Unfavorable impact of cancer cachexia on activity of daily living and need for inpatient care in elderly patients with advanced non-small-cell lung cancer in Japan: a prospective longitudinal observational study

This prospective longitudinal observational study was designed to estimate the impact of cachexia on ADL, length of hospital stay, and inpatient medical costs among elderly patients with advanced NSCLC receiving chemotherapy. The study was performed at the Shizuoka Cancer Center, Japan, from January 2013 to April 2016. The Shizuoka Cancer Center is a 615-bed prefectural hospital designated as an advanced treatment hospital by the Japanese Ministry of Health, Labour and Welfare. The eligibility criteria were as follows: (1) histologically and/or cytologically proven stage III or IV NSCLC including postoperative recurrence; (2) age ≥ 70 years, with scheduled first-line systemic chemotherapy; (3) no previous systemic chemotherapy or thoracic radiotherapy (adjuvant chemotherapy was not counted as prior chemotherapy); (4) Eastern Cooperative Oncology Group performance status of 0–2; (5) ability to ambulate, read, and respond to questions without assistance; and (6) expected survival of >12 weeks. Patients were excluded if they had a severe psychiatric disorder, active infectious disease, unstable cardiac disease, or untreated symptomatic brain or bone metastases that prevented safe assessment.

All patients provided written informed consent. The study was approved by the institutional review board and registered on the clinical trials site of the University Hospital Medical Information Network Clinical Trials Registry in Japan (registration number: UMIN000009768).

The first patient was enrolled on January 23, 2013, and the last on November 7, 2013. The study period for each patient was defined as the time between the date of study entry to the date of the last visit or the cutoff date (April 30, 2016). Baseline study assessments were performed by the attending physicians, physiotherapists, and national registered dietitians during the time between study entry and initiation of the first chemotherapy session.

Body weight (kg) was measured to the nearest 0.1 kg and the body mass index (BMI; kg/m²) was subsequently calculated. The registered dietitians (T.A. and H.S.) assessed nutritional status using the full version of the Mini Nutritional Assessment (full MNA®) [18]. The incremental shuttle-walking test was conducted according to the recent guidelines [19] and original protocol described by Singh et al. [20]. The 10-m course was established in the corridor of our hospital. Walking speed was dictated by a timed signal played on a CD recorder provided by the manufacturer (Japanese version, produced by the Graduate School of Biomedical Sciences, Nagasaki University, Japan, 2000). All patients were subjected to the test once under standardized conditions and were carefully observed during the test, so that they would not exceed their exercise limit. The maximal walking distance was described as incremental shuttle-walking distance. Hand-grip strength was measured using a grip strength dynamometer (GRIP-D, Takei Scientific Instruments Co., LTD, Niigata, Japan). One trial was performed for each hand, and the result from the strongest hand was used for the analysis. Lumbar skeletal muscle mass was measured by analyzing electronically stored computed tomography (CT) images using SYNAPSE VINCENT version 3 (FUJIFILM Medical Systems, Japan). The CT images were obtained with or without contrast enhancement at 5-mm slice thickness. The third lumbar vertebra (L3) was chosen as the standard landmark, and 2 consecutive CT images extending from L3 to the iliac crest were chosen to measure the cross-sectional area of the skeletal muscle that was identified based on Hounsfield unit thresholds of −29 to +150. The sum of the cross-sectional areas (cm²) of the muscles in the L3 region was computed for each image. The mean value of 2 images was normalized for height in meters squared and reported as the lumbar skeletal muscle index (cm²/m²) [21]. The disease stage was determined according to the TNM classification, and the best response to chemotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors.

Muscle depletion was defined based on lumbar skeletal muscle index cutoffs of <43.0 cm²/m² for men with a BMI <25.0 kg/m², <53.0 cm²/m² for men with a BMI ≥25.0 kg/m², and <41.0 cm²/m² for women [22]. Malnutrition or at risk of malnutrition was defined based on a full MNA® score < 17 points [23]. Cancer cachexia was defined as unintentional weight loss of >5% during the preceding 6 months or >2% in patients with a BMI <20 kg/m², or the presence of muscle depletion according to the consensus criteria [6]. The patient’s weight 6 months before study entry was obtained by interviewing the patient and their family members at study entry.

For the assessment of ADL, the Barthel index was estimated by the attending physician or physiotherapists at each hospital visit. The disability-free survival (DFS) duration was calculated as the time between study enrollment and the date of onset of the disabling event. A disabling event was defined as a decrease in the Barthel index from the baseline value by >10 points. The event was confirmed as a true event if the condition persisted for >2 weeks from the initial report. In confirmed events, the dates of the initial reports were used as the event dates in the analysis.

The medical claims data, including the numbers of outpatient visits and hospitalizations, lengths of hospital stay, healthcare resource utilization items, and medical costs, were obtained from the electronic medical records of our hospital. For patients who received medical care at another hospital, medical claims data was obtained through the institutional coordination office of local clinics and hospitals. Inpatient medical costs were estimated by certified medical accountants. In this study, the medical costs refer to the actual revenue that the hospital was paid from the health insurance funds of the Japanese health care system. Medical costs for home care were not included. In the healthcare utilization analysis, visits (or hospitalizations) for supportive care were defined as all visits (or hospitalizations) that involved physician medical examinations, except for visits (or hospitalizations) for chemotherapy or radiotherapy. Outpatient visits for regular radiological/blood tests without a physician examination or visits for non-medical reasons were not included.

The overall survival (OS) and DFS rates were estimated using the Kaplan-Meier method. OS was censored at the date of the last visit for patients whose deaths could not be confirmed. DFS was censored at the date of the last visit for patients whose disabling event could not be confirmed. To compare categorical variables, chi-square or Fisher’s exact tests were used. Continuous measures were compared using the Wilcoxon rank-sum test. For all analyses, p-values <0.05 were considered significant. We used a mean cumulative function for recurrent event analysis [24] of the cumulative length of hospital stay and medical costs related to cancer care, as previously described [25, 26]. Exploratory subset analyses for patients without epidermal growth factor receptor (EGFR) gene mutation were performed. All statistical analyses were performed using JMP version 12.0 for Windows (SAS Institute Inc., USA).

Thirty-one patients were screened and 30 patients were enrolled into this study, with a median age of 74 years (range, 70–82 years). Seven patients (23.3%) had activating EGFR gene mutation. Cancer cachexia was diagnosed in 19 (63.3%) patients (Table 1). Cachectic patients were older (76 vs. 73 years, p < 0.05), had a larger weight loss in the past 6 months (−9.4 vs. −0.1%, p < 0.05), and had a higher incidence of malnutrition or were more frequently at risk for malnutrition (73.7 vs. 27.3%, p < 0.05). Cachectic men had poorer physical function than non-cachectic men in regard to the incremental shuttle-walking distance (283.4 vs. 413.8 m, p < 0.05) and hand-grip strength (29.5 vs. 39.3 kg, p < 0.05). There was no statistical difference in physical function between cachectic and non-cachectic women.

All patients received first-line chemotherapy within 1 week after the baseline assessment. All patients initially received a standard dose of chemotherapy with a standard schedule. The chemotherapy regimens included single-agent chemotherapy (docetaxel or vinorelbine) in 10 patients, platinum-based chemotherapy (carboplatin + paclitaxel, or cisplatin + pemetrexed, gemcitabine, or vinorelbine) in 14, and gefitinib in 6 patients with epidermal growth factor receptor gene mutations. An objective tumor response was seen in 12 patients (40.0%). There was no statistical difference in the response rate between cachectic and non-cachectic patients (42.1% vs. 36.4%, p = 0.75). During the study period (January 23, 2013 to April 30, 2016), 18 patients (60.0%) received second or higher lines of chemotherapy, including docetaxel, erlotinib, pemetrexed, gemcitabine, carboplatin + pemetrexed, S-1, or investigational drugs. There was no statistical difference in the proportion of patients receiving second or higher lines of chemotherapy between cachectic and non-cachectic patients. Eighteen patients (60.0%) received palliative radiotherapy during the study period, including cranial radiation (n = 10, 33.3%), bone radiation (n = 6, 20.0%), and thoracic radiation (n = 2, 6.7%). None of our patients received immunotherapy or molecular targeted treatment other than gefitinib or erlotinib during the study period. One patient was transferred to another hospital for personal reasons 19.4 weeks after study entry and continued chemotherapy. Three patients were transferred to another hospital for palliative care. Three patients received gamma knife surgery at another hospital during the study period. A total of 29 patients were eligible for the analysis of length of hospital stay and medical costs (Fig. 1). None of our patients received anti-cachexia treatment such as megestrol acetate, eicosapentaenoic acid, or multimodal intervention specific for cancer cachexia.

Among the 30 patients, 28 (93.3%) died at the cutoff date. The median follow-up period was 10.7 (95% confidence interval, 7.9–21.6) months. There was no significant difference in OS between cachectic and non-cachectic patients (p = 0.0960, Fig. 2a). In the exploratory analysis for patients without EGFR mutation, there was also no significant difference in OS between cachectic and non-cachectic patients (p = 0.2055).

Among the 30 patients, 27 (90.0%) were disabled at the cutoff date. Disabling events often affected multiple ADLs simultaneously. Frequently observed combinations of initial disabling events per the Barthel index included stair climbing (27 events, 100%), morbidity (26 events, 96.3%), bathing (24 events, 88.9%), toilet use (15 events, 55.6%), and transfer (11 events, 40.7%). Cachectic patients at baseline had a significantly shorter DFS than non-cachectic patients (7.5 vs. 17.1 months, p < 0.05, Fig. 2b). Additionally, cachectic patients had a longer post-disability survival than non-cachectic patients (2.5 vs. 0.7 months, p < 0.05, Fig. 3). In the exploratory analysis for patients without EGFR mutation, cachectic patients tended to have shorter DFS (6.8 vs. 10.3 months, p = 0.1078) and longer post-disability survival (2.6 vs. 0.6 months, p = 0.0541) than non-cachectic patients without statistical significance.

During the first year since study entry, we recorded 525 outpatient visits and 144 hospitalizations for the 29 patients. There were 42 unplanned outpatient visits (8.0% of all outpatient visits), including 14 visits (2.7%) to the emergency room. The reasons for the unplanned visits included anorexia or dehydration (17 visits, 41%), infection or febrile disease (9 visits, 21%), constipation or diarrhea (5 visits, 12%), respiratory symptoms (5 visits, 12%), and others (6 visits, 14%). There were 30 emergency hospitalizations (20.8% of all hospitalizations). The reasons for emergency hospitalizations included anorexia or dehydration (7 hospitalizations, 23%), respiratory symptoms (6 hospitalizations, 20%), infection or febrile disease (5 hospitalizations, 17%), urgent radiotherapy (4 hospitalizations, 13%), end-of-life care (3 hospitalizations, 10%), and others (5 hospitalizations, 17%). Hospitalization for non-medical reasons (e.g. social hospitalization) was not observed.

In the comparison of socioeconomic parameters during the first year of study entry, cachectic patients had a longer cumulative length of hospital stay (80.7 vs. 38.5 days/person, p < 0.05, Table 2), more frequent unplanned outpatient visits or emergency hospitalizations (4.2 vs. 1.7 times/person, p < 0.05, Table 2), and higher cumulative medical costs (¥5.0 vs. ¥3.3 million/person, p < 0.05, Table 2). In the exploratory analysis for patients without EGFR mutation, cachectic patients had a longer cumulative length of hospital stay (109.3 vs. 45.9 days/person, p < 0.05), more frequent unplanned outpatient visits or emergency hospitalizations (5.5 vs. 2.0 times/person, p < 0.05), and higher cumulative medical costs (¥5.3 vs. ¥3.3 million/person, p < 0.05). The differences in medical costs between the two groups were mainly attributed to the inpatient care (¥3.5 vs. 2.1 million, p < 0.05) and supportive care (¥1.2 vs. 0.4 million, p < 0.05), while the costs for outpatient care (¥1.5 vs. 1.3 million) and anticancer treatments, including radiotherapy (¥0.5 vs. 0.2 million) and chemotherapy (¥2.0 vs. 2.2 million), were similar between the groups (Table 2). The curves of cumulative hospital days (Fig. 4a) and inpatient medical costs (Fig. 4b) in cachectic and non-cachectic patients separated at 6 months and continued to diverge over the available follow-up period, with the length of hospitalization being 42.2 and 104.3 days (Fig. 4c) and in inpatient medical costs ¥1.5 and ¥4.2 million (Fig. 4d) at 12 and 24 months, respectively.