Christopher M. Booth

Association Between Time to Initiation of Adjuvant Chemotherapy and Survival in Colorectal Cancer: A Systematic Review and Meta-analysis

CONTEXT Adjuvant chemotherapy (AC) improves survival among patients with resected colorectal cancer. However, the optimal timing from surgery to initiation of AC is unknown. OBJECTIVE To determine the relationship between time to AC and survival outcomes via a systematic review and meta-analysis. data sources: MEDLINE (1975 through January 2011), EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched to identify studies that described the relationship between time to AC and survival. STUDY SELECTION Studies were only included if the relevant prognostic factors were adequately described and either comparative groups were balanced or results adjusted for these prognostic factors. DATA EXTRACTION Hazard ratios (HRs) for overall survival and disease-free survival from each study were converted to a regression coefficient (β) and standard error corresponding to a continuous representation per 4 weeks of time to AC. The adjusted β from individual studies were combined using a fixed-effects model. Inverse variance (1/SE(2)) was used to weight individual studies. Publication bias was investigated using the trim and fill approach. RESULTS We identified 10 eligible studies involving 15,410 patients (7 published articles, 3 abstracts). Nine of the studies were cohort or population based and 1 was a secondary analysis from a randomized trial of chemotherapy. Six studies reported time to AC as a binary variable and 4 as 3 or more categories. Meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both overall survival (HR, 1.14; 95% confidence interval [CI], 1.10-1.17) and disease-free survival (HR, 1.14; 95% CI, 1.10-1.18). There was no significant heterogeneity among included studies. Results remained significant after adjustment for potential publication bias and when the analysis was repeated to exclude studies of largest weight. CONCLUSION In a meta-analysis of the available literature on time to AC, longer time to AC was associated with worse survival among patients with resected colorectal cancer.

Progression-Free Survival: Meaningful or Simply Measurable?

The last few years have seen an increase in the number of randomized controlled trials (RCTs) of new agents in metastatic solid tumors using progression-free survival (PFS) as the primary end point. Some trials showing improvement in PFS, without a correspondingincreaseinoverallsurvival(OS),haveledtoapprovalofnew drugs and/or changes in standard of care. This suggests a growing belief in the oncology community that delaying progression in metastaticdiseaseisaworthygoal,evenifOSisnotimproved.Butisanew treatment that improves PFS really an advance for patients? Or is it only lowering the bar to declare active some of our much-heralded new molecular targeted therapies? We believe that as a community, this trend requires discussion and debate.

The Impact of Socioeconomic Status on Stage of Cancer at Diagnosis and Survival: A Population-Based Study in Ontario, Canada

Lower socioeconomic status (SES) is associated with worsened cancer survival. The authors evaluate the impact of SES on stage of cancer at diagnosis and survival in Ontario, Canada.

Evolution of the Randomized Controlled Trial in Oncology Over Three Decades

PURPOSE The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs. METHODS Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non-small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure. RESULTS A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively). CONCLUSION RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm.

Translating New Medical Therapies Into Societal Benefit : The Role of Population-Based Outcome Studies

PHASE 4 STUDIES HAVE TRADITIONALLY MONITORED safety of new drugs and occasionally served as marketing tools for pharmaceutical companies. In the 1990s these “seeding studies” came under criticism for the substantial influence industry had on study design and interpretation. Recently, innovative study designs and access to large electronic databases have allowed investigators to evaluate outcomes in the general population and provide information regarding uptake, safety, and outcomes in the real world. These population-based outcome studies may have important potential roles in clinical research. In this Commentary, we describe several examples that demonstrate the emerging roles of these studies and propose that they could be considered as adjuncts to and occasionally as substitutes for randomized controlled trials.

Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement

PURPOSE To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the European Association of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting the use of chemoradiotherapy for select patients with MIBC and recommending a preference for clinical trials in the treatment of metastatic disease in the second-line setting. RECOMMENDATIONS Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is recommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin.Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki.

Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer in the Elderly: A Population-Based Study in Ontario, Canada

PURPOSE Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant chemotherapy. However, the elderly were under-represented in these studies, raising concerns regarding the reproducibility of the study results in clinical practice. PATIENTS AND METHODS By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and ≥ 80 years. As a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to 2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks of surgery served as a proxy of severe chemotherapy-related toxicity. RESULTS In all, 2,763 (43.8%) of 6,304 surgical patients were elderly (age ≥ 70 years). Uptake of adjuvant chemotherapy in the elderly increased from 3.3% (2001 to 2003) to 16.2% (2004 to 2006). Among evaluable elderly patients, 70% received cisplatin and 28% received carboplatin-based regimens. Requirements for dose adjustments or drug substitutions were similar across age groups. Hospitalization rates within 6 to 24 weeks of surgery were similar across age groups (28.0% for patients age < 70 years; 27.8% for patients age ≥ 70 years; P = .54). Four-year survival of elderly patients increased significantly (47.1% for patients diagnosed from 2001 to 2003; 49.9% for patients diagnosed from 2004 to 2006; P = .01). Survival improved in all subgroups except patients age ≥ 80 years. CONCLUSION Uptake of adjuvant chemotherapy for NSCLC increased in patients age 70 years or older following reporting of pivotal adjuvant chemotherapy trials, but it remained below that for patients younger than age 70 years. Adoption of adjuvant chemotherapy appears to be associated with significant survival benefit in the elderly (age ≥ 70 years), with tolerability apparently similar to that of patients who are younger than age 70 years.

Adoption of adjuvant chemotherapy for non-small-cell lung cancer: a population-based outcomes study.

PURPOSE Since 2004, several clinical trials have demonstrated that adjuvant chemotherapy (ACT) improves survival in patients with early-stage non-small-cell lung cancer (NSCLC). Here, we evaluate the uptake of ACT and its impact on outcomes in the general population of Ontario, Canada. METHODS All patients diagnosed with NSCLC in Ontario from 2001 to 2006 who underwent surgical resection (n = 6,304) were identified using the Ontario Cancer Registry. We linked electronic records of treatment to the registry. We described uptake of ACT and compared survival of all patients with surgically resected NSCLC diagnosed from 2001 to 2003 with patients diagnosed from 2004 to 2006. As a proxy measure of ACT-related toxicity, we evaluated hospitalizations within 6 months of surgery. RESULTS Demographic, disease, and treatment-related characteristics did not differ between the 2001 to 2003 and 2004 to 2006 study cohorts. Over the study period, the proportion of patients receiving ACT increased from 7% (192 of 2,950 patients) to 31% (1,032 of 3,354 patients; P < .001). The proportion of patients admitted to hospital within 6 months of surgery remained stable and (36% in the 2001 to 2003 cohort and 37% in the 2004 to 2006 cohort). However, within 2 years of surgery, there was a 33% reduction in the proportion of patients admitted to hospital with metastatic disease (P < .001). During the study period, there was a substantial improvement in 4-year survival among surgically resected patients, from 52.5% (2001 to 2003) to 56.1% (2004 to 2006; P = .001). CONCLUSION There has been a rapid uptake of ACT for NSCLC, which was not associated with an increased rate of hospitalization. The adoption of ACT was associated with a substantial improvement in overall survival, suggesting that the benefits seen in clinical trials are generalizable to the general population.

Perioperative chemotherapy for muscle-invasive bladder cancer: A population-based outcomes study.

Practice guidelines recommend neoadjuvant chemotherapy (NACT) for bladder cancer. However, the evidence in support of adjuvant chemotherapy (ACT) is less robust. Here we describe whether the evidence of efficacy for NACT/ACT was sufficient to change clinical practice and whether the efficacy demonstrated in clinical trials was translated into effectiveness in the general population.

Reflections on Medical Oncology: 25 Years of Clinical Trials—Where Have We Come and Where Are We Going?

Twenty-five years ago in the first issue of Journal of Clinical Oncology, Tannock and Murphy appealed for better design and improved reporting of clinical trials in oncology, and proposed five areas in which journals and investigators could improve the quality of clinical cancer research. As shown in Figure 1, these recommendations pertain to three inter-related themes: appropriate design and size of trials, the selection of clinically relevant end points, and reporting that is free of bias. In this Silver Anniversary issue, we reflect on how well the evolution of clinical trials has adhered to these principles during the last 25 years.