[Show abstract][Hide abstract] ABSTRACT: It is estimated that millions of North Americans would qualify for lung cancer screening and that billions of dollars of national health expenditures would be required to support population-based computed tomography lung cancer screening programs. The decision to implement such programs should be informed by data on resource utilization and costs.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2014; · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Major issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up.
We analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer.
In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set.
Predictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. (Funded by the Terry Fox Research Institute and others; ClinicalTrials.gov number, NCT00751660.).
New England Journal of Medicine 09/2013; 369(10):910-9. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The epidermal growth factor receptor (EGFR) pathway is important in tumor growth, survival, and metastasis and is now the target of several therapeutic agents.
This paper seeks to review the EGFR pathway, the study and use of EGFR-directed agents in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC), and related new drug development.
PubMed was searched for English-language articles by MeSH and title terms of EGFR published from 2006 to 2013, using the limits of clinical trials as well as reviews. Reference lists were assessed for relevant articles, and guidelines were searched. Clinicaltrials.gov and meeting abstracts were queried for investigational agents. Eligible papers included those concerning EGFR biology, NSCLC or CRC studies involving EGFR-directed agents, and/or investigational drugs targeting EGFR and/or associated pathways.
The activity of oral tyrosine kinase inhibitors (TKIs) against EGFR has improved survival in NSCLC, and these agents particularly effective in cancers with an EGFR mutation. Resistance to TKIs is most commonly related to a second, T790M, mutation, or to MET amplification, with newer agents directed against these mechanisms. Conversely, in CRC, TKIs have been ineffective, whereas monoclonal antibodies have improved survival. Both primary and secondary KRAS mutations in CRC abrogate mAb effectiveness. Several targets, including MET, BRAF, and PI3K, may serve useful in combination with anti-EGFR drugs.
Exploitation of EGFR-directed therapies has offered improvement in survival and quality of life in NSCLC and CRC. New therapies directed at EGFR may offer further improvements. However, resistance mechanisms suggest that combination therapies or multitargeted agents will be crucial in making significant future advances.
[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with brain metastases from non-small-cell lung cancer (nsclc) is poor. However, some reports suggest that patients with brain metastases at the time of initial diagnosis have a more favourable survival than do patients with advanced nsclc without brain metastases.
In a retrospective cohort of all new lung cancer patients seen at a Canadian tertiary centre between July 2005 and June 2007, we examined survival after a diagnosis of brain metastases for patients with brain metastases at initial diagnosis and patients who developed brain metastases later in their illness.
During the 2-year period, 91 of 878 patients (10.4%) developed brain metastases. Median age in this cohort was 64 years. In 45, brain metastases were present at initial diagnosis, and in 46, brain metastases developed later in the course of the illness. Median survival in the entire cohort was 7.8 months. Survival after the diagnosis of brain metastases was similar for patients with brain metastases at diagnosis and later in the illness (4.8 months vs. 3.7 months, p = 0.53). As a result, patients who developed brain metastases later in their illness had a longer overall survival than did patients with brain metastases at diagnosis (9.8 months vs. 4.8 months). Among patients who received chemotherapy, the survival of patients with brain metastases at diagnosis was still poor (6.2 months).
Our data show limited survival in patients with brain metastases from nsclc. Careful patient selection for more aggressive treatment approaches is necessary.
Current Oncology 08/2013; 20(4):e300-6. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recruitment to clinical trials remains poor, and patient knowledge of clinical trials is one barrier to recruitment. To identify knowledge deficits, we conducted and compared surveys measuring actual patient knowledge and clinical trialist priorities for patient knowledge.
Consenting patients at a tertiary cancer centre answered a survey that included 2 opinion questions about their own knowledge and willingness to join a trial, and22 knowledge questions. Clinical researchers at the centre were asked 13 questions about the importance of various trials factors.
Of 126 patients surveyed, 16% had joined a clinical trial, and 42% had a secondary school education or less. The mean correct response rate on the knowledge questions was 58%. Higher rates of correct responses were associated with lower age (p = 0.05), greater education (p = 0.006), prior trial participation (p < 0.001), agreement or strong agreement with perceived understanding of trials (p < 0.001), and willingness to join a clinical trial (p = 0.002). Trialists valued an understanding of the rationale for clinical trials and of randomization, placebo, and patient protection, but those particular topics were poorly understood by patients.
Patient knowledge about clinical trials is poor, including knowledge of several concepts ranked important by clinical trialists. The findings suggest that when developing education interventions, emphasis should be placed on the topics most directly related to patient care, and factors such as age and education level should be considered.
Current Oncology 06/2013; 20(3):e193-205. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: The aim of this study was to develop a decision support tool to assess the potential benefits and costs of new healthcare interventions. Methods: The Canadian Partnership Against Cancer (CPAC) commissioned the development of a Cancer Risk Management Model (CRMM)-a computer microsimulation model that simulates individual lives one at a time, from birth to death, taking account of Canadian demographic and labor force characteristics, risk factor exposures, and health histories. Information from all the simulated lives is combined to produce aggregate measures of health outcomes for the population or for particular subpopulations. Results: The CRMM can project the population health and economic impacts of cancer control programs in Canada and the impacts of major risk factors, cancer prevention, and screening programs and new cancer treatments on population health and costs to the healthcare system. It estimates both the direct costs of medical care, as well as lost earnings and impacts on tax revenues. The lung and colorectal modules are available through the CPAC Web site (www.cancerview.ca/cancerrriskmanagement) to registered users where structured scenarios can be explored for their projected impacts. Advanced users will be able to specify new scenarios or change existing modules by varying input parameters or by accessing open source code. Model development is now being extended to cervical and breast cancers.
International Journal of Technology Assessment in Health Care 03/2013; · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SUMMARY Background: Rising healthcare costs will increasingly require policy-makers to make difficult decisions based on the potential benefits and costs of new healthcare interventions. The Canadian Partnership Against Cancer commissioned the development of the Cancer Risk Management Model as a tool to aid such decisions. This computer microsimulation model projects future population health and economic impacts of cancer control programs in Canada. Lung cancer was the first simulation module to be developed and was selected because of the magnitude of lung cancer burden in Canada and recent screening and treatment interventions that require policy decisions. Methods: The model simulates one individual life at a time, from birth to death, taking account of Canadian demographic and labor force characteristics, risk factor exposures and health histories, and then combines this information from all the simulated lives to produce aggregate measures of health outcomes for the Canadian population as a whole or for particular subpopulations. The direct costs of medical care can be estimated, as well as lost earnings and impacts on tax revenues. Results: The lung module is available through the Canadian Partnership Against Cancer website to registered users where structured scenarios can be explored for their projected impacts. Conclusion: The Cancer Risk Management Model for lung cancer is now available via the internet to assist healthcare policy analysts, researchers and decision-makers in their work.
[Show abstract][Hide abstract] ABSTRACT: Response rate (RR), the most common early means of assessing oncology drugs, is not suitable as the sole endpoint for phase II trials of drugs which induce disease stability but not regression. Time to progression (TTP) may be more sensitive to such agents, but induces recruitment delays in multistage studies. Early progressive disease (EPD) is the earliest signal of time to progression, but is less intuitive to investigators, To study drugs with unknown anti-tumour effect, we designed the Combination Stopping Rule (CSR), which allows investigators to establish a hypothesis using RR and TTP, while the program also employs early progressive disease (EPD) to assess for drug inactivity during the first stage of study accrual.
A computer program was created to generate stopping rules based on specified error rates, trial size, and RR and median TTP of interest and disinterest for a two-stage phase II trial. Rules were generated for stage II such that the null hypothesis (H(nul)) was rejected if either RR or TTP met desired thresholds, and accepted if both did not. Assuming an exponential distribution for progression, EPD thresholds were determined based on specified TTP values. Stopping rules were generated for stage I such that Hnul was accepted and the study stopped if both RR and EPD were unacceptable.
Patient thresholds were generated for RR, median TTP, and EPD which achieved specified error rates and which allowed early stopping based on RR and EPD. For smaller proportional differences between interesting and disinteresting values of RR or TTP, larger trials are required to maintain alpha error, and early stopping is more common with a larger first stage.
Stopping rules are provided for phase II trials for drugs which have either a desirable RR or TTP. In addition, early stopping can be achieved using RR and EPD.
BMC Medical Research Methodology 12/2011; 11:164. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive malignancy that most often presents at an advanced, incurable stage. After the failure of standard first-line cisplatin/antifolate chemotherapy, there is no accepted treatment. The vascular endothelial growth factor pathway may be a relevant therapeutic target in MPM.
This open-labeled phase II trial evaluated single-agent sunitinib, an inhibitor of multiple receptor tyrosine kinases including the vascular endothelial growth factor receptors, given at 50 mg daily orally for 4 weeks followed by a 2-week rest, in patients with advanced MPM. Two cohorts were studied: cohort 1, in which patients had previously received cisplatin-based chemotherapy, and cohort 2, consisting of previously untreated patients. A two-stage design was used for both cohorts; the primary outcome was objective response rate as determined by the RECIST criteria modified for MPM. Secondary outcomes included rates and duration of disease control, progression-free survival and overall survival, and safety and tolerability.
A total of 35 eligible patients were enrolled (17 to cohort 1 and 18 to cohort 2). Neither cohort met the criteria for continuing to the second stage of accrual; only one objective response, confirmed by independent review, was observed in a previously untreated patient. Median progression-free and overall survivals were 2.8 and 8.3 months in cohort 1, and 2.7 and 6.7 months in cohort 2, respectively. Observed toxicity was within that expected for sunitinib.
Sunitinib, similar to other angiogenesis inhibitors, has limited activity in MPM. Future trials of angiogenesis inhibitors given as single agents in unselected patients with MPM are not warranted.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2011; 6(11):1950-4. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dyspnea is common in lung cancer and may be partially attributable to increased ventilatory drive due to muscle weakness. The sympathetic component of this pathway might be mitigated by β-blockers.
A retrospective review of new patients with stage III-IV non-small lung cancer or any small cell lung cancer was undertaken to assess the impact of β-blocker use on dyspnea and fatigue. Data were abstracted for clinical characteristics, β-blocker use, and pre-treatment Edmonton Symptom Assessment System dyspnea and fatigue scores.
Of 348 patients assessed, 202 met eligibility criteria. The median age was 67, 55.4% were female, 18.8% had chronic obstructive pulmonary disease (COPD), and 5.9% had active coronary artery disease. Over 60% of patients scored 4/10 or higher on their dyspnea and fatigue scores. While dyspnea and fatigue were moderately associated, no association was found between β-blocker use and either symptom. Recorded dosages of β-blockers were low. COPD was associated with dyspnea and fatigue, while anemia was associated with fatigue.
Dyspnea and fatigue are prevalent and increased in the presence of COPD and anemia. No association between β-blocker use and dyspnea or fatigue scores was observed. This may be attributable to inadequate dosing or to retrospective bias.
Palliative Medicine 08/2011; 26(6):797-803. · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Response rate (RR) alone may be insensitive to drug activity in phase II trials. Early progressive disease (EPD) could improve sensitivity as well as increase stage I stopping rates. This study compares the previously developed dual endpoint stopping rule (DESR), which incorporates both RR and EPD into a two-stage, phase II trial, with rules using only RR.
Stopping rules according to the DESR were compared with studies conducted under the Fleming (16 trials) or Gehan (23 trials) designs. The RR hypothesis for the DESR was consistent with the comparison studies (ralt = 0.2, rnul = 0.05). Two parameter sets were used for EPD rates of interest and disinterest respectively (epdalt, epdnul): (0.4, 0.6) and (0.3, 0.5).
Compared with Fleming, the DESR was more likely to allow stage two of accrual and to reject the null hypothesis (Hnul) after stage two, with rejection being more common with EPD parameters (0.4, 0.6) than (0.3, 0.5). Compared with Gehan, both DESR parameter sets accepted Hnul in 15 trials after stage I compared with 8 trials by Gehan, with consistent conclusions in all 23 trials after stage II.
The DESR may reject Hnul when EPD rates alone are low, and thereby may improve phase II trial sensitivity to active, cytostatic drugs having limited response rates. Conversely, the DESR may invoke early stopping when response rates are low and EPD rates are high, thus shortening trials when drug activity is unlikely. EPD parameters should be chosen specific to each trial.
BMC Medical Research Methodology 06/2011; 11:95. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The number of cancer-related clinical trials has been rapidly increasing over the past decade. Along with this increase, oncology studies stopped early for benefit or harm have also been more common. Clinicians treating cancer patients often are faced with the challenge of having to decide whether or not to incorporate information from these new studies into their daily clinical practice. This review article explains the role of the Data and Safety Monitoring Committee in stopping trials early; provides examples of oncology trials stopped early; and reviews some of the controversies and statistical concepts associated with early stopping rules. In addition, a simple and practical approach to interpreting the findings of trials that are stopped early is provided to assist clinicians in deciding how to incorporate information from these studies into their daily practice.
European journal of cancer (Oxford, England: 1990) 06/2011; 47(16):2381-6. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium.
Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival.
Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months.
Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.
Investigational New Drugs 04/2011; 30(3):1203-7. · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-small cell lung cancer (NSCLC) frequently presents at an incurable stage, and a majority of patients will be considered for palliative chemotherapy at some point in their disease. This article reviews the growing evidence for first-line treatment in NSCLC.
Studies of first-line chemotherapy regimens including new agents (docetaxel, gemcitabine, irinotecan, paclitaxel, pemetrexed, and vinorelbine) and targeted agents (bevacizumab, erlotinib, and gefitinib) were identified through Medline, Embase, the Cochrane databases, and web sites of guideline organizations.
Two evidence-based guidelines, 10 systematic reviews, and forty-six randomized trials were eligible for inclusion. Randomized studies suggest that platinum-based doublets (platinum plus new agent) are the standard of care for first-line systemic therapy. No one new agent is clearly superior for use in combination with a platinum agent. The survival advantage of platinum-based doublets over nonplatinum combinations or older combinations is modest. The addition of bevacizumab to carboplatin and paclitaxel has shown improved survival, although multiple exclusion criteria limit the applicability of these data to a subset of patients. In patients at least 70 years of age or with Eastern Collaborative Oncology Group performance status 2, a new single agent is an alternative. Treatment beyond four to six cycles impedes quality of life without prolonging life. Emerging data suggest that the choice of chemotherapy agent may be influenced by histologic subtype.
In NSCLC, a combination of a platinum agent plus a new agent continues to be the standard of care. As differences between regimens are small, toxicity and patient preference should help guide regimen choice.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2010; 5(2):260-74. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phase II oncology trials traditionally have used response rate (RR) as the primary end point, but newer targeted agents require the consideration of alternative end points. High rates of early progressive disease (EPD) suggest inadequate drug activity and may be useful in the early stopping of trials. This study used a simulation to define a set of rules to assess a combined end point of RR and EPD.
The simulation assumed a two-stage trial with a specified alpha error and power. It randomly generated the true response rate, r, of the agent under study and its true rate of early progressive disease, epd, for each run of the simulation. Two pairs of parameters were specified: (r(nul), epd(nul)) and (r(alt), epd(alt)). A drug was considered uninteresting for further development if r was less than or equal to r(nul) and epd was greater than or equal to epd(nul) (ie, the null hypothesis) and interesting for further development if r was greater than or equal to r(alt) or epd was less than or equal to epd(alt) (ie, the alternate hypotheses). Thresholds for the required number of patients with responses, n(r) and EPD, n(p), were generated for each set of parameters.
Thresholds for n(r) and n(p) that satisfied the specified error rates were generated. There was at least an 89% likelihood that a study would be stopped at the first stage of accrual if r and epd were uninteresting.
The simulation was able to establish stopping rules by combining the RR and the EPD that achieved the desired error rates. High rates of early stopping suggest that this design could shorten phase II trials of inactive agents.
Journal of Clinical Oncology 09/2008; 26(22):3715-20. · 18.04 Impact Factor