Reduction In Cancer-specific Mortality Research Articles

The impact of intraductal carcinoma of the prostate on the site and timing of recurrence and cancer‐specific survival

To investigate the effect of intraductal carcinoma of the prostate (IDC-P) in radical prostatectomy (RP) specimens in the context of the site of recurrence, time to recurrence, and cancer-specific survival in two academic cohorts of locally, regionally, or distantly recurrent prostate cancer. Our cohort included men enrolled into two academic tissue repositories from 1993 to 2011, who were treated with first-line RP who later experienced local recurrence, regional recurrence, or distant metastasis (together termed clinical recurrence, CR). RP material was reviewed to identify IDC-P and to update grading to current standards. The primary endpoint was the initial location of CR. Secondary endpoints included time to CR and cancer-specific survival. Pearson's chi-square, Welch's t-test, Mann-Whitney U test and Fisher's exact test were performed for univariate analyses. Multinomial logistic regression was used for multivariate analyses. Cancer-specific survival was analyzed with the generalized Wilcoxon test and Cox regression. Eighty-five patients with CR were included in the analysis. IDC-P was present in 78.5% of patients from Center 1 and 70.0% from Center 2 (P = 0.547). IDC-P was independently associated with distant metastasis at initial CR (multivariate odds ratio = 6.27, P = 0.015). IDC-P status did not affect time to recurrence; median survival without recurrence was at 53 months for IDC-P(+) and at 50 months for IDC-P(-) (P = 0.441). Distant metastases at the initial CR event had a 36% reduction of cancer-specific survival compared to local recurrences (P = 0.007). Additionally, prostatic-bed radiotherapy (adjuvant or salvage for biochemical recurrence before distant metastasis) was associated with a 25% reduction in cancer-specific mortality compared to no radiotherapy (P = 0.023). Similar reduction in cancer-specific mortality was observed in the subgroup of patients with distant metastasis and IDC-P when treated with radiotherapy (29%, P = 0.050). In our cohort, presence of IDC-P was an independent factor for distant metastasis at initial CR, but did not have a significant impact on time to CR. Furthermore, metastatic patients showed statistically reduced cancer-specific mortality when treated with radiotherapy. This reduction in cancer-specific mortality was also identified in patients with IDC-P. Future large scale validation studies should take into account the presence of IDC-P and confirm its impact on disease progression.

The Effect of Metformin on Mortality Among Diabetic Cancer Patients: A Systematic Review and Meta-analysis.

BackgroundMost data suggest that cancer patients with diabetes have worse outcomes, which may be reversed with metformin. Metformin might modulate the clinical outcomes of diabetic cancer patients. We performed a systematic review and meta-analysis based on published studies over the past five years to summarize the effects of metformin on diabetic cancer patients.MethodsWe systematically searched for studies that were published over the past five years. Then, we evaluated these studies for inclusion and extracted the relevant data. The summary risk estimates for the association between metformin treatment and all-cause mortality (ACM) and cancer-specific mortality (CSM) were analyzed using random or fixed-effects models. Stratified analyses by cancer site and country were also conducted.ResultsBased on the 42 studies included in our analysis (37 015 diabetic cancer patients), we found a significant benefit associated with metformin treatment on survival corresponding to 27% and 26% reductions in ACM (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.68 to 0.79, P < .001) and CSM (HR = 0.74, 95% CI = 0.64 to 0.86, P < .001), respectively. The ACM rates for colorectal cancer, endometrial cancer, breast cancer, prostate cancer, and ovarian cancer showed significant benefits associated with metformin treatment in our stratified analyses by cancer site. Stratified analyses by cancer site also showed a significant reduction in CSM for breast cancer. This association between metformin treatment and reduced CSM for diabetic breast cancer patients was also observed in our country subgroup analyses.ConclusionsWe found an association between metformin exposure and reduced ACM and CSM in diabetic patients with cancer. Our findings suggest that metformin treatment could be an effective treatment option for diabetic cancer patients.

Pre-diagnostic statin use, lymph node status and mortality in women with stages I\u2013III breast cancer

Background:Recent meta-analyses suggest that pre-diagnostic statin use is associated with reduced breast cancer-specific mortality. Studies have shown that high breast tumour expression of the statin target (3-hydroxy-3-methylglutaryl coenzyme-A reductase) is associated with lymph-node negative cancer. Therefore, we examined the association between pre-diagnostic statin use and; lymph node status, breast cancer-specific and all-cause mortality.Methods:Women with stages I–III breast cancer were identified from the National Cancer Registry of Ireland (N=6314). Pre-diagnostic statin users were identified from linked prescription claims data (N=2082). Relative risks were estimated for associations between pre-diagnostic statin use and lymph node status. Hazard ratios (HR) were estimated for associations between pre-diagnostic statin use and breast cancer-specific and all-cause mortality.Results:Pre-diagnostic statin use was not associated with lymph node negative status at diagnosis. In multivariate analyses, pre-diagnostic statin use was associated with reduced all-cause (HR 0.78 95% confidence interval (CI) 0.69, 0.89) and breast cancer-specific mortality (HR 0.81 95% CI 0.68, 0.96). This reduction in cancer-specific mortality was greatest in statin-users with oestrogen (ER) receptor-positive tumours (HR 0.69 95% CI 0.55, 0.85).Conclusion:Patients with pre-diagnostic statin exposure had a significant reduction in breast cancer-specific mortality, which was even more pronounced in women with ER+ tumours.

Statin use after esophageal cancer diagnosis and survival: A population based cohort study

BackgroundA recent epidemiological study of esophageal cancer patients concluded statin use post-diagnosis was associated with large (38%) and significant reductions in cancer-specific mortality. We investigated statin use and cancer-specific mortality in a large population-based cohort of esophageal cancer patients. MethodsNewly diagnosed [2009–2012] esophageal cancer patients were identified from the Scottish Cancer Registry and linked with the Prescribing Information System and Scotland Death Records (to January 2015). Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by post-diagnostic statin use (using a 6 month lag to reduce reverse causation) and to adjust these HRs for potential confounders. Results1921 esophageal cancer patients were included in the main analysis, of whom 651 (34%) used statins after diagnosis. There was little evidence of a reduction in esophageal cancer-specific mortality in statin users compared with non-users after diagnosis (adjusted HR=0.93, 95% CI, 0.81, 1.07) and no dose response associations were seen. However, statin users compared with non-users in the year before diagnosis had a weak reduction in esophageal cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.79, 0.99). ConclusionsIn this large population-based esophageal cancer cohort, there was little evidence of a reduction in esophageal cancer-specific mortality with statin use after diagnosis.

Indolence versus aggression in non-small cell lung cancer: defining heterogeneity to impact clinical outcomes

While important new findings in the treatment of advanced non-small cell lung cancer (NSCLC) have led to significant progress, it has been incremental. In the past 30 years the five-year survival rate for lung cancer has increased by only 5% (1). Despite the major survival advantage conferred to patients with localized disease, only 17% of NSCLC diagnoses were made at stage I–II as of 2014 (2). For this reason, considerable efforts have historically focused on improving early detection through development of screening programs. Following the publication of the NCI-funded National Lung Screening Trial (NLST), the Centers for Medicare and Medicaid Services (CMS) added annual low-dose computed tomography (LDCT) as a preventive service benefit in 2015. This has led to a rapid expansion of lung cancer screening programs. The NLST demonstrated a 20% relative reduction in cancer-specific mortality with annual LDCT screening in high-risk patients and resulted in a much improved probability of early stage disease at diagnosis (3). Specifically, amongst patients with screen-detected lung cancers, approximately 70% were stage I–II at diagnosis and over 50% were stage IA (3). The observation that screen-detected lung cancer is more likely to be at an early, localized stage is consistent with the findings of other large-scale prospective screening studies. Thus, the implementation of lung cancer screening programs is expected to lead to a stepwise increase in early stage diagnoses.

Cost-effectiveness of the Norwegian breast cancer screening program.

The Norwegian Breast Cancer Screening Programme (NBCSP) has a nation-wide coverage since 2005. All women aged 50-69 years are invited biennially for mammography screening. We evaluated breast cancer mortality reduction and performed a cost-effectiveness analysis, using our microsimulation model, calibrated to most recent data. The microsimulation model allows for the comparison of mortality and costs between a (hypothetical) situation without screening and a situation with screening. Breast cancer incidence in Norway had a steep increase in the early 1990s. We calibrated the model to simulate this increase and included recent costs for screening, diagnosis and treatment of breast cancer and travel and productivity loss. We estimate a 16% breast cancer mortality reduction for a cohort of women, invited to screening, followed over their complete lifetime. Cost-effectiveness is estimated at NOK 112,162 per QALY gained, when taking only direct medical costs into account (the cost of the buses, examinations, and invitations). We used a 3.5% annual discount rate. Cost-effectiveness estimates are substantially below the threshold of NOK 1,926,366 as recommended by the WHO guidelines. For the Norwegian population, which has been gradually exposed to screening, breast cancer mortality reduction for women exposed to screening is increasing and is estimated to rise to ∼30% in 2020 for women aged 55-80 years. The NBCSP is a highly cost-effective measure to reduce breast cancer specific mortality. We estimate a breast cancer specific mortality reduction of 16-30%, at the cost of 112,162 NOK per QALY gained.

Statin use and survival in colorectal cancer: Results from a population-based cohort study and an updated systematic review and meta-analysis

BackgroundThe aim of this study was to investigate the association between statin use and survival in a population-based colorectal cancer (CRC) cohort and perform an updated meta-analysis to quantify the magnitude of any association. MethodsA cohort of 8391 patients with newly diagnosed Dukes’ A-C CRC (2009–2012) was identified from the Scottish Cancer Registry. This cohort was linked to the Prescribing Information System and the National Records of Scotland Death Records (until January 2015) to identify 1064 colorectal cancer-specific deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by statin use were calculated using time dependent Cox regression models. The systematic review included relevant studies published before January 2016. Meta-analysis techniques were used to derive combined HRs for associations between statin use and cancer-specific and overall mortality. ResultsIn the Scottish cohort, statin use before diagnosis (HR=0.84, 95% CI 0.75–0.94), but not after (HR=0.90, 95% CI 0.77–1.05), was associated with significantly improved cancer-specific mortality. The systematic review identified 15 relevant studies. In the meta-analysis, there was consistent (I2=0%,heterogeneity P=0.57) evidence of a reduction in cancer-specific mortality with statin use before diagnosis in 6 studies (n=86,622, pooled HR=0.82, 95% CI 0.79–0.86) but this association was less apparent and more heterogeneous (I2=67%,heterogeneity P=0.03) with statin use after diagnosis in 4 studies (n=19,152, pooled HR=0.84, 95% CI 0.68–1.04). ConclusionIn a Scottish CRC cohort and updated meta-analysis there was some evidence that statin use was associated with improved survival. However, these associations were weak in magnitude and, particularly for post-diagnosis use, varied markedly between studies.

Physical Activity and Cancer Outcomes: A Precision Medicine Approach.

There is increasing interest in applying a precision medicine approach to understanding exercise as a potential treatment for cancer. We aimed to inform this new approach by appraising epidemiologic literature relating postdiagnosis physical activity to cancer outcomes overall and by molecular/genetic subgroups. Across 26 studies of breast, colorectal, and prostate cancer patients, a 37% reduction was seen in risk of cancer-specific mortality, comparing the most versus the least active patients (pooled relative risk = 0.63; 95% confidence interval: 0.54-0.73). Risks of recurrence or recurrence/cancer-specific death (combined outcome) were also reduced based on fewer studies. We identified ten studies of associations between physical activity and cancer outcomes by molecular or genetic markers. Two studies showed statistically significant risk reductions in breast cancer mortality/recurrence for the most (versus least) physically active estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) patients, while others showed risk reductions among ER-PR- and triple-negative patients. In colorectal cancer, four studies showed statistically significant risk reductions in cancer-specific mortality for patients with high (versus low) physical activity and P21 expression, P27 expression, nuclear CTNNB1-, PTGS2 (COX-2)+, or IRS1 low/negative status. One prostate cancer study showed effect modification by Gleason score. As a means to enhance this evidence, future observational studies are needed that will measure physical activity objectively before and after diagnosis, use standardized definitions for outcomes, control for competing risks, assess nonlinear dose-response relations, and consider reverse causality. Ultimately, randomized controlled trials with clinical cancer outcomes and a correlative component will provide the best evidence of causality, relating exercise to cancer outcomes, overall and for molecular and genetic subgroups. Clin Cancer Res; 22(19); 4766-75. ©2016 AACR.

Combined Biomarker and Computed Tomography Screening Strategies for Lung Cancer: Projections of Health and Economic Tradeoffs in the US Population.

Background: Lung cancer screening with computed tomography (CT) of individuals who meet certain age and smoking history criteria is the current standard-of-care. Methods: Using a published simulation model, we compared outcomes associated with seven biomarker + CT screening strategies to CT screening alone using Centers for Medicare & Medicaid Services eligibility criteria. We assumed that the biomarker had conditionally independent performance; was used for first-line screening in some, or all, individuals screened; and could be extended to Centers for Medicare & Medicaid Services–ineligible smokers. Strategies differed by inclusion criteria (e.g., pack-years) and proportion of individuals for whom CT remained the first-line test. Each model run simulated a combined cohort of one million men and one million women born in 1950. Primary outcomes were cancer-specific mortality reduction and screening costs; biomarker costs were measured relative to CT. Efficiency frontiers identified optimal health and economic tradeoffs. Sensitivity analysis evaluated the stability of results. Results: Standard-of-care screening yielded an 8.3% cancer-specific mortality reduction in the simulated US population (screened + unscreened individuals). For a biomarker test with 75% sensitivity and 95% specificity, mortality reductions across biomarker + CT strategies ranged from 7.0% to 23.9%. If the biomarker’s cost was >0.86× that of CT, standard-of-care screening remained on the efficiency frontier, indicating that health and economic tradeoffs were equally (or more) efficient relative to all biomarker + CT strategies. Biomarker + CT strategy costs were principally driven by biomarker specificity; mortality reduction was driven by sensitivity. Conclusion: Combined biomarker + CT strategies have the potential to improve future lung cancer screening effectiveness in the United States and achieve economic efficiency that is greater than the current standard-of-care.

Lung cancer screening in high-risk subjects: early detection with LDCT and risk stratification using miRNA-based blood test

Lung cancer still remains a high mortality disease in the face of developments in diagnostic and therapeutic methods that occurred in the last 20 years. The analysis of the experiences from the first studies - in which chest X-ray (CXR) was adopted, associated or not with sputum cytology - has failed to show a reduction in lung cancer specific mortality. Subsequent screening studies that have introduced the use of low-dose computed tomography (LDCT) have revealed a large number of early-stage lung cancers, thus potentially curable; however, this has not allowed us to demonstrate a decrease in lung cancer-specific mortality. With the results of the American study National Lung ScreeningTrial (NLST), published in 2011, for the first time a lung cancer-specific mortality reduction by 20% thanks to the use of LDCT compared to RXT, was highlighted. However, a false discovery rate of 96.4% was also described with an overdiagnosis that can be up to 78.9% for bronchioalveolar lung cancer. Due to the high sensitivity of LDCT, able to identify a non-calcified pulmonary nodule in one subject on two, it becomes necessary to avail instruments to more accurately identify suspicious nodules. Until some time ago, the possible use of lung tumour markers was not viable in view of the poor organ specificity. The study and development was, then, pushed to organ- and tissue-specific markers such as microRNA (miRNA), noncoding RNA sequences involved in many processes and expression of oncogenic activity of the microenvironment. The use of biomarkers such as circulating miRNA implemented in LDCT screening has highlighted a reduction of 5 times for the rate of false positives, going from 19.4% to 3.7%, with a sensitivity of 87%, a specificity of 81%, and a negative predictive value of 99%. The need to appropriately use the available resources commensurate with the disease to treat will push more and more towards the implementation of LDCT biomarkers based screenings, stable and easily reproducible, as circulating miRNAs, obviating to problems such as false positives, unnecessary procedures of invasive surgery for benign lesions, and optimizing the cost benefit ratios.The development of new specific biomarkers appears to offer new promising prospects.

Collaborative Modeling of the Benefits and Harms Associated With Different U.S. Breast Cancer Screening Strategies.

Controversy persists about optimal mammography screening strategies. To evaluate screening outcomes, taking into account advances in mammography and treatment of breast cancer. Collaboration of 6 simulation models using national data on incidence, digital mammography performance, treatment effects, and other-cause mortality. United States. Average-risk U.S. female population and subgroups with varying risk, breast density, or comorbidity. Eight strategies differing by age at which screening starts (40, 45, or 50 years) and screening interval (annual, biennial, and hybrid [annual for women in their 40s and biennial thereafter]). All strategies assumed 100% adherence and stopped at age 74 years. Benefits (breast cancer-specific mortality reduction, breast cancer deaths averted, life-years, and quality-adjusted life-years); number of mammograms used; harms (false-positive results, benign biopsies, and overdiagnosis); and ratios of harms (or use) and benefits (efficiency) per 1000 screens. Biennial strategies were consistently the most efficient for average-risk women. Biennial screening from age 50 to 74 years avoided a median of 7 breast cancer deaths versus no screening; annual screening from age 40 to 74 years avoided an additional 3 deaths, but yielded 1988 more false-positive results and 11 more overdiagnoses per 1000 women screened. Annual screening from age 50 to 74 years was inefficient (similar benefits, but more harms than other strategies). For groups with a 2- to 4-fold increased risk, annual screening from age 40 years had similar harms and benefits as screening average-risk women biennially from 50 to 74 years. For groups with moderate or severe comorbidity, screening could stop at age 66 to 68 years. Other imaging technologies, polygenic risk, and nonadherence were not considered. Biennial screening for breast cancer is efficient for average-risk populations. Decisions about starting ages and intervals will depend on population characteristics and the decision makers' weight given to the harms and benefits of screening. National Institutes of Health.

DNA methylation analysis of secreted frizzled-related protein 2 gene for the early detection of colorectal cancer in fecal DNA.

Background:The early detection of colorectal cancer (CRC) with high sensitivity screening is essential for the reduction of cancer-specific mortality. Abnormally methylated genes that are responsible for the pathogenesis of cancers can be used as biomarkers for the detection of CRC. The methylation status of the secreted frizzled-related protein 2 (SFRP2) gene was evaluated for their use as a marker in the noninvasive detection of CRC.Materials and Methods:Methylation-specific polymerase chain reaction was performed to analyze the promoter CpG methylation of SFRP2 in the fecal DNA of 25 patients with CRC and 25 individuals exhibiting normal colonoscopy results.Results:Promoter methylation levels of SFRP2 in CRC patients and in healthy controls were 60% and 8%, respectively. Methylation of the SFRP2 promoter in fecal DNA is associated with the presence of colorectal tumors.Conclusion:Hence, the detection of aberrantly methylated DNA in fecal samples may present a promising, noninvasive screening method for CRC.

Cystic renal cell carcinoma carries an excellent prognosis regardless of tumor size

IntroductionCystic renal cell carcinoma (cystic RCC) is thought to carry an improved prognosis relative to clear cell RCC (CCRCC); however, this is based on small case series. We used a population-based tumor registry to compare clinicopathologic features and cancer-specific mortality (CSM) of cystic RCC with those of CCRCC. Materials and methodsThe Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed and treated for cystic RCC and CCRCC between 2001 and 2010. Clinical and pathologic factors were compared using t tests and chi-square tests as appropriate. Kaplan-Meier survival analysis compared CSM differences between cystic RCC and CCRCC. ResultsA total of 678 patients with cystic RCC and 46,677 with CCRCC were identified. The mean follow-up duration was 52 and 40 months, respectively. When compared with CCRCC patients, those with cystic RCC were younger (mean age 58 vs. 61y, P <0.001), more commonly black (22% vs. 9%, P<0.001), and female (45% vs. 41%, P = 0.02). Cystic RCCs were more commonly T1a tumors (66% vs. 55%, P<0.001), well differentiated (33% vs. 16%, P<0.001), and smaller (mean size = 3.8 vs. 4.5cm, P<0.001). Cystic RCC was associated with a reduction in CSM when compared with CCRCC (P = 0.002). In a subset analysis, this reduction in CSM was seen only for those with T1b/T2 tumors (P = 0.01) but not for those with T1a RCCs lesions (P = 0.31). ConclusionsWe report the largest series of cystic RCC and corroborate the findings of improved CSM when compared with CCRCC for larger tumors; however, no difference was noted in smaller tumors, suggesting that tumor biology becomes more relevant to prognosis with increasing size. These data may suggest a role for active surveillance in appropriately selected patients with small, cystic renal masses.

Abstract 4681: Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC)

Abstract Background The US Preventive Services Task Force (USPSTF) recommends against serum prostate specific antigen (PSA) based screening for prostate cancer, on the grounds that the expected harms of screening (mainly overdiagnosis and subsequent overtreatment) outweigh the potential benefits (mainly reduction in cancer-specific mortality). This study aims to estimate the mean sojourn time (MST) and sensitivity and then use these estimates to derive the probability of overdiagnosis by polygenic risk group. Methods We calculated the polygenic risk score based on genotypes of 66 known prostate cancer susceptibility variants for 4,967 men from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC). We stratified the 80,179 Finnish trial participants into two risk groups below and above 50th percentile risk. Using a maximum likelihood method based on interval cancers, we estimated the MST and episode sensitivity. We calculated the expected number of non-overdiagnosed screen-detected cancers over three rounds of screening. We estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers. We derived overall and separate estimates of overdiagnosis by polygenic risk group. Result Men in the above average genetic risk group accounted for 74 percent of the prostate cancers cases. The episode sensitivity was 0.55 (95% CI 0.45 to 0.65) and MST 6.3 (95% CI 4.2 to 8.3) years. The overall overdiagnosis was 42% (95% CI 37 to 52) with 58% (95% CI 54 to 65) in the lower risk group and 37% (95% CI 31 to 47) in the higher risk group. Targeting screening to men in the higher polygenic risk group would reduce screening episodes by half while detecting 80% of the non-overdiagnosed cancers and preventing 38% of the overdiagnosed cancers at a cost of missing 20% of the non-overdiagnosed cancers. Conclusion Polygenic risk-stratified screening for prostate cancer is a promising approach to decrease overdiagnosis. Further research is needed to study the effect of targeted screening on cancer-specific mortality. Citation Format: Nora Pashayan, Paul D.P. Pharoah, Johanna Schleutker, Kirsi Talala, Teuvo LJ Tammela, Liisa Määttänen, Patricia Harrington, Jonathan Tyrer, Rosalind Eeles, Stephen W. Duffy, Anssi Auvinen. Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2015-4681

People’s willingness to accept overdetection in cancer screening: population survey

Objectives To describe the level of overdetection people would find acceptable in screening for breast, prostate, and bowel cancer and whether acceptability is influenced by the magnitude of the benefit...

Fecal DNA testing for colorectal cancer screening: Molecular targets and perspectives.

The early detection of colorectal cancer with effective screening is essential for reduction of cancer-specific mortality. The addition of fecal DNA testing in the armamentarium of screening methods already in clinical use launches a new era in the noninvasive part of colorectal cancer screening and emanates from a large number of previous and ongoing clinical investigations and technological advancements. In this review, we discuss the molecular rational and most important genetic alterations hallmarking the early colorectal carcinogenesis process. Also, representative DNA targets-markers and key aspects of their testing at the clinical level in comparison or/and association with other screening methods are described. Finally, a critical view of the strengths and limitations of fecal DNA tests is provided, along with anticipated barriers and suggestions for further exploitation of their use.

Exercise-induced lung cancer regression: mechanistic findings from a mouse model.

It has been demonstrated that regular exercise improves the quality of life in patients undergoing treatment for lung cancer and has been associated with reductions in cancer-specific mortality in patients with colon and breast cancer. The direct effects of cardiovascular exercise on lung cancer tumor biology, however, remain unknown. The authors evaluated the effects of cardiovascular exercise in a mouse model of lung adenocarcinoma. Luciferase-tagged A549 lung adenocarcinoma cells were injected through the tail vein of nude male mice. Then, the mice underwent weekly bioluminescent imaging until lung tumors were clearly identified. After lung tumors were identified, the mice were randomized to daily wheel running versus no wheel running, and they were imaged weekly. After 4 weeks, all mice were killed, and the lung tumors were harvested. Western blot and immunohistochemical analyses were conducted on tumor tissues to identify potential differences in protein expression levels in exercising mice versus sedentary mice. Lung tumors in exercising mice grew significantly more slowly relative to sedentary mice. There was no change in the development of metastatic lesions between the 2 groups. Protein analysis by Western blot or immunohistochemical analysis demonstrated increased p53 protein levels in exercising mice relative to sedentary mice as well as increased mediators of apoptosis, including Bax and active caspase 3, in tumor tissues. In both groups of mice, no normal tissue toxicity was observed in other organs. Daily cardiovascular exercise appears to mitigate the growth of lung adenocarcinoma tumors, possibly by activation of the p53 tumor suppressor function and increased apoptosis.

Do we know (or just believe) that partial nephrectomy leads to better survival than radical nephrectomy for renal cancer?

Partial nephrectomy (PN) has become the gold standard for treating small renal masses amenable to such an approach. Surprisingly, the single randomized controlled trial of PN versus radical nephrectomy (RN) indicated an overall survival benefit for RN over PN. Recent studies have shed light on this discordance, and this review will attempt to discern what is known at present. Multiple retrospective observational studies have demonstrated superior outcomes with PN compared with RN. Whether the observed survival benefit with PN is the result of renal functional advantages or the result of selection bias and other unmeasured variables is up for discussion. A meta-analysis of 21 studies including the EORTC 30904 found a 19 % reduction in all-cause mortality (p = 0.0001) and 29 % reduction in cancer-specific mortality (p = 0.0002) with PN versus RN. Recent analysis of SEER-Medicare data revealed that patients undergoing RN had similar survival when compared with non-cancer controls, further supporting concerns about selection biases in prior observational series. Although PN is clearly of benefit for those likely to experience end-stage renal disease with RN, a survival benefit with PN in the elective setting is not proven at present. While experts may still believe PN to improve survival for these patients, the only level I evidence in the field would suggest otherwise, and selection bias is undoubtedly responsible for a significant part of the improved survival observed in retrospective studies. Given recent evidence, any further push to limit the role of RN should be tempered until we know PN is indeed superior.

Adjuvant chemotherapy is associated with decreased mortality after radical cystectomy for locally advanced bladder cancer

We sought to evaluate the association of adjuvant chemotherapy with the risk of subsequent mortality among patients with locally advanced urothelial carcinoma (UC) of the bladder undergoing radical cystectomy (RC). We identified 675 patients who underwent RC for pT2-4 and/or N+ UC between 1980 and 2005. Adjuvant chemotherapy was defined as treatment within 90 days of RC. Survival was estimated using the Kaplan-Meier method and compared according to receipt of adjuvant chemotherapy with the log-rank test. Multivariate models were used to analyze the impact of adjuvant chemotherapy on disease progression and survival. A total of 80 (12 %) patients received adjuvant chemotherapy. Median age was 69 years [interquartile range (IQR) 63, 76]. Median follow-up was 11 years (IQR 8, 16). Patients receiving adjuvant chemotherapy were more likely to have pT3-4 tumors (71 vs. 61 %; p < 0.001) and pN+ (85 vs. 19 %; p < 0.001). The 5-year cancer-specific survival was 46 % in those receiving adjuvant chemotherapy and 51 % in those that did not (p = 0.63). The 5-year overall survival was 39 % in those receiving adjuvant chemotherapy and 38 % in those that did not (p = 0.24). When controlling for age, sex, stage, and performance status, adjuvant chemotherapy was associated with a 29 % decrease in the risk of bladder cancer death (HR 0.71, p = 0.06) and a 39 % decrease in the risk of all-cause mortality (HR 0.61, p = 0.002). After controlling patient and tumor features, adjuvant chemotherapy was associated with a trend toward reduction in cancer-specific mortality and a statistically significant reduction in all-cause mortality.

Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study.

1520 Background: Few studies have examined the prognostic importance of cardiorespiratory fitness (CRF) to predict cancer incidence or cause-specific mortality following a cancer diagnosis in men. Accordingly, we examined the relationships between baseline CRF and incidence of prostate, lung, or colorectal cancer in men at Medicare age and subsequent cause-specific mortality among men diagnosed with cancer. Methods: The Cooper Center Longitudinal Study (CCLS) is a prospective observational cohort study of participants undergoing a preventive health examination including CRF assessment at the Cooper Clinic in Dallas, Texas. We studied 17,049 men with a complete CCLS medical exam and cardiovascular risk factor assessment at a mean age of 50± 9 years. Cancer incidence was defined using Medicare claims data. Cox proportional models were used to estimate the risk of adjusted primary cancer incidence and cause-specific mortality after cancer according to baseline age-specific CRF quintiles (Q). Results: The mean times from CRF assessment to cancer incidence and death were 20.2 ± 8.2 years and 24.4 ± 8.5 years, respectively. During this period, 2885 men were diagnosed with prostate, lung, or colorectal cancer and 769 died. Compared with men in lowest CRF quintile, the adjusted hazard ratio (HR) for incident lung, colorectal, and prostate cancer incidence among men in the highest CRF quintile was 0.32 (95% CI: 0.20 to 0.51, p&lt;0.001), 0.62 (95% CI: 0.40 to 0.97, p=0.05), 1.13 (95% CI: 0.97 to 1.33, p=0.14), respectively. In men developing cancer, both cancer-specific mortality and cardiovascular-specific mortality declined across increasing CRF quintiles (p’s &lt;0.001). A 1-MET increase in CRF was associated with a 14% reduction in cancer-specific mortality (HR 0.86, 95% CI: 0.81-0.91, p&lt;0.001), and 23% reduction in cardiovascular-specific mortality (HR 0.77, 95% CI: 0.69-0.85, p&lt;0.001). Conclusions: Fitness is a strong independent predictor of incident lung and colorectal cancer and remained a robust predictor of cause-specific mortality in middle-aged and older men diagnosed with lung, prostate, or colorectal cancer.