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ABSTRACT: BACKGROUND: The central goal of cancer care is to improve patient outcomes through advancing medical knowledge. Therefore, participation in clinical trials is encouraged to demonstrate efficacy and understand toxicities of medical interventions. In the oncology setting, these interventions are also frequently accompanied by clinical care to maintain bone health throughout the course of disease. In this study we examined the use of a study screener to enhance accrual and highlight bone health issues in a tertiary referral cancer center. PATIENTS AND METHODS: A study screener was introduced into 4 separate genitourinary clinics in a tertiary referral cancer center. Over a retrospective and subsequent prospective 10-week period, clinical trial accrual and bone health parameters were measured. RESULTS: There were no statistically significant differences between the retrospective and prospective periods in probability of approaching a patient for clinical trials (P = .60), accrual rates (P = .80), or proportion of patients later found ineligible (P = .31). The difference in initiation of calcium and vitamin D between the retrospective and prospective patients was statistically significant (P < .0001) and the difference between cohorts for starting treatment with zoledronic acid or denosumab was statistically significant (P = .02) and approached significance for the prostate cancer patients (P = .12). CONCLUSION: This pilot study suggests that in an academic setting, there is appropriate physician awareness of clinical trial availability, however the use of medication to improve bone health is suboptimal, and requires further research to identify and remove barriers to appropriate use including additional evidence of beneficial toxicity-benefit and cost-benefit ratios.
Clinical Genitourinary Cancer 05/2013; · 2.61 Impact Factor
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ABSTRACT: PURPOSEUncertainty exists regarding benefits of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation (CAD) for treatment of prostate cancer. On the basis of a systematic review of evidence, our aim was to formulate a recommendation for either IAD or CAD to treat relapsing, locally advanced, or metastatic prostate cancer. METHODS
We searched literature published up to September 2012 from MEDLINE, EMBASE, the Cochrane Library, and major conference proceedings. We included randomized controlled trials comparing IAD and CAD if they reported overall survival (OS) or biochemical/radiologic time to disease progression.ResultsNine studies with 5,508 patients met our criteria. There were no significant differences in time-to-event outcomes between the groups in any studies. The pooled hazard ratio (HR) for OS was 1.02 (95% CI, 0.94 to 1.11) for IAD compared with CAD, and the HR for progression-free survival was 0.96 (95% CI, 0.76 to 1.20). More prostate cancer-related deaths with IAD tended to be balanced by more deaths not related to prostate cancer with CAD. Superiority of IAD for sexual function, physical activity, and general well-being was observed in some trials. Median cost savings with IAD was estimated to be 48%. CONCLUSION
There is fair evidence to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation. This recommendation is based on evidence against superiority of either strategy for time-to-event outcomes and substantial decrease with IAD in exposure to androgen deprivation, resulting in less cost, inconvenience, and potential toxicity.
Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
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Srikala S Sridhar,
Mary J Mackenzie,
Sebastien J Hotte,
Som D Mukherjee, Ian F Tannock,
Nevin Murray,
Christian Kollmannsberger,
Masoom A Haider,
Eric X Chen,
Robert Halford,
Lisa Wang,
S Percy Ivy,
Malcolm J Moore
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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; · 3.36 Impact Factor
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ABSTRACT: Poor distribution of anticancer drugs within solid tumors may limit their effectiveness. Here we characterize the distribution within solid tumors of biomarkers of drug effect. γH2aX, cleaved-caspase -3 or -6 and Ki-67 were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and immunohistochemistry. To validate their use we compared their time-dependent distribution with that of (i) fluorescent doxorubicin and (ii) a monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to quantify the distribution of docetaxel in relation to tumor blood vessels. Activation of γH2aX was evaluated following in vitro exposure of tumor cells to multiple drugs. Distributions of doxorubicin in MDA-MB-231 and MCF-7 xenografts and of melphalan-induced DNA adducts in MCF-7 & EMT-6 tumors decreased with distance from blood vessels, similar to the distributions of (i) γH2aX at 10 minutes, (ii) cleaved caspase-3 or -6 and (iii) change in Ki-67 at 24 hours following treatment. The distribution of these biomarkers following treatment with docetaxel also decreased with increasing distance from tumor blood vessels. Activation of γH2aX occurred within 1 hour after exposure to several drugs in culture. Multiple anticancer drugs show a decrease in activity with increasing distance from tumor blood vessels; poor drug distribution is an important cause of drug resistance. The above biomarkers may be employed in designing strategies to overcome therapeutic resistance by modifying or complementing the limited spatial distribution of drug activity in solid tumors.
Molecular Cancer Therapeutics 01/2013; · 5.23 Impact Factor
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ABSTRACT: The TAX 327 trial was pivotal in establishing docetaxel in castration refractory metastatic prostate cancer. Various commonly prescribed and over-the-counter co-administered medications are thought to exhibit anti-neoplastic properties and/or could potentially have pharmacokinectic interactions with docetaxel lessening the effectiveness of chemotherapy.
To examine the effect of on prostate cancer outcomes within this trial, we examined overall survival, prostate-specific antigen (PSA) response, percent PSA reduction, pain response and QOL responses for 14 families of medications including metformin, digoxin, verapamil, proton pump inhibitors, nitrates, statins, cox-2 inhibitors, warfarin, heparins, ascorbic acid, selenium, tocopherol, antidepressants and erythropoietin.
Our findings did not reveal any medication that had a significant additive or synergistic effect with docetaxel. We did note, however, that patients on digoxin or verapamil had poorer overall survival, possibly due to a trend of fewer cycles of administered chemotherapy being administered to the verapamil group, consistent with a pharmacokinectic interaction.
These data are only hypothesis-generating given the statistical limitations, but may form a basis for similar future analysis in other malignancies. The data suggest the need to be aware of pharmacokinectic interactions with medications that may interact with docetaxel.
Canadian Urological Association journal = Journal de l'Association des urologues du Canada 01/2013; 7(1-2):E74-81. · 1.24 Impact Factor
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ABSTRACT: Enhanced drug extrusion from cells due to the overexpression of the ATP-binding cassette (ABC) drug transporters inhibits the cytotoxic effects of structurally diverse and mechanistically unrelated anticancer agents and is a major cause of multidrug resistance (MDR) of human malignancies. Multiple compounds can suppress the activity of these efflux transporters and sensitize resistant tumor cells, but despite promising preclinical and early clinical data, they have yet to find a role in oncologic practice. Based on the knowledge of the structure, function, and distribution of MDR-related ABC transporters and the results of their preclinical and clinical evaluation, we discuss probable reasons why these inhibitors have not improved the outcome of therapy for cancer patients. We also outline new MDR-reversing strategies that directly target ABC transporters or circumvent relevant signaling pathways.
CANCER AND METASTASIS REVIEW 10/2012; · 9.35 Impact Factor
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ABSTRACT: Registration of new anticancer drugs is usually based on results of randomized controlled trials (RCTs) showing improved efficacy when compared with standard therapy. There is relatively less emphasis on toxicity. In our study, we analyze serious toxicities of newly approved anticancer drugs reported in pivotal RCTs used for drug registration.
We identified RCTs evaluating agents for the treatment of solid tumors approved by the US Food and Drug Administration between 2000 and 2010. Odds ratios (OR) and 95% CI were computed for three end points of safety and tolerability: treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events (AEs). These were then pooled in a meta-analysis. Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed.
Thirty-eight RCTs were analyzed. Compared with control groups, the odds of toxic death was greater for new agents (OR, 1.40; 95% CI, 1.15 to 1.70; P < .001) as were the odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22 to 1.45, P < .001). Grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35 to 1. 71; P < .001) were also more common with new agents, especially nonhematologic AEs such as diarrhea, skin reactions, and neuropathy. There were no significant correlations between safety end points and OS or PFS.
New anticancer agents that lead to improvements in time-to-event end points also increase morbidity and treatment-related mortality. The balance between efficacy and toxicity may be less favorable in clinical practice because of selection of fewer patients with good performance status and limited comorbidities. Patients' baseline health characteristics should be considered when choosing therapy.
Journal of Clinical Oncology 07/2012; 30(24):3012-9. · 18.37 Impact Factor
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ABSTRACT: OBJECTIVES:: Despite substantial variability in individual risk of skeletal complications, patients with metastatic bone disease are treated with bisphosphonates at the same dose and dosing interval. This study assessed the feasibility of conducting a randomized trial of less frequent bisphosphonate administration in women with breast cancer and low-risk bone metastases. METHODS:: A randomized feasibility study was conducted. Patients receiving intravenous bisphosphonates for ≥3 months and with low-risk baseline serum C-telopeptide (CTx) levels (<600 ng/L) were assigned to pamidronate 90 mg intravenously every 3 to 4 weeks (control) or every 12 weeks (de-escalated). CTx, bone alkaline phosphatase, and pain scores (Brief Pain Inventory and Functional Assessment of Cancer Therapy-Bone Pain) were collected every 12 weeks for 48 weeks. RESULTS:: Fifty-four patients were approached, 44 consented, and 38 were randomized. Median age was 55 (range, 29 to 77) and median baseline CTx was 163 ng/L (range, 10 to 526). Fourteen control group participants (73.7%) and 13 de-escalated group participants (68.4%) maintained CTx in the low-risk range (P=0.64). All patients changing to higher-risk range had progressive extraskeletal disease. Compared with the control group, there was a time-dependent increase in CTx in the de-escalated group. There were no significant differences in bone alkaline phosphatase, Brief Pain Inventory, or Functional Assessment of Cancer Therapy-Bone Pain. CONCLUSIONS:: It is feasible to conduct randomized trials of de-escalated pamidronate in low-risk women treated with ≥3 months of prior bisphosphonate therapy. De-escalated scheduling satisfied our predefined definition of noninferiority compared with 3- to 4-weekly treatment. Larger trials should assess whether increasing CTx levels with de-escalated therapy lead to higher rates of skeletal complications.
American journal of clinical oncology 07/2012; · 2.21 Impact Factor
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ABSTRACT: Surviving cells may repopulate tumors between courses of chemotherapy, thereby reducing the effectiveness of treatment. Using a novel quantitative method, we characterize the influence of the tumor microenvironment on repopulation of surviving cells in human tumor xenografts after paclitaxel treatment and evaluate the potential of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, to inhibit repopulation.
High-EGFR-expressing A431 xenografts and low-EGFR-expressing MCF-7 xenografts were treated with paclitaxel or gefitinib. Time-dependent changes in cell proliferation (Ki67) and apoptosis (cleaved caspase 3) in relation to total and functional tumor blood vessels (recognized by CD31 and a flow marker), and regions of hypoxia (recognized by EF5) were quantified using fluorescence microscopy.
Decrease in functional tumor vasculature and in cell proliferation and increase in apoptosis were observed in A431 xenografts after treatment with either paclitaxel or gefitinib. There was a rebound in functional vasculature and cell proliferation ≈ 12 days after treatment with paclitaxel, and repopulation was observed from tumor cells close to regions of hypoxia. Cell proliferation increased ≈ 5 days after the last dose of gefitinib. There were minimal effects of paclitaxel or gefitinib on cell proliferation, cell death, or tumor vasculature in MCF-7 xenografts.
Repopulation in A431 xenografts after treatment with paclitaxel was associated with changes in functional tumor vasculature. Gefitinib decreased cell proliferation in EGFR-overexpressing tumor xenografts, suggesting its potential to inhibit repopulation when used in sequence with chemotherapy.
Neoplasia (New York, N.Y.) 04/2012; 14(4):324-34. · 5.48 Impact Factor
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ABSTRACT: What's known on the subject? and What does the study add? To date, there has been limited impetus to examine the use of cytarabine in prostate cancer. We presented preliminary laboratory data to suggest its utility in the castration refractory prostate cancer (CRPC) population which, combined with a previous case report, suggested it may have hitherto unrecognized utility in this setting. Embedded in this study was peripheral blood sampling for TMPRSS2-ERG and SPINK1, two genes that are believed to define prostate cancer genotypes, to assess their utility as biomarkers This study suggests that at the delivered doses, cytarabine has limited efficacy and significant myelotoxicity suggesting, it does not have a role in the treatment of docetaxel-refractory CRPC. The presence of serum TMPRSS2-ERG and SPINK1 mRNA biomarkers recovered from blood suggest that their analysis is worthy of further study.
To run a phase II clinical trial of cytarabine in men with docetaxel-refractory, castration-resistant prostate cancer (CRPC), based on evidence that cytarabine might be effective in men with abnormalities of ERG oncogenes. To measure mRNA levels of prostate cancer-related genes in blood as biomarkers.
Ten of a planned maximum of 30 men received i.v. cytarabine at doses of 0.25-1g/m(2) at 21-day intervals. The primary endpoint was prostate-specific antigen (PSA) response. Archival tumour samples were assessed by fluorescence in-situ hybridization for TMPRSS2:ERG translocation, and by immunohistochemistry for serine peptidase inhibitor Kazal type 1 (SPINK1). Blood was processed for mRNA quantification of TMPRSS2:ERG (exon1:exon4), SPINK1 and PSA.
A PSA response was not observed in any patient. The trial was stopped at the end of stage 1 of a modified Flemming design. The median number of cycles administered was 3. Grade 3-4 haematological toxicity was common. Five patients were subsequently excluded from the study for toxicity, and five for disease progression. Analysis of whole blood mRNA for T1:E4 translocation in TMPRSS2:ERG was consistent with that in the tumour in 8/9 evaluable cases (one was concordantly positive, seven were concordantly negative), SPINK1 results were concordant in 9/10 cases (two were concordantly positive, seven were concordantly negative [P = 0.047 for the predictive value]). There was no correlation between PSA or SPINK protein and their respective mRNA copy levels in blood.
Cytarabine at the doses used is ineffective for men with CRPC. Blood mRNA levels of prostate cancer genes may represent a novel aspect of monitoring prostate cancer and have implications for the understanding of tumour-derived mRNA.
BJU International 02/2012; 110(6):840-5. · 2.84 Impact Factor
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Eitan Amir,
Naomi Miller,
William Geddie,
Orit Freedman,
Farrah Kassam,
Christine Simmons,
Maria Oldfield,
George Dranitsaris,
George Tomlinson,
Andreas Laupacis, Ian F Tannock,
Mark Clemons
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ABSTRACT: Decisions about treatment for women with metastatic breast cancer are usually based on the estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor 2 (HER2) status of the primary tumor. Retrospective data suggest that discordance between primary and metastatic lesions leads to detrimental outcome. This prospective study investigated receptor status of primary tumors and metastases in the same patient and assessed the impact of discordance on patient management and survival.
Biopsies of suspected metastases were analyzed for ER, PgR, and HER2. Primary tumors and metastases were analyzed using similar methodology. The treating oncologist indicated a treatment plan before and after biopsy to determine whether the result influenced management. Patients were followed up for progression or death.
Of 121 women undergoing biopsy, 80% could be analyzed for receptor status. Discordance in ER, PgR, and HER2 between the primary and the metastasis was 16%, 40%, and 10%, respectively. Biopsy led to a reported change of management in 14% of women (95% CI, 8.4% to 21.5%). Fine-needle aspiration and biopsy of bone led to reduced ability to analyze receptors. After a median follow-up of 12 months, there were no trends for an association between receptor discordance and either time to treatment failure or overall survival.
Biopsy of metastases is technically feasible. Clinicians alter immediate management in one of seven patients on the basis of results of the biopsy, and discordance is not then associated with detrimental effects on outcome. Tissue confirmation should be considered in women with breast cancer and suspected metastatic recurrence.
Journal of Clinical Oncology 11/2011; 30(6):587-92. · 18.37 Impact Factor
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ABSTRACT: It can be difficult to identify endpoints that accurately reflect patient benefit in metastatic solid tumors. Overall survival (OS) is the gold standard although progression-free survival (PFS) is sometimes used as a surrogate for OS. Statistical modelling has suggested that the association between OS and PFS becomes weaker in diseases with longer survival post-progression (SPP). To evaluate these statistical hypotheses we determined the relationship between PFS and OS in control and experimental arms of randomised trials conducted in the last 10years, which have led to drug approval. Our data confirm that PFS is a poor surrogate for OS when SPP is long, but it is a better surrogate where SPP is short. In cancers with short SPP designing trials to show OS benefit is feasible and, therefore, remains the preferred approach. In tumours with long SPP, PFS is not clinically meaningful unless it is also associated with improvement in patient reported outcomes such as quality of life. The oncology community should consider the further development and validation of composite endpoints including patient reported outcomes and PFS across different disease sites. Such endpoints have been successfully used in cancer trials in the past. With improvements in therapy and prolonged survival of patients with many cancers, and with increasing pressure from healthcare payers to prove that treatment leads to patient benefit, the choice of optimal endpoints for clinical trials is increasingly important. Composite measures comprising patient reported outcomes and intermediate endpoints such as PFS may be the solution and should be investigated further.
European journal of cancer (Oxford, England: 1990) 11/2011; 48(3):385-8. · 4.12 Impact Factor
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ABSTRACT: OBJECTIVES: The TAX 327 trial was pivotal in establishing docetaxel in castration refractory metastatic prostate cancer. Various commonly prescribed and over-the-counter co-administered medications are thought to exhibit anti-neoplastic properties and/or could potentially have pharmacokinectic interactions with docetaxel lessening the effectiveness of chemotherapy. METHODS: To examine the effect of on prostate cancer outcomes within this trial, we examined overall survival, prostate-specific antigen (PSA) response, percent PSA reduction, pain response and QOL responses for 14 families of medications including metformin, digoxin, verapamil, proton pump inhibitors, nitrates, statins, cox-2 inhibitors, warfarin, heparins, ascorbic acid, selenium, tocopherol, antidepressants and erythropoietin. RESULTS: Our findings did not reveal any medication that had a significant additive or synergistic effect with docetaxel. We did note, however, that patients on digoxin or verapamil had poorer overall survival, possibly due to a trend of fewer cycles of administered chemotherapy being administered to the verapamil group, consistent with a pharmacokinectic interaction. CONCLUSIONS: These data are only hypothesis-generating given the statistical limitations, but may form a basis for similar future analysis in other malignancies. The data suggest the need to be aware of pharmacokinectic interactions with medications that may interact with docetaxel.
Canadian Urological Association journal = Journal de l'Association des urologues du Canada 11/2011; · 1.24 Impact Factor
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ABSTRACT: Phase III clinical trials and Food and Drug Administration (FDA) regulatory decisions are critical for success of new drugs and can influence a company's market valuation. Knowledge of trial results before they are made public (ie, "inside information") can affect the price of a drug company's stock. We examined the stock prices of companies before and after public announcements regarding experimental anticancer drugs owned by the companies.
We identified drugs that were undergoing evaluation in phase III trials or for regulatory approval by the US FDA from January 2000 to January 2009. Stock prices of companies that owned such drugs were analyzed for 120 trading days before and after the first public announcement of 1) results of clinical trials with positive and negative outcomes and 2) positive and negative regulatory decisions. All statistical tests were two-sided.
We identified public announcements from 23 positive trials and 36 negative trials and from 41 positive and nine negative FDA regulatory decisions. The mean stock price for the 120 trading days before a phase III clinical trial announcement increased by 13.7% (95% confidence interval = -2.2% to 29.6%) for companies that reported positive trials and decreased by 0.7% (95% confidence interval = -13.8% to 12.3%) for companies that reported negative trials (P = .09). In a post hoc analysis comparing the stock price averaged over 60 trading days before and after day -60 relative to the clinical trial announcement, the mean stock price increased by 9.4% for companies that reported positive trials and decreased by 4.5% for companies that reported negative trials (P = .03). Changes in company stock prices before FDA regulatory decisions did not differ statistically between companies with positive decision and companies with negative decisions.
Trends in company stock prices before the first public announcement differ for companies that report positive vs negative trials. This finding has important legal and ethical implications for investigators, drug companies, and the investment industry.
CancerSpectrum Knowledge Environment 09/2011; 103(20):1507-12. · 14.07 Impact Factor
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ABSTRACT: Pneumocystis jirovecii (formerly carinii) pneumonia (PJP) is an opportunistic infection well-recognized in patients with profound T cell immunodeficiency. It is much less common in patients with solid tumors unless they have other major predisposing factors such as prolonged treatment with corticosteroids or T4 lymphocyte counts of less than 200 cells/mm(3). We present a previously unreported case of fatal PJP in a breast cancer patient with bone metastases who was receiving a first-line treatment with weekly paclitaxel, trastuzumab, and dexamethasone as premedication for paclitaxel. She had received eight doses of paclitaxel at 80 mg/m(2), trastuzumab 2 mg/m(2), and dexamethasone 10 mg for just over 7 weeks when she was diagnosed with PJP. While the patient's granulocyte counts were normal throughout her treatment, the total lymphocyte counts reached the nadir of 400 cells/mm(3) a few days after the eighth dose of chemotherapy - around the time of PJP diagnosis. Both dexamethasone and the total lymphocyte nadir predisposed this patient to PJP.
Journal of Oncology Pharmacy Practice 09/2011; 18(2):293-5.
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ABSTRACT: Most men with metastatic prostate cancer respond to various types of androgen ablation but progress to castration-resistant disease. The TAX 327 and Southwest Oncology Group (SWOG) 99-16 clinical trials established docetaxel-based chemotherapy as preferred first-line treatment for most men with symptomatic metastatic castration-resistant prostate cancer (mCRPC). However, only about half receive benefit from docetaxel, and those who respond initially progress and eventually die of (or with) mCRPC. Both cellular mechanisms and the tumor microenvironment are implicated in the development of resistance to docetaxel. New agents are being evaluated for men with mCRPC, either as first-line treatment in combination with docetaxel, or in men progressing during or after treatment with docetaxel. Thus far, agents evaluated in phase III trials in combination with docetaxel have not improved outcome, including the vaccine GVAX, high-dose vitamin D (DN-101), and the antiangiogenic agent bevacizumab. In contrast, cabazitaxel, a taxane that is not cross-resistant to docetaxel, substantially improved the outcome of men progressing during or after treatment with docetaxel-based chemotherapy when compared with mitoxantrone and prednisone. However, translation of benefit of cabazitaxel demonstrated in the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer) trial into general oncologic practice will be challenging because this agent may cause serious toxicity. With the approval of less toxic hormonal agents (eg, abiraterone acetate) in the setting of docetaxel-resistant mCRPC, clinicians will have an opportunity to balance benefits and harms of new agents in an individual patient and may be able to use different agents in sequence.
Journal of Clinical Oncology 08/2011; 29(27):3686-94. · 18.37 Impact Factor
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ABSTRACT: Many phase III trials presented at annual meetings of the American Society of Clinical Oncology (ASCO) remain unpublished. The results of these unpublished trials, if more generally known, might have an impact on clinical practice.
Abstracts of large phase III trials evaluating systemic cancer treatment were identified from conference proceedings of the 1989 to 2003 ASCO annual meetings. PubMed, Medline, and Embase were searched for corresponding publications. A compendium of unpublished phase III trials was assembled. Clinical significance of nonpublication was determined by disease site-specific oncology experts from two academic cancer centers in Canada.
A total of 709 phase III trials were identified of which 66 (9.3%) remain without a subsequent publication at a minimum of 6.5 years of follow-up and 94 (13%) were published after a delay of ≥ 5 years from their initial presentation. Of the unpublished trials, 48% were presented as oral sessions at an ASCO meeting, and 71% of the abstracts reported negative results. The experts judged that 70% of the unpublished trials addressed an important question and 59% might have had clinical impact if their results had been published promptly.
A substantial number of cancer clinical trials with potential influence on clinical practice remain unpublished and many other trials are published after a substantial delay. Nonpublication of clinical trials breaks an implicit contract with participants, institutional review boards, and sponsors.
Journal of Clinical Oncology 08/2011; 29(23):3133-9. · 18.37 Impact Factor
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ABSTRACT: The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear.
A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS).
An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles.
Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion.
The number of men receiving 10 cycles was similar (p=0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9-95.4%) and 74.6% (CI, 67.2-80.5%) in TAX-327, compared with 92.8% (CI, 85.5-96.5) and 63.4% (CI, 51.8-72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply.
A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.
European urology 06/2011; 61(2):363-9. · 7.67 Impact Factor
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ABSTRACT: The relationship between market pricing of new anticancer drugs and the magnitude of clinical benefit caused by them has not been reported.
Randomized clinical trials (RCTs) that evaluated approved new agents for solid tumors by the U.S. Food and Drug administration since the year 2000 were assessed. Hazard ratios (HRs) and 95% CIs were extracted for time-to-event end points described for each RCT. HRs were pooled for three groups: agents directed against a specific molecular target, for which the target population is selected by a biomarker (group A); less specific biologic targeted agents (group B); and chemotherapeutic agents (group C). Monthly market prices of these different drugs were compared.
For overall survival (OS), the pooled HR was 0.69 (95% CI, 0.59 to 0.81) for group A (six drugs, six trials); it was 0.78 (95% CI, 0.74 to 0.83) for group B (seven drugs, 14 trials); and it was 0.84 (95% CI, 0.79 to 0.90) for group C (eight drugs, 12 trials). For progression-free survival (PFS), the pooled HR was 0.42 (95% CI, 0.36 to 0.49) for group A (six drugs, seven trials); it was 0.57 (95% CI, 0.51 to 0.64) for group B (seven drugs, 14 trials); and it was 0.75 (95% CI, 0.66 to 0.85) for group C (six drugs, 10 trials). Tests for heterogeneity between subgroups were highly significant for PFS (P < .001) and OS (P = .02). The median monthly prices for standard doses of drugs were $5375 for group A, $5644 for group B, and $6584 for group C (P = .87).
New agents with specific molecular targets are clinically the most beneficial, but their monthly market prices are not significantly different from those of other anticancer agents.
Journal of Clinical Oncology 06/2011; 29(18):2543-9. · 18.37 Impact Factor
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ABSTRACT: Non-invasive in vivo imaging of drug distribution enables real-time monitoring and prediction of therapeutic responses to treatment. We have developed a thermosensitive liposomal formulation (HaT: Hyperthermia-activated-cytoToxic) consisting of DPPC and Brij78, a formulation that enhanced drug delivery compared to the lyso-lipid temperature sensitive liposomes (LTSL). Here we report the development of a multifunctional HaT liposome co-encapsulating Gd-DTPA (an MRI probe) and doxorubicin (DOX), which simultaneously releases and reports on drug delivery in a locally heated tumor. The temperature-dependent release profiles of DOX from HaT were closely related to the change in the MR T(1) relaxation time, in which DOX was 100% released at 40-42 °C in 3 min, accompanied by a 60% reduction in T(1). By T(1) relaxometry analysis, no Gd-DTPA leakage was detected in 30 min at 30-37 °C. In the in vivo study, DOX uptake in the tumor was quantitatively correlated with T(1) response (R(2) = 0.98) and the patterns of the T(1) image and the intratumoral DOX uptake were matched, in which both signals were predominantly detected in the highly perfused tumor periphery. Finally, the extent of T(1) relaxation enhancement in the heated tumor successfully predicted the antitumor efficacy in a standard pharmacological response model (R(2) = 0.98).
Biomaterials 06/2011; 32(27):6570-8. · 7.40 Impact Factor
