This prospective multicenter study demonstrated that chemotherapy toxicity is common in older adults, with 53% experiencing at least one grade 3 to 5 toxicity. Among these, 2% experienced a treatment-related mortality. A predictive model was developed to identify those patients at greatest risk, including factors obtained in everyday practice (patient age, number of chemotherapy drugs, dosing, and laboratory values) and factors not typically used in everyday oncology practice (geriatric assessment variables). This model had a greater ability to discriminate risk of chemotherapy toxicity than the KPS, which is commonly used in oncology practice.
Older adults are at increased risk for chemotherapy toxicity; however, oncologists are left with little guidance when it comes to identifying risk factors other than chronologic age. It is generally recognized that chronologic age does not equate to physiologic age. Geriatricians perform a geriatric assessment to identify clinical predictors of morbidity and mortality15
; however, this assessment has not been routinely incorporated into oncology care because of the time and resource requirements. Furthermore, there is a lack of guidelines regarding how to interpret the findings in the context of oncology care.
The predictive model identified patient age, tumor, treatment, laboratory values, and geriatric assessment variables as risk factors for chemotherapy toxicity. There is a rational explanation for why each of these factors may predict chemotherapy toxicity. Although older age is associated with an accumulation of physiologic deficit, there is controversy about which chronologic age defines an individual as “older.” Age ≥ 72 years as a risk factor for chemotherapy toxicity provides evidence for the seventh decade of life as a time when the cumulative effects of aging are associated with increased vulnerability.
Tumor and treatment variables were identified as risk factors for chemotherapy toxicity. Patients with GI and GU cancers were at increased risk for toxicity, possibly reflective of the type of chemotherapy delivered or alterations in physiology (diarrhea/impaired fluid balance) associated with the cancer or the treatment. Receipt of polychemotherapy and/or standard dosing of chemotherapy were associated with an increased risk of toxicity. Aging is associated with decreased bone marrow reserve and an increased risk of myelosuppressive-associated complications from chemotherapy.37,38
The receipt of polychemotherapy further increases the risk of myelosuppressive effects from chemotherapy and can potentially amplify the physiologic stress of a regimen secondary to overlapping toxicities.
Laboratory values (anemia and renal dysfunction) were identified as risk factors for chemotherapy toxicity. The presence of anemia can further increase susceptibility to myelosuppression with certain antineoplastic drugs that are heavily bound to RBCs (epipodophyllotoxins, anthracyclines, camptothecins) by increasing the volume of distribution of these drugs.39
In the geriatric population, anemia is an independent predictor of hospitalization and mortality, perhaps representing a global measure of decreased reserve.40
There is an age-related decrease in renal function which could impact the pharmacokinetics of renally metabolized drugs.17
Geriatric assessment variables were a critical part of the predictive model. Among geriatric patients, functional status is a strong predictor of morbidity and mortality.18
Four questions that reflected the patient's functional status were included in the model (ability to walk one block, decreased social activities because of physical or emotional problems, falls in the last 6 months, and the need for assistance with taking medications). The need for assistance with taking medications could also be a surrogate measure of cognitive function, grip strength (unable to open the bottle), or vision (unable to see the instructions). A decrease in social activities because of physical or emotional problems may represent both a functional measure and a measure of psychological state. Finally, poor hearing was identified as a risk factor for chemotherapy toxicity, potentially reflecting whether the patient could hear the instructions regarding potentialadverse effects, supportive care medications, and indications of when to seek medical attention.
These findings contribute to an ongoing paradigm shift in oncology assessment. The commonly used oncology performance status measure (KPS) did not identify older adults at increased risk for chemotherapy toxicity, reflecting the limitations of trying to use one global assessment measure of functional status to describe the heterogeneity in the geriatric population. Furthermore, the KPS might be misleading. In older adults it is difficult to discriminate between a KPS of 80% (“normal activity with effort; some signs or symptoms of disease”) and a KPS of 60% (“requires occasional assistance, but is able to care for most of his/her needs”).
There are limitations to this study. This study reported on grade 3 to 5 toxicity; however, some grade 2 toxicities (diarrhea, neuropathy) may also be relevant to the geriatric population. Our study population was heterogeneous, consisting of patients with different tumor types and treatment regimens. Our rationale behind studying a heterogeneous population was to determine whether there are common factors that are predictive of vulnerability in the geriatric oncology population; however, there may be additional or different risk factors that are predictive of toxicity based on tumor type or treatment regimen. Exploratory analyses revealed that the ROC of the model was similar when applied to the different tumor types; however, our future research will focus on refining the model among patients with specific tumor types who are receiving specific treatment regimens. Finally, although the model was internally validated, these findings need to be validated externally in an independent cohort.
This study fills critical gaps in the knowledge of predictors for chemotherapy toxicity in older adults, something that does not currently exist and for which there is an enormous and growing need. It unites the fields of geriatrics and oncology by incorporating geriatric correlates of vulnerability, studying their impact in a diverse population of older adults with cancer, and identifying common risk factors for chemotherapy toxicity. Ultimately, these data will provide the basis for future intervention studies aimed at decreasing the risk of chemotherapy toxicity and maintaining the function and health of older adults with cancer.