Introduction
Lung cancer remains one of the most prevalent malignancies and the leading cause of cancer-related mortality worldwide. According to Global Cancer Observatory (GLOBOCAN) 2022 data, lung cancer accounts for 12.4% of all newly diagnosed cancer cases (2.5 million cases) and 18.7% of cancer-related deaths (1.8 million deaths) globally. It is broadly classified into non–small cell lung cancer (NSCLC), which comprises 80–85% of cases, and small cell lung cancer (SCLC), accounting for 10-15% [1,2]. Current treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Despite advances in these approaches, clinical outcomes remain suboptimal due to the lack of reliable prognostic biomarkers and the frequent development of chemoresistance. The overall 5-year survival rate is approximately 18% across all stages and declines to around 5% in advanced-stage disease, reflecting a poor prognosis [1,2].
Adjunctive therapies have been explored to improve treatment outcomes in lung cancer. Among these, vitamin D has been studied for its effects on pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and anti-inflammatory cytokines such as interleukin-10 (IL-10). Evidence suggests that vitamin D modulates the production of these cytokines, indicating its potential role as an immunomodulatory agent [3]. IFN-γ plays a central role in antitumor immunity. It promotes M1 macrophage polarization, enhances dendritic cell maturation, and upregulates major histocompatibility complex (MHC) class I and II expression. In addition, IFN-γ drives T-cell differentiation toward the Th1 phenotype while suppressing Th2 and Th17 responses. It is also essential for CD8+ effector T-cell maturation and cytotoxic activity and inhibits regulatory T cells, thereby strengthening antitumor immune responses [4].
Active Hexose Correlated Compound (AHCC®) is a mushroom-derived extract obtained from Basidiomycete species, including shiitake (Lentinus edodes) and shimeji (Lyophyllum shimeji). It consists of a mixture of amino acids, minerals, lipids, and polysaccharides enriched with α-1,4-linked glucans. AHCC® has demonstrated immunomodulatory effects and has been associated with improved prognosis and quality of life in patients with liver, lung, and head and neck cancers [5-7].
The clinical effects of AHCC® supplementation have been investigated across various malignancies, including placebo-controlled trials, open-label studies, and case reports. Overall, AHCC® has been suggested to improve prognosis and quality of life, potentially through modulation of cytokine production, regulation of lymphocyte populations, and enhancement of natural killer (NK) cell activity. Clinically, AHCC® is commonly used as an adjunct to standard therapies such as surgery, chemotherapy, and radiotherapy. Available evidence indicates that AHCC® is generally safe when combined with most chemotherapeutic agents; however, caution is warranted for drugs metabolized via CYP450 2D6, as AHCC® may induce this pathway. Preclinical studies have also demonstrated reduced chemotherapy-related toxicity and enhanced antitumor activity when combined with agents such as cisplatin and liposomal doxorubicin. Although preliminary human studies support its safety and potential benefits, further well-designed clinical trials are needed to confirm these findings [8-11]. Therefore, this study aimed to evaluate the effects of AHCC® supplementation on IFN-γ levels and quality of life (QoL) in patients with NSCLC undergoing platinum-based chemotherapy.
Methods
This prospective, double-blind randomized controlled study was conducted at Adam Malik Hospital and Prof. Dr. Chairuddin P. Lubis USU Hospital, Indonesia, following approval from the Health Research Ethics Committee of the Faculty of Medicine, Universitas Sumatera Utara/Adam Malik Hospital (No. 336/KEPK/2025).
The study population consisted of patients with histopathologically confirmed NSCLC undergoing platinum-based chemotherapy. Participants were recruited using consecutive sampling based on predefined inclusion and exclusion criteria until the required sample size was achieved. The sample size was determined to ensure adequate statistical power for inferential analysis. Participants were randomly assigned to either an intervention group receiving AHCC® supplementation or a control group receiving a placebo, with both groups continuing the same chemotherapy regimen.
Baseline demographic and clinical characteristics were obtained from medical records and patient interviews, including sex, age, histopathological subtype (adenocarcinoma or squamous cell carcinoma), clinical stage (I–IV), and smoking history assessed using the Brinkman Index (categorized as mild, moderate, or severe). Venous blood samples were collected prior to chemotherapy initiation and during the first and fourth chemotherapy cycles. Serum IFN-γ levels were measured using an enzyme-linked immunosorbent assay (ELISA). Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).
Statistical analyses were performed using SPSS software. Categorical variables were presented as frequencies and percentages, while continuous variables were expressed as mean ± standard deviation or median (range), as appropriate. Data normality was assessed prior to selecting statistical tests. Within-group comparisons were analyzed using paired t-tests or their nonparametric equivalents, while between-group comparisons were conducted using independent t-tests or Mann–Whitney U tests. A p-value <0.05 was considered statistically significant.
Results
A total of 50 patients with NSCLC undergoing platinum-based chemotherapy were enrolled and equally allocated to the AHCC® group (n = 25) and the control group (n = 25). Baseline demographic and clinical characteristics were comparable between the two groups (p > 0.05) (Table 1), indicating well-balanced study populations. The majority of participants were male, with mean ages of 61 and 59 years in the AHCC® and control groups, respectively. Pulmonary adenocarcinoma was the predominant histopathological subtype, and most patients were diagnosed at advanced stages (IVA–IVB). Carboplatin plus paclitaxel was the most commonly administered chemotherapy regimen in both groups.
Analysis of IFN-γ levels showed no statistically significant differences between the AHCC® and control groups at baseline (p = 0.580) or after chemotherapy (p = 0.327) (Table 2). Within-group analyses demonstrated a reduction in median IFN-γ levels in both groups; however, these changes were not statistically significant (AHCC®: p = 0.904; control: p = 0.798). Furthermore, the comparison of changes (Δ) in IFN-γ levels between groups revealed no significant difference (p = 0.808) (Table 3), indicating that AHCC® supplementation did not significantly influence IFN-γ levels.
Quality of life (QoL) outcomes varied across domains. At baseline, the AHCC® group had significantly higher social functioning scores (p = 0.004), while the control group reported significantly higher fatigue levels (p = 0.013). Following chemotherapy, a significant between-group difference was observed only in appetite loss, with better outcomes in the AHCC® group (p = 0.008) (Table 4).
Within-group analyses demonstrated significant improvements in physical functioning (p = 0.040) and overall QoL (p < 0.001) in the AHCC® group after treatment. Similar trends of improvement were observed in the control group. However, comparisons of changes between groups showed no statistically significant differences across most QoL domains (p > 0.05) (Table 5).
Overall, although both groups showed improvements over time, AHCC® supplementation did not provide additional statistically significant benefits in IFN-γ levels or overall QoL compared with standard chemotherapy alone.
Table 1: Demographic Characteristics of NSCLC Patients
| Demographic Characteristics | AHCC® (n = 25) | Control (n = 25) | p-value |
| Sex, n (%) | |||
| Male | 24 (96) | 23 (92) | 1.000a |
| Female | 1 (4) | 2 (8) | |
| Age, years | 61 (27–76) | 59 (37–71) | 0.232b |
| Ethnicity, n (%) | |||
| Batak | 15 (60) | 13 (52) | |
| Javanese | 9 (36) | 11 (44) | 0.845c |
| Malay | 1 (4) | 1 (4) | |
| Family History of Lung Cancer, n (%) | |||
| No | 24 (96) | 24 (96) | 1.000a |
| Yes | 1 (4) | 1 (4) | |
| History of Tuberculosis, n (%) | |||
| No | 16 (64) | 18 (72) | 0.544d |
| Yes | 9 (36) | 7 (28) | |
| Histopathology, n (%) | |||
| Large Cell Carcinoma | 1 (4) | 0 (0) | |
| Non–Small Cell Lung Carcinoma | 1 (4) | 0 (0) | - |
| Pulmonary Adenocarcinoma | 16 (64) | 14 (56) | |
| Squamous Cell Lung Cancer | 7 (28) | 11 (44) | |
| Stage, n (%) | |||
| IIIA | 2 (8) | 2 (8) | |
| IIIB | 0 (0) | 2 (8) | |
| IIIC | 3 (12) | 2 (8) | 0.648c |
| IVA | 18 (72) | 18 (72) | |
| IVB | 2 (8) | 1 (4) | |
| Pleural Effusion, n (%) | |||
| No | 12 (48) | 14 (56) | 0.571d |
| Yes | 13 (52) | 11 (44) | |
| Chemotherapy Regimen, n (%) | |||
| Carboplatin + Paclitaxel | 17 (68) | 17 (68) | |
| Carboplatin + Pemetrexel | 3 (12) | 5 (20) | 0.613c |
| Cisplatin + Pemetrexed | 5 (20) | 3 (12) |
ᵃ Fisher’s Exact Test; ᵇ Independent t-test or Mann–Whitney test; ᶜ Chi-square test; ᵈ Fisher’s Exact alternative.
Table 2. Comparison of Interferon-Gamma (IFN-γ) Levels Between AHCC® and Control Groups Before and After Chemotherapy
| Inflammatory Marker | AHCC® (n=25) | Control (n=25) | p-value | |
| Interferon-γ | Before Chemotherapy | 50.44 (15.96–122.41) | 71.47 (17.55–391103.45) | 0.580* |
| After Chemotherapy | 32.93 (2.89–186.51) | 48.53 (12.09–467.34) | 0.327* |
Data are presented as median (range). *Mann–Whitney test
Table 3: Comparison of Changes (Δ) in Interferon-γ Levels Between AHCC® and Control Groups
| Inflammatory Marker | AHCC® (n=25) | Control (n=25) | p-value |
| Δ Interferon-γ | 2.6 ± 70.21 | -6.52 (-424.38–391073.39) | 0.808 |
Data are presented as mean ± SD and median (range). *Mann–Whitney test
Table 4: Comparison of Quality of Life Scores Between AHCC® and Control Groups Before and After Chemotherapy
| Quality of Life Domain | AHCC® (n=25) | Control (n=25) | p-value |
| Physical Functioning | |||
| Before chemotherapy | 38.4 ± 20.21 | 40 (0–66.67) | 0.544ᵃ |
| After chemotherapy | 51.47 ± 29.66 | 49.33 ± 25.53 | 0.786ᵇ |
| Role Functioning | |||
| Before chemotherapy | 33.33 (0–66.67) | 16.67 (0–66.67) | 0.199ᵃ |
| After chemotherapy | 50 (0–100) | 66.67 (0–100) | 0.444ᵃ |
| Emotional Functioning | |||
| Before chemotherapy | 50 (41.67–66.67) | 50 (41.67–66.67) | 0.547ᵃ |
| After chemotherapy | 58.33 ± 32.67 | 58.33 (0–100) | 0.682ᵃ |
| Cognitive Functioning | |||
| Before chemotherapy | 16.67 (0–66.67) | 33.33 (0–66.67) | 0.405ᵃ |
| After chemotherapy | 50 (0–100) | 50 (0–100) | 0.890ᵃ |
| Social Functioning | |||
| Before chemotherapy | 66.67 (16.67–83.33) | 33.33 (16.67–83.33) | 0.004ᵃ |
| After chemotherapy | 50.67 ± 25.68 | 33.33 (0–100) | 0.890ᵃ |
| Fatigue | |||
| Before chemotherapy | 33.33 (0–66.67) | 44.44 (0–66.67) | 0.013ᵃ |
| After chemotherapy | 44.44 (0–100) | 55.56 (0–100) | 0.898ᵃ |
| Nausea and Vomiting | |||
| Before chemotherapy | 33.33 (0–66.67) | 33.33 (0–66.67) | 0.905ᵃ |
| After chemotherapy | 33.33 (0–100) | 33.33 (0–100) | 0.278ᵃ |
| Pain | |||
| Before chemotherapy | 33.33 (0–83.33) | 33.33 (0–83.33) | 0.820ᵃ |
| After chemotherapy | 50 (0–100) | 50 (0–100) | 0.898ᵃ |
| Dyspnea | |||
| Before chemotherapy | 33.33 (0–66.67) | 33.33 (0–66.67) | 0.456ᵃ |
| After chemotherapy | 33.33 (0–100) | 66.67 (0–100) | 0.252ᵃ |
| Insomnia | |||
| Before chemotherapy | 33.33 (0–66.67) | 33.33 (0–66.67) | 0.186ᵃ |
| After chemotherapy | 33.33 (0–100) | 33.33 (0–100) | 0.532ᵃ |
| Appetite Loss | |||
| Before chemotherapy | 33.33 (0–100) | 33.33 (0–100) | 0.187ᵃ |
| After chemotherapy | 66.67 (0–100) | 33.33 (0–100) | 0.008ᵃ |
| Constipation | |||
| Before chemotherapy | 66.67 (0–100) | 33.33 (0–100) | 0.507ᵃ |
| After chemotherapy | 66.67 (0–100) | 33.33 (0–100) | 0.150ᵃ |
| Diarrhea | |||
| Before chemotherapy | 66.67 (0–100) | 66.67 (0–100) | 0.616ᵃ |
| After chemotherapy | 33.33 (0–100) | 66.67 (0–100) | 0.451ᵃ |
| Financial Difficulties | |||
| Before intervention | 33.33 (0–66.67) | 33.33 (0–66.67) | 0.914ᵃ |
| After intervention | 33.33 (0–100) | 33.33 (0–100) | 0.778ᵃ |
| Global Health Status | |||
| Before chemotherapy | 41.67 (16.67–83.33) | 50 (16.67–83.33) | 0.426ᵃ |
| After chemotherapy | 41.67 (0–100) | 51.67 ± 28.87 | 0.231ᵃ |
| Overall Quality of Life (Mean Score) | |||
| Before chemotherapy | 41.41 ± 7.28 | 40.42 ± 6.17 | 0.605ᵇ |
| After chemotherapy | 49.16 ± 7.47 | 49.48 (26.52–61.22) | 0.698ᵃ |
Data are presented as mean ± SD or median (range).
ᵃ Mann–Whitney test
ᵇ Independent t-test
Table 5: Comparison of Quality of Life Before and After Chemotherapy in the AHCC® Group
| Quality of Life Domain | Before Treatment (n=25) | After Treatment (n=25) | p-value |
| Physical Functioning | 38.4 ± 20.21 | 51.47 ± 29.66 | 0.040ᵃ |
| Role Functioning | 33.33 (0–66.67) | 50 (0–100) | 0.135ᵇ |
| Emotional Functioning | 50 (41.67–66.67) | 58.33 ± 32.67 | 0.316ᵇ |
| Cognitive Functioning | 16.67 (0–66.67) | 50 (0–100) | 0.072ᵇ |
| Social Functioning | 66.67 (16.67–83.33) | 50.67 ± 25.68 | 0.093ᵇ |
| Fatigue | 33.33 (0–66.67) | 44.44 (0–100) | 0.025ᵇ |
| Nausea and Vomiting | 33.33 (0–66.67) | 33.33 (0–100) | 0.756ᵇ |
| Pain | 33.33 (0–83.33) | 50 (0–100) | 0.356ᵇ |
| Dyspnea | 33.33 (0–66.67) | 33.33 (0–100) | 0.124ᵇ |
| Insomnia | 33.33 (0–66.67) | 33.33 (0–100) | 0.036ᵇ |
| Appetite Loss | 33.33 (0–100) | 66.67 (0–100) | 0.101ᵇ |
| Constipation | 66.67 (0–100) | 66.67 (0–100) | 0.170ᵇ |
| Diarrhea | 66.67 (0–100) | 33.33 (0–100) | 0.706ᵇ |
| Financial Difficulties | 33.33 (0–66.67) | 33.33 (0–100) | 0.807ᵇ |
| Global Health Status | 41.67 (16.67–83.33) | 41.67 (0–100) | 0.587ᵇ |
| Overall Quality of Life (Mean Score) | 41.41 ± 7.28 | 49.16 ± 7.47 | <0.001ᵃ |
Data are presented as mean ± SD or median (range).
ᵃ Paired t-test
ᵇ Wilcoxon signed-rank test
Discussion
This study aimed to evaluate the clinical response of patients with non–small cell lung cancer (NSCLC) receiving systemic therapy with AHCC® supplementation. The demographic profile showed a marked predominance of male participants (96% in the AHCC® group and 92% in the control group), with no statistically significant difference between groups (p = 1.000). This finding is consistent with previous reports, including global epidemiological analyses, which indicate higher incidence and mortality rates of lung cancer in men compared with women. This disparity is largely attributed to behavioral risk factors, particularly smoking, which is more prevalent among men. In the present study, all participants had a history of smoking, consistent with data from the National Cancer Institute indicating that approximately 85-90% of lung cancer cases in men are attributable to cigarette smoking [12,13].
The mean ages of participants (61 and 59 years) fall within the high-risk category defined by the National Comprehensive Cancer Network (≥50 years), although they are younger than the median age at diagnosis reported in developed countries (68-70 years). The relatively earlier onset observed in Indonesia often 10-15 years younger than in Western populations suggests a substantial contribution of local risk factors, including early smoking initiation and environmental pollution, which may accelerate carcinogenesisc [12-14].
The predominance of Batak ethnicity (60% and 52% in the respective groups) reflects the regional population served by the study centers rather than indicating genetic susceptibility. Furthermore, the absence of a family history of cancer in most patients suggests that environmental and behavioral factors play a more prominent role than hereditary predisposition in this cohort [12-14].
Histopathological findings demonstrated that adenocarcinoma was the predominant subtype (64% in the AHCC® group and 56% in the control group), consistent with the global epidemiological shift in which adenocarcinoma has surpassed squamous cell carcinoma as the most common subtype. Evidence from population-based cancer registries supports this shift, which has been attributed to changes in cigarette design and increased exposure to fine particulate matter (PM2.5). In Asian populations, adenocarcinoma accounts for approximately 55–65% of cases and is often associated with a higher prevalence of driver mutations such as EGFR [12-14].
Most patients were diagnosed at advanced stages (IVA–IVB), with pleural effusion observed in approximately half of the cases. Malignant pleural effusion is a common manifestation in advanced lung cancer, particularly adenocarcinoma, and is associated with pleural dissemination. This finding aligns with previous reports indicating that 40–50% of lung cancer patients develop pleural effusion during the disease course [15,16]. Importantly, the absence of significant differences between groups in disease stage and chemotherapy regimen—most commonly carboplatin plus paclitaxel—supports the comparability of the study populations and minimizes potential confounding effects [17-19].
No statistically significant differences in interferon-gamma (IFN-γ) levels were observed between the AHCC® and control groups, either at baseline or after chemotherapy (p > 0.05). Although a reduction in median IFN-γ levels was noted in the AHCC® group (50.44 pg/mL to 32.93 pg/mL), this change was not statistically significant (p = 0.904). These findings support the concept that AHCC® functions as an “immune balancer” rather than a potent immunostimulant. Mechanistically, AHCC® may modulate immune responses through regulation of inflammatory signaling pathways, including inhibition of NF-κB and STAT1 activation, which are key regulators of pro-inflammatory cytokine production [20-24].
In the context of platinum-based chemotherapy, which is often associated with systemic inflammation and immune dysregulation, a moderate reduction in IFN-γ levels may reflect a protective mechanism against excessive inflammatory responses. The decline observed in the control group (p = 0.798) likely represents chemotherapy-induced immunosuppression or natural biological variability. Importantly, the absence of excessive IFN-γ elevation in the AHCC® group suggests that supplementation does not induce harmful hyperinflammatory responses. This interpretation is supported by previous studies reporting that AHCC® may reduce chemotherapy-related toxicity while maintaining immune homeostasis [20-24].
Quality of life (QoL) outcomes demonstrated clinically relevant improvements. The AHCC® group showed significant improvements in physical functioning (p = 0.040) and reductions in fatigue (p = 0.025). These findings are clinically important, as NSCLC patients frequently experience functional decline due to chemotherapy-related adverse effects. Similar findings have been reported in previous studies, suggesting that AHCC® may enhance cellular energy metabolism and reduce oxidative stress. Although improvements were also observed in the control group, these are likely attributable to tumor burden reduction following chemotherapy [25-28].
Notably, worsening dyspnea was observed in the control group (p = 0.012), whereas the AHCC® group remained relatively stable. This finding suggests a potential role of AHCC® in mitigating respiratory symptom progression or chemotherapy-related pulmonary toxicity. Improvements in insomnia and emotional functioning in the AHCC® group further support the hypothesis that cytokine modulation may influence neuroimmune pathways and overall well-being [25-28].
At the end of the study period, the AHCC® group demonstrated a significant improvement in overall QoL (p < 0.001), along with a significant reduction in appetite loss compared with the control group (p = 0.008). This effect may be mediated through suppression of pro-inflammatory cytokines such as IL-6 and TNF-α, which are known contributors to anorexia and fatigue in cancer patients. These findings are consistent with previous reports highlighting the role of cytokine modulation in alleviating chemotherapy-related symptoms [25-28].
Although between-group comparisons of change scores were not statistically significant across most QoL domains, the consistent trend toward improvement in the AHCC® group suggests a potential supportive benefit. AHCC® should not be considered a replacement for standard chemotherapy; rather, it may serve as an adjunctive immunomodulatory therapy that helps preserve functional status and improve patient-reported outcomes during treatment. Overall, these findings indicate that AHCC® supplementation is safe and may provide clinically meaningful supportive benefits in patients with NSCLC, particularly in maintaining functional capacity and alleviating symptoms that negatively impact quality of life during chemotherapy.
Limitation
This study has several important limitations. First, the study population was highly homogeneous, with 92-96% of participants being male and all having a history of smoking, thereby limiting the generalizability of the findings to female patients and never-smokers with lung cancer. Second, substantial biological variability was observed, particularly in inflammatory markers such as IFN-γ, especially within the control group where values showed a wide range. This variability may have reduced the statistical power to detect significant differences between groups.
Third, changes observed in certain quality-of-life domains, such as social functioning, may have been influenced by external psychosocial factors including family support, socioeconomic status, and social stigma rather than the intervention alone. In addition, improvements in physical functioning in the control group may reflect reductions in tumor burden following chemotherapy, thereby complicating the interpretation of the independent effect of AHCC® supplementation.
Finally, although favorable trends were observed across several outcomes, most between-group comparisons did not reach statistical significance. This may be attributable to the relatively small sample size and limited statistical power, highlighting the need for larger studies to validate these findings.
Conclusion
In this study, patients with NSCLC were predominantly middle-aged to elderly males with a history of smoking, while a family history of cancer was relatively uncommon. IFN-γ levels did not differ significantly between the AHCC® and control groups, although a non-significant decline was observed following chemotherapy in both groups, with a greater reduction in the AHCC® group.
Notably, AHCC® supplementation was associated with significant improvements in physical functioning and overall quality of life within the intervention group. However, the absence of statistically significant differences in most between-group comparisons suggests that these findings should be interpreted with caution.
Overall, AHCC® appears to be a safe supportive adjunct for patients with NSCLC undergoing platinum-based chemotherapy, with potential benefits in maintaining functional status and alleviating treatment-related symptoms, particularly fatigue. Further large-scale, well-powered studies with longer follow-up are warranted to confirm its clinical efficacy and to better elucidate its immunomodulatory mechanisms.
Declarations
Acknowledgments
The authors would like to express their sincere gratitude to the management and medical staff at the study sites for their invaluable support and cooperation throughout the research process. We are particularly grateful to the oncology and pulmonary teams for their assistance with patient recruitment, clinical data collection, and monitoring during chemotherapy administration.
Conflict of Interest
There are no conflicts of interest.
Funding
This study was supported in kind by Amino Up Co., Ltd. (Sapporo, Japan), which supplied AHCC® and a matching placebo at no cost. Further support was provided by PT Interbat. The sponsors were not involved in the study design, data collection, data analysis, interpretation of results, preparation of the manuscript, or the decision to submit the manuscript for publication.