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Chi K.N.,University of British Columbia | Higano C.S.,Fred Hutchinson Cancer Research Center | Blumenstein B.,Trial Architecture Consulting | Ferrero J.-M.,Center Antoine Lacassagne | And 12 more authors.
The Lancet Oncology | Year: 2017

Background Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. Methods SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Findings Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9–24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5–24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79–1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. Interpretation Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. Funding OncoGenex Technologies. © 2017 Elsevier Ltd


PubMed | The Ottawa Hospital Cancer Center, British Columbia Cancer Agency, McGill University, Atlantic Clinical Cancer Research Unit and 13 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan.Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks. Randomization was stratified by prior bevacizumab therapy. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, safety, and PK.In total, 158 patients were randomized, but only 153 received treatment (49 on mFOLFOX-6, 52 on RAM+mFOLFOX-6, and 52 on ICR+mFOLFOX-6). Median PFS was 18.4 weeks on mFOLFOX-6, 21.4 weeks on RAM+mFOLFOX-6, and 15.9 weeks on ICR+mFOLFOX-6 (RAM+mFOLFOX-6 versus mFOLFOX-6, stratified hazard ratio [HR] 1.116 [95% CI 0.713-1.745], P = 0.623; ICR+mFOLFOX-6 versus mFOLFOX-6, stratified HR 1.603 [95% CI 1.011-2.543], P = 0.044). Median survival was 53.6 weeks on mFOLFOX-6, 41.7 weeks on RAM+mFOLFOX-6, and 42.0 weeks on ICR+mFOLFOX-6. The most frequent adverse events reported on the ramucirumab arm (RAM+mFOLFOX-6) were fatigue, nausea, and peripheral sensory neuropathy; those on the icrucumab arm (ICR+mFOLFOX-6) were fatigue, diarrhea, and peripheral sensory neuropathy. Grade 3 serious adverse events occurred at comparable frequency across arms.In this study population, combining ramucirumab or icrucumab with mFOLFOX-6 did not achieve the predetermined improvement in PFS.NCT01111604.


Freedman O.C.,Durham Regional Cancer Center | Fletcher G.G.,McMaster University | Gandhi S.,Sunnybrook Health Science Center | Mates M.,Kingston University | And 3 more authors.
Current Oncology | Year: 2015

Background Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question “What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?” The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and HER2 (human epidermal growth factor receptor 2)–targeted therapy. Methods For the systematic review, the literature in the medline and EMBASE databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were “breast cancer” and “systemic therapy” (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (RCTS), guidelines, systematic reviews, and meta-analyses. Results Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group encompassed many of the RCTS found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Summary The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 PEBC guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here; the evidence for chemotherapy and HER2-targeted treatment—and the final clinical practice recommendations—are presented separately in this supplement. © 2015 Multimed Inc.


Amir E.,Princess Margaret Hospital | Freedman O.,Durham Regional Cancer Center | Allen L.,Mount Sinai Hospital | Colgan T.,Mount Sinai Hospital | Clemons M.,The Ottawa Hospital Cancer Center
Breast | Year: 2010

At present, there is no gold standard test for the investigation of ovarian function in pre-menopausal breast cancer patients who develop amenorrhea after chemotherapy. Clinical, biochemical and biophysical investigations continue to be utilized in clinical practice, despite concerns regarding their predictive value for menopause. The resulting uncertainty about a woman's actual menopausal status has important consequences for patient management. These include choice of appropriate endocrine therapy, assessment of residual ovarian function and its effect on breast cancer recurrence, fertility issues and the prediction of the likelihood of conception. It is hoped that the development of novel surrogates may allow clinicians to more accurately assess menopausal status and thereby facilitate tailored and individualised therapy for this common group of patients. © 2010 Elsevier Ltd.


Knight G.,Grand River Regional Cancer Center | Earle C.C.,Odette Cancer Center | Cosby R.,McMaster University | Coburn N.,Odette Cancer Center | And 3 more authors.
Gastric Cancer | Year: 2013

Background: Gastric cancer is a global health problem accounting for 10% of all new cancer cases and 12% of all cancer deaths worldwide. Many clinical trials and meta-analyses have explored the value of neoadjuvant or adjuvant chemotherapy and radiation therapy in gastric cancer; however, these studies have produced conflicting results. The purpose of this guidance document was to determine whether patients with resectable gastric cancer should receive neoadjuvant or adjuvant therapy in addition to surgery. Outcomes of interest were overall survival, disease-free survival, and adverse events. Methods: A systematic review was undertaken to inform recommendations regarding neoadjuvant and adjuvant therapy in resectable gastric cancer in Ontario, Canada. MEDLINE and EMBASE databases, as well as American Society of Clinical Oncology (ASCO) annual meeting proceedings and American Society for Therapeutic Radiology and Oncology (ASTRO) proceedings were systematically searched from 2002 to 2010. Oral fluoropyrimidine trials were excluded owing to the unavailability of these agents in North America. Results: Overall, 22 randomized controlled trials (RCTs), 13 meta-analyses, and two secondary analyses were included. The systematic review informed the development of a clinical practice guideline with the following recommendations. Postoperative 5-fluorouracil-based chemoradiotherapy based on the Macdonald approach or perioperative ECF (epirubicin, cisplatin, fluorouracil) chemotherapy based on the Cunningham/MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) approach are both acceptable standards of care in North America. Choice of treatment should be made on a case-by-case basis. Adjuvant chemotherapy is a reasonable option for those patients for whom the Macdonald and MAGIC protocols are contraindicated. All patients with resectable gastric cancer should undergo a pretreatment multidisciplinary assessment to determine the best plan of care. Conclusions: Overall survival in patients with resectable gastric cancer is significantly improved with the use of either postoperative chemoradiation (Macdonald approach) or perioperative ECF (MAGIC protocol). © 2012 The International Gastric Cancer Association and The Japanese Gastric Cancer Association.


Holly R.,University of Toronto | Holly R.,Durham Regional Cancer Center | Morton G.C.,University of Toronto | Sankreacha R.,University of Toronto | And 5 more authors.
Brachytherapy | Year: 2011

Purpose: To determine the magnitude of catheter displacement between time of planning and time of treatment delivery for patients undergoing high dose-rate (HDR) brachytherapy, the dosimetric impact of catheter displacement, and the ability to improve dosimetry by catheter readjustment. Methods and Materials: Twenty consecutive patients receiving single fraction HDR brachytherapy underwent kilovoltage cone-beam CT in the treatment room before treatment. If catheter displacement was apparent, catheters were adjusted and imaging repeated. Both sets of kilovoltage cone-beam CT image sets were coregistered off-line with the CT data set used for planning with rigid fusion of anatomy based on implanted fiducials. Catheter displacement was measured on both sets of images and dosimetry calculated. Results: Mean internal displacement of catheters was 11mm. This would have resulted in a decrease in mean volume receiving 100% of prescription dose (V 100) from the planned 97.6% to 77.3% (p<0.001), a decrease of the mean dose to 90% of the prostate (D 90) from 110.5% to 72.9% (p<0.001), and increase in dose to 10% of urethra (urethra D 10) from 118% to 125% (p=0.0094). Each 1cm of catheter displacement resulted in a 20% decrease in V 100 and 36% decrease in D 90. Catheter readjustment resulted in a final treated mean V 100 of 90.2% and D 90 of 97.4%, both less than planned. Mean urethra D 10 remained higher at126% (p=0.0324). Conclusions: Significantly, internal displacement of HDR catheters commonly occurs between time of CT planning and treatment delivery, even when only a single fraction is used. The adverse effects on dosimetry can be partly corrected by readjustment of catheter position. © 2011 American Brachytherapy Society.


Escudier B.,Institute Gustave Roussy | Michaelson M.D.,Massachusetts General Hospital | Motzer R.J.,Sloan Kettering Cancer Center | Hutson T.E.,Sammons Cancer Center | And 12 more authors.
British Journal of Cancer | Year: 2014

Background:In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines.Methods:In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ≥median), and tumour burden (baseline sum of the longest diameter < vs ≥median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated.Results:Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy.Conclusions:AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC. © 2014 Cancer Research UK.


Gandhi S.,Sunnybrook Health Science Center | Fletcher G.G.,McMaster University | Eisen A.,Sunnybrook Health Science Center | Mates M.,Kingston University | And 3 more authors.
Current Oncology | Year: 2015

Background The Program in Evidence-Based Care (Kinston) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question “What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?” The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (HER2)– directed therapy. Methods For the systematic review, the MEDLINE and EMBASE databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were “breast cancer” and “systemic therapy” (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (RCTS), guidelines, systematic reviews, and meta-analyses. Results Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists’ Collaborative Group meta-analyses encompassed many of the RCTS found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite– based regimens (for example, cyclophosphamide– methotrexate–5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline–taxane-based polychemotherapy regimens are, overall, considered superior to earliergeneration regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work. Conclusions The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 PEBC guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and HER2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement. © 2015 Multimed Inc.


Mates M.,Kingston University | Fletcher G.G.,McMaster University | Freedman O.C.,Durham Regional Cancer Center | Eisen A.,Sunnybrook Health Science Center | And 3 more authors.
Current Oncology | Year: 2015

Background This systematic review addresses the question “What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (HER2)–positive breast cancer?” Methods The MEDLINE and EMBASE databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. Results Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (HERA, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (DFS) and overall survival (OS) to no trastuzumab; trastuzumab showed no benefit in one trial (PACS 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for DFS: one trial showed superiority (FINHER), one trial could not demonstrate noninferiority (PHARE), another trial showed equivalent results (E 2198), and one trial is still ongoing (PERSEPHONE). Longer trastuzumab duration (HERA: 2 years vs. 1 year) showed no improvement in DFS or OS and a higher rate of cardiac events. Newer HER2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (NeoALTTO, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-HER2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (ALTTO) or with placebo (TEACH), was not superior in DFS. The results of the completed aphinity trial, evaluating the role of dual HER2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (RESPECT) and in patients with low HER2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). Conclusions Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with HER2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population. © 2015 Multimed Inc.


Ocana A.,Albacete University Hospital | Ocana A.,University of Toronto | Freedman O.,Durham Regional Cancer Center | Amir E.,University of Toronto | And 2 more authors.
Cancer and Metastasis Reviews | Year: 2014

The potential for synergistic interactions between anticancer drugs has been used to justify combinations of agents in clinical trials. However, most combinations of targeted agents and chemotherapies have been tested in the clinic without previous systematic evaluation of their potential benefit. Preclinical studies may help in the identification of synergistic or antagonistic interactions. For antineoplastic therapies, these studies may reveal synergy or antagonism of the drug combinations. Synergy occurs when two agents given together produce higher antitumoral activity than the sum of each individual drug. This represents the ideal setting for the development of combinations of targeted agents and chemotherapies. On the other side, certain drug combinations have shown adverse results, indicative of an antagonistic effect. In this article, we review the preclinical molecular bases that justify approved combinations of targeted agents with chemotherapy including examples of synergistic and antagonistic combinations. We also discuss scenarios for rational associations of targeted agents based on biological data and propose strategies that may improve the success of combinations of anticancer agents. © 2013 Springer Science+Business Media New York.

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