Table 2.

Summary of systematic reviews reporting on the predictive value or association of GAs/GA domains

Review Characteristics			Reported outcomes as mapped to core areas of COMET taxonomy
Author (Year)	Number /Types of included studies	GA as defined by review criteria	Death	Life impact		Resource use	Adverse events
			Mortality	Treatment completion and other treatment-related outcomes	Other outcomes	Healthcare use	Treatment-related toxicity or complications	Peri-operative complications
Puts (2012) [14]	73 – cohort, cross-sectional or chart reviews	Not explicitly defined	- Impairments on GA domains associated with mortality varied across 8/16 studies			- Age, poorer mental health associated with greater use of social resources in single study -Cognitive impairment predicted visits to emergency department in single study	- Impairments on GA domains associated with treatment complications varied across 6/9 studies
Puts (2014) [23]	34 - longitudinal observation, cross-sectional, retrospective studies, phase II/III trials	Not explicitly defined	- Impairments on varied GA domains associated with increased mortality risk across 11 studies			- Increased frailty associated with increased hospital costs, discharge to care facility and re-admission rates in single study	- Impairments on varied GA domains predicted treatment toxicity/complications across 7 studies
Hamaker (2012) [30]	37 – prospective, retrospective studies	Assessment using validated assessment tools composed of ≥ 2 domains.	- Frailty (3/4 studies), nutritional status (in all 4 studies), and comorbidity assessed by the Cumulative Illness Rating Scale for Geriatrics (in 4/5 studies) predicted all-cause mortality	-Cognitive function (in 2/3 studies) and ADL impairment (2/3 studies) associated with lower completion or dose reduction -Comorbidity predicted lower completion rates in 3/4 studies			- Summary score based on GA associated with chemotherapy-related toxicity in 2/3 studies	- IADL impairment predicted peri-operative complications in 3/4 studies
Ramjaun (2013) [33]	9 – prospective cohort studies	Conducted before treatment which included functional status or autonomy, nutritional status, cognitive function, polypharmacy and the presence of geriatric syndromes	- Nutrition (HR 1.84 to 2.54), function (HR 1.04 to 1.22) and geriatric syndromes seemed to be most important predictors across 7 studies				- Functional status and the presence of geriatric syndromes, such as impaired hearing most frequently associated with chemotherapy-related toxicity across 3 studies	- Severe comorbidity highly associated with severe complications and functional status significantly associated with experiencing any complication in single study
Hamaker (2013) [27]	15 – cohort studies	Assessment using validated assessment tools composed of ≥ 2 domains.	- Impairments in IADL (55%), cognition (83%), physical function (100%) and malnutrition (67%) were associated with mortality across 10 studies	- Univariate analysis showed poor performance status, falls, IADL dependency associated with treatment non-completion in single study	- Two studies reporting changes in GA domains. -Improvement in depressive symptoms or emotional functioning and subjective measure of health across two studies - Improvement in fatigue post induction chemotherapy in single study		- Comorbidity as risk factor for grade 3–4 chemotherapy-related non-haematological toxicity (OR = 6.13, 95% CI 1.65–22) in single study
Versteeg (2014) [31]	13 - cohort studies, non-randomized trials	Not explicitly defined	- Nutritional status consistent predictor of mortality across 3/5 studies.				- No consistent factors that predicted toxicity across 6 studies
Caillet (2014) [24]	35 - prospective, cross-sectional, randomised trials	Assessment of at least five CGA domains	- IADL dependency or ECOG-PS, mobility impairment, cognition, depressive mood, malnutrition, comorbidities independent predictors or mortality across nine studies.				- IADL dependency or ECOG-PS, mobility impairment, cognition, malnutrition, social difficulties, polypharmacy independent significant associated with chemotoxicity across four studies.
Feng (2015) [32]	6 – prospective studies	Any combination of CGA components were included.	- No CGA domains predicted post-operative mortality across 4 studies			- Frailty, IADL, depression predicted discharge to nonhome institution across 2 studies - ADLs (n = 1), nutrition (n = 2), inability to feed or shop for oneself (n = 1) and polypharmacy (n = 1) associated with longer length of stay − 1/2 studies reported worse frailty scores predicted postoperative readmission		- IADL (n = 1), fatigue (n = 1), frailty (n = 2) predicted overall complications - Cognition (n = 1), frailty (n = 2), ADL (n = 1), IADL (n = 1), depression (n = 2) predicted major complications.
Schulkes (2016) [25]	18 – cohort studies	Assessment using validated tools, composing ≥ 2 domains	- Univariate and multivariate analysis of 6 studies demonstrated association between objective physical capacity, nutritional status, and mortality	− 2/4 studies reported associations between GA and treatment completion -IADL as factors across both studies			− 2/5 studies reported associations between GA and chemotherapy-related toxicity
Molina-Garrido (2017) [29]	8 – cohort studies	Not explicitly defined.	- Frailty was associated with overall survival (frail taxane treated patients had better overall survival, p = .025 compared to no taxane-treated patients with prostate cancer) in single study	- statistically significant relationship between basal information and presence of early chemotherapy discontinuation (p = .037) reported in single study
van Deudekom (2016) [44]b	31 – longitudinal studies	Not reported - only specified functional, cognitive impairment, social environment and frailty.	- Function (9/12 studies) associated with overall survival - Marital status (in 6/8 studies) and living situation (in 1 study) associated with overall survival - Depression was a predictor of overall survival in 1/3 studies		- Depressive symptoms (in 4 studies) associated with lower quality of life. -Patients with no partner (in 2 studies) had lower quality of life than those who had a partner.	- Moderate-severe depressive symptoms predicted longer length of stay in a single study - Significant association between IADL dependence and prolonged length of stay in single study (RR 1.97, 95% CI 1.07–3.61)		- Cognitive impairment (aHR = 3.83, (95% CI 1.70–8.63)) (n = 1) and living alone (n = 1) significantly more frequent post-operative delirium
van Deudekom (2018) [43]b	19 – longitudinal studies	Not reported - only specified functional, cognitive impairment, social environment and frailty.	- Karnosfky performance score associated with survival in a single study			- Decreased function status associated with increased length of stay in single study	- No statistically significant association between functional status and risk of grade 3 toxicity in a single study	- Statistically significant association between physical functioning and postoperative complications in single study (OR = 28.3 95% CI = 3.5–227.7) - Cognitive impairment associated with postoperative delirium reported in single study - Depression associated with postoperative delirium reported in single study
Szumacher (2018) [26]	12 - retrospective, cross-sectional, prospective trials	Not explicitly defined.	- Lower G8 scores correlated with increased frequency of mortality in two studies	-Trend towards lower treatment completion rates for vulnerable patients based on G8 or VES-13 across 2 studies - Non statistically significant association between CGA and treatment tolerance across 6 studies	-Cancer specific CGA predicted fatigue (beta 1.75, standard error 0.49) in single study
Xue (2018) [36]	6 – cohort studies	CGA – not explicitly defined.						• Meta-analysis (6 studies) identified predictive value of comorbidity (measured by CCI), polypharmacy (≥ 5 drugs/day) and impairments ADL with 30-day postoperative major complications • Polypharmacy, pain scale score > 0 and ≥ 10% weight loss were related to 90-day postoperative major outcomes in single study
Bruijnen (2019) [16]	46 – prospective, retrospective studies	Excluded comorbidity as GA domain as considered routine oncological workup.	- Physical function (5/8 studies) and nutrition (13/23 studies) were most associated with mortality				- Physical function (in all 4 studies) and nutrition (in 5/6 studies) were most associated with chemotherapy-related outcomesa	- Physical function (in 3/4 studies) commonly associated with post-operative complications
Couderc (2019) [45]	40 – observational studies, randomised clinical trials, non-randomised intervention studies	Not defined.	- Significant association between functional status and overall survival in 11/22 studies	- ADL predicted changes in treatment decisions in 2/3 studies - IADL predicted treatment feasibility in 2/5 studies			- IADL significantly associated with chemotoxicity 2/7 studies	- Functional status predicted postoperative complications in 4/6 studies
Salazar (2019) [34]	7 – cohort studies	Must include ≥ 2 of the following domains: nutrition, cognition, functional status, polypharmacy, social support, and/or comorbidities	- Meta-analysis of 3/7 studies demonstrated significant increased hazard ratio for death in patients with ADL ≤ 4 (HR = 1.576; 95% CI, 1.051–2.102; P = .647)				-Significant increased risk of nonhematologic adverse events in frail patients compared to fit patients across 3 studies ( HR = 2.169; 95% CI, 1.002–2.336; P = .221)
Scheepers (2020) [28]	44 – Not reported	Assessment composed of ≥ 2 domains.	- Univariate analysis (27/29 studies) showed significant association between at least one geriatric impairment and mortality	- Frailty (based on screening tool or summarised GA) associated with higher risk of non-completion across 4 studies		− 6/7 studies reported association between geriatric impairments and healthcare use - Impaired physical capacity associated with increased used in 4 studies	−6/10 studies reported association for treatment toxicity -Frailty (based on summarised GA) associated with treatment-toxicity in 4 studies
Szabat (2021) [35]	10 – retrospective controlled clinical trial, cohort studies,	Not defined.						- Functional impairment as reliable risk factor for postoperative complications in most studies - Function impairment predicted post-operative delirium in single study - Cognition (n = 1), comorbidity (n = 1), polypharmacy (n = 1), depression (n = 2) associated with increased risk of post-operative complications

ADL activies of daily living, IADL independent activies of daily living, CCI Charlson Comorbidity Index, CIRS-G Cumulative Illness Rating Scale for Geriatrics, ECOG-PS Eastern Cooperative Oncology Group Performance Status CI confidence interval, OR odds ratio, HR hazard ratio, aHR adjusted for age hazard ratio

^a Chemotherapy-related outcomes included toxicity, early withdrawal, functional decline after chemotherapy. ^b Outcomes reported in these reviews were generally grouped or reported together as “adverse outcome”. This was defined as mortality, functional or cognitive decline, adverse events during treatment, prolonged length of hospitalization and health related quality of life