists (PTEN loss vs no loss) on IHC assessment was 37/51 (73%). In specimens with concordant IHC assessment, concordance between IHC and Taqman® copy number in PTEN loss assessment was 25/37 (68%). CONCLUSION: Assessment PTEN loss in colorectal cancer is limited by the inter-observer variability of IHC, and discordance of CNV with loss of protein expression. An understanding of the genetic mechanisms of PTEN loss and implementation of improved and standardized methodologies of PTEN assessment are required to clarify the role of PTEN as a biomarker in colorectal cancer.Christopher Hocking, Jennifer E Hardingham, Vy Broadbridge, Joe Wrin, Amanda R Townsend, Niall Tebbutt, John Cooper, Andrew Ruszkiewicz, Chee Lee, and Timothy J Pric
Overview of biomarkers in metastatic colorectal cancer: tumour, blood and patient-related factors
No full textDuring the last 20 years there have been major therapeutic developments in colorectal cancer (CRC) with the introduction of multiple novel therapeutic agents into routine clinical practice. This has improved survival in both the adjuvant and advanced disease settings. However, improvements have come with substantial increases in expense to the community and potential toxicity to the patient. There has been substantial research to identify tumour factors in CRC that predict treatment response and survival outcomes. This research has identified clinically useful predictive biomarkers to aid clinical decision making, such as the presence or absence of KRAS gene mutations which can determine the benefit of using epidermal growth factor receptor (EGFR) inhibiting antibodies. However, less attention has been paid to the identification and impact of predictive patient-derived factors such as age, gender and the presence of comorbid conditions or evidence of a systemic inflammatory response. In this article, the current concepts of tumour and patient-related predictive factors in CRC management are reviewed.Stephen J. Clarke, Christos S. Karapetis, Peter Gibbs, Nick Pavlakis, Jayesh Desai, Michael Michael, Niall C. Tebbutt, Tim J. Price and Josep Taberner
Current opinion on optimal treatment choices in first-line therapy for advanced or metastatic colorectal cancer: Report from the Adelaide Colorectal Tumour Group Meeting; Stockholm, Sweden; September 2008
No full textThe medical treatment of patients with metastatic colorectal cancer (mCRC) has evolved greatly in the past 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of the targeted monoclonal antibodies bevacizumab, cetuximab, and panitumumab in the treatment of patients with mCRC is now well-established, but the optimal timing of their use requires careful consideration in order to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and epidermal growth factor receptor-targeted biologic agents (cetuximab and panitumumab) in the treatment of patients with mCRC. This article reviews the evidence in support of modern treatments for mCRC and the decision making behind the treatment choices as well as their benefits and toxicities. An evidence-based algorithm is proposed that incorporates the use of these biologic agents early in the treatment of patients with initially nonresectable mCRC based on clearly defined tumor-related factors dependent on the immediate treatment goal. Real-world application of this algorithm is dependent on an individual countries' approval of access to new biologic agents.Timothy J. Price, Niall C. Tebbutt, Christos S. Karapetis, Eva Segelov, Nick Pavlakis, David Cunningham, Alberto F. Sobrero, Daniel G. Halle and Jeremy D. Shapir
Current opinion on optimal treatment for colorectal cancer
No full textThe medical treatment of colorectal cancer (CRC) has evolved greatly in the last 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Advances in adjuvant therapy have been limited to the addition of oxaliplatin and the substitution of oral fluoropyrimidine (e.g., capecitabine) for intravenous 5-fluorouracil with no evidence for improved outcome with biological agents. Clinical benefit from the use of the targeted monoclonal antibodies, bevacizumab, cetuximab and panitumumab, in the treatment of metastatic CRC is now well established, but the optimal timing of their use requires careful consideration to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC. This article reviews the evidence in support of modern treatments for CRC and the decision-making behind the treatment choices, their benefits and toxicities.Timothy J Price, Eva Segelov, Matthew Burge, Daniel G Haller, Stephen P Ackland, Niall C Tebbutt, Christos S Karapetis, Nick Pavlakis, Alberto F Sobrero, David Cunningham and Jeremy D Shapir
Does the chemotherapy backbone impact on the efficacy of targeted agents in metastatic colorectal cancer? A systematic review and meta-analysis of the literature
No full textIMPORTANCE The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. OBJECTIVE To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts. STUDY SELECTION Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations. DATA EXTRACTION AND SYNTHESIS Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity. RESULTS EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81–1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69–0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87–1.09) and PFS HR 0.92 (95% CI 0.83–1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72–0.94) compared to capecitabine (HR 1.09; 95% CI 0.91–1.30) and bolus 5FU (HR 1.07; 95% CI 0.79–1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002). CONCLUSION AND RELEVANCE The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.David L. Chan, Nick Pavlakis, Jeremy Shapiro, Timothy J. Price, Christos S. Karapetis, Niall C. Tebbutt, Eva Segelo
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