Introduction: Cancer and Frailty
Cancer is a disease of older adults. About 60% of cancers occur in people 65 years of age or older. Furthermore, about 70% of the deaths caused by cancers occur in this stage (White et al., 2019). Frailty - whether defined by comprehensive geriatric assessment (CGA), deficit accumulation indices (DAI) or the physical frailty phenotype criteria (PFP) - is prevalent among those with cancer. In a 2015 meta-analysis of nearly 3000 participants, prefrailty and frailty were diagnosed in half of older adults with cancer, while only roughly a third were classified as fit by a CGA (Handforth et al., 2015).
Fitness and frailty matter to cancer management choices, as they are frequently associated with age-related declines in renal, hepatic, marrow and muscle function (Pal & Hurria, 2010). Frail, vulnerable older adults with a new cancer diagnosis have an impaired ability to withstand anticancer therapies and an increased risk of poor outcomes (White et al., 2019).
Cancer or cancer treatments can also worsen frailty. Certain cancers can accelerate aging biology and functional declines: patients with prostate cancer manifest with falls, fractures and cognitive impairment (Morgans et al., 2021) while those with cancers of the head and neck can present with nutritional deficits and related comorbidities (Noor et al., 2018). The impact of cancer and cancer therapy on physical function and the progression of frailty is a critical consideration, especially for those who survive and achieve remission. By 2040, these cancer survivors will grow to 26 million individuals and represent 73% of those aged 65 years and older and almost 50% of those over 75 (Sedrak et al., 2021).
Impact of Frailty on Cancer Outcomes
The increased prevalence of frailty among those living with cancer has a substantial long-term impact on geriatric-centric outcomes. Frailty, defined by the DAI approach, is associated with an increased risk of hospitalization and long-term care admission in older patients with cancer. (Williams et al., 2019). In one study of older women with non-metastatic breast cancer, those who were frail, also defined by DAI, had both worse baseline and follow-up cognition even years after treatment (Mandelblatt et al., 2018). Indicators of frailty have also been found to correlate with worse quality of life in post-surgical patients with colorectal cancer (Rønning et al., 2014). Frailty is also associated with an elevated risk of serious postoperative complications (Kristjansson et al., 2012), need for reoperation, and readmission (Kristjansson et al., 2010) among surgical oncology patients. Older breast cancer survivors with deficits, including comorbidity and psychosocial impairment, suffered as a result of poor treatment tolerance (Clough-Gorr et al., 2010). Similarly, decreased tolerance was seen in a cohort of older women from the Cancer and Aging Research Group -Breast Cancer (CARG-BC), with outcomes including more falls and limited mobility (Magnuson et al., 2021). The impact of frailty on radiation-related outcomes is still very preliminary, and more research is needed (Ethun et al., 2017).
Impact of Cancer and its Therapies on Frailty
The etiology of frailty in cancer is multifactorial and unique aspects of different cancers and treatments have specific consequences for the aging cancer patient, but many of the mechanisms are in common:
- Cellular Changes: Various cancer treatment modalities induce biological changes in function on the cellular level that accelerate aging. These include telomere attrition, stem cell exhaustion, cellular senescence, DNA damage, and epigenetic alterations. These changes can contribute to secondary cancers, chronic organ dysfunction, and cognitive impairment among cancer survivors (Wang et al., 2021). Cancers themselves can also change cellular function. For example, metastasis with bone invasion is associated with a vicious cycle of excessive osteoclast activation, bone resorption, transforming growth factor β (TGF-ß) release stimulating cancer cell growth and osteoblastic activity resulting in the formation of poor-quality bone replacing previously healthy bone (Pauk et al., 2022).
- Hormone Changes: One important tumor factor for many patients is the development of cachexia. Age-related reductions in muscle quality and quantity (sarcopenia) from an accumulation of comorbidities, declines in activity and changes in anabolic hormones, are compounded by cancer-related changes that heighten a protein-deficit state (Williams et al., 2019). Cancer cachexia occurs in part as a result of tumor release of soluble factors such as inflammatory cytokines, exosomes, and metabolites that enhance host metabolism and suppress appetite (Fearon et al., 2012). In addition, some cancer treatment modalities induce hormone changes that accelerate frailty. For example, in prostate cancer, one of the most common cancers diagnosed in older adults, the primary treatment modality causes androgen depletion, which accelerates sarcopenia and frailty, leading to high-grade falls and fractures (Mohile et al., 2009).
- Organ Damage: Certain cancer treatment modalities may lead to direct organ damage that accelerate aging. For example, in cancers of the head and neck, surgical resection of the tumors can cause permanent damage to nearby vital organs. The local effects of radiation and chemotherapy can cause mucositis (inflammation of the mouth and throat) and subsequent swallowing problems can result in malnutrition, and weight loss, and may even necessitate the placement of a feeding tube. Long-term side effects include dental cavities, degeneration of bone and scaring of local tissue (radiation fibrosis syndrome) that further impact nutritional and quality of life for survivors (Dickstein et al., 2022).
Adult cancer survivors in their seventh decade of life and older are often frail, with some prevalence estimates as high as 60% varying with the history of treatment exposures, other chronic diseases, lifestyle, and access to care (Ness & Wogksch, 2020). Smoking, obesity, sedentary behavior, radiation exposure to the brain or body, extremity amputation, thoracic surgery, platinum exposure, hematopoietic stem cell transplantation, and the development of severe neurologic or cardiopulmonary complications have all been implicated as potential contributors to the high prevalence of frailty in cancer survivors (Ness & Wogksch, 2020).
Applying Knowledge of Frailty in Cancer
An Expert Panel convened by the American Society of Clinical Oncology in 2018 supports the use of a comprehensive geriatric assessment (CGA) to identify vulnerabilities not captured in the routine oncology visit of patients ≥ 65 years old receiving chemotherapy. This assessment should include measures of function, comorbidity, falls, depression, cognition, and nutrition. The results of a CGA should inform and guide the development of a personalized approach to the cancer management plan.
CGA-guided interventions should also seek to manage any health problems contributing to frailty identified by this assessment (Mohile et al., 2018). Referral to physical or occupation therapy for strength and balance training, the management of polypharmacy, targeted treatment of depression, and nutritional rehabilitation represents some of the proposed frailty-targeting interventions recommended by this group that can be coupled with cancer treatment. The goal is to improve the ability of the patient to tolerate cancer treatment and minimize progression of frailty.
Four randomized clinical trials (RCT) support the implementation of CGA‐guided interventions in older adults with cancer as they lead to improvements in quality of life and decreased treatment toxicity without compromising survival. One of the largest and most innovative RCTs, GAP‐70 by Mohile et al. (2021), provided CGA‐based recommendations to treating oncologists at 40 community practice sites in the U.S. where geriatricians were unavailable for adults aged 70 and older with at least one impaired CGA domain. CGA-guided interventions resulted in less toxicity and fewer falls as well as deprescribing of inappropriate medications, with similar rates of survival compared to the non-intervention group.
Barriers to implementation of CGA-guided interventions such as organizational challenges, lack of time, limited staffing, lack of training, and knowledge of available tools are all common challenges that require a coordinated effort to solve (Dale et al., 2021). Telehealth may facilitate access to geriatricians in areas that lack local expertise.
The identification of frailty might be an indication to significantly alter treatment aggressiveness, but research in this space has had mixed results (Soto-Perez-de-Celis et al., 2020). Prior RCTs like GAP-70 can be a roadmap to designing future treatment adaptation studies, which are much needed to challenge the “more is better” paradigm (Shah et al., 2021). Innovative technologies and digital solutions such as the consultative processing and extraction of real-world geriatric data from electronic medical records or the use of remote sensors could also be leveraged to improve the care of older patients with cancer (Extermann et al., 2022).
Geriatric oncology remains an exciting area for aging- and frailty-related research. With the transformative changes in general cancer therapeutics over the last decade, there is immense potential to improve the lives and well-being of older adults who live with or survive cancer and its treatments.