Geriatric assessment and intervention in older vulnerable patients undergoing surgery for colorectal cancer: a protocol for a randomised controlled trial (GEPOC trial)

Colorectal cancer (CRC) is the third most common cancer worldwide accounting for 1.8 million new cases in 2018 [1]. The incidence of CRC increases with age [2], with a median age at time of diagnosis of 70 years in Denmark [3]. As the population is getting older, an increasing number of older patients with CRC is expected in the future [4, 5].

The mainstay in treatment of localised CRC is resection [6]. Implementation of better perioperative care, minimal invasive surgery and enhanced recovery pathways have made cancer surgery available for a larger proportion of patients with CRC [7]. Surgery itself and complications from surgery increase the risk of functional decline and loss of independence which can be difficult to regain [8]. The burden of treatment as well as possible treatment outcomes are strong determinants of older patients’ preferences [9]. Maintenance of independence and health related quality of life represent preferred treatment outcomes over standard oncological outcomes (e.g. disease free survival) for older patients [9‐11]. In general, surgery is considered safe for older patients and the primary risk factor for poor surgical outcome, usually defined as surgical complications or survival, is not age but comorbidity [12], frailty [13, 14] and sarcopenia [15]. However, loss of independence is reported in 1 in 5 patients older than 65 years undergoing surgery for CRC [8, 16].

Frailty is recognised as an independent risk factor and has been described as “A medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death” [17]. Frail patients are more susceptible to adverse effects from external stressors such as surgery [13]. Identifying frail people is therefore crucial for more careful planning of surgery and treatment. Merely screening for frailty brings awareness of patient comorbidity and capacity and is associated with reduced mortality after surgery [18]. Frailty is not a permanent state but potentially reversible [19] since some comorbidities are modifiable, as are both physical capacity and nutritional status.

Comprehensive Geriatric assessment (CGA) is hitherto the most appropriate way to examine the overall health situation of the older frail patient [20]. CGA is a multidomain and usually multidisciplinary work tool used for systematic assessment of an older person’s medical, psychosocial, as well as functional capabilities and limitations in order to develop an overall plan for interventions and follow-up [21]. CGA assesses known pathology and can uncover unrecognized health issues [22]. Furthermore, a prospective study has shown that CGA can assess the risk of postoperative complications in older patients undergoing elective CRC surgery [23]. Nonetheless, CGA is time consuming and may not be needed for all older patients. Several more rapid frailty screening tools have therefore been developed to identify which patients will benefit from a CGA [24]. The recommendations from the International Society for Geriatric Oncology (SIOG) from June 2014 [25] find the G8 questionnaire to be equally sensitive or superior when compared to other screening tools. For patients with an abnormal G8 score (≤ 14/17) a full CGA is recommended [26, 27].

One of the most important factors leading to frailty is low muscle strength, functional performance and low muscle mass (i.e. sarcopenia) [17]. Progressive resistance training is the single most effective intervention to increase muscle strength, muscle mass and functional performance in healthy older individuals [28] and in different patient populations [29‐32]. Physical exercise is therefore recommended by WHO [33] and is shown to be safe and beneficial among older patients with cancer [34, 35].

Yet, there is a need for randomised controlled trials investigating the effect of the CGA in cancer surgery with patient-centred outcomes as preferred by the older patients. Thus, the aim of the present study is to evaluate the effect of pre-operative CGA and physical exercise, post-operative geriatric in-ward review and exercise, and post-operative geriatric rehabilitation on patients´ physical and functional performance.

The present study is a RCT evaluating the effect of geriatric intervention in frail older patients undergoing surgery for primary CRC. The development of ERAS pathways and minimal invasive surgical technique have made surgery feasible for a broader population, including older patients. However, treatment decisions made today are often based on studies with younger and fitter patients, as the older frail population is often underrepresented in clinical trials [61]. Apart from observational studies [7], there is an urgent need for interventional studies focusing on patient-relevant outcomes as treatment goals for the older frail patients differ from their younger counterparts with an increased emphasis on independence, quality of life and physical capacity [9].

The CGA is a well-known tool in the intervention of older frail patients. In a meta-analysis of randomised trials, CGA-based interventions in patients admitted to the hospital for medical conditions increased the likelihood of being alive and living at home 6 months after hospital discharge [20]. The positive effect was greatest for geriatric wards, but geriatric teams also had a positive effect.

In orthopaedic surgery a beneficial effect in terms of 4 and 12  month physical function and increased independence was found for older patients with hip fractures randomised to comprehensive geriatric care compared to usual orthopaedic care [62]. For patients undergoing elective surgery, the incorporation of pre-operative CGA and post-operative inpatient geriatric review is seen in the UK with the Perioperative care of Older people undergoing Surgery (POPS) service. The POPS model was evaluated in a pre- and post-study and showed fewer postoperative medical complications, fewer multidisciplinary issues and a reduced length of hospitalisation [63]. The POPS concept was subsequently proved effective in a RCT of patients undergoing elective aorta or lower limb vascular surgery [64]. The RCT showed significantly reduced length of stay in the CGA group compared to standard care. The study did not use post-operative geriatric inpatient review but created a postoperative care plan providing advice on prevention and management of postoperative complications.

Few studies have investigated the effect of CGA in cancer surgery. In a recent Norwegian RCT, Ommundsen et al. [65] investigated the effect of preoperative geriatric intervention on postoperative complications (grade II-IV Clavien-Dindo classification) in patients undergoing elective surgery for CRC. No immediate difference was found between groups. When adjusted for prespecified prognostic factors, there was a statistically significant difference in favour of the intervention group when all complications (grade I-V) were taken into account. The study did not use post-operative geriatric inpatient review but made the geriatric assessment available to the surgical team and made general recommendations regarding medical and multidisciplinary issues (e.g. delirium and mobilisation). The study did not investigate the effect of CGA on functional status, quality of life or independence.

Older frail patients are prone to medical complications and loss of independence after surgery even if provided with optimal pre-operative care. Therefore, a major strength of the GEPOC study is expected to be the planned post-operative geriatric inpatient review. Furthermore, the broad collection of outcomes both in terms of physical testing, patient reported outcomes, body composition and serum biomarkers allow for a detailed insight in the effect of CGA based intervention in the population. To our knowledge no RCTs have been published investigating the effect of both pre-operative CGA and post-operative geriatric inpatient review for patients undergoing cancer surgery.

The CGA-based exercise programme is delivered throughout the GEPOC study. The pre-operative part is in line with the increasing interest in prehabilitation in the field of perioperative medicine. Prehabilitation is described by Carli et al. as “the process of enabling patients to withstand the stress of surgery through augmenting functional capacity” [66]. Prehabilitation focuses on preconditioning through exercise, nutrition, smoking cessation and anxiety reducing elements. A meta-analysis has shown effect on lean body mass [67], but results are still lacking in important outcomes e.g. complications to surgery, HRQOL, independence and physical capacity. Carli et al. showed no difference between groups in a RCT published in 2020 comparing prehabilitation to rehabilitation [68] but larger international studies are ongoing [69]. In the GEPOC study, the preconditioning period is short due to Danish cancer care plans which ensure surgery within 2 weeks from diagnosis. This challenges the ability to detect a measurable effect of the pre-operative exercise programme. However, the pre-operative physical exercise serves to improve neuromuscular adaptation and enable patients to get familiar with the exercise facilities and the training programme, thus facilitating a safe and effective return in the rehabilitation period. As older frail patients often have complex pathology going into surgery, a strength of CGA-based exercise in the GEPOC study is the assessment and individually tailored interventions ensuring a more personalised and holistic treatment approach also targeting possible modifiable barriers for exercise (e.g. dizziness as a result of too aggressive antihypertensive treatment). Furthermore, the effect of rehabilitation is well proven, and we hypothesize that combining prehabilitation and rehabilitation rather than only applying one of these would serve as a more beneficial treatment option for frail older patients. A limitation to this study setup is that it is unable to evaluate the effect of either prehabilitation or rehabilitation as a separate intervention.

Sarcopenia is reported in the GEPOC study and is regarded as one of the physical drivers of frailty. It is acknowledged as a separate entity characterised by muscle failure [70]. This is primarily defined by low muscle strength and can be confirmed by reduced muscle quantity and/or quality. If muscle functioning is impaired as well, sarcopenia is considered severe [48]. Sarcopenia has multiple contributing factors including the ageing process itself, insufficient nutrition, inactivity (sedentary lifestyle) and chronic diseases like cancer. The association between frailty and sarcopenia has not been fully elucidated, but they are linked with many of the same clinical outcomes e.g. low survival and complications to surgery [71]. It has also been suggested that the role of an aged immune system, with the age-related decline in immune function and a state of chronic inflammation, could play at potential role in the pathophysiology of both frailty and sarcopenia [72]. Interventions for treatment of sarcopenia are often multimodal with resistance exercise and diet advice on adequate protein and calorie intake [73, 74] which also are domains addressed in the CGA. In the GEPOC study we perform serial assessments of sarcopenia throughout the study period allowing for obtaining valuable information on the effect of CGA on sarcopenia. Identifying and treating sarcopenia could be a key factor in preventing negative implications of frailty in an ageing population of patients with cancer.