Impact of Comorbidity on Chemotherapy Use and Outcomes in Solid Tumors: A Systematic Review Linda Lee, Winson Y. Cheung, Esther Atkinson, and Monika K. Krzyzanowska J Clin Oncol 29: R4 채정민 /Prof 백선경

Introduction cancer patients with comorbidities –not well studied in the literature –often excluded from clinical trials –incidence increases with age –complexity to cancer management –high burden of comorbidity → higher mortality rate but the underlying mechanisms ??

Introduction a systematic review –for the influence of comorbidity on clinical outcomes in cancer patients in relation to systemic cancer treatment –focused on chemotherapy hypothesis –the lower rate of survival seen among cancer patients with comorbidities is largely attributable to suboptimal chemotherapy purpose –help optimize cancer care for this vulnerable polulation –better define areas that need to be addressed in future studies

Methods – article selection MEDLINE and EMBASE databases for English-language articles between January 1, 1990 and December 31, 2009 MeSH headings and keywords such as “neoplasms”; “antineoplastic agents” or “antineoplastic combined chemotherapy protocols” or “chemotherapy, adjuvant” or “chemotherapy:.mp”; and “comorbidity” or “comorbid:.mp.” included –studies evaluating chemotherapy as part of multimodality treatment or specifically to chemotherapy use and outcomes excluded –studies of hematologic malignancies –those addressing HIV-infected patients –those examining mainly psychological or mental comorbidities –case reports, letters, editorials, review articles, abstract-only publications

Methods – data abstraction study design and results –extracted from each eligible article by one reviewer (L.L.) –type of study –method of data collection –source of data –study population –country of study –study duration –comorbidities examined and comorbidity measures used

Methods – data abstraction abstracted outcome –chemotherapy use –quality of treatment delivery (dose delays, dose reductions, or early discontinuation) –tolerability (frequency and severity of toxicities) –overall survival a second reviewer (W.C.) extracted data from a random sample of 10 studies to ensure reliability of the data abstraction process agreement between the two data abstractors was 90% on all items

Methods – assessment of study quality using a 28-item checklist adapted from STROBE statement (the Strengthening the Reporting of Observational Studies in Epidemiology) individual articles were graded –fully present (score 1) –partially present (score 0.5) –absent (score 0) final score: averaging the scores from both reviewers

Methods – data synthesis and analysis summary statistics –describe our main outcomes of interests stratified by the presence of comorbidity forest plots –for the two outcomes (chemotherapy use and survival) odds ratio (OR) in treatment use –for receiving treatment with comorbidity compared to those without hazard ratios (HRs) in survival –for death, comparing patients with comorbidity to those without

Results – study quality highly heterogeneous and generally poor generally well reported –background information –details about study design –definition of comorbidity not well reported –potential sources of bias –handling of missing data –external validity of the results

Results – delivery 5 studies examined chemotherapy delivery, but each examined different end points 1 study in ovarian cancer –greater delays in initiating chemotherapy (OR 1.23) 2 studies –more frequent dose delays 1 study in NSCLC –more frequent dose reductions 2 studies –decreased ability to complete planned chemotherapy 1 study –no difference in chemotherapy completion for patients with comorbidities

Results – tolerability 10 studies –the measures used to assess tolerability heterogeneous 7 studies: grade of adverse effects –5 studies: higher rate of grade 3 to 4 toxicity in patients with comorbidities 2 study: evaluated hospitalization rates 1 study: complication rates in the first year –no differences

Discussion in cancer patients with comorbiditis –decreased use of chemotherapy –worse survival the precise relationship between these two outcomes remains unclear we need future study with a more specific focus –individual comorbidity –homogeneous population of cancer patients

Discussion  not cross-compatible index systems CCI (Charlson Comorbidity Index) –the most widely used –not consider the degree of severity of individual diseases –tends to be right-skewed in cancer populations Adult Comorbidity Evaluation –chart-based instrument developed specifically for cancer patients –used less often Cumulative Illness Rating Scale –the most comprehensive index –best applied in prospective studies these comorbidity indices –not cross-compatible –not in clinical settings effect on estimation of treatment benefit

Discussion  not specified contents chemotherapy use –referral to an oncologist or receipt of treatment –skip intermediate steps (patient acceptance of the referral appointment, physician decision to offer treatment, patient consent to treatment) worse survival –suboptimal quality of treatment –decreased tolerability tumor site and staging comorbidity definition –disease specific measures

Discussion  lack of adequate data retrospective data –limited information on treatment delivery or tolerability population-based database –miss comorbidities –underestimate their severity –fail to address confounding factors such as performance status clinical trials databases –no information about rates of chemotherapy use in routine practice –trial participants is a highly selected population → more likely to be excluded from these trials

Discussion  marked heterogeneity of the studies (study population and design)  poor quality of reporting –we created a checklist based on the STROBE statement –not define and address confounding variables and sources of bias  reciprocal relationship of how cancer diagnosis and treatment influence management and outcomes of comorbidities

Discussion  treatment decision –based on benefit-to-risk ratio especially in early stage cancer as adjuvant chemotherapy consider potential for such treatment to affect the underlying comorbidity (use of oxaliplatin or taxanes in patients with diabetic neuropathy)

Conclusion chemotherapy use and outcomes among cancer patients with comorbidities are generally inferior but the existing evidence is limited and of insufficient quality to determine the relationship between decreased use and inferior survival further studies that are prospective and site and stage specific are warranted