The impact of preoperative nutritional status on recovery of physical function after lung resection for non-small cell lung cancer

Abstract

[Purpose] This study examined the association between the Controlling Nutritional Status (CONUT) score, an indicator for preoperative nutritional status, and postoperative recovery of physical function after lung resection in participants with non-small cell lung cancer (NSCLC). [Participants and Methods] This study included 82 participants with NSCLC. Participants were classified into a normal group (0–1 point) and a light malnutrition group (2–4 points) based on their CONUT scores. The primary outcome was the postoperative 6-minute walk distance (6MWD), and regression analysis was performed to estimate the coefficient for the preoperative 6MWD against the light malnutrition group. [Results] Of the 82 participants, 26 had light malnutrition (31.7%). The incidence of postoperative complications was significantly higher in the light malnutrition group than in the normal group. In addition, the postoperative 6MWD and 6MWD recovery were significantly lower in the light malnutrition group. In regression analysis preoperative light malnutrition was associated with postoperative 6MWD (β=−36.1; 95% confidence interval, −69.5 to −2.62). However, this association was attenuated in Model 3 after adjusting for postoperative complications. [Conclusion] Preoperative light malnutrition is associated with delayed postoperative recovery of physical function, suggesting a possible mediation pathway involving an increased risk of postoperative complications.

INTRODUCTION

In Japan, rapid population aging has increased the age at cancer diagnosis and the number of older adult patients¹⁾. Furthermore, this demographic shift, combined with a declining birthrate, is shrinking the workforce. Against this backdrop, supporting the early social reintegration and the continued employment of cancer survivors has become a critical challenge for maintaining the workforce. Surgical resection is the primary treatment with curative intent for non-small cell lung cancer (NSCLC)²⁾. Advances in surgical techniques have expanded the eligibility for surgery to include older adults in good general health³⁾. However, a postoperative decline in physical function due to surgical trauma may hinder a patient’s return to home and social life. Therefore, minimizing postoperative physical decline and facilitating the earliest potential return to normal life are the primary rehabilitation goals for older adults and working-age patients.

In recent years, the preoperative nutritional status has gained attention as a key factor influencing postoperative functional recovery. Patients with cancer often develop nutritional disorders, and a high incidence of malnutrition has been reported in older patients with lung cancer⁴⁾. Among the nutritional assessment tools for patients with NSCLC, the Controlling Nutritional Status (CONUT) score⁵⁾ provides a simple method for objectively evaluating nutritional status based on preoperative biochemical tests. The CONUT score is calculated from the following objective blood test values: serum albumin level, total lymphocyte count, and total cholesterol level. The total score is used to evaluate the degree of nutritional impairment at four levels ranging from normal to severe malnutrition (Appendix Table 1). The CONUT score is associated with the occurrence of postoperative complications (POC) and long-term prognosis^{6, 7)}, rendering it a crucial factor to consider in pre- and postoperative rehabilitation interventions.

Furthermore, exercise tolerance is crucial for patients with NSCLC because exercise tolerance is a predictive factor for long-term survival⁸⁾. The 6-minute walk distance (6MWD) serves as an objective indicator of exercise tolerance in patients with lung cancer, allowing for the assessment of changes during and after treatment⁹⁾. Exercise tolerance declines in the early postoperative period following lung cancer surgery, with the 6MWD decreasing by postoperative day 7 compared with preoperative values¹⁰⁾. To achieve early functional recovery, the factors that contribute to early postoperative decline must be identified. However, evidence regarding the association between preoperative nutritional status assessed using the CONUT score and postoperative exercise tolerance recovery remains unclear.

Therefore, this study aimed to investigate the association between preoperative nutritional status, assessed using the CONUT score, and postoperative recovery of exercise tolerance.

PARTICIPANTS AND METHODS

This retrospective study was conducted at the Department of Rehabilitation and Thoracic Surgery, Shinkomonji Hospital (Kitakyushu, Japan) between April 2017 and November 2020. A total of 104 participants who underwent lung resection for NSCLC during the study period were included in this study. Exclusion criteria were as follows: treatment for other diseases prioritized (n=1), moderately poor or worse preoperative nutritional status (n=4), and lung cancer in clinical stages III and IV (n=17). Participants with moderate or severe malnutrition were excluded to focus on a relatively healthy cohort with stable baseline status. After these exclusions, 82 participants were included in the analysis (Fig. 1). The mean age of the participants was 74.1 ± 9.8 years, the mean height was 160 ± 10.0 cm, and the mean weight was 58.0 ± 11.3 kg. Furthermore, no participants in this study cohort received neoadjuvant chemotherapy or radiotherapy. This study was approved by the Ethics Committee of Shinkomonji Hospital (approval No. 2021004). Given the retrospective nature of the study, the requirement for written informed consent was waived, and an opt-out process was implemented by disclosing the study information on the hospital website.

Fig. 1.

Patient flow diagram.

NSCLC: non-small cell lung cancer; CONUT score: controlling nutritional status score.

The primary exposure factor was the preoperative nutritional status. The participants were classified into a normal group (0–1 point) and a light malnutrition group (2–4 points) based on the CONUT score calculated from the blood test values obtained within 2 weeks preoperatively. All participants received usual care, and no specific nutritional intervention was provided based on the CONUT stage.

The primary outcome was the degree of postoperative recovery of physical function, with the 6MWD used as the primary end point, reflecting exercise tolerance. The 6-minute walk test was conducted according to the American Thoracic Society guidelines. The measurement location was a 30-m hospital corridor, and the participants were instructed to walk as far as possible within 6 min. The 6-minute walk test was performed on the first or second day of admission and 1–3 days before discharge. Secondary outcomes included the percentage recovery of the postoperative 6MWD (calculated as [postoperative 6MWD / preoperative 6MWD] ×100) relative to the preoperative value, occurrence of POC (defined as Clavien–Dindo classification grade II or higher) within 30 days, and number of days to recovery of the Eastern Cooperative Oncology Group performance status (PS) to baseline. Additionally, PS and Functional Independence Measure (FIM) scores for activities of daily living were assessed at admission and discharge. Other covariates, including sex, age, Brinkman Index, presence of chronic obstructive pulmonary disease, Charlson Comorbidity Index (CCI), as well as preoperative respiratory function parameters (forced vital capacity [FVC], forced expiratory volume in 1-second [FEV₁], and FEV₁/FVC), were obtained from the medical records.

In statistical analysis, continuous variables are expressed as mean ± standard deviation and categorical variables as absolute numbers and percentages. Intergroup comparisons were performed using unpaired t-tests or χ² tests. A linear regression analysis was performed with the postoperative 6MWD as the dependent variable to understand the association between the postoperative 6MWD and preoperative nutritional status. The following variables were considered potential confounding factors: sex, age, Brinkman index, presence of chronic obstructive pulmonary disease, CCI, and preoperative values for 6MWD, PS, FIM, and respiratory function parameters. Among these, the preoperative respiratory function parameters were excluded from the multivariate models because their variance inflation factor (VIF) exceeded 10. For the multivariate analysis, three models were constructed: model 1 was adjusted for sex, age, and preoperative 6MWD, model 2 was adjusted for the other confounding factors, excluding the respiratory parameters removed through VIF analysis, and model 3 incorporated the occurrence of postoperative complications into model 1 to evaluate the extent of mediation. Statistical significance was set at p<0.05. All tests were two-tailed. All statistical analyses were performed using Stata/MP 19 (StataCorp LLC; College Station, TX, USA).

RESULTS

Of the 104 eligible cases identified during the study period, 22 met the exclusion criteria, leaving 82 for analysis (Fig. 1). Baseline characteristics and assessment items according to nutritional status are summarized in Table 1. Compared with the normal group, the light malnutrition group had significantly higher CCI scores and significantly lower FEV1/FVC, preoperative PS, and preoperative FIM scores.

Table 1. Basic characteristics of the participants.

		Normal (n=56)	Light (n=26)
Female, n (%)		21 (37.5)	8 (30.8)
Age (years)		72.9 ± 10.1	76.6 ± 8.7
Brinkman index		613 ± 605	542 ± 613
COPD complication, n (%)		21 (37.5)	10 (38.5)
CCI (points)		2.3 ± 2.3	3.3 ± 2.9
FVC (L)		3.13 ± 0.97	3.01 ± 1.18
FEV1 (L)		2.30 ± 0.79	2.03 ± 0.92
FEV1/FVC (%)		73.8 ± 10.0	67.6 ± 12.5*
Preoperative
	6MWD (m)	361 ± 149	304 ± 200
	PS	0.6 ± 0.7	1.1 ± 1.1*
	FIM (score)	123 ± 6.2	110 ± 24.3**
Postoperative
	6MWD (m)	334 ± 135	248 ± 172*
	6MWD assessment day (days)	9.6 ± 6.8	11.2 ± 5.3
	PS	0.7 ± 0.8	1.2 ± 1.3*
	FIM (score)	123 ± 6.1	108 ± 27.1**
	6MWD recovery rate (%)	94.7 ± 19.8	82.2 ± 27.0**
	Complications, n (%)	8 (14.3)	14 (53.8)**
	PS recovery day (days)	5.7 ± 4.1	9.4 ± 5.9*

^*p<0.05, ^**p<0.01. Mean ± (standard deviation); COPD: chronic obstructive pulmonary disease; CCI: Charlson comorbidity index; 6MWD: 6-minute walk distance; PS: performance status; FIM: functional independence measure.

The mean postoperative day on which we performed the second 6MWT did not significantly differ between the normal nutritional group and the light malnutrition group (9.6 ± 6.8 days vs. 11.2 ± 5.3 days, p=0.29). Regarding postoperative functional outcomes, the light malnutrition group had significantly lower postoperative 6MWD and 6MWD recovery rates than the normal group. Additionally, the light malnutrition group showed a significantly higher incidence of POC and a longer time to recovery of PS to baseline. Furthermore, the postoperative PS and FIM scores were significantly lower in the light malnutrition group.

Linear regression analysis was performed to investigate the association between the preoperative nutritional status and postoperative 6MWD recovery. The results demonstrated that poor preoperative nutritional status was significantly associated with a reduced postoperative 6MWD (Table 2). In model 1, adjusted for sex, age, and preoperative 6MWD, the decrease in postoperative 6MWD associated with light malnutrition was β=−39.5. In model 2, adjusted for all confounding factors, the decrease due to poor preoperative nutritional status remained statistically significant (β=−36.1), indicating a 36.1 m reduction in 6MWD in the light malnutrition group. In Model 3 (Table 3), after adjusting for postoperative complications, the association between the preoperative CONUT score and the postoperative 6MWD was attenuated and lost statistical significance (p=0.19). Furthermore, the adjusted R² values for Models 1, 2, and 3 were 0.83, 0.83, and 0.85, respectively.

Table 2. Univariate and multiple linear regression analyses for factors associated with postoperative 6-minute walk distance.

Variable	Coefficient and 95% confidence interval
	Crude		Model 1a		Model 2b
Light malnutrition (CONUT score 2−4)	−85.7*	(−156, −15.9)	−39.5*	(−69.7, −9.30)	−36.1*	(−69.5, −2.62)
6MWD	0.82**	(0.74, 0.90)	0.77**	(0.67, 0.87)	0.72**	(0.59, 0.85)
PS	−118**	(−147, −89.5)			−18.1	(−46.3, 10.1)
FIM	5.32	(3.52, 7.13)			−0.41	(−1.88, 1.05)

^*p<0.05, ^**p<0.01. ^aAdjusted for sex, age, preoperative 6MWD. ^bAdjusted for sex, age, Brinkman Index, COPD, CCI, and preoperative 6MWD, PS, and FIM. COPD: chronic obstructive pulmonary disease; CCI: Charlson comorbidity index; CONUT score: controlling nutritional status score. 6MWD: 6-minute walk distance; PS: performance status; FIM: functional independence measure. The adjusted R² was 0.83 for both model 1 and model 2.

Table 3. Multiple linear regression analysis evaluating the mediating role of postoperative complications on postoperative 6-minute walk distance.

Variable	Coefficient and 95% confidence interval
	Model 3
Female	−21.0	(−48.8, 6.77)
Age	−0.80	(−2.42, 0.82)
Light malnutrition (CONUT score 2−4)	−20.4	(−51.2, 10.4)
6MWD	0.73**	(0.64, 0.83)
Complications	−55.1**	(−88.7, −21.5)

^*p<0.05, ^**p<0.01. CONUT score: controlling nutritional status score; 6MWD: 6-minute walk distance. The adjusted R² for Model 3 was 0.85.

DISCUSSION

This study examined the association between preoperative nutritional status, assessed using the CONUT score, and postoperative recovery of exercise tolerance.

The light malnutrition group had a higher incidence of POC than the normal group. In addition, they had lower 6MWD, 6MWD recovery rate, and FIM scores and experienced delayed recovery of PS to baseline.

The multivariate analysis revealed that although the preoperative CONUT score was associated with the postoperative 6MWD after adjusting for multiple confounding factors, including the preoperative 6MWD, this association was attenuated when adjusting for postoperative complications, suggesting a possible mediation pathway.

The proportion of older patients with NSCLC is increasing. Older patients with lung cancer have a higher risk of complications^11,12,13), making preoperative and postoperative risk management crucial. Furthermore, reports indicate that the risk of postoperative complications is associated with age, comorbidities, preoperative nutritional status¹⁴⁾ and reduced 6MWD¹⁵⁾, making these crucial predictors of postoperative outcomes. The CONUT score is a nutritional screening index that reflects systemic inflammation and nutritional status. It has been reported to be an independent predictor of POC and survival in lung cancer^{6, 7)}. Our current results also suggest a possible mediation pathway involving postoperative complications, indicating that preoperative nutritional status influences functional recovery through the occurrence of these complications. The most important finding was that the CONUT score was associated with the postoperative 6MWD, even after adjusting for the preoperative 6MWD. This suggests that not only preoperative exercise tolerance (6MWD) but also individual nutritional status may influence the recovery of exercise tolerance following surgery.

The reduction in 6MWD (36.1 m) demonstrated in this study corresponds to the minimal clinically important difference⁹⁾ for the 6MWD in patients with lung cancer. Previous studies have reported that a decrease of ≥30 m in postoperative 6MWD is associated with an increased risk of readmission¹⁶⁾. Therefore, patients with light malnutrition may be at a higher risk of readmission. Such delayed functional recovery is expected to prolong hospitalization and rehabilitation periods, thereby increasing healthcare costs. Moreover, discharge 6MWD is a predictor of exercise tolerance at 6 weeks and 3 months postoperatively¹⁷⁾, and a reduced discharge 6MWD may hinder early social reintegration and continued employment of cancer survivors. Thus, the preoperative identification of malnutrition risk using the CONUT score is essential. Comprehensive interventions that integrate nutritional support and exercise therapy may facilitate an earlier return to home and social life.

This study has several limitations. First, because this was a single-center retrospective study, facility bias may have existed. Second, we excluded participants with moderately poor or worse preoperative nutritional status to focus on a relatively healthy cohort and avoid the confounding effects of severe systemic debility. However, we recognize that this vulnerable population is precisely the group that most requires targeted perioperative rehabilitation. Third, the timing of the postoperative 6MWT varied among participants, as it was conducted 1 to 3 days prior to discharge. Although no significant difference in the mean assessment day was observed between the normal and light malnutrition groups, this variability in timing could introduce measurement bias. Fourth, the small sample size limits the generalizability of the results and introduces a potential risk of overfitting in our multiple linear regression models. Due to this methodological constraint, applying advanced adjustments like propensity score matching was unfeasible, as it would have excluded unmatched participants and severely compromised statistical power. Fifth, we lacked data on objective body composition or muscle mass, such as the skeletal muscle index. In geriatric oncology, nutritional status cannot be fully separated from sarcopenia or cachexia; thus, the inability to evaluate muscle depletion is a major limitation. Given these limitations, our results should be interpreted with caution. Therefore, future prospective multicenter collaborative studies combining the CONUT score with body composition analysis and incorporating nutritional interventions are required to verify the effects of comprehensive interventions on postoperative exercise tolerance recovery.

In conclusion, preoperative light malnutrition is associated with delayed postoperative recovery of physical function, suggesting a possible mediation pathway involving an increased risk of postoperative complications. These findings highlight the importance of objective preoperative nutritional assessments and comprehensive interventions that integrate nutrition and exercise.

Funding and Conflict of interest

The authors declare that they have no conflicts of interest.

Appendix

Appendix Table 1. Assessment of undernutrition degree by CONUT

Parameter	Undernutrition degree
	Normal	Light	Moderate	Severe
Serum albumin (g/dL)	3.5–4.5	3.0–3.49	2.5–2.9	<2.5
Score	0	2	4	6
Total lymphocytes/mL	>1,600	1,200–1,599	800–1,199	<800
Score	0	1	2	3
Cholesterol (mg/dL)	>180	140–180	100–139	<100
Score	0	1	2	3
Screening Total Score	0–1	2–4	5–8	9–12

Ignacio de Ulíbarri J et al: CONUT: a tool for controlling nutritional status. First validation in a hospital population. Nutr Hosp 20: 38-45, 2005.