This single-center, open-label, randomized, controlled trial evaluated the efficacy of ninjin’yoeito against perioperative physical symptoms in patients with primary lung cancer, who underwent lobectomy and lymph node dissection between September, 2020 and February, 2024. The protocol was established in accordance with the principles of the Declaration of Helsinki. The current study was approved by the Clinical Research Area Ethics Committee of Kobe University Graduate School of Medicine (#C190015) and was registered in the Japan registry of clinical trials (jRCTs051200009).

This study included patients aged > 20 years who were scheduled to undergo lobectomy for suspected clinical stage I primary lung cancer under VATS (video-assisted thoracic surgery) or RATS (robot-assisted thoracic surgery). The primary exclusion criteria were as follows: patients with a history of allergy to ninjin’yoeito or its ingredients, those who had taken herbal medicine preparations within 2 weeks, those with low hepatic or renal function, and those not eligible for the study based on the investigators’ discretion. The postoperative exclusion criteria were as follows: patients who underwent thoracotomy, those who underwent resection of greater than two lobes, and those who could not start drinking fluids within 3 days after surgery. Patients who did not meet the postoperative exclusion criteria were randomized. Patient information was extracted through physical examination, medical history taking, respiratory function testing, chest radiography examination, and peripheral blood analysis. All preoperative evaluations were performed routinely within 56 days before surgery.

Ninjin’yoeito Extract Granules Kracie® (Kracie Pharmaceutical Ltd., Japan) were used in this study. Ninjin’yoeito comprises 12 herbal medicines including ginseng, Japanese angelica root, peony root, rehmannia root, atractylodes rhizome, poria sclerotium, cinnamon bark, astragalus root, citrus unshiu peel, polygala root, schisandra fruit, and glycyrrhiza. Participants who had one of the indicators for ninjin’yoeito (physical strength decline, fatigue, anorexia, perspiration during sleep, cold limbs, and anemia) received the medicine.

The participants were assigned randomly to either the conventional treatment group or the conventional treatment plus ninjin’yoeito group (ninjin’yoeito group) at an allocation ratio of 1:1. The ninjin’yoeito group patients started taking ninjin’yoeito (7.5 g/day) in two divided doses, before breakfast and before dinner, for 16 weeks after resuming oral fluids postoperatively. Peripheral blood analysis, questionnaire survey, and weight measurements were taken after resuming oral fluid intake at the start of internal administration and then 1, 8, and 16 weeks postoperatively. Respiratory function tests were performed 8 weeks postoperatively. Peripheral blood analysis, a questionnaire survey, and weight measurements at the start of internal administration were defined as the baseline parameters. The changes in each item from the baseline were assessed 1, 8, and 16 weeks postoperatively.

The primary evaluation visit was 8 weeks postoperatively and the primary endpoint was the change in the total Cancer Fatigue Scale (CFS) score from the baseline. The secondary endpoints included dyspnea measured using the Visual Analog Scale (VAS), the Cancer Dyspnea Scale (CDS) score, the MD Anderson Symptom Inventory (MDASI) score, the Kihon Checklist (KC) score, respiratory function test findings, weight measurements, and peripheral blood analysis results.

The CFS is a 15-item scale comprising 3 subscales (physical, emotional, and cognitive) used to assess fatigue in cancer patients. [14]. Higher CFS scores indicate stronger fatigue. The VAS can quantify the assessment of pain using method that plots the intensity of pain on a straight line [15]. The CDS score can be used to assess three subjective measures: respiratory effort, anxiety, and discomfort [16]. A higher CDS score indicates worse dyspnea. The MDASI is a 19-item questionnaire used to assess patients with cancer [17]. This scoring system has 13 items for evaluating the intensity of symptoms and the disruption in activities of daily living. The KC is a comprehensive self-report health checklist designed by the Japanese government’s Ministry of Health, Labour and Welfare, and used as a predictive tool for frailty [18].

Monitoring was done to assess whether the study was conducted in accordance with the protocol, and the data were collected appropriately. An assigned individual who was not a researcher in the current study reviewed the consent forms from the participants, the medical records, and the case report forms of all participants.

Randomization was performed using a randomized table generated independently from the researchers, using permuted block randomization with a block size mixture of 4 and 6.

There have been no previous clinical studies published on ninjin’yoeito. Thus, a previous study that evaluated fatigue in patients with advanced-stage cancer using the CFS after intervention with reflexology was used as a reference [19]. The intervention methods differ, but if the efficacy of ninjin’yoeito is not similar to that of reflexology, its significance could be limited. The mean and standard deviation of the difference in the CFS scores before and after the intervention was 4.6 ± 9.6. Using this value as a reference, the mean CFS score between the intervention and control groups was found to be 4.6, with a significance level of 5% and a power of 80%. In total, 69 patients were required per group. Considering the number of cases that can be collected in our department, the sample size was set at 70 patients per group, with a total of 140, to achieve a power of 80%.

The CFS was correlated with the 6-min walking distance (6MWD), with a two-point improvement in CFS corresponding to a 58-m increase in 6MWD [20]. Furthermore, an improvement of > 50 m in the 6MWD is necessary for patients to perceive an improvement in their exercise capacity. Therefore, if the administration of ninjin’yoeito results in a 4.6-point improvement in CFS, it could lead to a recovery in walking ability, perceived improvement in exercise capacity, increased activity levels, and a smoother return to society.

All analyses were performed based on the intention-to-treat principle. The demographic characteristics of the patients are expressed as means and the standard deviation for continuous variables and as the frequency and proportion for categorical variables. All continuous outcomes were analyzed using the mixed-effects models for repeated measurements with a compound symmetry covariance structure. The presence or absence of issues in the KC was analyzed using a generalized linear model with a binomial distribution and an identity link function, using robust standard errors. All statistical models included the indicators of the group and visit, their interaction, and baseline values as covariates. All statistical tests were evaluated at a two-sided significance level of 0.05. Analyses were performed using the R software version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and the SAS software version 9.4 (SAS Institute, Cary, NC, the USA).