Background
The addition of CDK 4/6-inhibitors to endocrine therapy as 1st or 2nd line treatment in patients with advanced hormone receptor-positive (HR+)/HER2-negative breast cancer has shown to improve survival in all patient subgroups including older patients.
Despite the advances in the treatment of HR+/HER2-negative breast cancer, the five-year overall survival is approximately 40% according to real-world evidence, thus classifying this disease as refractory in terms of overall survival. Current evidence from both randomized trials and real-world evidence studies suggests that older breast cancer patients derive clinical benefit from the addition of CDK 4/6-inhibitors to endocrine therapy but with higher risk for adverse events and treatment discontinuation compared to younger patients.
Currently, the recommended starting dose for CDK 4/6-inhibitors is the same irrespective of patient characteristics. Considering the higher risk for, and impact of, adverse events in older patients, it seems reasonable to initiate CDK 4/6-inhibitors at a lower dose as a more tailored treatment strategy. In fact, this clinical approach seems to be a relatively common practice among older breast cancer patients according to real-world evidence studies.
However, no randomized evidence exists on initiating with a lower dose of CDK 4/6-inhibitors, so this practice is merely based on clinical observation rather than existing evidence. If we also take into consideration the heterogeneity of the older cancer population, we argue that a proposed dose optimization approach should rely on a more individualized decision-making strategy rather than a one-size-fits-all dose reduction.
Challenge #1
No randomized evidence exists on initiating with a lower dose of CDK 4/6-inhibitors for patients with advanced HR+/HER2-negative breast cancer.
An important aspect for older patients with advanced HR+/HER2-negative breast cancer is that they are underrepresented in pivotal clinical trials for CDK 4/6-inhibitors. This issue is not observed only to this group but is a general issue for older cancer patients and clinical trial participation. A recent call to action10 review recognizes the design of clinical trials dedicated to older cancer patients as the most promising strategy to solve the evidence gap in geriatric oncology highlighting the need for these dedicated trials to be pragmatic with broad eligibility criteria and measuring endpoints that are relevant for the older cancer patient population.
Challenge #2
There is a paucity of evidence on how to overcome the under-representation of older cancer patients in clinical trials.
Considering the higher risk for, and impact of, adverse events in older patients, it seems reasonable to initiate CDK 4/6-inhibitors at a lower dose as a more tailored treatment strategy. In fact, this clinical approach seems to be a relatively common practice among older breast cancer patients according to real-world evidence studies. However, no randomized evidence exists on initiating with a lower dose of CDK 4/6-inhibitors, so this practice is merely based on clinical observation rather than existing evidence. If we also take into consideration the heterogeneity of the older cancer population, we argue that a proposed dose optimization approach should rely on a more individualized decision-making strategy rather than a one-size-fits-all dose reduction.
Challenge #3
Cancer clinical trials are designed to collect a narrow set of cancer-specific endpoints as efficacy outcomes and toxicity to prove drug safety and efficacy. However, incorporating a wide range of relevant outcomes when a cancer treatment strategy is studied in a clinical trial seems to be beneficial not only for improving the shared decision-making process but also for supporting healthcare policy makers in their decisions. Such a cancer treatment strategy is more likely to be approved for reimbursement while treatments with greatest clinical benefit are associated with faster times to Health Technology Assessment (HTA) decision.
Challenge #4
Cancer care usually focuses on specific aspects of the problem and not the continuum of care, providing solutions on different timescales and focus areas.
A very large number of worthwhile initiatives, public and private institutes, scientific organizations, SMEs etc., form a vast ecosystem for cancer treatment and care. These stakeholders do pursue collaboration through joint activities for cancer services, however, due to the complexity of the disease and the significant impact it bears on the society and economy, their efforts focus on very specific aspects of the problem, inadvertently creating siloed activities and propagating fragmentation. There is a need to intensify collaboration for cancer services through a holistic approach that incorporates more aspects like engagement, behavioural and psychological issues, costs etc.
Challenge #5
Even though technological tools can provide innovative solutions, the healthcare sector needs time to incorporate them inside the existing practices and operations.
In recent years, multiple innovative technological solutions have been created that have the ability to improve the healthcare sector services and reduce its costs. Even though the transition towards digitalization seems difficult, such solutions can address many existing challenges across multiple levels. For instance, adopting decentralised approaches that combine participant-centered design with innovative technologies to reduce the need for physical in-person interaction between participants and researchers seems to be a pragmatic approach that could improve patients’ willingness to enrol in clinical trials, including older cancer patients as well.