Lung cancer is the second most frequently diagnosed cancer and the most common cause of cancer-related deaths worldwide (1). There is a high prevalence of lung cancer-related malnutrition with reported rates ranging from 34.5 to 69%. Lung cancer-related malnutrition is particularly prevalent in patients who have been hospitalized and in those with advanced or metastatic disease (2).

Cancer-related malnutrition, also known as anorexia/cachexia, is an important adverse effect of cancer, which is associated with impaired physical function, diminished tolerance to anticancer therapy, and reduced survival rates (3, 4). Our understanding of malnutrition/cachexia has been greatly improved over the past decades; however, there was no guidelines or standards of care for the treatment of cancer malnutrition/cachexia were universally established until now (4–6). Appetite stimulants such as megestrol acetate (MA), glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and dronabinol have been extensively studied in patients with cancer-related malnutrition and were reported to stimulate appetite (7). Unfortunately, the use of these appetite stimulants does not often translate to clinically meaningful improvements in lean body mass or functional outcomes (8, 9). Anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain; however, the availability of drug limits its use (10).

Cancer patients with malnutrition have increased energy needs. In addition to macronutrients, micronutrients such as vitamins and microelements may be beneficial for the treatment of cancer-related malnutrition (11). Therefore, an effective approach is likely to be a combined approach that improves the outcomes of cancer-related malnutrition. As noted in the American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines, enteral nutrition (EN) is preferred over parenteral nutrition (PN) based on the outcomes of hospitalized patients receiving EN therapy. ONS consists of proteins, carbohydrates, fat, vitamins, and minerals, which could be used as the only source of EN or as nutritional supplements (12–14).

The objective of this single-center prospective cohort study was to investigate the efficacy and safety of MA combined with ONS in the treatment of lung cancer-related malnutrition patients.

Considering that adequate nutrition has important effects on health outcomes, both nutritional risk screening and nutritional assessment in cancer patients are critical. Nutrition risk score 2002 (NRS2002) and PG-SGA are recommended for nutritional risk screening and nutritional assessment in cancer patients (9–12). Dietetic assessment and intervention in lung cancer (DAIL) trial revealed that PG-SGA identified 78% of patients required specialist nutritional advice, with 52% patients having a critical need for dietetic input and symptom management (16). Higher malnutrition risk and elevated inflammatory status in patients with lung cancer were associated with poor overall survival independently (17).

In our study, 94 (59.5%) out of 158 lung cancer patients had nutritional risks (NRS ≥ 3). Moreover, nutritional risks were significantly associated with age and ECOG. Out of these 94 patients, 26 (27.7%) were PG-SGA grade B, and 68 (72.3%) were PG-SGA grade C. PG-SGA was significantly associated with ECOG. Abbass et al. Showed that compared to low nutrition risk, patients at moderate to high risk had poor ECOG, elevated frailty index, elevated modified Glasgow prognostic score (17); However, further research is required to determine whether a low nutritional score leads to a low ECOG or a low ECOG contributes to a low nutritional score.

MA was approved for cancer-associated malnutrition in Europe, consequently, the most commonly prescribed drug for this condition. MA stimulates appetite by affecting metabolism and proinflammatory cytokine synthesis (15, 18). Many articles had reported that MA was more effective than other drugs, such as dronabinol and fluoxymesterone (19, 20). Combined medical therapy using MA and fish oil, dronabinol, or NSAIDs resulted in no changes in weight or appetite compared to MA alone (21, 22). Beta-hydroxy beta-methyl butyrate/arginine/glutamine(HMB/Arg/Gln) may work together to decrease muscle damage from reactive oxygen species and pro-inflammatory cytokine; however, recent data demonstrated that HMB/Arg/Gln supplementation couldn't improve the loss of lean body mass in patients with advanced lung cancer (23).

Compared to PN, EN causes fewer complications, is cheaper, and equally effective. EN carries a low risk of serious complications, reduces bacterial translocation from the intestinal tract to the systemic circulation, derating levels of circulating inflammatory cytokines, helps to restore normal intestinal function, and cut down infectious complications and overall costs of care (24).

Because of appetite stimulants such as MA and the others (including dronabinol, fluoxymesterone and NSAIDs et al.) alone could not translate appetite increase to clinically meaningful improvements in lean body mass or functional outcomes (8, 9). We tried to compare the efficacy and safety of two management approaches (appetite stimulants combined EN) in lung cancer patients with malnutrition. Compared with MA alone, MA combined with ONS significantly improved MAC, BMI, ECOG and serum levels of pre-albumin and albumin. This outcome may be associated with that MA + ONS improved the quality and quantity of nutrients intake on the basis of stimulating appetite. Treatment-related toxicity was negligible and comparable between arms, and patient compliance was adequate.

This study suffered from a few limitations that deserve to be underlined. Firstly, our study was limited by its single-center design. Secondly, we were unable to provide alternative methods to measure anthropometric parameters, e.g., dual-energy-x-ray absorptiometry or body plethysmography; However, it should be noted that BMI and MAC were still considered reliable and inexpensive anthropometric measurement (25).

Our study revealed that MA combined with ONS may be an effective and safe treatment option for lung cancer-related malnutrition.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shaanxi Provincial People's Hospital. The patients/participants provided their written informed consent to participate in this study.

BD, YP, LH, YaZ, LL, YH, RJ, and RZ were involved in the design of the study, the conception of the case report form, patients' recruitment, data collection, and drafting of the manuscript. YuZ and JB supervised the study design. YaZ and BD contributed to data interpretation and manuscript preparation. YP, YC, and JB contributed to statistical analysis and interpretation of data. All authors contributed to the critical revising and the final approval of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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