David E. Dawe

Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: A systematic review and meta-analysis

In stage III non-small cell lung cancer (NSCLC), the standard of care in young patients is chemoradiotherapy, but this standard is not as clearly established for older patients. We aimed to determine the efficacy and harm associated with chemoradiotherapy versus radiotherapy alone in elderly (≥70 years), stage III NSCLC patients through a systematic review. We conducted a systematic search of MEDLINE, EMBASE, CENTRAL, Scopus, Web of Science and conference proceedings. Two reviewers independently identified randomized trials (RCT) and extracted trial-level data. Risk of bias was assessed and meta-analysis was conducted looking at survival and safety outcomes. We included three trials and subgroup data from one systematic review. The three RCTs had high risk of bias due primarily to lack of blinding and the systematic review scored 4/11 using the AMSTAR tool. Overall survival (HR 0.66, 95% CI 0.53-0.82; I2 0%; 3 trials; 407 patients) and progression-free survival (HR 0.67, 95% CI 0.53-0.85; I2 0%; 2 trials; 327 patients) both favored chemoradiotherapy. Risk of treatment-related death and grade 3+ pneumonitis were not significantly different between groups. In conclusion, treatment of stage III NSCLC patients 70 years or older with chemotherapy and radiotherapy is associated with improved overall survival compared to radiotherapy alone. With the exception of increased hematological toxicity, CRT appears to be tolerable in fit elderly patients and represents a reasonable standard of clinical care.

The Treatment of Metastatic Non-Small Cell Lung Cancer in the Elderly: An Evidence-Based Approach

An increasing proportion of patients with advanced non-small cell lung cancer (NSCLC) are over 70 years old, raising unique challenges for treatment decision-making. While these patients are underrepresented in clinical trials, there is an emerging body of evidence associated with this group. The lesson of comprehensive geriatric assessment is that chronological age does not always correlate with physiological age and a variety of important co-morbidities and geriatric syndromes can go undetected in a typical history and physical. These co-morbidities and expected physiologic changes due to aging complicate decision-making around appropriate treatment. This review discusses geriatric assessment in elderly cancer patients and evaluates the current evidence for chemotherapy and targeted therapy for patients with advanced NSCLC aged ≥70 years.

Brain metastases in non-small-cell lung cancer.

Up to 50% of patients with advanced non-small-cell lung cancer will develop brain metastases at some point during their illness. These metastases cause a substantial burden in morbidity and mortality, which has motivated research and technological innovation over the past 2 decades. Surgery, radiotherapy, and systemic therapies have each played a role in management, with the greatest changes associated with the popularization of stereotactic radiosurgery. In this review, the evidence behind each modality used in the management of brain metastases for non-small-cell lung cancer patients is examined, and recommendations regarding the current standards of care and areas of future research focus are provided.

Geographical Variation and Factors Associated with Non-Small Cell Lung Cancer in Manitoba

Background Screening decreases non-small cell lung cancer (NSCLC) deaths and is recommended by the Canadian Task Force on Preventive Health Care. We investigated risk factor prevalence and NSCLC incidence at a small region level to inform resource allocation for lung cancer screening. Methods NSCLC diagnoses were obtained from the Canadian Cancer Registry, then geocoded to 283 small geographic areas (SGAs) in Manitoba. Sociodemographic characteristics of SGAs were obtained from the 2006 Canadian Census and Canadian Community Health Survey. Geographical variation was modelled using a Bayesian spatial Poisson model. Results NSCLC incidence in SGAs ranged from 1 to 343 cases per 100,000 population per year. The highest incidence rates were in the Southeastern, Southwestern, and Central regions of Manitoba, while most of Northern Manitoba had lower rates. Poisson regression suggested areas with higher proportions of Aboriginal people and higher average income, and immigrants had lower NSCLC incidence whereas areas with higher proportions of smokers had higher incidence. Conclusion On an SGA level, smoking rates remain the most significant factor driving NSCLC incidence. Socioeconomic status and proportions of immigrants or Aboriginal peoples independently impact NSCLC rates. We have identified SGAs in Manitoba to target in policy and infrastructure planning for lung cancer screening.

Challenges in Implementing Personalized Medicine for Lung Cancer within a National Healthcare System

The traditional approach to the treatment of advanced non-small cell lung cancer (NSCLC) relied on the uniform use of cytotoxic chemotherapy. Over the last eight years, this paradigm of care has been shifting towards the use of molecularly targeted agents. Epidermal growth factor receptor (EGFR) mutations have emerged as an important biomarker for these targeted agents and multiple studies have shown that tyrosine kinase inhibitors (TKI) that inhibit EGFR are superior to traditional chemotherapy in patients possessing an EGFR mutation. Nationally funded health care systems face a number of challenges in implementing these targeted therapies, most related to the need to test for biomarkers that predict likelihood of benefiting from the drug. These obstacles include the challenge of getting a large enough tissue sample, workload of involved specialists, reliability of subtyping in NSCLC, differences in biomarker tests, and the disconnect between the funding of drugs and the related biomarker test. In order to improve patient outcomes, in a national healthcare system, there is a need for governments to accept the changing paradigm, invest in technology and build capacity for molecular testing to facilitate the implementation of improved patient care.

Methods to improve the estimation of time-to-event outcomes when data is de-identified: Methods to improve estimation of de-identified time-to-event data

Technological advancements in recent years have sparked the use of large databases for research. The availability of these large databases has administered a need for anonymization and de-identification techniques, prior to publishing the data. This de-identification alters the data, which in turn can impact the results derived post de-identification and potentially lead to false conclusions. The objective of this study is to investigate if alterations to a de-identified time-to-event data set may improve the accuracy of the estimates. In this data set, a missing time bias was present among censored patients as a means to preserve patient confidentiality. This study investigates five methods intended to reduce the bias of time-to-event estimates. A simulation study was conducted to evaluate the effectiveness of each method in reducing bias. In situations where there was a large number of censored patients, the results of the simulation showed that Method 4 yielded the most accurate estimates. This method adjusted the survival times of censored patients by adding a random uniform component such that the modified survival time would occur within the final year of the study. Alternatively, when there was only a small number of censored patients, the method that did not alter the de-identified data set (Method 1) provided the most accurate estimates.

The effect of age on referral to an oncologist and receipt of chemotherapy among small cell lung cancer patients in Ontario, Canada

OBJECTIVES Small cell lung cancer (SCLC) represents a significant health burden. There is a lack of information about patterns of referral and treatment for older patients over 70 years of age, in comparison to younger patients with SCLC. MATERIALS AND METHODS A population-based retrospective cohort study was undertaken for patients identified from the Ontario Cancer Registry, Canada. All cases of SCLC diagnosed between January 2000 and December 2010 were eligible. Data were extracted on demographic variables, treatment and outcome. Logistic regression analyses were performed as appropriate. RESULTS There were 9021 cases of SCLC, with 10% of cases ≥80 years and 32.8% of cases aged 70-79 years and 53% male. Older patients were less likely to be referred to a medical oncologist (OR 0.28 ≥ 80 years, OR 0.60 70-79 years) and less likely to receive chemotherapy (OR 0.19 ≥ 80 years, OR 0.52 70-79 years) compared to younger patients (age < 70). Age, higher comorbidity and prior receipt of home care services were all prognostic of a lower likelihood of referral to a medical oncologist and receipt of chemotherapy. Local health region was also prognostic for referral to and receipt of chemotherapy, indicative of significant regional variation in practice. CONCLUSIONS Older patients with SCLC are less likely to be referred for treatment and less likely to receive treatment than younger patients. These data represent a potential gap in knowledge translation.

The use of chemotherapy in older patients with stage II and III colon cancer: Variation by age and era of diagnosis

OBJECTIVE We aim to examine the use and outcomes of adjuvant chemotherapy in older patients with stage II and III colon cancer. MATERIAL AND METHODS Using data from the SEER-Medicare database, we analyzed patients aged 66 or greater, diagnosed with stage II or III colon cancer between 1991 and 2007 who received surgery. Using Medicare claims, receipt of adjuvant chemotherapy was identified, and compared between age bands. Logistic regression modeling was performed to assess predictors of receipt of adjuvant chemotherapy, and Cox proportional hazards modeling was performed to assess predictors of mortality. RESULTS A total of 31,990 patients were identified: 4371 aged 66-69, 6922 (70-74), 7673 (75-79), 6807 (80-84), 4266 (85-89), and 1951 (90+). The percent starting adjuvant chemotherapy decreased by age cohort: 57% in the 66-69 age cohort, 48% (70-74), 37% (75-79), 20% (80-84), 8% (85-89), and 1% (90+). Multivariable analysis showed that stage III disease was the strongest positive predictor of chemotherapy receipt. Multivariable analysis for mortality risk showed that adjuvant chemotherapy was associated with an increased risk of mortality in stage II patients. Adjuvant chemotherapy was associated with a decreased risk of mortality in stage III patients, consistent across all age cohorts, with the exception of the 90+ cohort, in whom adjuvant chemotherapy appeared to increase mortality. CONCLUSION Administration of adjuvant chemotherapy for stage II/III colon cancer decreases with advancing age, but improved outcomes are seen in stage III patients under 90 years of age.

The effect of statin use on the incidence of prostate cancer: A population-based nested case-control study: Effect of statin use on incidence of prostate cancer

Preclinical studies suggest statins may help prevent prostate cancer (PC), but epidemiologic results are mixed. Many epidemiological studies have relatively short prediagnosis drug exposure data, which may miss some statin use. We completed a nested case–control study investigating the impact of statin use on PC diagnosis and clinically significant PC using data from men aged ≥40 years in the Canadian province of Saskatchewan between 1990 and 2010. Drug exposure histories were derived from a population‐based prescription drug database. We used conditional logistic regression to model use of statins as a class and stratified analyses for groups defined by lipophilicity. Clinically significant PC was defined as Gleason score 8–10 OR stage C or D or III or IV at diagnosis. 12,745 cases of PC were risk‐set matched on age and geographic location to 50,979 controls. Greater than 90% of subjects had prediagnosis drug exposure histories >15 years. 2,064 (16.2%) cases and 7,956 (15.6%) controls were dispensed one or more statin prescriptions. In multivariable models, ever prescription of statins was not associated with PC diagnosis (OR 0.97; 95% CI 0.90–1.05). Neither lipophilic statins (OR 0.96, 95% CI 0.88–1.04) nor hydrophilic statins (OR 1.06, 95% CI 0.95–1.20) impacted PC diagnosis. There was no effect of the dose or duration of statin use. Diagnosis of clinically significant PC decreased with statin use (OR 0.84, 95% CI 0.73–0.97). Statin use is not associated with overall PC risk, regardless of duration or dose of statin exposure. Statin use is associated with a decreased risk of clinically significant PC.

Androgen Receptor and Ki67 Expression and Survival Outcomes in Non-small Cell Lung Cancer

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30–3.70; HR 1.92, 95% CI 1.07–3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31–4.36 for AR− Ki67+ vs HR 1.54, 95% CI 0.44–5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.