Management of Combined Therapy (Ceritinib, A. cinnamomea, G. lucidum, and Photobiomodulation) in Advanced Non-Small-Cell Lung Cancer: A Case Report

The 5-year survival rate of non-small-cell lung cancer (NSCLC) is still low (<21%) despite recent improvements. Since conventional therapies have a lot of side effects, combined therapy is strongly recommended. Here, we report a patient with advanced NSCLC who received combined therapy, including ceritinib, photobiomodulation (PBM), ACGL (Antrodia cinnamomea (A. cinnamomea), and Ganoderma lucidum (G. lucidum)). Based on combined therapy, suitable doses of A. cinnamomea, G. lucidum, and PBM are important for tumor inhibition. This case report presents clinical evidence on the efficacy of combined therapy in advanced NSCLC patients, including computed tomography (CT) scan, magnetic resonance imaging (MRI), carcinoembryonic antigen (CEA), and blood tests. The effective inhibition of human lung adenocarcinoma cells is demonstrated. Our case highlights important considerations for PBM and ACGL applications in NSCLC patients, the side effects of ceritinib, and long-term health maintenance.

Lung adenocarcinoma is the major subtype of lung cancer and approximately twothirds of patients have locally advanced or metastatic disease [10]. Patients usually receive conventional therapies (i.e., chemotherapy or radiation therapy). Henk and Ray reported that the mean total cost of treatment for more than 300 patients with advanced NSCLC ranged from USD 19,182 to USD 167,847 and USD 35,737 to USD 135,364 for first-line and second-line management, respectively [11]. Despite the fact that cancer therapy has been improved, the 5-year survival rate of lung cancer remains at a very low level (<21%) in the last four decades [12]. Thus, a suitable combined therapy in lung cancer treatment is necessary.
A suitable dose of photobiomodulation (PBM) can slow down tumor growth and prolong the life span of mice [13]. The immunoglobulin activity (IgA, IgM, and IgG) in 60 oncologic patients can be increased with PBM in the tumoural area or lymph nodes [14]. The ratio of IgA and IgG can be increased for nearly 1.86-fold and 6.33-fold, respectively, by external irradiation with an 890 nm laser on the second day. In addition, the ratio of IgM can be increased nearly four-fold on the fifth day. Recently, PBM has been used for managing chemoradiotheray in head and neck cancer patients [15,16]. PBM with adequate radiation time can induce apoptosis in human lung adenocarcinoma cells in cell culture [17]. Therefore, a suitable PBM therapy can be used to treat cancer.
Polysaccharide has been used as an adjunctive therapeutic drug for the side effects during cancer treatment [18]. G. lucidum is an oriental fungus which has been widely used for promoting health. A highly antitumor activity from the polysaccharides of the fruiting body of G. lucidum was found in an animal model, which is mainly activated by the branched (1→3)-β-D-glucans [19,20]. Previous studies report that the biologically active polysaccharides from G. lucidum show high antitumor activity while enhancing the host's immune response [20][21][22]. In addition, A. cinnamomea also shows antitumor activity that promotes a Th1-dominant state and natural killer (NK) cell activities through its polysaccharide components [23]. The triterpenoids from G. lucidum show a cytotoxicity-based carcinostatic effect on hepatoma cells in vitro [20]. The triterpenoids profile of A. cinnamomea fruiting bodies is richer than that of mycelia [24], and dish-cultured A. cinnamomea caused the tumor to shrink substantially for one small-cell lung cancer patient. The patient survived for 32 months without relapse after a 6-month treatment. In the present study, a combined therapy was administered to a lung adenocarcinoma patient in stage IVa.

Case Presentation
A 60-year-old Asian woman, with a history of cough for 1 year, was admitted to a hospital in November 2020. Computed tomography (CT) scan (Figure 1a) was used to evaluate the adenocarcinoma in situ and multiple pulmonary metastases. The brain metastases in NSCLC were checked by magnetic resonance imaging (MRI). The size of the left upper lung cancer tissue was larger than 5 cm (5.49 × 3.04 × 4.61 cm 3 ). After guided needle biopsy of the primary lung tumor, the woman was diagnosed with lung adenocarcinoma in clinical stage IVa NSCLC. She was treated with combined therapies, including PBM therapy, targeted therapy (ceritinib), ACGL (A. cinnamomea (50%), and G. lucidum (50%) at 450 mg ± 10%/capsule, manufactured by Well Shine Biothchnology Development Co., Ltd., Taipei, Taiwan). Three capsules of ceritinib per day (150 mg/capsule) and the oral administration of ACGL were prescribed. The dose of ACGL was increased to 12 capsules per day in August 2021. In addition, Multi-channel Laser Therapy System (Model: ID 310; wavelength: 830 nm and 650 nm; operation frequency: 10 Hz; 50% duty cycle; Jin-Ciang Technology Co., Ltd., Taiwan) was used to radiate on the apex of the lung and acupoints. The therapeutic protocol of the 830 nm laser was administered in four sequences once a day, each sequence for 10 min: (1) the Shaoshang (LU 11) and Zhongchong (PC 9) acupoints; (2) the Shaoshang (LU 11) and Guanchong (TE 1) acupoints; (3) the apex of the lung; and (4) the Feishu (BL 13) acupoint. The radiation position of the 830 nm laser is shown in Figure 2a. For transthoracic PBM therapy, the 830 nm array laser (7 laser diodes) was used to radiate on the chest (the apex of the lung) and the back area (BL 13 acupoint) for 10 min once a day.
According to the response evaluation criteria for tumor size (Figure 1b,c), the CT scans display a progressive decrease in the NSCLC tumor. The patient's clinical course is presented in Table 1. The good correlation between tumor volumes calculated with the formula π/6 × L × W × H and the actual tumor masses has been investigated [25]. After a year of combined therapy, the in situ volume of the adenocarcinoma tumor size became 47-fold smaller than the prior image on 10 November 2020 ( Figure 3a). Carcinoembryonic antigen (CEA) was significantly reduced (Figure 3b). The blood tests for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine (CRE) have also been checked for 1 year (Figure 3c).  According to the response evaluation criteria for tumor size (Figure 1b,c), the CT scans display a progressive decrease in the NSCLC tumor. The patient's clinical course is presented in Table 1. The good correlation between tumor volumes calculated with the formula π/6 × L × W × H and the actual tumor masses has been investigated [25]. After a year of combined therapy, the in situ volume of the adenocarcinoma tumor size became 47-fold smaller than the prior image on 10 November 2020 (Figure 3a). Carcinoembryonic  According to the response evaluation criteria for tumor size (Figure 1b,c), the CT scans display a progressive decrease in the NSCLC tumor. The patient's clinical course is presented in Table 1. The good correlation between tumor volumes calculated with the formula π/6 × L × W × H and the actual tumor masses has been investigated [25]. After a year of combined therapy, the in situ volume of the adenocarcinoma tumor size became 47-fold smaller than the prior image on 10 November 2020 (Figure 3a). Carcinoembryonic On the other hand, the lung meridian energy was evaluated in our case based on traditional Chinese medicine. According to the Meridian Energy Analysis Device (Model: ME-100; Medpex Inc., Taichung, Taiwan), when the current on an acupoint is less than 50 µA, it represents a deficiency syndrome of the relative meridian. A good progressive increase in the lung meridian was demonstrated (Figure 3d), changing from an extremely low (deficiency) to a normal state. Currently, the patient remains clinically stable, without any treatment-associated severe adverse events.  antigen (CEA) was significantly reduced (Figure 3b). The blood tests for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine (CRE) have also been checked for 1 year (Figure 3c). On the other hand, the lung meridian energy was evaluated in our case based on traditional Chinese medicine. According to the Meridian Energy Analysis Device (Model: ME-100; Medpex Inc., Taichung, Taiwan), when the current on an acupoint is less than 50 μA, it represents a deficiency syndrome of the relative meridian. A good progressive increase in the lung meridian was demonstrated (Figure 3d), changing from an extremely low (deficiency) to a normal state. Currently, the patient remains clinically stable, without any treatment-associated severe adverse events.  ACGL and PBM therapy: (1) 6 capsules of ACGL per day; (2) 830 nm laser (30 mW, 10 Hz, 50% duty cycle) was used to radiate on the acupoints and the target (Once a day). 4 steps of 830 nm laser radiation: (i) LU11 and PC 9 acupoints; (ii) LU 11 and TE 1 acupoints;

Discussion
Previous studies have suggested that PBM may increase proliferation of cells in some malignant cell lines [26][27][28]. However, the results cannot directly conclude that PBM would aggravate the tumor cell in vivo [29] because the human immune system can also be induced by PBM [14]. In addition, the survival and recurrence rates of 41 patients with stage II and III breast cancer treated by PBM have been investigated [30]. The result showed a higher survival rate (100% in stage II and 94.44% in stage III) with PBM radiation before and after the surgery for 2 years.
In targeted therapy, ceritinib is highly selective for driver oncogenes of ALK in NSCLC. Ceritinib led to the suppression of ALK phosphorylation, as well as the downstream signaling pathways that is active against ALK-positive cancer cells [31]. However, the treatment of ceritinib caused many adverse effects (AEs). Elevated transaminase is one of the AEs associated with the oral administration of ceritinib, which was manifested by the increase in AST and ALT. In addition, ceritinib increased BUN, red rashes, and severe diarrhea. Although diarrhea can be improved with the oral administration of Loperamide HCL, there will be the side effect of dizziness. In the present study, PBM was radiated on the target or acupoints to reduce the AEs. The concentration of ASL, ALT, and BUN returned to the normal state (Figure 3c) after an 830 nm laser was radiated on BL 18 (36.58 J/cm 2 ) and KI 1 (109.74 J/cm 2 ) acupoints twice a day for 1 month (Figure 2b). In addition, there were red rashes on the back of the hands associated with the oral administration of ceritinib for 1 month. A 650 nm laser (8.54 J/cm 2 ) was used to radiate on the target three times a day. The red rashes disappeared after a 10-day treatment. In addition, severe diarrhea stopped after the use of an 830 nm laser radiated on ST 25 acupoint (36.58 J/cm 2 ), ST 36 acupoint (109.74 J/cm 2 ), and stomach area (73.16 J/cm 2 ) (Figure 2c), and severe dizziness stopped after an 830 nm laser (73.16 J/cm 2 ) radiated on LU 11 and LU 07 acupoints (Figure 2d).
A. cinnamomea's antitumor activity has been studied [32,33]. It can induce the apoptosis of human breast cancer cells [32] and effectively impede the proliferation of human NSCLC [33]. An ethanol extract of A. cinnamomea has also been shown to inhibit the migration of highly metastatic CL1-5 human lung adenocarcinoma cells by reducing the expression of matrix metalloproteinase-2/9 via the mitogen-activated protein kinase and phosphatidylinositiol-3-kinase/Akt signaling pathways [34]. Antcin K is the most abundant triterpenoid, and it can be extracted from A. cinnamomea [35]. This extract was able to inhibit the metastasis of human hepatoma cells through the suppression of integrinmediated adhesion, migration, and invasion. On the other hand, scientists have investigated G. lucidum's high antitumor activity and its pathways in cancer cells [36][37][38][39]. Polysaccharides from G. lucidum can increase protein kinase C, p38 mitogen-activated protein kinase, and other tyrosine kinase (Hck and Lyn) activities [36]. Ganoderan B (a glycan of G. lucidum fruit bodies) significantly inhibits the growth, invasion, and migration of, as well as induces apoptosis inm NSCLC cells through the extracellular signal-regulated protein kinase signaling pathway [37]. Moreover, the dose-dependence of G. lucidum demonstrated different inhibition rates of Sarcoma-180 cells [40]. G. lucidum at 5.4 g per day for 12 weeks was administered to different patients with advanced cancer [38]. The results show a series of cellular immunological enhancements, including interleukin (IL)-2, IL-6, and interferon-γ secretion in plasma and NK cell activity, but the levels of IL-1 and tumor necrosis factor-α decreased in 30 assessable patients after G. lucidum treatment. In addition, the same dose of G. lucidum was given to advanced colorectal cancer patients [39]. A similar pathway can be found in the previous study [38]. The downregulation of TNF-α and IL-1 improved cancer cachexia [41,42]. Thus, A. cinnamomea and G. lucidum show a great potential for antitumor activity. The dose of G. lucidum in previous studies (5.4 g per day) [38,39] was consistent with ACGL (A. cinnamomea (50%) and G. lucidum (50%; 450 mg/capsule × 12 capsules = 5.4 g per day) in our study.
This study shows the following integrative effects. Owing to ceritinib, PBM, and ACGL, the size of the adenocarcinoma in situ was reduced from 40.26 to 4.07 cm 3 within 100 days. On the other hand, CEA was reduced from 97.37 to 1.40 (ng/mL) in a year.

Conclusions
In view of the supporting evidence for PBM and ACGL in cancer therapy, combined therapy was used to effectively inhibit human lung adenocarcinoma cells in this case. According to the chest CT and CEA marker, the primary lesion of the tumor responded well to combined therapy. The size of the adenocarcinoma in situ and multiple pulmonary metastases were reduced, and the CEA tumor marker level decreased rapidly. We recommend PBM and ACGL as complementary medicines for NSCLC patients. The present case may help clinicians develop a strategy for NSCLC treatment. However, more scientific evidence is needed to clarify the therapeutic strategies of PBM and ACGL. Informed Consent Statement: Informed consent was obtained from subject involved in the study. The subject has given written consent for data and image collection.

Data Availability Statement:
The data used to support the findings of this study are included within the article.

Conflicts of Interest:
The authors declare no conflict of interest.