Clinical effect of Almonertinib in treating epidermal growth factor receptor mutation-positive residual ground-glass opacities after stage I lung cancer resection

Abstract

Objective: To investigate the clinical effect of Almonertinib in in patients with epidermal growth factor receptor (EGFR) mutation-positive residual ground-glass opacities following resection of stage I lung cancer. Methods: A retrospective analysis of 75 patients with EGFR mutation-positive residual ground-glass opacities post-stage I lung cancer surgery was conducted at Tianjin Medical University Cancer Institute and Hospital between January 2021 and December 2023. Patients were categorized into the control group (CG, n = 33, treated with pemetrexed and cisplatin) and the observation group (OG, n = 42, treated with Almonertinib). Cellular immune markers, tumor markers, CT nodule characteristics (size, density), malignancy risk scores before (T0) and after treatment (T1), treatment efficacy at T1, and adverse drug reactions were evaluated. Results: At T1, both groups showed an increase in CD3+ and CD4+ levels, and a decrease in CD8+ levels compared to T0. The OG group had significantly higher CD3+ and CD4+ levels and lower CD8+ levels compared to the CG group (all P < 0.05). Serum levels of IL-6, IL-8, and TNF-α decreased significantly in both groups at T1, with greater reductions observed in the OG group (all P < 0.05). Additionally, the OG group demonstrated a more substantial reduction in serum carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 50, cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, and carbohydrate antigen 19-9 levels compared to the CG group (all P < 0.05). Nodule size and density also decreased in both groups, with more significant reductions in the OG group at T1 (all P < 0.05). The Mayo and Brock model predictions indicated a significantly lower risk of malignancy at T1 in the OG group compared to T0 (all P < 0.05). The objective response rate (ORR) and disease control rate (DCR) were significantly higher in the OG group (P < 0.05), and adverse reaction rates were lower in the OG group compared to the CG group at T1 (all P < 0.05). Conclusion: Almonertinib demonstrates good clinical efficacy and safety for the treatment of EGFR mutation-positive residual ground-glass opacities following stage I lung cancer resection.

Introduction

Lung cancer has the highest incidence among malignant tumors in China. In 2016, China reported approximately 828,000 new cases of lung cancer and nearly 657,000 deaths, accounting for 20.4% of total new cancer cases and 27.2% of cancer-related deaths, respectively [1]. By 2022, the number of new lung cancer cases had risen to 1.061 million, with 733,000 deaths, representing 22.0% incidence of all cancers and 28.5% of cancer-related mortality. Both of these are the highest rankings among malignant tumors [2].

Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases [3,4]. The early symptoms of NSCLC, such as chest discomfort, cough, and fever, resemble those of common respiratory conditions, often leading to delayed diagnosis until intermediate or advanced stages [5]. Currently, surgical resection is the primary treatment for NSCLC, with radiotherapy and chemotherapy serving as adjuncts, particularly effective for early or mid-stage patients. However, in advanced stages, systemic metastasis is frequent, leading to poor treatment outcome [1,6]. Studies indicate that patients with early-stage lung cancer have a 5-year survival rate exceeding 90%, whereas those with advanced disease have a survival rate of less than 15% [7].

Among early-stage lung cancer patients undergoing radical surgery, about 6% present with ground-glass nodules (GGNs) that cannot be resected concurrently [8]. Currently, no effective treatment exists for GGNs in western medicine. Postoperative pathology often reveals that GGNs represent early-stage lung adenocarcinoma, which typically does not require chemotherapy or radiotherapy. Only a small proportion of patients with large solid nodules or those with lymph node metastasis, require chemotherapy. There is no conclusive evidence supporting the benefit of molecular targeted therapy for GGN patients. However, for patients with compromised lung function, making surgery unfeasible, genetic testing is recommended to guide possible targeted therapy and prevent recurrence.

With the rapid advancement and widespread use of gene detection technology, numerous oncogenic driver genes have been identified. Among them, the epidermal growth factor receptor (EGFR) is the most common driver gene in patients with non-small cell lung cancer (NSCLC). Approximately 50% of Asian NSCLC patients and 15% of Caucasian NSCLC patients harbor mutations in the EGFR-tyrosine kinase domain [9-11]. Advances in understanding NSCLC driver genes and the development of targeted therapies have led to breakthroughs in treatment [12]. Compared to traditional chemotherapy, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated markedly prolonged intracranial disease control in EGFR-mutant NSCLC patients with brain metastases, establishing EGFR-TKIs as a standard treatment for EGFR-positive advanced lung cancer [13].

As a targeted therapy for NSCLC driver genes, EGFR-TKIs have significantly improved the prognosis of patients who can now be routinely treated with these inhibitors. However, most patients develop acquired resistance after about one year of first- or second-generation EGFR-TKI treatment, with approximately 60% exhibiting the EGFR T790M resistance mutation [14]. For patients with this mutation, third-generation EGFR-TKIs offer a more effective treatment option. Almonertinib, China’s first third-generation EGFR-TKI, was the first to undergo first-line treatment research in a Chinese population, making it most representative of the clinical benefits for Chinese NSCLC patients [15,16]. Currently, Almonertinib is widely used to treat advanced EGFR-mutant NSCLC [17,18]; however, there is no literature on its use for treating residual ground-glass nodules in EGFR mutation-positive patients after stage I lung cancer resection. Therefore, this study retrospectively analyzed 75 patients with EGFR mutation-positive residual ground-glass nodules after stage I lung cancer resection who were treated with Almonertinib for at least six months. The aim was to explore the clinical efficacy of Almonertinib and provide a scientific basis for future treatment.

Materials and methods

Materials

A retrospective analysis was conducted on the clinical data of 75 patients with EGFR mutation-positive residual ground-glass nodules who underwent stage I lung cancer resection at Tianjin Medical University Cancer Institute and Hospital between January 2021 and December 2023. The patients were divided into an observation (OG) group (n = 33, treated with Almonertinib) and the control (CG) group (n = 42, treated with pemetrexed and cisplatin), based on the treatment method.

Inclusion criteria: (1) Diagnosis of stage I NSCLC confirmed by surgery, imaging, and pathologic analysis; (2) Age ≥ 18 years; (3) EGFR mutations confirmed by next-generation sequencing; (4) Thin-slice CT scan showing round or irregular lesions with a diameter ≤ 1 cm in other lung lobes or segments, exhibiting ground-glass opacity; (5) Complete clinical data available.

Exclusion criteria: (1) Patients with mental disorders or congenital heart disease; (2) Estimated survival time < 3 months; (3) Patients unable to tolerate or cooperate with the treatment; (4) Pregnant or lactating patients; (5) Patients with other primary malignant tumors; (6) Patients with a history of targeted drug therapy.

This study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital.

Treatment methods

The control group (CG group) received pemetrexed and cisplatin. One month after surgery, following confirmation of stable physical condition, healed surgical incisions, and the absence of acute complications, patients began chemotherapy. On day 1 of each cycle, pemetrexed (Jiangsu Haosen Pharmaceutical Group Co., Ltd., Sinopharm H20093996) was administered intravenously at 500 mg/m², once daily. Cisplatin (Yunnan Plant Pharmaceutical Co., Ltd., H53021677) was infused intravenously at 75 mg/m² on days 1-3. Each chemotherapy cycle lasted 3 weeks, with a total of 6 cycles, and a review conducted after every 2 cycles.

The observation group (OG group) received Almonertinib targeted therapy in addition to the CG regimen. On the 7th day of cisplatin infusion, patients began oral Almonertinib (Jiangsu Haosen Pharmaceutical Group Co., Ltd., national drug approval H20200004, 55 mg/tablet) at 110 mg once daily. It was advised to take the medication at approximately the same time each day, with or without food. Chewing or crushing the tablet was discouraged, and doses missed by more than 12 hours were not to be made up. Patients were informed of potential side effects, such as rash, diarrhea, and stomatitis, and were advised on hygiene practices. For skin itching, patients were advised not to scratch, and skin cream or corticosteroid ointment was recommended for severe cases. Dietary recommendations included a light, non-spicy diet. Adjustments to the treatment were made as needed based on the patient’s response and adverse reactions. Both groups continued treatment for 6 cycles.

Observation indicators

The primary indicators were as follows: (1) Immune Index: Peripheral venous blood (5 mL) was collected from patients after fasting for more than 8 hours, 1 day before treatment (T0) and 1 day after 3 months of treatment (T1). The levels of mature T lymphocytes (CD3+, CD4+, CD8+) were measured using flow cytometry with immunofluorescence labeling. (2) Inflammatory factors: The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) were detected using a double antibody one-step sandwich enzyme-linked immunosorbent assay (ELISA) at T0 and T1. The assay kits were provided by Shanghai Jianglai Biological Co., Ltd. (No. JL14113, JL19291, JL19246). (3) Tumor markers: Levels of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 50 (CA50), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), neuron-specific enolase (NSE), and carbohydrate antigen 19-9 (CA19-9) were measured using flow fluorescence luminescence on an automatic chemiluminescence analyzer (Shanghai Huanxi Medical Device Co., Ltd.) at T0 and T1. (4) CT findings: Thin-layer chest CT data at T0 and T1 were analyzed to assess changes in lung nodule size and density. The Mayo and Brock models were used to evaluate the probability of malignant risk of the nodules [19,20]. (5) Efficacy determination [21]: After three treatment cycles, the effects were categorized as follows: Complete response (CR): Disappearance of all target lesions, with no new lesions, sustained for at least 4 weeks. Partial response (PR): A ≥ 50% reduction in the sum of the largest diameters of target lesions, sustained for at least 4 weeks. Stable disease (SD): Lesion reduction below PR thresholds or lesion expansion not exceeding 25-49% of the largest diameter. Progressive disease (PD): A < 25% reduction in lesion length. The overall response rate (ORR) was calculated as CR + PR, while the disease control rate (DCR) was defined as CR + PR + SD.

The secondary indicators included adverse reactions [22], such as rash, nausea, vomiting, and diarrhea. All adverse events were assessed according to the “International Adverse Reaction Evaluation System for Cancer Chemotherapy Drugs - Common Adverse Reaction Terminology Standards”.

Statistical analysis

Data were analyzed by professional statisticians using GraphPad Prism 7.0 and SPSS 20.0 software. Data following a normal distribution were expressed as mean ± standard deviation (x̅±sd), and analyzed with a two-sample t-test. For non-normally distributed data, medians and interquartile ranges [M (P25, P75)] were used, and paired data were analyzed using the Wilcoxon signed-rank test. Categorical data were presented as frequencies or rates (%), and the χ² test was applied. A P-value of < 0.05 was considered significant.

Results

Comparison of basic information

A total of 75 patients were included in this study. Based on treatment methods, 42 patients were treated with Almonertinib (OG group), while 33 received pemetrexed and cisplatin (CG group). There were no significant differences between the groups regarding gender, pathological type, age, body mass index (BMI), smoking history, diabetes mellitus, or hypertension (all P > 0.05), indicating comparability (Table 1).

Table 1.

Comparison of basic data

Items	OG group (n = 42)	CG group (n = 33)	t/χ2	P
Age (x̅ ± sd, years)	46.78 ± 14.52	47.03 ± 15.91	-0.71	0.943
Sex (n, %)			1.886	0.170
Males	27 (64.29)	16 (48.48)
Females	15 (35.71)	17 (51.52)
BMI (x̅ ± sd, kg/m2)	23.81 ± 2.13	23.43 ± 2.54	0.759	0.450
Course of disease (x̅ ± sd, year)	2.16 ± 0.50	2.32 ± 0.43	1.462	0.148
Pathologic type (n, %)			0.112	0.945
Adenocarcinoma infiltrating	19 (45.24)	16 (48.48)
Adenocarcinoma in situ	17 (40.48)	13 (39.39)
Others	6 (14.28)	4 (12.13)
Smoking history			0.640	0.424
Yes	23 (54.76)	15 (45.45)
No	19 (45.24)	18 (54.56)
Complicated with diabetes mellitus			1.566	0.211
Yes	12 (28.57)	14 (42.42)
No	30 (71.43)	19 (57.58)
Complicated with hypertension			3.544	0.060
Yes	18 (42.86)	21 (63.64)
No	25 (57.14)	12 (36.36)

Note: BMI: body mass index; CG group: control group; OG group: observation group.

Comparison of immune indicators

At T1, CD3+ (66.41 ± 3.28 vs. 58.25 ± 2.37; 61.29 ± 3.16 vs. 58.40 ± 2.36) and CD4+ (46.90 ± 3.28 vs. 32.71 ± 2.43; 42.28 ± 3.05 vs. 33.07 ± 2.56) levels were higher in both OG and CG groups compared to T0, while CD8+ (22.59 ± 1.87 vs. 29.33 ± 2.49; 25.18 ± 2.15 vs. 30.02 ± 2.37) was lower. CD3+ and CD4+ levels were significantly higher in the OG group compared to the CG group, while CD8+ levels were lower in the OG group (P < 0.05), as shown in Figure 1.

Figure 1.

Comparison of immune indexes. Note: *P < 0.05; A: CD3+; B: CD4+; C: CD8+; CD: cluster of differentiation; CG: control group; OG: observation group.

Comparison of inflammatory factors

At T1, serum levels of IL-6 (5.26 ± 1.50 vs. 16.36 ± 4.09; 6.45 ± 2.77 vs. 16.28 ± 4.16), IL-8 (9.21 ± 2.70 vs. 21.94 ± 4.59; 13.50 ± 3.48 vs. 21.15 ± 4.08), and TNF-α (3.23 ± 0.82 vs. 16.03 ± 2.27; 5.61 ± 1.38 vs. 16.25 ± 2.36) were significantly lower in both groups compared to T0. However, the levels were significantly lower in the OG group compared to the CG group at T1 (P < 0.05), as shown in Figure 2.

Figure 2.

Comparison of inflammatory factor levels. Note: *P < 0.05; A: IL-6; B: IL-8; C: TNF-α; IL-6: Interleukin-6; IL-8: Interleukin-8; TNF-α: tumor necrosis factor-α; CG: control group; OG: observation group.

Comparison of serum tumor markers

At T1, serum levels of CEA (10.47 ± 1.15 vs. 24.56 ± 2.39; 13.11 ± 1.29 vs. 25.13 ± 2.67), CA50 (13.55 ± 1.34 vs. 28.46 ± 2.67; 18.75 ± 1.51 vs. 29.19 ± 2.74), CA125 (38.40 ± 2.95 vs. 57.55 ± 4.56; 41.41 ± 3.16 vs. 58.03 ± 5.12), CYFRA21-1 (2.16 ± 0.51 vs. 5.28 ± 1.40; 3.92 ± 0.72 vs. 5.34 ± 1.39), NSE (6.65 ± 1.44 vs. 37.89 ± 6.37; 15.82 ± 3.26 vs. 38.18 ± 6.47), and CA19-9 (8.68 ± 1.85 vs. 38.96 ± 7.11) were significantly lower in both groups compared to T0, with the OG group showing more pronounced reductions than the CG group (all P < 0.05), as shown in Figure 3.

Figure 3.

Comparison of serum tumor markers. Note: *P < 0.05; A: CEA; B: CA50; C: CA125; D: CYFRA21-1; E: NSE; F: CA19-9; CEA: carcinoembryonic antigen; CA50: carbohydrate antigen 50; CA125: carbohydrate antigen 125; CYFRA21-1: cyto-keratin 19 fragment antigen 21-1; NSE: neuron specific enolase; CA19-9: carbohydrate antigen 19-9; CG: control group; OG: observation group.

Comparison of nodule size and density

Compared to T0, both groups exhibited reductions in nodule size and density, with the OG group showing significantly greater reductions than the CG group at T1 (P < 0.05), as shown in Table 2. This suggests that Almonertinib effectively reduced the size and density of pulmonary nodules.

Table 2.

Comparison of nodule size and nodule density (x̅ ± sd)

Groups	Nodule size (mm)		Nodule density (HU)
	T0	T1	T0	T1
OG group (n = 42)	12.63 ± 3.02	8.12 ± 2.26*	46.89 ± 10.12	21.56 ± 6.79*
CG group (n = 33)	12.45 ± 2.78	10.34 ± 2.47*	47.32 ± 9.56	37.18 ± 10.05*
t	0.255	-4.077	-0.211	-8.034
P	0.799	< 0.001	0.833	< 0.001

Note: VS the same group of T0:

^*P < 0.05.

CG group: control group; OG group: observation group.

Malignant risk probability of pulmonary nodules

Using the Mayo and Brock models, the probability of malignant risk at T1 was significantly lower than at T0 in both groups (P < 0.05), as shown in Table 3. This indicates that Almonertinib may reduce the risk of lung cancer recurrence or progression.

Table 3.

Malignant risk probability of pulmonary nodules before and after treatment in patients with ground-glass nodules [M (P25, P75), %]

Model	Times	OG group (n = 42)	CG group (n = 33)	Z	P
Mayo model	T0	2.81 (2.08, 3.70)	2.93 (2.00, 3.89)	-1.564	0.118
	T1	2.05 (1.34, 4.06)	2.41 (1.46, 3.46)	-4.945	< 0.001
Z		-5.646	-4.048
P		< 0.001	< 0.001
Brock model	T0	0.96 (0.71, 1.31)	0.80 (0.44, 1.13)	-1.587	0.112
	T1	0.26 (0.14, 0.39)	0.43 (0.28, 0.67)	-2.207	0.027
Z		-5.390	-4.460
P		< 0.001	< 0.001

Note: CG group: control group; OG group: observation group.

Comparison of clinical efficacy evaluation

At T1, the ORR and DCR of the OG group were 52.38% and 80.95%, respectively, which were significantly higher than those of the CG group (21.21%, 57.58%; χ² = 7.570, χ² = 4.087; both P < 0.05). These results confirm the superior efficacy of Almonertinib treatment (Table 4).

Table 4.

Comparison of clinical efficacy [n (%)]

Clinical efficacy	OG group (n = 42)	CG group (n = 33)	χ2	P
CR	4 (9.52)	0 (0.00)
PR	19 (45.24)	7 (21.21)
SD	11 (26.19)	12 (36.36)
PD	8 (19.05)	14 (42.42)
ORR	22 (52.38)	7 (21.21)	8.677	0.003
DCR	34 (80.95)	19 (57.58)	4.872	0.027

Note: CG group: control group; OG group: observation group. CR: complete remission; PR: partial response; SD: stable disease; PD: progressive disease; ORR: Overall response rate; DCR: Disease control rate.

Comparison of adverse reactions

The adverse reaction rate in the OG group was 2.38%, significantly lower than the CG group’s rate of 15.15% (χ² = 4.095, P = 0.043), indicating that Almonertinib treatment had better safety and higher patient tolerance (Table 5).

Table 5.

Comparison of adverse reactions [n (%)]

Adverse Reaction	OG group (n = 42)	CG group (n = 33)	χ2	P
Rash	1 (2.38)	2 (6.06)
Nausea and vomiting	0 (0.00)	0 (0.00)
Diarrhea	0 (0.00)	3 (9.09)
Total rate	1 (2.38)	5 (15.15)	4.095	0.043

Note: CG group: control group; OG group: observation group.

Discussion

Chronic inflammation is a key pathophysiologic feature of NSCLC. Studies have shown that IL-6 and IL-8 are associated with poor prognosis in NSCLC patients [23]. The results of this study demonstrated that levels of IL-6, TNF-α, and IL-8 were significantly lower in the OG group compared to the CG group at T1, suggesting that Almonertinib can significantly reduce pro-inflammatory factors in patients, thereby inhibiting tumor angiogenesis and slowing the progression of NSCLC.

Furthermore, CD3+, CD4+ and CD8+ are commonly used cellular immune markers to assess immune function, with unbalanced expression indicating immune dysfunction [24]. Impaired immune function can accelerate cancer progression and reduce drug tolerance [25]. Klumper et al. [26] found that NSCLC patients exhibited a lower proportion of CD4+ T cells and NK cells, while CD8+ T cells were elevated, which improved following anti-tumor therapy. This study revealed that at T1, the OG group had higher levels of CD3+ and CD4+ and lower CD8+ levels compared to the CG group, aligning with previous findings. This suggests that Almonertinib promotes immune recovery, benefiting prognosis in patients with EGFR mutation-positive residual ground-glass nodules after stage I lung cancer resection. However, given that the immune microenvironment in EGFR-mutant patients is immunosuppressive, if resistance to Almonertinib develops, the immune microenvironment may shift, transforming the tumor into a “hot tumor” with enhanced immune function due to immune cell aggregation, but with diminished anticancer effects. Therefore, further studies are needed to validate these conclusions.

CEA, CA50, CA125, CYFRA21-1, NSE, and CA19-9 are common tumor markers associated with ovarian and lung cancers. These markers are typically expressed at low levels or are absent in healthy individuals, but their expression is significantly elevated in EGFR mutation-positive advanced NSCLC, with higher levels indicating more aggressive tumor invasion [27,28]. This study showed that at T1, the OG group had higher ORR and DCR rates compared to the CG group, along with significantly lower serum levels of CEA, CA50, CA125, CYFRA21-1, NSE, and CA19-9, suggesting that Almonertinib offers superior therapeutic benefits for EGFR mutation-positive patients with residual ground-glass opacities post-stage I lung cancer surgery, possibly delaying disease progression more effectively. The reason for this may be that EGFR-TKIs significantly inhibit tyrosine kinase activity, promoting tumor cell apoptosis by blocking tumor neovascularization [29]. This effectively reduces tumor marker levels and slows disease progression.

Additionally, in this study, both nodule size and density decreased from T0 to T1 in both groups, with more significant reductions observed in the OG group compared to the CG group, indicating that Almonertinib can effectively reduce the volume and density of EGFR mutation-positive residual ground-glass nodules. This may be due to Almonertinib’s highly efficient and selective third-generation irreversible EGFR-TKI action, wherein its electrophilic acrylamide acts as a Michael receptor, irreversibly binding to the corresponding ATP site and inhibiting EGFR phosphorylation. This prevents tumor cell proliferation and division, thereby reducing tumor growth and volume, and alleviating symptoms [17].

In this study, the Mayo model and Brock model were used to assess the malignant risk of pulmonary nodules. Both the ACCP lung cancer diagnosis and treatment guidelines [30] and the NCCN lung cancer screening guidelines [31] recommend the Mayo model for malignant risk assessment of pulmonary nodules. The Mayo model includes six independent lung cancer predictors: age, smoking history, history of thoracic malignancy (> 5 years before nodule detection), nodule diameter, spiculation, and upper lobe location. The Brock model, developed by Brock University, predicts the probability of malignant nodules based on CT signs, with an area under the receiver operating characteristic curve reaching 0.9 [32]. Its predictors include age, gender, family history of lung cancer, emphysema, nodule diameter, nodule characteristics, nodule number, upper lobe location, and spiculation. These two models complement each other in this study. The predictions from both models showed that Almonertinib reduced the malignant risk of nodules, suggesting that it may lower the likelihood of secondary surgery, benefitting patients’ quality of life.

This study demonstrated that the OG group had superior overall efficacy and disease control rates compared to the CG group, confirming the potential of this therapeutic approach to improve disease management. Additionally, no serious adverse reactions associated with Almonertinib were observed. Most adverse events were mild, including rash, nausea, vomiting, diarrhea, and liver injury, indicating that Almonertinib is generally well tolerated and safe for patients with EGFR mutation-positive residual ground-glass nodules after stage I lung cancer resection. The low affinity of Almonertinib’s degradation products for EGFR and their weak inhibitory effects likely contribute to the reduced incidence of common side effects, such as diarrhea and rash [33,34]. However, despite the low incidence of adverse reactions, close monitoring is still necessary, and appropriate interventions should be taken when needed.

Drug resistance remains a major challenge for molecularly targeted therapies in clinical use [35]. Resistance during treatment can lead to diminished or ineffective therapeutic outcomes. Therefore, understanding the mechanisms of drug resistance in targeted therapies is crucial in order to develop new treatment strategies to overcome it. This study acknowledges its limitations, particularly its retrospective design, which introduces inherent biases. The sample size is also small, which restricts the generalizability of the findings. Future multi-center studies are needed to further validate these results.

Almonertinib offers significant therapeutic advantages for patients with EGFR-mutated residual ground-glass opacities following stage I lung cancer resection. It effectively reduces inflammatory factors and tumor marker levels, slows disease progression, and mitigates the negative impact of chemotherapy on immune function.

Disclosure of conflict of interest

None.