Oncology

Introduction: Cancer and Frailty

Image of cancer cellsCancer 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.

Nephrology

Frailty is highly prevalent among those with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). In patients treated with hemodialysis (the most common form of treatment for those with ESKD), two studies have reported physical frailty in 68%-73% of patients (Johansen et al., 2007; Bao et al., 2012).

Kidney Disease, Kidney Transplant, and Frailty

Introduction

Frailty is highly prevalent among those with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). In patients treated with hemodialysis (the most common form of treatment for those with ESKD), two studies have reported physical frailty in 68%-73% of patients (Johansen et al., 2007; Bao et al., 2012). A study of kidney transplant candidates and recipients, in contrast, reported 20% of patients were frail based on the physical frailty phenotype. The difference in these two sets of estimates suggests a potential effect of selection for surgical intervention, including a younger age (see below; Chu et al., 2020).

Both CKD and aging are risk factors for the physical frailty phenotype. Kidney disease is associated with physical and cognitive declines that are similar to those seen during aging, and is therefore considered to cause accelerated aging (McAdams-DeMarco. et al., 2015). Even among patients at early stages of CKD (stage<4), frailty prevalence is increased compared to healthy age-matched controls (Smyth et al., 2013). Similarly, there is a substantial burden of frailty even in younger patients when CKD is severe, such as among kidney transplant candidates and recipients (Chu, et al., 2020).

Kidney transplant (KT) is the optimal treatment for ESKD, yet many individuals are not considered for this because of decreased pre-transplant physical function, and specifically frailty (Haugen et al., 2019). The interdependence of frailty and ESKD makes this even more challenging to navigate clinically, as not undergoing transplant to improve renal function may then contribute to worsening physical function. Therefore, in order to improve care for ESKD, research is needed to improve our understanding of the differences and similarities in ESKD outcomes and KT in frail and non-frail patients, and whether treatments directed at one of these two conditions can to be leveraged to ameliorate the other, in order to optimize treatment decisions and develop effective interventions.

Impact of Frailty on Kidney Disease

In the interplay between aging, frailty, and kidney disease, CKD accelerates aging and aging hastens the progression of kidney disease. This latter phenomenon has been described as “senescent nephropathy” (Worthen & Tennankore, 2019). The combination leads to a vicious cycle with worse outcomes. Frailty is associated with higher mortality and hospitalizations in patients with ESKD (Bao et al., 2012; McAdams-DeMarco et al., 2013). Patients with ESKD awaiting transplant who are physically frail experience worse health-related quality of life (McAdams-Demarco et al., 2016) as well as increased mortality (McAdams-Demarco et al., 2018; Lai et al., 2014).

Frailty has been associated with a higher estimated glomerular filtration rate (eGFR) at dialysis initiation, which might suggest better renal function in this population. However, sarcopenia can partially explain this association, since eGFR overestimates true GFR among people with muscular atrophy. This patient population is also likely to have a higher symptom burden at a given eGFR, leading to what appears to be an “earlier” dialysis start in the hope of ameliorating such impacts. Improving the measures of renal function by incorporating an understanding of the impact of muscle mass, frailty and age on the traditional serum markers, is an active area of research (Pavkov & Nelson, 2019).

Kidney transplant itself, although the preferred treatment for ESKD overall, is less well tolerated in frail ESKD patients. After transplant surgery, frailty is associated with increased risk of many post-transplant complications. In a series of papers on a well-established 10-year prospective cohort study of aging and kidney transplantation at Johns Hopkins, increased risk has been documented for immediate poor outcomes such as delirium, longer length of stay, early hospital readmission as well as longer term problems with immunosuppression, intolerance, poor quality of life, cognitive decline and mortality. (See the list of references from this cohort below.)

The vast majority of kidney transplant programs in the US recognize frailty as an important variable to be considered in transplant candidates. However, the inclusion of this concept in practice has been challenging due to the diversity of available tools (see instruments page) and a lack of a validated single kidney-specific version to measure frailty (McAdams-DeMarco et al., 2020). It is important to note that the method used will influence the prevalence of frailty. A systematic review on frailty and CKD showed a lack of correlation between performance-based tests compared to questionnaires, which means that the relationships between frailty and CKD will be different in studies with different methods (Chowdhury et al., 2017).

Impact of Kidney Disease on Frailty

As with other conditions that accelerate aging (see HIV section), kidney disease predisposes to frailty through a variety of direct and indirect effects including elevated inflammation, low levels of physical activity, a substantial burden of comorbidity, and years of dialysis treatment. For example, the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor alpha, which may play a role in loss of muscle mass and sarcopenia, have been shown to be elevated in patients with CKD (Chowdhury et al., 2017). In fact, such markers of inflammation can be used to improve waitlist mortality prediction, consistent with a causal role in the declining health associated with CKD (McAdams-DeMarco et al., 2018).

The prevalence of frailty increases as eGFR declines, and is highest in patients receiving dialysis even at younger ages, suggesting a correlation between kidney disease and accelerated biological aging. In addition, advanced age, female sex, and hemodialysis (compared to peritoneal dialysis) have been independently associated with frailty (Johansen, JASN, 2007).

Applying Knowledge of Frailty in Kidney Disease and Kidney Transplant

Although the presence of frailty is clearly a risk factor for adverse outcomes in patients with CKD, it is not known yet whether intervention along the path from early CKD to ESKD would render frailty a reversible risk factor. Also, screening and better identifying frail patients, as well as flagging those at risk of progressing to frailty, may help inform discussions on the different therapeutic options in advanced kidney disease. Considering frailty will allow a more patient-centered approach including options like active medical management of kidney disease, palliative care, dialysis and/or transplantation (Crews et al., 2019).

Significant work is needed to identify interventions which will reduce the burden of frailty in ESKD and improve the tolerability of transplant in this population. It also is needed to rigorously evidence the efficacy of targeting treatment plans by frailty status. Doing so also requires a better research consensus on measuring frailty in patients with kidney disease. The American Society of Transplantation held a Consensus Conference in 2018 to address the measurement and use of frailty in transplantation (Kobashigawa et al., 2019). The Conference recommended identifying an optimal method to measure frailty for KT recipients, which can support efforts to develop novel interventions to reduce the risk of adverse post-KT outcomes among frail recipients.

References from a prospective cohort study of aging and kidney transplantation at Johns Hopkins:

Haugen CE, Mountford A, Warsame F, Berkowitz R, Bae S, A GT, Brown CHt, Brennan DC, Neufeld KJ, Carlson MC, Segev DL, McAdams-DeMarco M. Incidence, Risk Factors, and Sequelae of Post-kidney Transplant Delirium. J Am Soc Nephrol. 2018. Epub 2018/04/25. doi: 10.1681/ASN.2018010064. PubMed PMID: 29685884.

McAdams-DeMarco MA, King EA, Luo X, Haugen C, DiBrito S, Shaffer A, Kucirka LM, Desai NM, Dagher NN, Lonze BE, Montgomery RA, Walston J, Segev DL. Frailty, Length of Stay, and Mortality in Kidney Transplant Recipients: A National Registry and Prospective Cohort Study. Annals of surgery. 2016b. doi: 10.1097/SLA.0000000000002025. PubMed PMID: 27655240.

McAdams-DeMarco MA, Law A, Salter ML, Chow E, Grams M, Walston J, Segev DL. Frailty and early hospital readmission after kidney transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013;13(8):2091-5. Epub 2013/06/05. doi: 10.1111/ajt.12300. PubMed PMID: 23731461; PMCID: 4000567.

McAdams-DeMarco MA, Law A, Tan J, Delp C, King EA, Orandi B, Salter M, Alachkar N, Desai N, Grams M, Walston J, Segev DL. Frailty, mycophenolate reduction, and graft loss in kidney transplant recipients. Transplantation. 2015a;99(4):805-10. doi: 10.1097/TP.0000000000000444. PubMed PMID: 25393156; PMCID: PMC4382409.

McAdams-DeMarco MA, Olorundare IO, Ying H, Warsame F, Haugen CE, Hall R, Garonzik-Wang JM, Desai NM, Walston JD, Norman SP, Segev DL. Frailty and Postkidney Transplant Health-Related Quality of Life. Transplantation. 2018b;102(2):291-9. Epub 2017/09/09. doi: 10.1097/TP.0000000000001943. PubMed PMID: 28885489; PMCID: PMC5790611.

Chu NM, Gross AL, Shaffer AA, Haugen CE, Norman SP, Xue QL, Sharrett AR, Carlson MC, Bandeen-Roche K, Segev DL, McAdams-DeMarco MA. Frailty and Changes in Cognitive Function after Kidney Transplantation. J Am Soc Nephrol. 2019;30(2):336-45. Epub 2019/01/27. doi: 10.1681/ASN.2018070726. PubMed PMID: 30679381; PMCID: PMC6362628.

McAdams-DeMarco MA, Law A, King E, Orandi B, Salter M, Gupta N, Chow E, Alachkar N, Desai N, Varadhan R, Walston J, Segev DL. Frailty and mortality in kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015b;15(1):149-54. doi: 10.1111/ajt.12992. PubMed PMID: 25359393; PMCID: PMC4332809.