Do Older and Younger Patients Derive Similar Survival Benefits From Novel Oncology Drugs?

A Systematic Review and Meta-analysis

Vanessa S. Arciero; Sierra Cheng; Robert Mason; Erica McDonald; Ronak Saluja; Kelvin K. W. Chan

Disclosures

Age Ageing. 2018;47(5):654-660. 

In This Article

Abstract and Introduction

Abstract

Background: older patients are commonly believed to derive less benefit from cancer drugs, even if they fulfil clinical trial eligibility [Talarico et al. (2004, J Clin Oncol, 22(22):4626–31)]. We aim to examine if novel oncology drugs provide differential age-based treatment outcomes for patients on clinical trials.

Methods: a systematic review of randomised control trials (RCTs) cited for clinical efficacy evidence in novel oncology drug approvals by the Food and Drug Administration, European Medicines Agency and Health Canada between 2006 and 2017 was conducted. Studies reporting age-based subgroup analyses for overall or progression-free survival (OS/PFS) were included. Hazard ratios (HRs) and confidence intervals (CIs) for age-based subgroups were extracted. Meta-analyses with random effects were conducted, examining patient subgroups <65 and ≥65 years separately and pooled HRs of studies primary endpoints (OS or PFS) compared to examine if differences existed between age-based subgroups. Sensitivity analyses were conducted for cancer type, primary endpoint and systemic treatment.

Results: one-hundred-two RCTs, including 65,122 patients, met the inclusion criteria. One study reported age-based toxicity and none reported age-based quality of life (QOL) results. Pooled HRs [95% CIs] for patients <65 and ≥65 years were 0.61 [0.57–0.65] and 0.65 [0.61–0.70], respectively, with no difference between them (P = 0.14). Sensitivity analyses revealed similar results.

Conclusion: our results suggest that older and young patients, who fulfil clinical trial eligibility, may derive similar relative survival benefits from novel oncology drugs. There is, however, a need to report age-based toxicity and QOL results to support patient discussions regarding the balance of treatment benefit and harm, to encourage informed decision-making.

Introduction

Despite the immense disease burden among older individuals, this population is generally an underserved group. While ~60% of cancers and 70% of cancer-related mortalities occur in patients 65 years or older,[2] older patients' unique considerations often pose as a barrier to treatment and may limit the potential benefit they derive. Multiple theoretical reasons why older patients may derive less benefit or more toxicity from specific treatments are presented in the literature. For example, the physiology of ageing may be associated with changes in cancer biology[3] and drug metabolism.[4] Reduced liver mass and blood flow may result in decreased first-pass metabolism and bioavailability in older patients.[4] Additional physiological changes, such as decreased intestinal absorption, hepatic metabolism and renal excretion,[5] may alter the pharmacodynamics of drugs through changes in distribution and excretion.[6] Ultimately, this may increase the prevalence of high-grade toxicities and decrease the tolerance of low-grade toxicities in older patients,[5] due to increased drug exposure.[6]

Treatment-related toxicities, which greatly impact patients' daily activities, more commonly result in dose reductions in older adults, lessening treatment efficacy due to reduced dose intensity.[7] Prescribing physicians often opt to modify patients' doses early in an attempt to prevent future toxicity.[8] Such decisions may be based on demographics, co-morbidity and the nature of the prescribed regimen, amongst others.[8] In a recent secondary data analysis, Gajra et al.[8] determined that age alone was independently associated with a primary dose reduction for patients receiving chemotherapy with both curative and palliative intents.

This population, however, is an extraordinarily heterogeneous group. While frailty is more common with age, the progression towards frailty is considerably variable across older individuals. When considering functional status alone, trials typically describe their patient population in terms of the Eastern Cooperative Oncology Group Scale of Performance Status (PS). A recent systematic review and meta-analysis conducted to determine if patients of lesser PS-derived differential treatment benefits from novel oncology drugs in comparison with their 'excellent' counterparts, determined there was indeed no difference between the groups.[9] PS, however, is a measure of only one aspect of frailty. In addition to the concerns about frailty, PS, potential toxicity and dose reduction, older patients are more likely to have co-morbidities and die from other causes. The increased likelihood of death from another cause may attenuate or even negate the ability of cancer-specific treatments to improve progression-free survival (PFS) or overall survival (OS) in this group. While some studies suggested there may be differential age-based survival benefits,[10,11] others presented opposing results.[12–19] Most literature, however, is focused on older drugs with substantial side effects commonly affecting older patients. To date, there has been limited literature systematically examining the effects of age on the benefits of novel oncology drugs in contemporary medicine. Molecular-targeted agents, for example, are believed to be associated with decreased toxicities when compared with older, less specific targeted agents and chemotherapy regimens.[20] The decreased toxicity profile of novel oncology treatments may suggest potentially improved tolerability and outcomes in older patients.

Therefore, there is a need to systematically review the literature to determine if age is associated with the relative treatment-related efficacy and toxicity of novel oncology drugs. Such study can allow for the development of optimised medical care by better understanding the effects of older patients' co-morbidities and drug tolerance on the net clinical benefit of treatment. Additionally, it may help clinicians determine if age should be a considerable factor when making treatment decisions for generally well and fit older patients.

Thus, we aim to conduct a systematic review and meta-analysis to examine if novel oncology drugs provide differential treatment outcomes for older and young patients enroled in clinical trials.

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