The effect of geriatric intervention in frail elderly patients receiving chemotherapy for colorectal cancer: a randomized trial (GERICO)

Oncologists and geriatricians have begun to cooperate to individualize and improve treatment for elderly patients with cancer [31]. Elderly vulnerable patients are at high risk of severe toxicity [32]. During the last decade, there has therefore been an increased focus on the importance of individual patient assessment before treatment decisions are made. Chronological age per se should not be an exclusion criterion for adjuvant or palliative chemotherapy [33‐35]. Comorbidity and PS more than age alone influence treatment outcomes for both patients in adjuvant [36] and palliative therapy [23, 37]. The Comprehensive Geriatric Assessment (CGA) is a multidisciplinary comprehensive evaluation of an elderly individual’s functional status, physical performance, comorbidity, polypharmacy, cognitive and emotional function, nutritional status and need of social support [38, 39]. CGA in older patients with cancer can predict survival, chemotherapy toxicity and morbidity [40‐42]. The assessment can detect unknown geriatric problems and lead to change in treatment strategy for 20% to 49% of patients [43, 44]. To assess all those important factors, there is a need for a multidisciplinary approach in decision making, before and during treatment with chemotherapy, in elderly patients with CRC [31, 35].

Geriatric frailty assessment can predict 1- and 5-year survival in patients after surgery for CRC, and the impact of frailty on 5-year survival is comparable with the impact of TNM stage [45]. Interventions on identified health issues found by the CGA could reduce the side effects and thus increase the number of patients who complete chemotherapy. The supportive care could also improve coping strategies in dealing with adverse events and thereby improve treatment compliance. This could increase survival of the patients. In a recent randomized study, the impact of geriatric intervention on tolerance to chemotherapy in elderly patients (age > 70 years) was investigated. The patients who received CGA in the intervention group (N = 46) were more likely to complete planned chemotherapy without dose modifications, but there was no difference in grade 3+ toxicity between the two groups [46].

CGA is considered as the most appropriate way to examine the overall health situation of the elderly patient, but it is time consuming and not required for all patients, and other frailty screenings tools have been developed and validated. In the recommendations from the International Society for Geriatric Oncology (SIOG) from June 2014 [47], the G8 questionnaire is found to be the more or equally sensitive than other screening tools compared to CGA. For patients with an abnormal G8 score (≤ 14/17), full CGA is recommended [48].

The effect of geriatric intervention in patients undergoing chemotherapy for CRC has not been fully investigated. However, there is evidence for a beneficial effect of geriatric assessment for elderly admitted to hospitals for medical conditions. In a meta-analysis of randomized trials, CGA after appropriate interventions during hospitalization increased the likelihood of being alive and living at home 6 months after hospital discharge [49]. The beneficial effect was greatest for geriatric wards, but geriatric teams had also a positive effect.

Several studies have evaluated the cooperation between geriatricians and surgeons from different specialties, and a beneficial effect in terms of cost reduction and treatment outcomes was found, e.g. in elderly patients with hip fractures randomized to comprehensive geriatric care compared to usual orthopedic care, 4-month mobility improves [50]. Multi-disciplinary preoperative CGA with post-operative in-ward follow-up by geriatricians in elderly patients at risk of complications due to elective orthopedic surgery decreased the risk of complications and reduced length of hospital stay [51]. For elderly patients undergoing elective orthopedic, urological or gastrointestinal surgery, a preoperative CGA led to fewer cancelled procedures, a decrease in postoperative complications and a reduced length of stay [52].

To our knowledge, there are no intervention studies evaluating the beneficial effect of geriatric intervention on chemotherapy completion in patients undergoing chemotherapy for CRC. No such studies are described on clinical trials.​gov (search July 15, 2016). The present trial will therefore provide new and valuable knowledge about whether it is beneficial for the elderly patient with CRC to be simultaneously treated by a geriatrician.

There is no evidence for the effect of the full geriatric intervention in patients with CRC undergoing chemotherapy; however, different parts of the geriatric assessment have been shown to be predictive, and intervention has been shown to be beneficial.

In the last decade, there has been an increased focus on physical performance, exercise and their relation with a diagnosis of CC, treatment outcomes and quality of life during and after chemotherapy. Physical activity prevents risk of CC [53], and several studies suggest that physical activity after cancer diagnosis increases DFS and OS [54], and it is found to be associated with CC-and CRC-specific mortality [55, 56]. In mouse models, physical exercise reduces tumor growth, probably by increasing immune cell infiltration [57]. Jung et al. found that decreased muscle mass at the start of treatment was significantly associated with toxicity grades 3 to 4 in patients undergoing adjuvant chemotherapy [58]. Others have reported the beneficial effect of physical training on quality of life and fatigue during chemotherapy [59, 60]. In a recent study of 33 patients with CC, an 18-week exercise program significantly reduced physical and general fatigue [61]. In patients undergoing adjuvant chemotherapy for CRC, supervised exercise compared to usual care was superior in improvements of physical activity level, functional status and QOL, but the patients were younger than in GERICO (mean 56.5 years) [62]. Among breast cancer patients undergoing adjuvant treatment, both moderate to high-intensity exercise and low intensity home training programs resulted in better physical performance but also less pain and toxicity (e.g. nausea and vomiting) due to the treatment [63]. In patients med lung cancer, home-based walking has been shown to be feasible and have a beneficial effect on anxiety and depression [64]. In a meta-analysis, Meneses-Echáves et al. conclude that supervised physical activity interventions reduce cancer-related fatigue and suggest that combined aerobic and resistance exercise regimens should be included as a part of rehabilitation in people diagnosed with cancer [65].

Many elderly patients suffer from sarcopenia, an age-related decrease in muscle mass and strength leading to decline in physical performance. Sarcopenia is associated with falls, disabilities and increased risk of death [66]. Muscle strength is measured with handgrip strength, with a cut off of 20 kg for women and 30 kg for men [67]. Muscle mass can be measured with DXA scanning, and physical performance is assessed by different tests. Usual gait speed, which is commonly used, is associated with OS [68], and a gait speed over 4 m (at a threshold of 1 m/s) can predict adverse outcomes in community-dwelling older people [69]. Gait speed is also recommended as a frailty screening test in cancer patients 65 years of age and older [70]. Low handgrip strength and slow usual gait speed are independently associated with higher mortality [71].

Loss of weight in patients with cancer is associated with a poor prognosis [72], and nutritional support to malnourished patients with gastrointestinal cancer is recommended [73]. There are few studies evaluating the effect of nutrition intervention in cancer patients. In 358 patients with metastatic or locally advanced gastrointestinal, non-small cell lung cancer or mesothelioma undergoing chemotherapy, nutritional advice and supplements had no impact on 1-year mortality or quality of life [74]. In a meta-analysis of 1414 malnourished patients with different cancers included in 13 randomized controlled trials, nutritional intervention was found to be effective in increasing nutritional intake and improving some aspects of QOL, but the interventions had no effect on mortality [75]. In a randomized trial of 336 patients with cancer at risk of malnutrition, dietary counseling increased nutritional intake but had no impact on mortality, toxicity or other treatment outcomes [76]. The authors suggest that cancer cachexia anti-anabolism is responsible for the lack of effect.

The aim of the study is to investigate whether frail elderly patients (defined as age ≥ 70 years) with stages II–IV CRC will benefit from full comprehensive geriatric assessment and intervention before and during treatment with adjuvant or palliative first-line chemotherapy. We will evaluate whether optimizing all health conditions can increase the number of patients completing 6 months of adjuvant chemotherapy or first-line chemotherapy until disease progression.

Our hypothesis is that geriatric intervention can optimize the health and functional status of frail elderly patients with stages II–IV CRC. Due to this geriatric intervention, more patients will receive the scheduled doses and series of chemotherapy. As a consequence, the patients will have a longer OS and an improved quality of life.

The study is an open, randomized, prospective trial performed at the departments of oncology and medicine at Copenhagen University Hospital, Herlev and Gentofte, Denmark.

A total of 140 participants will be included: 70 participants in the intervention group and 70 participants in the control group.

All patients ≥70 years [77] who meet the criteria to either receive adjuvant chemotherapy after surgery for stage III and high-risk stage II CRC or palliative first-line chemotherapy for inoperable or metastatic CRC will be screened for frailty with the G8 questionnaire [78] at their first visit to the oncology outpatient clinic. Frail patients, defined as patients with ≤14/17 points in the G8 questionnaire, will be offered inclusion in the study. Other inclusion criteria are PS 0–2 and a life expectancy ≥3 months. All patients must provide informed signed consent to be eligible for inclusion. Exclusion criteria are other malignancies during the last 5 years (except basal cell carcinoma, squamous cell carcinoma in situ and cervical cancer), and simultaneous participation in a trial of a medical product. The patients with recurrence or metastatic disease must not have received prior adjuvant treatment in the GERICO protocol.

To achieve adequate participant enrolment, the single center research team notifies the oncologists about all patients eligible for screening. The research team obtains informed consent and collects all data.

After inclusion, the participants are randomized to either the intervention group or the control group. The randomization is made using ARRACT (A Real-time Randomization Application for Clinical Trials), a computer program developed and operated by the Department of Oncology Clinical Research at Herlev and Gentofte Hospital. The method used is "Stratified Balanced Allocation Method (n- Treatments)" [79, 80]. In the randomization, the PS of the patients (0 or 1+), and chemotherapy treatment (adjuvant or metastatic setting) are used as stratification variables.

The patients in the control group receive standard treatment with 6 months of adjuvant chemotherapy after surgery for CRC or palliative first-line chemotherapy until disease progression, operation or other scheduled change in treatment. If the patient has other health problems, those issues will be assessed either by the oncologist or by the general practitioner according to standard of care.

The patients in the intervention group also receive standard treatment with 6 months of adjuvant chemotherapy after surgery for CRC or first-line chemotherapy until disease progression, operation or other scheduled change of treatment. These patients will simultaneously be examined and treated by a geriatrician (CL), who will assess all other health issues.

Patients in both groups will fill out quality of life questionnaires (QLQ) prior to the start of chemotherapy, after 2 months, and at the end of the treatment using the validated QLQ C30 and QLQ ELD14 questionnaires from the European Organization for Research and Treatment of Cancer (EORTC). The adverse events are routinely recorded by the oncologist using the standardized CTC criteria version 4.0.

All patients in the intervention group will receive full geriatric assessment and a clinical examination at start of chemotherapy, after 2 months, and more frequently if needed. Invention will be performed on identified issues (Table 1).

In the present study, all patients in the intervention group are screened, as part of the geriatric assessment, with a Jamar Dynamometer for handgrip strength (cut off 20 kg for women and 30 kg for men) and with a 10-m gait speed (cut-off 1 m/s). With a test result under cut off, patients are referred to a standardized physical exercise program twice weekly at the hospital and home exercise once weekly for 12 weeks.

Furthermore, the patients in the intervention group are screened for risk of malnutrition, and the patients are referred to a dietitian if needed.

Review of patients’ medication lists will be performed with focus on polypharmacy and interactions [81] and inappropriate medication based on START STOPP criteria [82].

The standard adjuvant chemotherapy is outlined in Table 2. The standard dose is based on body surface area (BSA), with a possible 25% primary dose reduction in frail patients.

The first participant was included in April 2015. The recruitment period is 2–3 years. The last participant included is expected in June 2018. A total of 190 patients have been screened for frailty with the G8 questionnaire, and (131) 69% of the patients were frail, a little lower percentage than seen in other studies [86]. To date, 81 patients have been included. The number of included patients is lower than expected. One of the reasons is that 32 patients were not screened at all, since they were found to be too frail to receive treatment. Of the 131 patients screened frail with the G8 questionnaire, 19 patients did not start any treatment due to performance status, high age, comorbidity or patients’ refusal (Fig. 1). An additional five patients were excluded because of other malignancies. Since the start of the trial, eight patients that could have been included were missed.