Isamu Tengan, MD
Integrative Medical Center, Clinic Ginowan, Ginowan-Shi, Okinawa 903-0215, Japan; E-mail: dr.tengan.tmc@tougou.jp
Endometrial carcinoma (EC) is the sixth most common gynecologic tumor in women worldwide and the fourth most common in incidence among women in Europe and North America.1,2,3 EC is classified into several histological types, and its lung metastasis is the highest among gynecologic malignancies.4 Advanced EC is less sensitive to chemotherapy, causes distant metastases, and has a poor prognosis.3,4,5 Standard treatment for recurrent EC is chemotherapy; in this case, carboplatin and paclitaxel were combined with hormonal therapy. Bioactive ingredients derived from natural resources are considered suitable candidates as substitutes due to their low toxicity,6 and fucoidan isolated from edible brown algae can be recommended as a natural active ingredient.
Fucoidan has a structure in which sulfate groups, fu cose, etc., are bound to a heteropolysaccharide backbone,6,7 and exhibits anticancer activity.8-13 It induces autophagy and apoptosis in breast, ovarian, and endometrial cancers.14 It inhibited the growth of 5 types of ovarian cancer cell lines but not on normal cells.6 It also exhibits antitumor effects regardless of the presence or absence of estrogen receptors.15,16 It induced apoptosis by increasing reactive oxygen species in cancer cells.17 The suppression of PD-L1/PD-L2 expression by low molecular weight fucoidan extract (LMF) can be applied to treating other tumors.18 Based on the above, the authors concluded that fucoidan is effective for this patient.
Thus, in addition to Medroxyprogesterone acetate (MPA) hormone therapy, we prescribed the fucoidan product Low molecular weight fucoidan extract-Canavalia gladiata extract (LMF-CG) (trade name “Power Fucoidan® CG Jelly Type”, Daiichi Sangyo Co., Ltd., Osaka, Japan) for lung metastasis of endometrial adenocarcinoma.
A 71-year-old Japanese female was diagnosed with a metastatic lung tumor (stage IV) of primary endometrioid adenocarcinoma in 2018. She underwent a total hysterectomy and pelvic lymphadenectomy. After that, she received six cycles of adjuvant chemotherapy (docetaxel plus carboplatin (DC) therapy). Multiple pulmonary metastases were found three months later, and three nodules were detected in the right lung despite receiving DC therapy for an additional seven months (Figure 1 a-c). Then, MPA hormone therapy (600 mg/day) was initiated to suppress the progression of metastatic lung cancer (Figure 2).
Figure 1. Computed Tomography (CT) Image Taken on March 12, 2018. Multiple Metastatic Tumors in the Right Lung (a-d)
Metastasis to the Middle Lobe (a), Metastasis to the Lower Lobe (b), (c). Image (d) is the Same Tumor as (C) Taken at a Different Position.
Figure 2. NK Cell Activity Measurement, and MPA, LMF-CG Treatment Plans. NK Cell Activity was Evaluated as having High Immunity when the Values are 20 or more.44,45
MPA (600 mg/day): Treatment Period (blue right-pointing arrow). The Dose of LMF-CG was Gradually Reduced to 6, 3, 2, 1 pouches/day (p/d) (green right-pointing arrow). According to the Decrease of LMF, NK Cell Activity Decreased toward April 2020, but after 3 Years when the Tumor Disappeared NK Cell Activity Recovered to the Normal Range.
The patient visited Clinic Ginowan for a second opinion because she felt her condition did not seem to improve after receiving MPA therapy. Considering the patient’s chief complaint and physical condition, six pouches of LMF-CG (50 g/pouch) were prescribed daily in addition to MPA therapy. A positron emission tomography (PET) scan showed a cavitated nodule in the right lung three months later. In addition to the PET findings, as natural killer (NK) cell activity increased, LMF-CG intake was reduced to 3 pouches per day (Figure 2). At the same time, to reduce her anxiety, she was presented with advice for sleeplessness and information on hormones and diet. After four months, the LMF-CG was decreased to two pouches per day as the tumor had almost disappeared.
Because there was neither new cancer metastasis nor worsening of the symptoms during the LMF-CG intake period, the intake of LMF-CG was reduced to one pouch per day, and she is still taking LMF-CG. A computed tomography (CT) scan in September 2020 showed that the third nodule observed in Figures 1c and 1d wholly disappeared (Figure 2), and the other two nodules were undetectable. The third nodule (Figures 1c and 1d) image taken on March 12, 2018, appeared likely undergoing apoptosis and thus was followed up. C.T. scans taken on September 4, 2020 (Figure 3) and June 4, 2021 (Figure 4).
Figure 3. CT Image taken on September 4, 2020. The Image Shows the Metastatic Tumor Detected in Figure 1(c) Disappeared by Apoptosis (Inset: enlarged image of d)
Figure 4. CT Image Taken on June 4, 2021. Similar to the Image in Figure 2, it shows a Cavitated Tumor by Apoptosis
Supported by favorable results such as CT images and NK cell activity (Figure 2), the patient regained physical and mental health and physical condition and returned to farm work in September 2023, which she continues.
In this case, despite the patient with metastatic lung cancer having received chemotherapy, it recurred three months later. This patient had been on MPA hormone therapy as standard care following the initial surgery. MPA exerts its effects through risk.19-23 Chemotherapy- and radiation-induced necrosis is the disordered destruction of cells, releasing intracellular components and triggering an inflammatory response in the surrounding tissue. Chemotherapy, despite its effectiveness, causes acute and long-term side effects on normal cells and tissues in the human body.24 Thus, it is necessary to consider the appropriate dose when applying chemotherapy.25 Apoptosis is distinct from necrosis because harmful intracellular components released from dead cells are phagocytosed by surrounding phagocytic cells. Thus, MPAinduced effects are an anti-cancer strategy to switch the necroticto apoptotic-tumor cell death.26
Fucoidans, mainly extracted from Undaria pinnatifida and Fucus vesiculosus, have been regarded as a “Generally Recognized As Safe (GRAS)” agent by the United States Food and Drug Administration (USFDA). These extracts were also approved as a novel food by the Commission Implementing Regulation (E.U.) as of December 20, 2017, admitting to taking up to 250 mg daily. Canadian and Australian agencies have approved pharmaceutical products containing fucoidan extracts from such two algae species.27,28
Low molecular weight fucoidan extrac (LMF) is prepared by digesting crude fucoidan obtained from the brown seaweed Mozuku with abalone glycosidase and has different characteristics from other fucoidans.18,29,30 The molecular size composition of LMF consists of a digested low molecular weight fraction (72%) of less than 500 Da.31,32,33 Patients with advanced cancers of lung, uterine, and breast received 4 g of LMF daily for four weeks, proinflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) significantly reduced in two weeks.18
Recently, attention has focused on the role of immune checkpoint inhibitors that suppress the programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway by activating the immune system against cancer cells.18,34 Inhibition of PD-1 has been demonstrated to exert anti-tumor activity in certain solid tumors.34,35,36 Immunotherapy is effective for renal cell carcinoma and patients with non-small cell lung cancer and other cancers. However, anti-PD-1/PD-L1 therapeutics like other anti-cancer agents, also have various side effects.37
The authors devised a therapeutic strategy combining LMF-CG and hormone therapy for recurred metastatic lung cancer and succeeded in eradicating it. LMF was selected not only for its anti-cancer activity but also for its various biological effects.
Considering above drawbacks of immune checkpoint inhibitors, LMF can be recommended as an ideal drug.18 Presently prescribed fucoidan product LMF-CG consists of 91.03% LMF extract as the main constituent and 2.40% CG extract containing a minute amount of concanavalin A (Con A) as a minor ingredient in a 50 g pouch.38 Con A has been known as a Ca2+/ Mn2+-dependent and mannose/glucose-binding legume lectin to induce cell death in cultured cancer cells and to exert anti-inflammatory activity.39-43 Anti-cancer effects of Con A by induction of autophagy and apoptosis and inhibition of angiogenesis would be a model of LMF-CG.42
Still, the natural killer cells (NK cells) activities and quality-of-life (QoL) scores were mostly stable.43,44 Anti-inflammatory agents have anti-cancer effects, Increased NK cell activity after the disappearance of tumors suggested a good prognosis. Multiple biological function of LMF needs to be confirmed by more case reports and clinical trials.45
These co-treatments significantly induced cell-growth inhibition, apoptosis, as well as cell cycle modifications in MDAMB-231 and MCF-7 cells. LMF enhanced apoptosis in cancer cells that responded to treatment with chemotherapeutic drugs with downregulation of the anti-apoptotic proteins B-cell lymphoma-extra large (Bcl-xL) and Myeloid cell leukemia 1 (Mcl-1). The combination treatments led to an obvious decrease in the phosphorylation of ERK and Akt in MDA-MB-231 cells, but increased the phosphorylation of ERK in MCF-7 cells.46 LMF deserves further investigation as a natural anti-cancer and cancer preventive agent.
This case is the first report of complete remission of EC-derived metastatic lung cancer by combining hormone therapy and LMFCG. Further clinical studies are expected for various other cancers.
There are no conflicts of interest to declare.
The authors obtained the written consent from the patients to report.
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