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Geriatric impairments are associated with reduced quality of life and physical function in older patients with cancer receiving radiotherapy - A prospective observational study.

  • Guro Falk Eriksen
    Correspondence
    Corresponding author at: The Research Center for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, P.O Box 68, 2313 Ottestad, Norway.
    Affiliations
    The Research Center for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, 2313 Ottestad, Norway

    Department of Internal Medicine, Hamar Hospital, Innlandet Hospital Trust, Postboks 4453, 2326 Hamar, Norway

    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Pb 1171 Blindern, 0318 Oslo, Norway
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  • Jūratė Šaltytė Benth
    Affiliations
    The Research Center for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, 2313 Ottestad, Norway

    Institute of Clinical Medicine, Campus Ahus, University of Oslo, P.O.Box 1171, 0318 Blindern, Norway

    Health Services Research Unit, Akershus University Hospital, P.O.Box 1000, 1478 Lørenskog, Norway
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  • Bjørn Henning Grønberg
    Affiliations
    Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU),Trondheim, Norway

    Department of Oncology, St. Olavs Hospital, Trondheim University Hospital, NO-7491 Trondheim, Norway
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  • Siri Rostoft
    Affiliations
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Pb 1171 Blindern, 0318 Oslo, Norway

    Department of Geriatric Medicine, Oslo University Hospital, Pb 4956 Nydalen, 0424 Oslo, Norway
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  • Lene Kirkhus
    Affiliations
    Department of Oncology, Oslo University Hospital, Pb 4956 Nydalen, 0424 Oslo, Norway
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  • Øyvind Kirkevold
    Affiliations
    The Research Center for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, 2313 Ottestad, Norway

    The Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Postboks 2136, 3103 Tønsberg, Norway

    Faculty of Health, Care and Nursing, NTNU Gjøvik, Box 191, N-2802 Gjøvik, Norway
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  • Line Merethe Oldervoll
    Affiliations
    Center for Crisis Psycology, Faculty of Psychology, University of Bergen, PB 7807, 5020 Bergen, Norway

    Department of Public Health and Nursing, NTNU, PB 8905, 7491 Trondheim, Norway
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  • Asta Bye
    Affiliations
    Department of nursing and Health Promotion, Faculty of Health Sciences, Oslo Metropolitan University, Postboks 4, St. Olavs plass, 0130 Oslo, Norway
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  • Anne Hjelstuen
    Affiliations
    Department of Internal Medicine, Innlandet Hospital Trust, Kyrre Grepps gate 11, 2819 Gjøvik, Norway.
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  • Marit Slaaen
    Affiliations
    The Research Center for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, 2313 Ottestad, Norway

    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Pb 1171 Blindern, 0318 Oslo, Norway
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Open AccessPublished:September 27, 2022DOI:https://doi.org/10.1016/j.jgo.2022.09.008

      Abstract

      Introduction

      Quality of life (QoL) and function are important outcomes for older adults with cancer. We aimed to assess differences in trends in patient-reported outcomes (PROs) during radiotherapy (RT) between (1) groups with curative or palliative treatment intent and (2) groups defined according to the number of geriatric impairments.

      Materials and Methods

      A prospective observational study including patients aged ≥65 years receiving curative or palliative RT was conducted. Geriatric assessment (GA) was performed before RT, and cut-offs for impairments within each domain were defined. Patients were grouped according to the number of geriatric impairments: 0, 1, 2, 3, and ≥ 4. Our primary outcomes, global QoL and physical function (PF), were assessed by The European Organisation for Research and Treatment of Cancer Quality-of-Life Core Questionnaire (EORTC) (QLQ-C30) at baseline, RT completion, and two, eight, and sixteen weeks later. Differences in trends in outcomes between the groups were assessed by linear mixed models.

      Results

      301 patients were enrolled, mean age was 73.6 years, 53.8% received curative RT. Patients receiving palliative RT reported significantly worse global QoL and PF compared to the curative group. The prevalence of 0, 1, 2, 3 and ≥ 4 geriatric impairments was 16.6%, 22.7%, 16.9%, 16.3% and 27.5%, respectively. Global QoL and PF gradually decreased with an increasing number of impairments. These group differences remained stable from baseline throughout follow-up without any clinically significant changes for any of the outcomes.

      Discussion

      Increasing number of geriatric impairments had a profound negative impact on global QoL and PF, but no further decline was observed for any group or outcome, indicating that RT was mainly well tolerated. Thus, geriatric impairments per se should not be reasons for withholding RT. GA is key to identifying vulnerable patients in need of supportive measures, which may have the potential to improve treatment tolerance.
      Registered at clinicaltrials.gov (NCT03071640).

      Keywords

      1. Introduction

      The prevalence of older adults with cancer is increasing, and advancing age inherently leads to a gradual decline in functional reserves and reduced life expectancy. This can influence older adult patients' preferences regarding cancer treatment [
      • van Walree I.C.
      • van Soolingen N.J.
      • Hamaker M.E.
      • Smorenburg C.H.
      • Louwers J.A.
      • van Huis-Tanja L.H.
      Treatment decision-making in elderly women with ovarian cancer: an age-based comparison.
      ,
      • Pergolotti M.
      • Deal A.M.
      • Williams G.R.
      • Bryant A.L.
      • Bensen J.T.
      • Muss H.B.
      • et al.
      Activities, function, and health-related quality of life (HRQOL) of older adults with cancer.
      ,
      • Celis E.S.P.D.
      • Li D.
      • Sun C.-L.
      • Kim H.
      • Twardowski P.
      • Fakih M.
      • et al.
      Patient-defined goals and preferences among older adults with cancer starting chemotherapy (CT).
      ,
      • Shrestha A.
      • Martin C.
      • Burton M.
      • Walters S.
      • Collins K.
      • Wyld L.
      Quality of life versus length of life considerations in cancer patients: a systematic literature review.
      ]. Maintaining functional status and independence are important priorities for many older adults [
      • Celis E.S.P.D.
      • Li D.
      • Sun C.-L.
      • Kim H.
      • Twardowski P.
      • Fakih M.
      • et al.
      Patient-defined goals and preferences among older adults with cancer starting chemotherapy (CT).
      ,
      • Kenis C.
      • Decoster L.
      • Bastin J.
      • Bode H.
      • Van Puyvelde K.
      • De Grève J.
      • et al.
      Functional decline in older patients with cancer receiving chemotherapy: a multicenter prospective study.
      ,
      • Fried T.R.
      • Bradley E.H.
      • Towle V.R.
      • Allore H.
      Understanding the treatment preferences of seriously ill patients.
      ]. As a consequence, patient-centered outcomes such as quality of life (QoL) and function are crucial and should be addressed in clinical trials targeting older adults [
      • Scotte F.
      • Bossi P.
      • Carola E.
      • Cudennec T.
      • Dielenseger P.
      • Gomes F.
      • et al.
      Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide.
      ].
      Radiotherapy (RT) is a mainstay in cancer treatment, and it is estimated that approximately 50–60% of patients with cancer are offered irradiation at some point [
      • Somasundar P.
      • Mourey L.
      • Lozza L.
      • Maggi S.
      • Stepney R.
      Advances in geriatric oncology: a multidisciplinary perspective.
      ,
      • O’Donovan A.
      • Leech M.
      • Gillham C.
      Assessment and management of radiotherapy induced toxicity in older patients.
      ]. Curative RT may involve several weeks of daily treatment, and a transient decline in health status might be acceptable in exchange for longevity [
      • O’Donovan A.
      • Leech M.
      • Gillham C.
      Assessment and management of radiotherapy induced toxicity in older patients.
      ]. By contrast, the aim of palliative RT is to alleviate symptoms and/or provide local tumour control through a short treatment course, thereby improving QoL at minimal inconvenience [
      • Lutz S.T.
      • Jones J.
      • Chow E.
      Role of radiation therapy in palliative care of the patient with cancer.
      ,
      • Spencer K.
      • Parrish R.
      • Barton R.
      • Henry A.
      Palliative radiotherapy.
      ]. However, irrespective of treatment intent, RT can cause severe short- and long-term toxicities that could be localised depending on the radiated site, or generalised, such as fatigue. As shown in other oncologic treatment settings, vulnerable patients with several geriatric-related problems may be more prone to some of these negative consequences [
      • Nehlsen A.
      • Agarwal P.
      • Mazumdar M.
      • Dutta P.
      • Goldstein N.E.
      • Dharmarajan K.V.
      Impact of radiotherapy on daily function among older adults living with advanced cancer (RT impact on function in advanced cancer).
      ,
      • VanderWalde N.A.
      • Deal A.M.
      • Comitz E.
      • Stravers L.
      • Muss H.
      • Reeve B.B.
      • et al.
      Geriatric assessment as a predictor of tolerance, quality of life, and outcomes in older patients with head and neck cancers and lung cancers receiving radiation therapy.
      ,
      • Mohile S.G.
      • Heckler C.
      • Fan L.
      • Mustian K.
      • Jean-Pierre P.
      • Usuki K.
      • et al.
      Age-related differences in symptoms and their interference with quality of life in 903 Cancer patients undergoing radiation therapy.
      ,
      • Rostoft S.
      • O’Donovan A.
      • Soubeyran P.
      • Alibhai S.M.H.
      • Hamaker M.E.
      Geriatric assessment and management in cancer.
      ]. To fully consider the pros and cons, it is therefore essential to gain knowledge of how older adult patients undergoing RT perceive their QoL and function during the course of treatment.
      Geriatric assessment (GA) is a means to address the diversity in older adult patients' health status and entails a comprehensive appraisal of typical age-related health issues such as comorbidities, and physical- and cognitive functioning [
      • O’Donovan A.
      • Mohile S.G.
      • Leech M.
      Expert consensus panel guidelines on geriatric assessment in oncology.
      ]. Frailty is a broad term encompassing older adults' gradual loss of organ- and functional reserves leading to increased vulnerability to stressors and increased risk of negative outcomes [
      • Handforth C.
      • Clegg A.
      • Young C.
      • Simpkins S.
      • Seymour M.T.
      • Selby P.J.
      • et al.
      The prevalence and outcomes of frailty in older cancer patients: a systematic review.
      ]. For practical reasons, frailty is often defined as the presence of ≥1 or ≥ 2 impaired GA domains [
      • Handforth C.
      • Clegg A.
      • Young C.
      • Simpkins S.
      • Seymour M.T.
      • Selby P.J.
      • et al.
      The prevalence and outcomes of frailty in older cancer patients: a systematic review.
      ,
      • Balducci L.
      • Extermann M.
      Management of cancer in the older person: a practical approach.
      ]. There is emerging evidence that both individual GA domains and frailty are related to a decline in patient-reported outcomes (PROs) including QoL, physical function, and a higher symptom burden [
      • Pergolotti M.
      • Deal A.M.
      • Williams G.R.
      • Bryant A.L.
      • Bensen J.T.
      • Muss H.B.
      • et al.
      Activities, function, and health-related quality of life (HRQOL) of older adults with cancer.
      ,
      • Kirkhus L.
      • Saltyte Benth J.
      • Gronberg B.H.
      • Hjermstad M.J.
      • Rostoft S.
      • Harneshaug M.
      • et al.
      Frailty identified by geriatric assessment is associated with poor functioning, high symptom burden and increased risk of physical decline in older cancer patients: prospective observational study.
      ,
      • Williams G.R.
      • Deal A.M.
      • Sanoff H.K.
      • Nyrop K.A.
      • Guerard E.J.
      • Pergolotti M.
      • et al.
      Frailty and health-related quality of life in older women with breast cancer.
      ,
      • O’Donovan A.
      • Leech M.
      Personalised treatment for older adults with cancer: the role of frailty assessment.
      ,
      • Decoster L.
      • Quinten C.
      • Kenis C.
      • Flamaing J.
      • Debruyne P.R.
      • De Groof I.
      • et al.
      Health related quality of life in older patients with solid tumors and prognostic factors for decline.
      ,
      • VanderWalde N.
      • Hurria A.
      • Jagsi R.
      Improving consistency and quality of Care for Older Adults with Cancer: the challenges of developing consensus guidelines for radiation therapy.
      ]. Whether this applies to older patients undergoing RT is hitherto scarcely investigated [
      • VanderWalde N.
      • Hurria A.
      • Jagsi R.
      Improving consistency and quality of Care for Older Adults with Cancer: the challenges of developing consensus guidelines for radiation therapy.
      ,
      • Szumacher E.
      • Sattar S.
      • Neve M.
      • Do K.
      • Ayala A.P.
      • Gray M.
      • et al.
      Use of comprehensive geriatric assessment and geriatric screening for older adults in the radiation oncology setting: a systematic review.
      ,
      • Shinde A.
      • Vazquez J.
      • Novak J.
      • Sedrak M.S.
      • Amini A.
      The role of comprehensive geriatric assessment in radiation oncology.
      ]. Furthermore, in real life, frailty represents a continuum of a patient's reduced reserve capacity and can be understood as a syndrome of age-related accumulated deficits [
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • Bergman H.
      • Hogan D.B.
      • McDowell I.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      ,
      • Rockwood K.
      • Mitnitski A.
      Frailty in relation to the accumulation of deficits.
      ]. Whether the sum of these acquired deficits is reflected in a corresponding gradual decline in QoL and physical function remains uncertain.
      We have previously shown that the GA domains nutritional- and functional status were independently predictive of mortality in a cohort of older patients with cancer receiving RT with curative or palliative treatment intent [
      • Eriksen G.F.
      • Šaltytė Benth J.
      • Grønberg B.H.
      • Rostoft S.
      • Kirkhus L.
      • Kirkevold Ø.
      • et al.
      Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: a prospective observational study.
      ]. In the present paper, targeting the same population, we aimed to assess differences in trends in patient-reported QoL and function during the course of RT between (1) groups with different treatment intent and (2) groups defined according to the number of geriatric impairments identified by GA.

      2. Material and Methods

      2.1 Patients

      From February 2017 to July 2018, we conducted a prospective, single-centre observational study at the Radiotherapy Unit, Innlandet Hospital Trust, Norway. The inclusion criteria were referral for RT with curative or palliative treatment intent, age ≥ 65 years, histologically confirmed malignant disease, inhabitant of Innlandet County, fluent in oral and written Norwegian, and capable of answering self-report questionnaires.

      2.2 Assessments

      Prior to irradiation, patients underwent GA mainly performed by a trained oncology nurse, not a multi-disciplinary team, henceforth referred to as modified GA (mGA). The following nine mGA domains were assessed using validated scales: comorbidities, medications, nutritional status, mobility, falls, basic activities of daily living (ADL), instrumental ADL (IADL), and cognitive and emotional function (Table 1). The treating radiation oncologists were blinded for mGA results. Cut-off points for geriatric impairment within each domain were retrospectively set based on well-established and/or commonly used reference values (Table1), as elaborated in a previous publication [
      • Eriksen G.F.
      • Šaltytė Benth J.
      • Grønberg B.H.
      • Rostoft S.
      • Kirkhus L.
      • Kirkevold Ø.
      • et al.
      Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: a prospective observational study.
      ]. Patients with complete mGA were stratified into five groups according to the number of geriatric impairments present at baseline: 0, 1, 2, 3, or ≥ 4. This excluded three patients with missing Montreal Cognitive Assessment (MoCA) tests. Patients with missing Timed up and Go (TUG) due to the inability to perform the test (n = 19), were classified as having an impairment in this domain. Baseline sociodemographic and medical data were attained through patients' interviews supplemented by their electronic medical records. Data collected included Eastern Cooperative Oncology Group performances status (ECOG PS) (dichotomized to 0–1 or 2–4), cancer diagnosis (grouped as breast-, prostate-, lung- or other types of cancer), RT regimen, and treatment intent (curative or palliative).
      Table 1Geriatric assessment scales and cut-off points for geriatric impairments.
      DomainAssessmentRated byVariable nameScores and rangeInterpretationCut-off for impairment
      ComorbidityCharlson Comorbidity Index [
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ,
      • Sundararajan V.
      • Henderson T.
      • Perry C.
      • Muggivan A.
      • Quan H.
      • Ghali W.A.
      New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.
      ]
      Patient/NurseCCI0–26 (continuous)Higher score = more comorbidity≥2
      MedicationsRegistration of regular medications by ATC
      Anatomical Therapeutic Chemical Classification System.
      system
      NurseMedicationsNumber of daily medications≥5
      Nutritional statusMini Nutritional Assessment Short Form [
      • Rubenstein L.Z.
      • Harker J.O.
      • Salva A.
      • Guigoz Y.
      • Vellas B.
      Screening for undernutrition in geriatric practice: developing the short-form mini-nutritional assessment (MNA-SF).
      ]
      NurseMNA-SF0–14 (continuous)Higher score = better nutritional status≤11
      MobilityTimed Up and Go [
      • Podsiadlo D.
      • Richardson S.
      The timed “up & go”: a test of basic functional mobility for frail elderly persons.
      ]
      NurseTUGNumber of seconds (continuous)≥14
      Falls the last six monthsRegistration of number of fallsPatientFalls0–1 or ≥ 2 (dichotomized)≥2
      Basic activities of daily living (ADL)Barthel Index [
      • Mahoney F.I.
      • Barthel D.W.
      Functional evaluation: the Barthel index.
      ]
      PatientBarthel0–20 (continuous)Higher score = better function˂19
      Instrumental activities of daily living (IADL)Nottingham Extended Activities of Daily Living [
      • Gladman J.R.
      • Lincoln N.B.
      • Adams S.A.
      Use of the extended ADL scale with stroke patients.
      ]
      PatientNEADL0–66 (continuous)Higher score = better function˂44
      Cognitive functionMontreal Cognitive Assessment test [
      • Nasreddine Z.S.
      • Phillips N.A.
      • Bedirian V.
      • Charbonneau S.
      • Whitehead V.
      • Collin I.
      • et al.
      The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment.
      ]
      NurseMoCA0–30 (continuous)Higher score = better function65–75 years ≤23 > 75 years ≤21
      Depressive symptomsGeriatric Depression Scale-15 [
      • Sheikh J.I.
      • Yesavage J.A.
      Geriatric depression scale (GDS): recent evidence and development of a shorter version.
      ]
      PatientGDS-150–15 (continuous)Higher score = more depressive symptoms≥5
      a Anatomical Therapeutic Chemical Classification System.

      2.3 Outcome Assessments

      The European Organisation for Research and Treatment of Cancer Quality-of-Life Core Questionnaire version 3.0 (EORTC) (QLQ-C30) [
      • Aaronson N.K.
      • Ahmedzai S.
      • Bergman B.
      • Bullinger M.
      • Cull A.
      • Duez N.J.
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      ] and the Nottingham Extended Index of Activities of Daily Living (NEADL) [
      • Gladman J.R.
      • Lincoln N.B.
      • Adams S.A.
      Use of the extended ADL scale with stroke patients.
      ] were distributed to all patients at five different time points; at baseline (T0), at RT completion (T1) and two (T2), eight (T3) and sixteen (T4) weeks after completing RT. At T1, per protocol exceptions were made for QLQ-C30 for patients receiving a single RT fraction (n = 12), and for NEADL for patients receiving ˂10 fractions (n = 59). At T0 and T1, the questionnaires were handed out and collected by the study nurse at the Radiotherapy Unit. Subsequent forms were sent by mail accompanied by a prepaid return envelope. If no answer was received after a week, the patient received a reminder.
      Entailing 30 items, QLQ-C30 includes a global QoL scale, five functioning scales (physical-, role-, emotional-, cognitive- and social function), and nine symptom scales/items (fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). All items are scored from 1 (not at all) to 4 (very much), except for global QoL which is scored from 1 (very poor) to 7 (excellent). Before analyses, the raw scores were converted to scales ranging from 0 to 100. Higher scores on the global QoL- and functioning scales indicate better function, whereas higher scores on the symptom scales/items denote more symptoms. Missing items were imputed in accordance with the official manual [
      • Fayers P.
      • Aaronson N.K.
      • Bordal K.G.M.
      • Curran D.
      • Bottomley A.
      • on behalf of the EORTC Quality of Life Group
      The EORTC QLQ-30 Scoring Manual.
      ]. A difference of ≥10 points on any scale was considered clinically significant [
      • Osoba D.
      • Rodrigues G.
      • Myles J.
      • Zee B.
      • Pater J.
      Interpreting the significance of changes in health-related quality-of-life scores.
      ]. NEADL assesses IADL function by the subscales mobility, kitchen-, domestic-, and leisure activities. Each of the 22 items is scored from 0 to 3, and item scores are summarized into a total score ranging from 0 to 66, where higher scores indicate better function. Based on the estimated minimal clinically important difference in NEADL score of 2.4–6.1 [
      • Wu C.Y.
      • Chuang L.L.
      • Lin K.C.
      • Lee S.D.
      • Hong W.H.
      Responsiveness, minimal detectable change, and minimal clinically important difference of the Nottingham extended activities of daily living scale in patients with improved performance after stroke rehabilitation.
      ], we chose to use the most conservative value of 6 points as clinically significant. Missing single NEADL items were imputed for cases where at least half of the scale had been answered by generating an empirical distribution for each item based on non-missing values, and drawing a random number from it to replace the missing value. Pre-defined primary outcomes were global QoL and physical function (PF) assessed by QLQ-C30. Secondary outcomes were IADL function assessed by NEADL, role function (RF), fatigue, and pain reported on QLQ-C30.

      2.4 Statistical Analyses

      Baseline patient characteristics and mGA scores were presented for the total cohort and stratified according to the number of geriatric impairments. Categorical data were described with frequencies and percentages, and continuous data with means and standard deviations (SDs), or median and min-max values. Baseline mean scores for QLQ-C30 and NEADL were tabulated for groups defined according to the number of impairments. To assess differences in trends in primary and secondary outcomes between patients receiving curative and palliative treatment, we estimated a linear mixed model with fixed effects for (non-linear) time, treatment group, and interaction between the time and treatment group. Random effects for patients were included to control for within-patient correlations due to repeated measurements. Further, the results were adjusted for age, sex, ECOG PS, and cancer diagnosis by estimating bivariate and multiple linear mixed models. To assess differences in trends in outcomes between groups defined according to the number of impairments, we estimated the same model as above with fixed effect for treatment group substituted with the number of impairments. In addition to the aforementioned adjustment variables, treatment intent (curative/palliative) was included in the latter model. Significant interaction terms in the models would imply a significant difference in trend in outcomes between the groups being compared. Non-significant interactions were excluded from the models. For explorative purposes, similar models were estimated for the remaining QLQ-C30 symptom scales (except for financial difficulties). Results from unadjusted linear mixed models were presented graphically as estimated mean values with corresponding 95% confidence intervals (CIs) at each assessment point. Finally, as an explorative approach, growth mixture models were estimated to identify possible unobserved groups of patients following distinct trajectories in global QoL and PF. This approach assesses individual trajectories and attempts to group patients with similar profiles together. To determine the optimal number of groups, Bayes Information Criterion, where the smaller value means a better model, was applied. In addition, it was required that average within-group probabilities were larger than 0.8, 95% CIs for trajectories non-overlapping, and groups had reasonable size. The identified groups were compared according to baseline characteristics. All tests were two-sided and results with p-values below 0.05 were considered statistically significant. The analyses were performed in SAS v9.4 and STATA v16.

      2.5 Ethics

      All enrolled patients provided written informed consent. Guidelines with advice for actions in case mGA revealed previously unrecognized severe health problems were prepared before recruitment started. The study protocol was approved by the Regional Committee for Medical Research Ethics South East Norway and was registered at clinicaltrials.gov (NCT03071640).

      3. Results

      3.1 Patients

      During the recruitment period, 301 (59.1% of eligible) patients were enrolled, 298 patients completed the baseline self-report questionnaires, and were included in the present study. Reasons for non-inclusion were refusal to participate (148 [29.1%]), considered too sick (28 [5.5%]), and practical constraints (e.g., absent study nurse) (32 [6.3%]). Further details were not collected due to ethical regulations. The mean age among participants was 73.6 years (SD 6.3), 141 (47.3%) were female, 161 (54.0%) received RT with curative intent, and 254 (85.2%) had ECOG PS 0–1 (Table 2). Breast (31.9%), prostate (24.2%), and lung cancer (21.8%) were the most common diagnoses, and 22.1% had other types of cancer.
      Table 2Patient characteristics and mGA scores according to number of geriatric impairments.
      VariableTotal

      n = 298
      3 patients with missing MoCA test were not grouped according to number of geriatric impairments.
      0 geriatric impairment

      n = 49 (16.6%)
      1 geriatric impairment

      n = 67 (22.7%)
      2 geriatric impairments

      n = 50 (16.9%)
      3 geriatric impairments

      n = 48 (16.3%)
      ≥4 geriatric impairments

      n = 81 (27.5%)
      Age, mean (SD)73.6 (6.3)71.1 (5.1)72.2 (5.9)74.1 (5.7)73.4 (6.1)76.2 (7.1)
      Sex, female (%)141 (47.3)22 (44.9)35 (52.2)26 (52.0)28 (58.3)29 (35.8)
      RT intent, n (%)
       Curative161 (54.0)41 (83.7)49 (73.1)28 (56.0)20 (41.7)23 (28.4)
       Palliative137 (46.0)8 (16.3)18 (26.9)22 (44.0)28 (58.3)58 (71.6)
      Cancer type, n (%)
       Breast95 (31.9)20 (40.9)32 (47.8)15 (30.0)14 (29.2)14 (17.3)
       Prostate72 (24.2)18 (36.7)17 (25.4)10 (20.0)9 (18.8)18 (22.2)
       Lung65 (21.8)5 (10.2)8 (11.9)14 (28.0)11 (22.9)25 (30.9)
       Other66 (22.1)6 (12.2)10 (14.9)11 (22.0)14 (29.2)24 (29.6)
      ECOG PS, n (%)
       0–1254 (85.2)49 (100.0)67 (100.0)50 (100.0)47 (97.9)40 (49.4)
       2–444 (14.8)0001 (2.1)41 (50.6)
      Stage, n (%)
       I62 (20.8)17 (34.8)21 (31.3)10 (20.0)6 (12.5)8 (9.9)
       II41 (13.8)8 (16.3)10 (14.9)7 (14.0)7 (14.6)9 (11.1)
       III78 (26.2)18 (36.7)20 (29.9)12 (24.0)12 (25.0)15 (18.5)
       IV117 (39.2)6 (12.2)16 (23.9)21 (42.0)23 (47.9)49 (60.5)
      Distant metastasis, n (%)
       No187 (62.8)43 (87.8)51 (76.1)29 (58.0)28 (58.3)35 (43.2)
       Yes11 (37.2)6 (12.2)16 (23.9)21 (42.0)20 (41.7)46 (56.8)
      Total radiation dose (Gy)
       Median (min-max)40.0 (4.0–78.0)40.1 (4.0–78.0)40.0 (20.0–78.0)40.0 (20.0–78.0)39.5 (8.0–78.0)30.0 (8.0–78.0)
      Dose per fraction (Gy)
       Median (min-max)2.7 (1.0–8.0)2.7 (2.0–4.0)2.7 (1.5–4.0)2.8 (1.5–6.0)3.0(1.5–8.0)3.5 (1.0–8.0)
      No. of fractions
       Median (min-max)14.8 (1–39)19 (2–39)14.8 (5–39)4.8 (4–39)13.9 (1–39)10 (1–39)
      mGA domains
      CCI
       Mean (SD)1.1 (1.3)0.2 (0.4)0.4 (0.6)0.9 (1.1)1.4 (1.4)2.0 (1.7)
       No (%) with impairment80 (27.1)04 (6.0)10 (20.0)20 (41.7)46 (56.8)
      Medications
       Mean (SD)5.5 (3.6)2.0 (1.5)3.6 (2.4)5.0 (2.6)6.2 (2.2)8.9 (3.3)
       No (%) with impairment161 (54.6)020 (29.9)29 (58.0)38 (79.2)74 (91.4)
      MNA-SF
       Mean (SD)10.6 (2.3)12.6 (0.9)11.5 (1.7)10.7 (2.1)10.3 (2.4)8.8 (2.1)
       No (%) with impairment161 (54.6)027 (40.3)29 (58.0)31 (64.6)74 (91.4)
      TUG
       missing19
      19 patients with missing TUG were classified as having an impairment in the domain mobility.
      002017
       Mean (SD)10.5 (5.6)7.5 (1.4)8.2 (1.8)9.3 (3.2)10.3 (2.1)16.3 (8.7)
       No (%) with impairment60 (20.3)003 (6.0)4 (8.3)53 (65.4)
      Falls
       0 or 1, n (%)264 (88.6)49 (100)66 (98.5)48 (96)36 (75.0)62 (76.5)
       ≥2 = impairment, n (%)34 (11.4)01 (1.5)2 (4)12 (25.0)19 (23.5)
      NEADL
       Mean (SD)53.2 (14.0)61.6 (5.4)61.5 (5.2)59.4 (6.3)56.2 (5.536.1 (13.6)
       No (%) with impairment61 (20.7)0001 (2.1)60 (74.1)
      Barthel Index
       Mean (SD)19.0 (2.2)19.9 (0.2)19.9 (0.3)19.7 (0.5)19.4 (0.8)17.2 (3.3)
       No (%) with impairment56 (19.0)001 (2.0)8 (16.7)47 (58.0)
      MoCA
       missing3ᵃ00000
      n = 65–75 years1964049333143
      n > 75 years99918171738
       Mean (SD)24.0 (3.7)26.2 (2.0)25.6 (2.8)24.2 (3.2)24.3 (2.8)21.1 (4.1)
       No (%) with impairment103 (34.9)013 (19.4)17 (34.0)18 (37.5)55 (67.9)
      GDS-15
       Mean (SD)2.9 (2.6)1.1 (1.1)2.0 (1.7)2.5 (2.3)3.5 (2.7)4.7 (2.8)
       No (%) with impairment61 (20.7)02 (3.0)9 (18.0)12 (25.0)38 (46.9)
      Abbreviations: mGA, modified geriatric assessment; SD, standard deviation; RT, radiotherapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Gy, Gray; CCI, Charlson Comorbidity Index; MNA-SF, Mini Nutritional Assessment Short Form; TUG, Timed Up and Go; NEADL, Nottingham Extended Activities of Daily Living; MoCA, Montreal Cognitive Assessment test; GDS-15, Geriatric Depression Scale-15.
      a 3 patients with missing MoCA test were not grouped according to number of geriatric impairments.
      b 19 patients with missing TUG were classified as having an impairment in the domain mobility.

      3.2 Survival and PROs Completion Rate

      During a median observation period of 24.2 months, 123 (41.3%) patients died. No patients died during RT, but 13, 26, and 41 patients died within two, eight, and sixteen weeks after completion of RT, respectively. Of the 41 patients who were dead by sixteen weeks, 39 (95.1%) received RT with palliative intent, 22 (53.7%) had lung cancer, and 24 (58.5%) had ≥4 impairments. During follow-up, seven patients declined to answer further questionnaires, but did not withdraw consent for analyses of the data already provided. Accounting for deaths and per protocol exceptions [
      • Coens C.
      • Pe M.
      • Dueck A.C.
      • Sloan J.
      • Basch E.
      • Calvert M.
      • et al.
      International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL consortium.
      ], the completion rate of QLQ-C30 at T0, T1, T2, T3 and T4 was 100% (298/298), 96.5% (276/286), 91.2% (260/285), 93.0% (253/272) and 89.1% (229/257), respectively. For NEADL the corresponding completion rates were 100% (298/298), 83.6% (200/239), 90.5% (258/285), 93.0% (253/272), 89.9% (231/257).

      3.3 Geriatric Impairments Identified by mGA

      The overall most prevalent geriatric impairments were polypharmacy (n = 161 [54.6%]), compromised nutritional status (n = 161 [54.6%]), and cognitive impairment (n = 103 [34.9%]) (Table 2). Impairments in TUG (n = 60 [20.3%]), GDS-15 (n = 61 [20.7%]), NEADL (n = 61 [20.7%]), and Barthel Index (n = 56 [19.0%]) were also common. Among patients grouped according to the number of impairments (n = 295), 16.6%, 22.7%, 16.9%, 16.3% and 27.5% had 0, 1, 2, 3 and ≥ 4 impairments, respectively (Table 2). The proportion of patients receiving palliative treatment, and having lung or “other types of” cancer, stage IV disease, distant metastasis, and ECOG PS 2–4 successively increased with the increasing number of impairments (Table 2).

      3.4 Quality of Life, Physical Function, and Symptoms in Relation to Treatment Intent

      Compared to patients treated for palliative purposes, those who received curative RT reported statistically and clinically significantly better overall mean scores for global QoL, PF, NEADL, RF, fatigue, and pain (all p < 0.001) (Table 3, Fig. 1). This was also the case for the symptoms of dyspnoea, appetite loss, constipation, and nausea/vomiting, but not for diarrhoea and insomnia (data not shown). There was a significant non-linear trend in global QoL, fatigue, and pain, which for global QoL and fatigue were significantly different between patients receiving curative and palliative treatment (significant interactions) (Table 3). Adjustments did not alter these results. Significant non-linear trends were also found for dyspnoea and insomnia, and for insomnia the trend was significantly different between the two groups (data not shown). None of the observed trends represented a clinically significant change (>10 points).
      Table 3Results of the linear mixed model assessing the trend in primary and secondary outcomes stratified by treatment intent (palliative vs curative, n = 298).
      UnadjustedAdjusted
      Adjusted for age, sex, cancer type, and ECOG PS.
      RC (SE)p-valueRC (SE)p-value
      Global quality of life
      Intercept73.69 (1.72)<0.00181.48 (12.10)<0.001
      Time−1.31 (0.64)0.041−1.30 (0.64)0.042
      Time^2
      Second-order time component.
      0.18 (0.09)0.0390.18 (0.09)0.040
      Time^3
      Third-order time component.
      −0.006 (0.003)0.052−0.006 (0.003)0.053
      Treatment intent, palliative−15.82 (2.53)<0.001−9.33 (2.91)0.001
      Time x Treatment intent1.40 (0.98)0.1521.35 (0.98)0.168
      Time^2 x Treatment intent−0.34 (0.14)0.016−0.34 (0.14)0.016
      Time^3 x Treatment intent0.01 (0.005)0.0070.01 (0.005)0.007
      Physical function
      Intercept80.89 (1.84)<0.001126.69 (12.83)<0.001
      Time−0.30 (0.40)0.450−0.32 (0.40)0.423
      Time^20.01 (0.06)0.8090.01 (0.06)0.803
      Time^3−0.00002 (0.002)0.991−0.00002 (0.002)0.993
      Treatment intent, palliative−24.19 (2.57)<0.001−11.02 (2.70)<0.001
      Role function
      Intercept78.28 (2.32)<0.00198.99 (16.61)<0.001
      Time−0.04 (0.64)0.947−0.08 (0.64)0.895
      Time^2−0.06 (0.09)0.544−0.05 (0.09)0.547
      Time^30.003 (0.003)0.4280.003 (0.003)0.420
      Treatment intent, palliative−28.13 (3.14)<0.001−13.97 (3.49)<0.001
      Fatigue
      Intercept30.33 (2.02)<0.0012.70 (14.77)0.855
      Time3.22 (0.70)<0.0013.22 (0.70)<0.001
      Time^2−0.43 (0.10)<0.001−0.43 (0.10)<0.001
      Time^30.01 (0.003)<0.0010.01 (0.003)<0.001
      Treatment intent, palliative15.43 (2.98)<0.00110.65 (3.47)0.002
      Time x Treatment intent
      Time^2 x Treatment intent Time^3 x Treatment intent−2.01 (1.07)

      0.39 (0.15)
      0.061

      0.011
      −1.98 (1.07)

      0.39 (0.15)
      0.065

      0.011
      −0.01 (0.005)0.009−0.01 (0.005)0.009
      Pain
      Intercept22.24 (2.14)<0.00122.35 (16.84)0.186
      Time−1.36 (0.63)0.032−1.34 (0.63)0.035
      Time^20.21 (0.09)0.0220.21 (0.09)0.022
      Time^3−0.007 (0.003)0.023−0.007 (0.003)0.023
      Treatment intent, palliative14.98 (2.85)<0.00112.50 (3.54)<0.001
      NEADL
      Intercept59.06 (1.06)<0.00183.12 (6.90)<0.001
      Time−0.25 (0.22)0.252−0.28 (0.22)0.197
      Time^20.01 (0.03)0.6820.02 (0.03)0.613
      Time^3−0.0001 (0.001)0.917−0.0002 (0.001)0.856
      Treatment intent, palliative−12.99 (1.50)<0.001−3.58 (1.45)0.014
      Abbreviations: RC, regression coefficient; SE, standard error; NEADL, Nottingham Extended Activities of Daily Living.
      a Adjusted for age, sex, cancer type, and ECOG PS.
      b Second-order time component.
      c Third-order time component.
      Fig. 1
      Fig. 1Trends in primary and secondary outcomes for patients receiving curative and palliative radiotherapy (RT), unadjusted results of the linear mixed model.
      Abbreviations: NEADL, Nottingham extended activates of daily living. T0 = baseline, T1 = at RT completion, T2 = two, T3 = eight, T4 = sixteen weeks after completing RT.
      Mean values with 95% CIs for primary and secondary outcomes assessed by QLQ-C30 (scale range 0–100), and NEADL (scale range 0–66). Fig. A: For quality of life and all functioning scales, higher scores indicate better function. Fig. B: For all symptom scales, higher scores indicate more symptoms.

      3.5 Quality of Life, Physical Function, and Symptoms in Relation to the Number of Geriatric Impairments

      Baseline scores showed a gradual decrease in global QoL, all QLQ-C30 function scales, and NEADL, and a similar increase in symptoms with the increasing number of geriatric impairments (Table 4). These baseline differences between groups defined according to the number of impairments persisted during follow-up. There were no significant changes in these outcomes over time, except for fatigue and pain, where a statistically significant non-linear trend below clinical significance (<10 points) was present. According to unadjusted linear mixed models, there were also no significant differences in trend between the groups (no significant interaction terms) (Table 5, Fig. 2). For all primary and secondary outcomes, there were overall statistically and clinically significant differences between the group with no impairment and the groups with two or more impairments (0 vs 2, 3, and ≥ 4) (for NEADL only 0 vs 3, and ≥ 4 impairments), between the group with one impairment and the groups with three or more (1 vs 3, and ≥ 4), and between the groups with two impairments and four or more (2 vs ≥4) (Fig. 2). The results were only slightly altered when adjusting for age, sex, ECOG PS, cancer diagnosis, and treatment intent (Table 5). Explorative analyses assessing the remaining QLQ-C30 symptom scores showed no trend that was both statistically and clinically significant, and no differences in trend between groups (Fig. 2). The overall differences between groups with no impairment and two or more impairments were clinically and statistically significant for dyspnoea and constipation. For insomnia and nausea/vomiting and appetite loss, the differences were similarly significant between groups with no impairment and three or more impairments (Fig. 2).
      Table 4Baseline EORTC QLQ-C30 and NEADL mean scores stratified by number of geriatric impairments.
      Total n0 geriatric impairment

      n (%)
      1 geriatric impairment

      n (%)
      2 geriatric impairments

      n (%)
      3 geriatric impairments

      n (%)
      ≥4 geriatric impairments

      n (%)
      298
      Among the 298 patients with complete QLQ-30 and NEADL, 3 patients had incomplete mGA (missing MoCA) and therefore 295 patients were grouped according to number of geriatric impairments.
      49 (16.6)67 (22.7)50 (16.9)48 (16.3)81 (27.5)
      Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD
      Global quality of life66.9 (23.0)81.6 (19.0)74.9 (16.3)68.8 (21.0)60.6 (20.5)51.5 (22.4)
      Functional scales
      Physical function69.8 (26.2)90.7 (14.7)84.2 (18.0)75.1 (18.6)70.2 (20.3)43.4 (21.6)
      Role function65.0 (34.0)90.1 (22.8)80.6 (23.1)71.7 (24.1)65.6 (26.0)34.8 (33.4)
      Emotional function82.0 (18.4)86.8 (15.1)84.3 (14.8)86.3 (16.3)78.5 (21.9)76.6 (20.4)
      Cognitive function83.6 (17.7)89.6 (13.1)90.5 (14.3)86.3 (13.3)83.0 (15.6)73.5 (20.9)
      Social function75.6 (24.8)86.1 (20.7)82.1 (19.0)75.7 (20.5)72.9 (20.8)66.5 (31.2)
      Symptom scales/items
      Fatigue37.5 (25.4)18.5 (18.2)29.0 (22.4)36.9 (18.9)43.1 (23.9)52.6 (25.0)
      Nausea/vomiting6.7 (13.3)1.7 (5.1)2.2 (6.4)6.7 (13.5)12.5 (16.3)10.1 (16.6)
      Pain29.4 (32.0)11.2 (18.1)15.4 (22.7)30.0 (28.6)33.0 (31.0)48.1 (36.4)
      Dyspnoea29.2 (32.6)12.5 (24.4)21.9 (26.9)28.0 (28.1)31.3 (32.5)42.0 (36.0)
      Insomnia27.3 (28.0)19.7 (21.4)21.2 (25.2)27.3 (24.9)34.0 (30.4)32.5 (32.0)
      Appetite loss17.9 (29.0)1.4 (9.5)11.4 (22.1)12.0 (25.0)28.5 (34.4)30.9 (33.2)
      Constipation22.6 (29.5)7.6 (15.7)13.4 (23.3)24.0 (28.6)25.0 (30.4)37.5 (33.7)
      Diarrhoea15.5 (24.8)11.8 (23.3)15.9 (20.4)12.0 (23.1)20.1 (29.0)16.3 (27.0)
      Financial difficulties4.1 (13.4)0.7 (4.8)4.5 (11.5)1.3 (6.6)8.3 (17.5)4.9 (17.6)
      NEADL53.2 (14.0)61.3 (5.4)61.5 (5.2)59.4 (6.3)56.2 (5.5)36.1 (13.6)
      Abbreviations: The European Organisation for Research and Treatment of Cancer Quality-of-Life Core Questionnaire; NEADL, Nottingham Extended Activities of Daily Living; SD, standard deviation.
      a Among the 298 patients with complete QLQ-30 and NEADL, 3 patients had incomplete mGA (missing MoCA) and therefore 295 patients were grouped according to number of geriatric impairments.
      Table 5Results of the linear mixed model assessing the trend in primary and secondary outcomes stratified by the number of geriatric impairments (n = 295).
      UnadjustedAdjusted
      Adjusted for age, sex, cancer type, ECOG PS, and treatment intent (palliative vs curative).
      RC (SE)p-verdiRC (SE)p-verdi
      Global quality of life
      Intercept83.49 (2.41)<0.00176.69 (11.16)<0.001
      Time−0.80 (0.49)0.103−0.83 (0.49)0.090
      Time^2
      Second-order time component.
      0.06 (0.07)0.4140.06 (0.07)0.399
      Time^3
      Third-order time component.
      −0.001 (0.002)0.699−0.001 (0.002)0.684
      No.of impairments (0 – ref.)
       1−8.90 (3.02)0.003−7.83 (2.90)0.007
       2−13.89 (3.23)<0.001−10.63 (3.18)0.001
       3−23.58 (3.28)<0.001−19.15 (3.29)<0.001
       ≥4−31.54 (2.95)<0.001−24.91 (3.46)<0.001
      Physical function
      Intercept91.19 (2.63)<0.001117.38 (11.53)<0.001
      Time

      Time^2
      −0.32 (0.40)

      0.01 (0.06)
      0.424

      0.795
      −0.34 (0.40)

      0.02 (0.06)
      0.394

      0.777
      Time^3−0.00003 (0.002)0.989−0.00006 (0.002)0.976
      No.of impairments (0 – ref.)

       1


      −6.71 (3.37)


      0.047


      −4.87 (3.02)


      0.108
       2−17.25 (3.61)<0.001−11.46 (3.31)0.001
       3−23.63 (3.66)<0.001−16.57 (3.42)<0.001
       ≥4−46.35 (3.27)<0.001−30.66 (3.59)<0.001
      Role function
      Intercept90.18 (3.41)<0.00189.16 (15.36)<0.001
      Time−0.18 (0.64)0.778−0.23 (0.64)0.721
      Time^2−0.04 (0.09)0.658−0.04 (0.09)0.681
      Time^30.002 (0.003)0.5150.002 (0.003)0.527
      No.of impairments (0 – ref.)
       1−10.91 (4.30)0.011−9.24 (4.01)0.021
       2−17.56 (4.60)<0.001−12.45 (4.39)0.005
       3−24.82 (4.68)<0.001−18.76 (4.54)<0.001
       ≥4−53.76 (4.19)<0.001−37.67 (4.77)<0.001
      Fatigue
      Intercept19.59 (2.98)<0.0019.18 (14.13)0.516
      Time2.43 (0.53)<0.0012.44 (0.53)<0.001
      Time^2−0.27 (0.08)<0.001−0.28 (0.08)<0.001
      Time^30.008 (0.003)0.0020.008 (0.003)0.002
      No.of impairments (0 –ref.)
       110.34 (3.77)0.0068.53 (3.70)0.021
       215.29 (4.03)<0.00111.38 (4.05)0.005
       322.64 (4.10)<0.00117.59 (4.18)<0.001
       ≥433.18 (3.67)<0.00126.59 (4.39)<0.001
      Pain
      Intercept11.75 (3.26)<0.00133.01 (15.80)0.038
      Time−1.27 (0.64)0.046−1.25 (0.64)0.050
      Time^20.20 (0.09)0.0270.20 (0.09)0.029
      Time^3−0.007 (0.003)0.026−0.007 (0.003)0.028
      No.of impairments (0 –ref.)
       15.52 (4.10)0.1794.76 (4.13)0.249
       215.14 (4.39)0.00114.93 (4.52)0.001
       324.58 (4.46)<0.00123.58 (4.67)<0.001
       ≥433.63 (4.00)<0.00131.10 (4.91)<0.001
      NEADL
      Intercept62.73 (1.38)<0.00175.22 (5.95)<0.001
      Time−0.25 (0.22)0.253−0.30 (0.22)0.173
      Time^20.01 (0.03)0.7150.02 (0.03)0.580
      Time^3−0.00005 (0.001)0.962−0.0003 (0.001)0.825
      No.of impairments (0 – ref.)
       1−0.67 (1.77)0.7060.03 (1.55)0.985
       2−5.16 (1.89)0.007−2.53 (1.70)0.137
       3−7.40 (1.92)<0.001−4.33 (1.75)0.014
       ≥4−26.31 (1.72)<0.001−16.92 (1.84)<0.001
      Abbreviations: RC, regression coefficient; SE, standard error; No. of impairments, number of geriatric impairments; NEADL, Nottingham Extended Activities of Daily Living.
      a Adjusted for age, sex, cancer type, ECOG PS, and treatment intent (palliative vs curative).
      b Second-order time component.
      c Third-order time component.
      Fig. 2
      Fig. 2Trends in primary and secondary outcomes, and symptoms depending on the number of geriatric impairments, unadjusted results of the linear mixed model.
      Abbreviations: GI, geriatric impairments; NEADL, Nottingham extended activates of daily living. T0 = baseline, T1 = at RT completion, T2 = two, T3 = eight, T4 = sixteen weeks after completing RT.
      Mean values with 95% CIs for primary and secondary outcomes assessed by QLQ-C30 (scale range 0–100), and NEADL (scale range 0–66). Fig. A: For quality of life and all functioning scales, higher scores indicate better function. Fig. B: For all symptom scales, higher scores indicate more symptoms.

      3.6 Results of Growth Mixture Model

      The growth mixture model analysis identified four groups of patients with distinct trajectories for both global QoL and PF, named poor, fair, good, and excellent with non-overlapping 95% CIs and clinically significant differences in mean baseline scores (supplementary table S-A, supplementary fig. S-A). The trajectories were relatively stable for both outcomes in all groups with no clinically significant changes observed during follow-up. Considering both global QoL and PF, the proportion of patients having ECOG PS 2–4 and receiving RT with palliative intent was highest in the poor group, and decreased in the fair and good groups, with the lowest proportion in the excellent group (Supplementary table S B). Furthermore, the number of impairments decreased from the highest in the poor group to the lowest in the excellent group.

      4. Discussion

      To the best of our knowledge, this is the first study on older adults with cancer receiving RT where longitudinally retrieved PROs were assessed in relation to treatment intent and the number of geriatric impairments as identified by pre-treatment mGA. We found that patients receiving palliative RT had worse scores on all outcomes compared to those who received potentially curative treatment and that global QoL and PF gradually decreased while symptom burden increased with an increasing number of impairments. These differences persisted from start to sixteen weeks after RT, but no clinically significant change was observed for any groups or outcomes.
      The pronounced differences in global QoL, function, and symptoms between patients receiving treatment with palliative and curative intent complies with common knowledge, confirmed in studies from other cancer settings [
      • van Laarhoven H.W.
      • Schilderman J.
      • Bleijenberg G.
      • Donders R.
      • Vissers K.C.
      • Verhagen C.A.
      • et al.
      Coping, quality of life, depression, and hopelessness in cancer patients in a curative and palliative, end-of-life care setting.
      ]. Previous studies on older adults with cancer have reported frailty or impairments in geriatric domains to have significant negative impact on PROs [
      • Pergolotti M.
      • Deal A.M.
      • Williams G.R.
      • Bryant A.L.
      • Bensen J.T.
      • Muss H.B.
      • et al.
      Activities, function, and health-related quality of life (HRQOL) of older adults with cancer.
      ,
      • Kirkhus L.
      • Saltyte Benth J.
      • Gronberg B.H.
      • Hjermstad M.J.
      • Rostoft S.
      • Harneshaug M.
      • et al.
      Frailty identified by geriatric assessment is associated with poor functioning, high symptom burden and increased risk of physical decline in older cancer patients: prospective observational study.
      ,
      • Williams G.R.
      • Deal A.M.
      • Sanoff H.K.
      • Nyrop K.A.
      • Guerard E.J.
      • Pergolotti M.
      • et al.
      Frailty and health-related quality of life in older women with breast cancer.
      ,
      • Kirkhus L.
      • Harneshaug M.
      • Saltyte Benth J.
      • Gronberg B.H.
      • Rostoft S.
      • Bergh S.
      • et al.
      Modifiable factors affecting older patients’ quality of life and physical function during cancer treatment.
      ]. Similar studies from RT settings are scarce, but an association between IADL dysfunction and poorer QoL scores was demonstrated in a smaller study (n = 46) on older adults with head and neck cancer [
      • VanderWalde N.A.
      • Deal A.M.
      • Comitz E.
      • Stravers L.
      • Muss H.
      • Reeve B.B.
      • et al.
      Geriatric assessment as a predictor of tolerance, quality of life, and outcomes in older patients with head and neck cancers and lung cancers receiving radiation therapy.
      ]. Our study substantially expands this knowledge by demonstrating that not only did geriatric impairments negatively affect important aspects of older adults' lives but that an increasing number of impairments was followed by a consistent deterioration in all PROs, independent of treatment intent. These findings were further supported by the results of our exploratory growth mixture model analyses, which were performed to investigate if there were unobserved groups of patients with particularly poor trajectories requiring specific attention and supportive measures. Overall, our findings underline that frailty should be regarded as a continuum of increased vulnerability that has a profound impact on patients' perceptions of QoL and function.
      We found that mean scores for all study-specific outcomes were remarkably stable during follow-up. This applied to groups defined according to treatment intent and the number of geriatric impairments, as well as groups with distinct global QoL and PF trajectories. The paucity of age-specific studies addressing PROs in the RT setting hampers comparisons to existing knowledge. One study including 903 patients aged 18–92 years found that participants reported a similar symptom burden before and after RT, regardless of age [
      • Mohile S.G.
      • Heckler C.
      • Fan L.
      • Mustian K.
      • Jean-Pierre P.
      • Usuki K.
      • et al.
      Age-related differences in symptoms and their interference with quality of life in 903 Cancer patients undergoing radiation therapy.
      ]. However, patients aged ≥65 years were more likely to report that symptoms interfered with walking after RT [
      • Mohile S.G.
      • Heckler C.
      • Fan L.
      • Mustian K.
      • Jean-Pierre P.
      • Usuki K.
      • et al.
      Age-related differences in symptoms and their interference with quality of life in 903 Cancer patients undergoing radiation therapy.
      ], but RT treatment intent or frailty status were not accounted for. We expected that an increasing number of impairments would be associated with a functional decline during follow-up. This was not confirmed, and supported by studies on older patients with prostate cancer reporting that no GA domains were predictive of RT tolerance [
      • Goineau A.
      • Campion L.
      • d’Aillières B.
      • Vié B.
      • Ghesquière A.
      • Béra G.
      • et al.
      Comprehensive geriatric assessment and quality of life after localized prostate cancer radiotherapy in elderly patients.
      ,
      • Goineau A.
      • Campion L.
      • Commer J.M.
      • Vié B.
      • Ghesquière A.
      • Béra G.
      • et al.
      Can comprehensive geriatric assessment predict tolerance of radiotherapy for localized prostate Cancer in men aged 75 years or older?.
      ]. Our findings for the group receiving curative treatment are largely in line with recent studies in older patients treated for localised breast or prostate cancer [
      • Goineau A.
      • Campion L.
      • d’Aillières B.
      • Vié B.
      • Ghesquière A.
      • Béra G.
      • et al.
      Comprehensive geriatric assessment and quality of life after localized prostate cancer radiotherapy in elderly patients.
      ,
      • Goineau A.
      • Campion L.
      • Commer J.M.
      • Vié B.
      • Ghesquière A.
      • Béra G.
      • et al.
      Can comprehensive geriatric assessment predict tolerance of radiotherapy for localized prostate Cancer in men aged 75 years or older?.
      ,
      • Battisti N.M.L.
      • Hatton M.Q.
      • Reed M.W.R.
      • Herbert E.
      • Morgan J.L.
      • Bradburn M.
      • et al.
      Observational cohort study in older women with early breast cancer: use of radiation therapy and impact on health-related quality of life and mortality.
      ]. We anticipated an improvement in PROs in the palliative group, which did not occur. However, we did not distinguish between specific RT indications, e.g., irradiation for respiratory symptoms or painful bone metastases, and the study was not designed to capture changes in PROs related to this. Thus, the lack of improvement may be due to disease progression, and scores could potentially be worse had it not been for the RT provided.
      Overall, our findings indicate that tolerance for the RT regimens was good regardless of treatment intent and number of impairments, i.e., RT did not significantly influence patients' perceived global QoL and functioning. This suggests that existing impairments should not be seen as contraindications for RT per se. However, it is important to note that patients with accumulated impairments reported persistently very poor QoL, functioning, and high symptom burden, and we have previously shown that they also had higher mortality risk [
      • Eriksen G.F.
      • Šaltytė Benth J.
      • Grønberg B.H.
      • Rostoft S.
      • Kirkhus L.
      • Kirkevold Ø.
      • et al.
      Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: a prospective observational study.
      ]. Aimed at preserving function and well-being, these findings emphasize the need for continuous broad evaluations of patients´ needs and to apply appropriate interventions before, during, and after RT [
      • Ferrell B.R.
      • Temel J.S.
      • Temin S.
      • Alesi E.R.
      • Balboni T.A.
      • Basch E.M.
      • et al.
      Integration of palliative care into standard oncology care: American Society of Clinical Oncology clinical practice guideline update.
      ]. Such targeted interventions may also mitigate modifiable geriatric impairments and have the potential to improve overall survival [
      • Eriksen G.F.
      • Šaltytė Benth J.
      • Grønberg B.H.
      • Rostoft S.
      • Kirkhus L.
      • Kirkevold Ø.
      • et al.
      Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: a prospective observational study.
      ]. Preferably, this evaluation should be performed by GA [
      • Wildiers H.
      • Heeren P.
      • Puts M.
      • Topinkova E.
      • Janssen-Heijnen M.L.
      • Extermann M.
      • et al.
      International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer.
      ,
      • Mohile S.G.
      • Dale W.
      • Somerfield M.R.
      • Schonberg M.A.
      • Boyd C.M.
      • Burhenn P.S.
      • et al.
      Practical assessment and Management of Vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
      ] supplied by systematic symptom assessment. GA with management (GAM) based on individual needs has been shown to improve outcomes in other oncologic settings [
      • Rostoft S.
      • O’Donovan A.
      • Soubeyran P.
      • Alibhai S.M.H.
      • Hamaker M.E.
      Geriatric assessment and management in cancer.
      ,
      • Mohile S.G.
      • Mohamed M.R.
      • Xu H.
      • Culakova E.
      • Loh K.P.
      • Magnuson A.
      • et al.
      Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study.
      ,
      • Li D.
      • Sun C.L.
      • Kim H.
      • Soto-Perez-de-Celis E.
      • Chung V.
      • Koczywas M.
      • et al.
      Geriatric assessment-driven intervention (GAIN) on chemotherapy-related toxic effects in older adults with cancer: a randomized clinical trial.
      ], and systematic symptom assessment followed by targeted interventions can ameliorate symptoms and improve QoL [
      • Basch E.
      • Deal A.M.
      • Kris M.G.
      • Scher H.I.
      • Hudis C.A.
      • Sabbatini P.
      • et al.
      Symptom monitoring with patient-reported outcomes during routine Cancer treatment: a randomized controlled trial.
      ]. Moreover, as we have demonstrated in this study, patients receiving RT with curative and palliative intent are distinct entities and may have different needs. It may therefore be a favourable approach for future studies to test the effect of GAM for patients referred to curative and palliative RT, or combined modality therapy, separately. Finally, our findings underline the need for careful individual considerations of treatment burden versus benefits. Patients with accumulated impairments, in particular those who have advanced cancer, may profit from modified RT regimens alongside targeted supportive care [
      • O’Donovan A.
      • Morris L.
      Palliative radiation therapy in older adults with Cancer: age-related considerations.
      ]. In some cases, even omitting RT and providing other palliative measures might be the best option [
      • Vanbutsele G.
      • Pardon K.
      • Van Belle S.
      • Surmont V.
      • De Laat M.
      • Colman R.
      • et al.
      Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial.
      ,
      • Bakitas M.A.
      • Tosteson T.D.
      • Li Z.
      • Lyons K.D.
      • Hull J.G.
      • Li Z.
      • et al.
      Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial.
      ].
      Strengths of this study are the prospective design, relatively large sample size, and the use of reliable and validated scales to assess mGA domains. Moreover, a designated oncology nurse and a resident physician, both specially trained, performed all the mGAs. The PRO completion rate was fairly good during follow-up. Furthermore, the QLQ-C30, including the translated Norwegian version, is validated and its responsiveness well documented in patients with cancer [
      • Fayers P.
      • Bottomley A.
      Quality of life research within the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of Cancer.
      ]. Assessing an unselected cohort of older adults with cancer, many of whom had advanced cancer and limited life expectancy, our study contributes valuable knowledge about a large group of patients that are often excluded from clinical trials. However, this heterogeneity may also represent a limitation. Previous cancer treatment and other factors not accounted for could have influenced patients' perceptions of the outcomes assessed. Among potentially eligible patients, 40.1% were not included, mainly because the patient declined participation or was considered too sick. Hence, it is possible that the study cohort represent the fittest of older adults referred to RT which may have affected our results. Representing mean values, our results reflect RT tolerance on a group level and should therefore be interpreted with caution. Finally, patients treated for palliative purposes, who also frequently had several accumulated impairments, were more likely to die during follow-up [
      • Eriksen G.F.
      • Šaltytė Benth J.
      • Grønberg B.H.
      • Rostoft S.
      • Kirkhus L.
      • Kirkevold Ø.
      • et al.
      Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: a prospective observational study.
      ], and this may have introduced attrition bias.
      In conclusion, our results show that older adults tolerate RT well, and the accumulation of geriatric impairments (i.e., frailty) should not be decisive when considering RT. However, uncovering age-related health issues by GA is key to identifying vulnerable patients so that RT adaptions and/or targeted supportive measures that may improve PROs could be provided. Studies implementing GAM and specifically assessing PROs in the RT setting are warranted.
      The following are the supplementary data related to this article.
      • Supplementary Table S1

        Results of the growth mixture model analysis identified four groups with distinct trajectories for both global quality of life and physical function, named poor, fair, good and excellent.

      Declaraltion of Competing Interest

      The authors have no conflict of interests to declare.

      Ethics Approval and Consent to Participate

      This study was approved by the Regional Committee for Medical Research Ethics South East Norway and was registered at clinicaltrials.gov (NCT03071640). All patients included provided written informed consent.

      Consent for Publication

      All authors have approved the final version. Participating patients provided consent to data being used in publications. Confidentiality is guaranteed.

      Availability of Data and Materials

      According to Norwegian regulations, research data is confidential due to patients' privacy protection. On individual, specific request, anonymised data could be made available.

      Author Contributions

      Conceptualization: Marit Slaaen.
      Methodology: All authors.
      Data curation: Guro Falk Eriksen, Marit Slaaen.
      Validation: All authors.
      Formal analysis: Jūratė Šaltytė Benth, Guro Falk Eriksen, Marit Slaaen.
      Visualization: Guro Falk Eriksen.
      Writing - original draft: Guro Falk Eriksen.
      Writing - review & editing: All authors.
      Funding acquisition: Marit Slaaen.
      Supervision: Marit Slaaen.

      Funding

      This work was funded by Innlandet Hospital Trust , Norway.

      Acknowledgements

      We are very grateful to all patients who participated in this study. A special thanks to Bodil Sem Kolsgaard, the dedicated study nurse who performed most of the patients interviews and mGAs. She also distributed the self-report questionnaires to patients and managed the practicalities involved in this comprehensive work. We also value the collaboration with all employees at the RTU at Gjøvik hospital who facilitated the conduct of this study.

      References

        • van Walree I.C.
        • van Soolingen N.J.
        • Hamaker M.E.
        • Smorenburg C.H.
        • Louwers J.A.
        • van Huis-Tanja L.H.
        Treatment decision-making in elderly women with ovarian cancer: an age-based comparison.
        Int J Gynecol Cancer. 2019; 29: 158-165
        • Pergolotti M.
        • Deal A.M.
        • Williams G.R.
        • Bryant A.L.
        • Bensen J.T.
        • Muss H.B.
        • et al.
        Activities, function, and health-related quality of life (HRQOL) of older adults with cancer.
        J Geriatr Oncol. 2017; 8: 249-254
        • Celis E.S.P.D.
        • Li D.
        • Sun C.-L.
        • Kim H.
        • Twardowski P.
        • Fakih M.
        • et al.
        Patient-defined goals and preferences among older adults with cancer starting chemotherapy (CT).
        J Clin Oncol. 2018; 36: 10009
        • Shrestha A.
        • Martin C.
        • Burton M.
        • Walters S.
        • Collins K.
        • Wyld L.
        Quality of life versus length of life considerations in cancer patients: a systematic literature review.
        Psychooncology. 2019; 28: 1367-1380
        • Kenis C.
        • Decoster L.
        • Bastin J.
        • Bode H.
        • Van Puyvelde K.
        • De Grève J.
        • et al.
        Functional decline in older patients with cancer receiving chemotherapy: a multicenter prospective study.
        J Geriatr Oncol. 2017; 8: 196-205
        • Fried T.R.
        • Bradley E.H.
        • Towle V.R.
        • Allore H.
        Understanding the treatment preferences of seriously ill patients.
        N Engl J Med. 2002; 346: 1061-1066
        • Scotte F.
        • Bossi P.
        • Carola E.
        • Cudennec T.
        • Dielenseger P.
        • Gomes F.
        • et al.
        Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide.
        Ann Oncol. 2018; 29: 1718-1726
        • Somasundar P.
        • Mourey L.
        • Lozza L.
        • Maggi S.
        • Stepney R.
        Advances in geriatric oncology: a multidisciplinary perspective.
        Tumori. 2018; 104: 252-257
        • O’Donovan A.
        • Leech M.
        • Gillham C.
        Assessment and management of radiotherapy induced toxicity in older patients.
        J Geriatr Oncol. 2017; 8: 421-427
        • Lutz S.T.
        • Jones J.
        • Chow E.
        Role of radiation therapy in palliative care of the patient with cancer.
        J Clin Oncol. 2014; 32: 2913-2919
        • Spencer K.
        • Parrish R.
        • Barton R.
        • Henry A.
        Palliative radiotherapy.
        BMJ. 2018; 360k821
        • Nehlsen A.
        • Agarwal P.
        • Mazumdar M.
        • Dutta P.
        • Goldstein N.E.
        • Dharmarajan K.V.
        Impact of radiotherapy on daily function among older adults living with advanced cancer (RT impact on function in advanced cancer).
        J Geriatr Oncol. 2021; 13: 45-54
        • VanderWalde N.A.
        • Deal A.M.
        • Comitz E.
        • Stravers L.
        • Muss H.
        • Reeve B.B.
        • et al.
        Geriatric assessment as a predictor of tolerance, quality of life, and outcomes in older patients with head and neck cancers and lung cancers receiving radiation therapy.
        Int J Radiat Oncol Biol Phys. 2017; 98: 850-857
        • Mohile S.G.
        • Heckler C.
        • Fan L.
        • Mustian K.
        • Jean-Pierre P.
        • Usuki K.
        • et al.
        Age-related differences in symptoms and their interference with quality of life in 903 Cancer patients undergoing radiation therapy.
        J Geriatr Oncol. 2011; 2: 225-232
        • Rostoft S.
        • O’Donovan A.
        • Soubeyran P.
        • Alibhai S.M.H.
        • Hamaker M.E.
        Geriatric assessment and management in cancer.
        J Clin Oncol. 2021; 39 (Jco2100089): 2058-2067
        • O’Donovan A.
        • Mohile S.G.
        • Leech M.
        Expert consensus panel guidelines on geriatric assessment in oncology.
        Eur J Cancer Care (Engl). 2015; 24: 574-589
        • Handforth C.
        • Clegg A.
        • Young C.
        • Simpkins S.
        • Seymour M.T.
        • Selby P.J.
        • et al.
        The prevalence and outcomes of frailty in older cancer patients: a systematic review.
        Ann Oncol. 2015; 26: 1091-1101
        • Balducci L.
        • Extermann M.
        Management of cancer in the older person: a practical approach.
        Oncologist. 2000; 5: 224-237
        • Kirkhus L.
        • Saltyte Benth J.
        • Gronberg B.H.
        • Hjermstad M.J.
        • Rostoft S.
        • Harneshaug M.
        • et al.
        Frailty identified by geriatric assessment is associated with poor functioning, high symptom burden and increased risk of physical decline in older cancer patients: prospective observational study.
        Palliat Med. 2019; 33: 312-322
        • Williams G.R.
        • Deal A.M.
        • Sanoff H.K.
        • Nyrop K.A.
        • Guerard E.J.
        • Pergolotti M.
        • et al.
        Frailty and health-related quality of life in older women with breast cancer.
        Support Care Cancer. 2019; 27: 2693-2698
        • O’Donovan A.
        • Leech M.
        Personalised treatment for older adults with cancer: the role of frailty assessment.
        Tech Innov Patient Support Radiat Oncol. 2020; 16: 30-38
        • Decoster L.
        • Quinten C.
        • Kenis C.
        • Flamaing J.
        • Debruyne P.R.
        • De Groof I.
        • et al.
        Health related quality of life in older patients with solid tumors and prognostic factors for decline.
        J Geriatr Oncol. 2019; 10: 895-903
        • VanderWalde N.
        • Hurria A.
        • Jagsi R.
        Improving consistency and quality of Care for Older Adults with Cancer: the challenges of developing consensus guidelines for radiation therapy.
        Int J Radiat Oncol Biol Phys. 2017; 98: 721-725
        • Szumacher E.
        • Sattar S.
        • Neve M.
        • Do K.
        • Ayala A.P.
        • Gray M.
        • et al.
        Use of comprehensive geriatric assessment and geriatric screening for older adults in the radiation oncology setting: a systematic review.
        Clin Oncol (R Coll Radiol). 2018; 30: 578-588
        • Shinde A.
        • Vazquez J.
        • Novak J.
        • Sedrak M.S.
        • Amini A.
        The role of comprehensive geriatric assessment in radiation oncology.
        J Geriatr Oncol. 2020; 11: 194-196
        • Rockwood K.
        • Song X.
        • MacKnight C.
        • Bergman H.
        • Hogan D.B.
        • McDowell I.
        • et al.
        A global clinical measure of fitness and frailty in elderly people.
        Cmaj. 2005; 173: 489-495
        • Rockwood K.
        • Mitnitski A.
        Frailty in relation to the accumulation of deficits.
        J Gerontol A Biol Sci Med Sci. 2007; 62: 722-727
        • Eriksen G.F.
        • Šaltytė Benth J.
        • Grønberg B.H.
        • Rostoft S.
        • Kirkhus L.
        • Kirkevold Ø.
        • et al.
        Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: a prospective observational study.
        Acta Oncol. 2021; 1-10
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Sundararajan V.
        • Henderson T.
        • Perry C.
        • Muggivan A.
        • Quan H.
        • Ghali W.A.
        New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.
        J Clin Epidemiol. 2004; 57: 1288-1294
        • Rubenstein L.Z.
        • Harker J.O.
        • Salva A.
        • Guigoz Y.
        • Vellas B.
        Screening for undernutrition in geriatric practice: developing the short-form mini-nutritional assessment (MNA-SF).
        J Gerontol A Biol Sci Med Sci. 2001; 56: M366-M372
        • Podsiadlo D.
        • Richardson S.
        The timed “up & go”: a test of basic functional mobility for frail elderly persons.
        J Am Geriatr Soc. 1991; 39: 142-148
        • Mahoney F.I.
        • Barthel D.W.
        Functional evaluation: the Barthel index.
        Md State Med J. 1965; 14: 61-65
        • Gladman J.R.
        • Lincoln N.B.
        • Adams S.A.
        Use of the extended ADL scale with stroke patients.
        Age Ageing. 1993; 22: 419-424
        • Nasreddine Z.S.
        • Phillips N.A.
        • Bedirian V.
        • Charbonneau S.
        • Whitehead V.
        • Collin I.
        • et al.
        The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment.
        J Am Geriatr Soc. 2005; 53: 695-699
        • Sheikh J.I.
        • Yesavage J.A.
        Geriatric depression scale (GDS): recent evidence and development of a shorter version.
        Clin Gerontol. 1986; 5: 165-173
        • Aaronson N.K.
        • Ahmedzai S.
        • Bergman B.
        • Bullinger M.
        • Cull A.
        • Duez N.J.
        • et al.
        The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
        J Natl Cancer Inst. 1993; 85: 365-376
        • Fayers P.
        • Aaronson N.K.
        • Bordal K.G.M.
        • Curran D.
        • Bottomley A.
        • on behalf of the EORTC Quality of Life Group
        The EORTC QLQ-30 Scoring Manual.
        3rd ed. European Organisation for Research and Treatment of Cancer, Brussels2001
        • Osoba D.
        • Rodrigues G.
        • Myles J.
        • Zee B.
        • Pater J.
        Interpreting the significance of changes in health-related quality-of-life scores.
        J Clin Oncol. 1998; 16: 139-144
        • Wu C.Y.
        • Chuang L.L.
        • Lin K.C.
        • Lee S.D.
        • Hong W.H.
        Responsiveness, minimal detectable change, and minimal clinically important difference of the Nottingham extended activities of daily living scale in patients with improved performance after stroke rehabilitation.
        Arch Phys Med Rehabil. 2011; 92: 1281-1287
        • Coens C.
        • Pe M.
        • Dueck A.C.
        • Sloan J.
        • Basch E.
        • Calvert M.
        • et al.
        International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL consortium.
        Lancet Oncol. 2020; 21: e83-e96
        • van Laarhoven H.W.
        • Schilderman J.
        • Bleijenberg G.
        • Donders R.
        • Vissers K.C.
        • Verhagen C.A.
        • et al.
        Coping, quality of life, depression, and hopelessness in cancer patients in a curative and palliative, end-of-life care setting.
        Cancer Nurs. 2011; 34: 302-314
        • Kirkhus L.
        • Harneshaug M.
        • Saltyte Benth J.
        • Gronberg B.H.
        • Rostoft S.
        • Bergh S.
        • et al.
        Modifiable factors affecting older patients’ quality of life and physical function during cancer treatment.
        J Geriatr Oncol. 2019; 10: 904-912
        • Goineau A.
        • Campion L.
        • d’Aillières B.
        • Vié B.
        • Ghesquière A.
        • Béra G.
        • et al.
        Comprehensive geriatric assessment and quality of life after localized prostate cancer radiotherapy in elderly patients.
        PLoS One. 2018; 13e0194173
        • Goineau A.
        • Campion L.
        • Commer J.M.
        • Vié B.
        • Ghesquière A.
        • Béra G.
        • et al.
        Can comprehensive geriatric assessment predict tolerance of radiotherapy for localized prostate Cancer in men aged 75 years or older?.
        Cancers (Basel). 2020; 12
        • Battisti N.M.L.
        • Hatton M.Q.
        • Reed M.W.R.
        • Herbert E.
        • Morgan J.L.
        • Bradburn M.
        • et al.
        Observational cohort study in older women with early breast cancer: use of radiation therapy and impact on health-related quality of life and mortality.
        Radiother Oncol. 2021; 161: 166-176
        • Ferrell B.R.
        • Temel J.S.
        • Temin S.
        • Alesi E.R.
        • Balboni T.A.
        • Basch E.M.
        • et al.
        Integration of palliative care into standard oncology care: American Society of Clinical Oncology clinical practice guideline update.
        J Clin Oncol. 2017; 35: 96-112
        • Wildiers H.
        • Heeren P.
        • Puts M.
        • Topinkova E.
        • Janssen-Heijnen M.L.
        • Extermann M.
        • et al.
        International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer.
        J Clin Oncol. 2014; 32: 2595-2603
        • Mohile S.G.
        • Dale W.
        • Somerfield M.R.
        • Schonberg M.A.
        • Boyd C.M.
        • Burhenn P.S.
        • et al.
        Practical assessment and Management of Vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
        J Clin Oncol. 2018; 36: 2326-2347
        • Mohile S.G.
        • Mohamed M.R.
        • Xu H.
        • Culakova E.
        • Loh K.P.
        • Magnuson A.
        • et al.
        Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study.
        Lancet. 2021; 398: 1894-1904
        • Li D.
        • Sun C.L.
        • Kim H.
        • Soto-Perez-de-Celis E.
        • Chung V.
        • Koczywas M.
        • et al.
        Geriatric assessment-driven intervention (GAIN) on chemotherapy-related toxic effects in older adults with cancer: a randomized clinical trial.
        JAMA Oncol. 2021; 7: e214158
        • Basch E.
        • Deal A.M.
        • Kris M.G.
        • Scher H.I.
        • Hudis C.A.
        • Sabbatini P.
        • et al.
        Symptom monitoring with patient-reported outcomes during routine Cancer treatment: a randomized controlled trial.
        J Clin Oncol. 2016; 34: 557-565
        • O’Donovan A.
        • Morris L.
        Palliative radiation therapy in older adults with Cancer: age-related considerations.
        Clin Oncol (R Coll Radiol). 2020; 32: 766-774
        • Vanbutsele G.
        • Pardon K.
        • Van Belle S.
        • Surmont V.
        • De Laat M.
        • Colman R.
        • et al.
        Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial.
        Lancet Oncol. 2018; 19: 394-404
        • Bakitas M.A.
        • Tosteson T.D.
        • Li Z.
        • Lyons K.D.
        • Hull J.G.
        • Li Z.
        • et al.
        Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial.
        J Clin Oncol. 2015; 33: 1438-1445
        • Fayers P.
        • Bottomley A.
        Quality of life research within the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of Cancer.
        Eur J Cancer. 2002; 38: S125-S133