Instead, small cell lung cancer (SCLC) represents about 15% of all lung cancer cases. This histological subtype is characterized by a high sensitivity to chemotherapy, but also by a rapid cell growth and early metastatic spread [3].

Most patients with thoracic cancer are metastatic at the time of diagnosis, featuring a high percentage of brain metastases, and therefore, their prognosis remains poor, despite new therapeutic frontiers [4].

In this context, the innovative treatments, as precision medicine, targeted therapy and immunotherapy have begun to change the natural history of patients with lung cancer, contributing to an improvement in outcomes and life expectancy [5]. Indeed, new specific therapeutic approaches are emerging: these drugs selectively attack tumor cells and act on the microenvironment, which is also related to progression, metastasis and drug resistance mechanisms. Tumor cells seem to be able to modify the metabolic reprogramming of the tumor microenvironment through the induction of cytokines and harmful metabolites [4]. Consequently, it is very important to understand not only the physiopathology of tumor cells, but also to focus on the importance of microenvironment dynamicity, since it may represent the target of therapeutic intervention influencing the tumoral cell trophism, growth, survival and resistance mechanisms.

New molecules are also under investigation as adjuvants to antiblastic agents, to design synergistic and more effective therapeutic approaches. Many researchers are focusing their attention on well-known molecule, called Silibinin, whose benefits have not yet been fully understood. Indeed, it seems that this molecule can have an adjuvant role in antitumor mechanisms [6].

Silybum marianum belongs to the Asteraceae family, also known as milk thistle. This plant is indigenous to Southern Europe, Australia, North and South America, Northern Africa, and some parts of Asia. From ancient times until now, milk thistle has been used for treatment of liver diseases and increasing milk production in lactating mothers [7-10].

Silymarin, the major constituent of milk thistle extract (collection of flavonolignans such as Silybin A and B, Isosilybin A and B, Silibinin, Silydianin, and Silychristin) is found in the seeds, leaves, and fruits of S. marianum [11-14]. Silibinin is the major constituent of silymarin and has the most active therapeutic effects among the other flavonolignans. Oral bioavailability of Silymarin is low due to little solubility in water. However, especial formulations were made that increased its solubility and absorption [15].

These evidences had led us to integrate Silibinin in our clinical practice, and here we summarize our experience with Silibinin in patients with diagnosis of lung cancer and central nervous system (CNS) involvement.

ANTITUMOR MECHANISMS OF SILIBININ

Silibinin has been demonstrated to be able to selectively inhibit Signal Transducer and Activator of Transcription 3 (STAT3), a JAK-activated intracellular transcription factor involved in immunologic tolerance, cell proliferation and apoptosis [6,16].

JAK/STAT3 dysregulation seems to be underlying the loss of control of the cell cycle, leading to uncontrolled cell proliferation, carcinogenesis, metastatic processes and finally immune resistance. For this reason, it represents a potential therapeutic target in different types of tumors, raising interest in the development of a new class of antineoplastic drugs, the STAT3 inhibitors [6,12].

Both in vivo studies on murine models and studies conducted on small cohorts of patients (n=18) affected by brain metastases from different tumor histologies, have demonstrated how the sole inactivation of pSTAT3 through the use of Silibinin produces high rates of stabilization of secondary brain lesions, and an improvement in the quality of life in approximately 90% of treated patients [16]. Studies have shown that this molecule can inhibit the growth of tumor cells and induce their apoptosis [17].

In this context, Silibinin has documented anti-inflammatory properties, even in combination with chemotherapeutic agents and therefore could give us future hope to reduce drug-related toxicity and increase their therapeutic potential.

Silibinin has been shown to have interesting antitumor activity against several types of cancers including liver, lung, breast, prostate, colorectal, skin and bladder cancers [6].

It appears promising for cancer therapy because it has anti-inflammatory and antioxidant, antiproliferative, pro-apoptotic, antimetastatic and anti-angiogenic action. In particular, Silibinin is able to modulate several signaling pathways involved in the development and progression of cancer.

It acts through PI3K/Akt, NF-κB, Wnt/β-catenin and MAPK pathways, thereby suppressing cancer cell proliferation, and promoting apoptosis. Furthermore, since Silibilin is a natural compound, it also has the advantage of having a favorable safety profile as well as synergistic effects with conventional therapies [17,18].

Some authors studied the Zein-β-cyclodextrin complex to encapsulate Silibinin and evaluate the induced cell death and cytotoxic impacts on human tumor cells [19].

Further research has focused on studying of CCK-8 and has performed morphological analyses to evaluate the cytotoxic impacts of Silibinin on lung cancer cells in vitro. They better delineated the role of Silibinin in the induction of apoptosis and necrosis: by inhibiting necrosis it could switch cell death to apoptosis and consequently enhance the inhibitory effect of Silibinin [20].

Silibinin appears to be related also in the inhibition of cell proliferation and the induction of apoptosis of tumor cells through a calpain-dependent pathway and in the induction of ROS generation [21-24].

In addition to this mechanism, other actions of Silibinin have been described, including the epithelial-mesenchymal transition and the inhibition of glioma cell migration through mitochondrial fusion and inhibition of ROS [25].

Studies are also underway on the mechanism of action of this molecule on EGFR [26,27].

ROLE OF SILIBININ IN FIGHTING CANCER IN REAL LIFE

The literature is recently documenting the antitumor effects of Silibinin and demonstrating its efficacy. Recently, some authors have reported promising data also for gliomas [6,28]. These are the brain tumors with the worst prognosis since, to date, there are still no effective treatment strategies [29].

Furthermore, current treatments have significant side effects that sometimes require the suspension of chemotherapy. For this reason, natural compounds are being studied that can reduce the side effects of these treatments as well as increase their efficacy and Silibinin is one of them [30].

Regarding metastatic processes, Silibinin could also have a beneficial role for brain metastases that are the most common lesions of the CNS in adults (over 50%). At the brain level metastasis process is more difficult for tumor cells, due to the presence of the blood-brain barrier (BBB) and the tumor microenvironment [31]. Metastatic cells manage to escape natural defense mechanisms by interacting with various cell types within the cellular microenvironment; this way, they influence their activity in a pro-metastatic manner and therefore promote their own survival [32-34].

In particular, in brain metastases STAT 3 controls the interaction between endothelial cells and tumor cells. Brain metastases affect the cellular microenvironment also activating the STAT3 pathway in reactive astrocytes. The latter then exert a modulatory effect on the immune system to the advantage of metastatic cells. Recent studies have shown that STAT3 inhibition suppresses brain metastases of solid tumors, and it seems that glioblastoma is also characterized by a greater activation of STAT3 compared to normal brain tissue [35-39].

The possibility of having specific drugs that act on STAT 3 could play an important role. Silibinin, in addition to having the advantage of being a natural derivative with few side effects, acts precisely on STAT 3.

SILIBININ TOLERANCE

Reported side effects of Silibinin are very rare; however, there may be digestive problems such as nausea, vomiting, loss of appetite, abdominal swelling and pain, flatulence, diarrhea, or vague symptoms such as asthenia, headache, dizziness.

Below are the studies that demonstrated the absence of side effects: Zhu et al tested the administration of oral Silymarin at a dose of 140 mg three times a day for 28 days without any harmful effects. Di Pierro [40] studied 50 healthy breastfeeding women who were administered an oral dose of 420 mg of Silymarin daily for 63 days and in these cases, there were also no side effects [39-43].

Even in the study by Valentova [43], Silibilin did not show toxicity in 22 healthy volunteers at an oral dose of 400 mg per day [41].

Other authors have used oral capsules containing 175 mg of milk thistle extract or 140 mg of Silymarin three times a day for 14 days and no adverse reactions were observed. Even in 60 patients with malignant neoplasia, oral administration of 140 mg of Silymarin twice a day before taking cisplatin did not document any problems [42-44]. The absence of side effects was demonstrated even with the dosage of 420 mg/daily before cisplatin infusion [44].

Instead, in a study on patients with prostate cancer, who took oral Silibilina phytosome (Siliphos) at increasing dosages, three times a day for a month, gastrointestinal disturbances, increases in bilirubin, calcium and creatinine were reported [45].

In another study conducted on patients with head and neck cancer, the authors evaluated the effects of Silymarin in reducing mucositis due to radiotherapy and demonstrated good tolerance and the absence of side effects at a dosage of 420 mg per day [46].

Vidlar [47] demonstrated that Silymarin, in association with selenium, is effective in preventing the progression of prostate cancer and does not cause toxicity at a dosage of 570 mg per day [47].

In a study on patients with colorectal cancer the authors studied the association between 188 mg per day of Silybin, 288 mg of phosphatidylcholine and 60 mg of vitamin E in combination with regorafenib and also in these cases there were no toxic effects [48,49].

Therefore, it can be stated that milk thistle is safe and has a good tolerance and at therapeutic dosage has few side effects which are mainly gastrointestinal.

For this reason, we have evaluated the tolerance of this molecule in patients affected by thoracic neoplasia with brain metastases, referring to our lung unit, who take Silibinin as a supplement.

Therefore, we consecutively collected from April 2020 to August 2024 the clinical, biological and radiological data of patients affected by lung cancer who were continuously taking Silibinin and who were referred to our Lung Unit-Thoracic Oncology.

To our knowledge, we report the first collection of a large number of patients affected by lung cancer with brain metastasis, taking Silibinin as a supplement, in order to analyze the tolerability of this molecule showing the possible side effects or benefits of this integration to standard antiblastic treatments.

CASE REPORT

From April 2020 to August 2024, we consecutively analyzed data of a series of patients admitted to our Lung Unit, department of Thoracic Oncology, who assumed supplements in association with active oncological treatment. Among these patients we considered only those diagnosed with thoracic neoplasm with brain secondary lesions, who used Silibinin.

Patients’ Clinical Data and disease biological features:

In total, 75 patients took Silibinin: 35 males (46.47%) and 40 females (53.33%) with an average age of 67.69 months (median: 69.74 months) years.

All patients were suffering from pulmonary neoplasm and among these 62 (82.67%) had a diagnosis of Non-Small Cell Lung Cancer (NSCLC) of which 57 (91,93%) were adenocarcinomas and 4 patients (6,5%) were squamous carcinomas; among total patients, 10 (13.3%) were affected by Small Cell Lung Cancer (SCLC) and 3 (4%) by neuroendocrine neoplasia (Figure 1).

Biomolecular profile analysis was carried out for patients with diagnosis of NSCLC adenocarcinoma subtype: 19 patients were EGFR positive (31%), 3 patients had ALK translocation (5%), 1 patient has ROS1 alteration (2%), while KRAS positivity was detected in 21% (13 patients).

Concerning clinical conditions, the performance status (PS) according to ECOG was 0 in 18.67% (14 patients), 1 in 45.33% of cases (34 patients) and 2 in 27% of cases (36 patients).

All patients underwent a nutritional analysis: the average BMI (Body Max Index) was 24.25 with a median of 23.83.

As regards to smoking habits, 16 patients were current smokers (21.33%), 36 were ex-smokers (48%) and 23 patients (30.67%) had never smoked. The tobacco exposure of the population analyzed was 40.04 packs /years (median 30).

The majority (69.33%) of patients with NSCLC who referred to our department had metastatic disease, while 8% were in advanced stage and only 6.67% in early stage. All patients with SCLC and neuroendocrine neoplasia had extended disease (ED). In particular, patients with diagnosis of NSCLC had lung metastases in 51.61%, pleural in 20.97%, hepatic in 27.42%, renal in 3.23%, adrenal in 25.81%, bone in 40.32%, lymph node in 22.58%, splenic in 3.23%, skin in 1.61%.

SCLC patients had lung metastatic disease in 30% of cases, pleural in 20%, liver in 30%, kidney in 10%, adrenal in 40%, bone in 20%, lymph node involvement in 10%.

Patients with non-small cell neuroendocrine neoplasia had bone metastases in 66.67%, liver in 33.33% and adrenal in 33.33%, all had pulmonary metastases.

18 patients (24%) were receiving standard chemotherapy agents, 6(8%) immunotherapy alone, 23(30,7%) chemoimmunotherapy combination regimens, 22 patients (29,3%) were taking oral target therapy because of their biomolecular profile, while 6 patients (8%) were not under treatment at the moment of Silibinin assumption (Figure 2). All patients had brain metastases and for this reason they were taking Silibinin as a supplement.

In Table 1 the summary of overall population characteristics.

Brain metastasis

Among patients with brain metastases 38.67% (29 patients) had only one brain lesion, 26.67% (number 20) had 1 to 4 brain metastases and 34.67% (26 patients) had more than 5 lesions.

The mean size of the brain lesions was 13.75 mm with a median of 10 mm.

58.67% of patients with metastatic brain disease had been treated with a radiotherapy approach at the time of diagnosis: among these 10.67% had undergone a second radiotherapy treatment and approximately 10% were treated further with radiotherapy.

Silibinin tolerance

Patients referring to our Lung Unit undergo periodic checks and therefore their general clinical conditions are constantly evaluated and any ongoing treatments related side effects is reported and investigated. In fact, we also collected any side effects caused by the integration of Silibinin. We therefore asked periodically to our patients whether they experienced any side effect, such as loss of appetite, nausea, vomiting, abdominal pain, dyspepsia, flatulence, swelling, diarrhea; headache, dizziness, fatigue during the assumption of Silibinin. Our experience is coherent with available literature about Silibinin use in oncological patients.

Patients’ outcomes

At the time of data analysis, 29 patients were alive (38.67%), while 61.33% (number 46) had died.

In total, patients had achieved a mean overall survival (OS) of 35.03 months (median 27.86).  In particular, the OS of patients with NSCLC was 36 months (median 27,86), while that of patients with SCLC and neuroendocrine neoplasia was 14.69 months (median 11.12).

For better control of the quality of life of patients, we followed their treatment path by administering specific questionnaires at baseline and at their first restaging follow-up evaluation. In particular, the questionnaires applied were the following: QLQ-BN20, QLQ-C30, EQ5D and QoL Visual analogue scale. These questionnaires are always administered to our patients as usual clinical practice in order to monitor their perceived quality of life.

The EORTC QLG Core questionnaire (EORTC QLQ-C30) consists of 30 items that assess different aspects of the quality of life of cancer patients. It was the first instrument to be developed in 1993 after a decade of multidisciplinary research and is applied in several experimental and non-experimental oncology clinical studies.

From the data collected the QLQ-C30 symptoms median score was 22.22 at baseline, showing a trend towards mild worsening at the time of restaging (median 27.78, range 0.00-75.00) with a p-value = 0.07155. When compared to baseline results, QLQ-C30 global QoL at reassessment failed to show statistically significant variations (p-value = 0.6275), with a baseline median of 50 (range 0.00-91.65) and median at reassessment of 66.67 (range 16.67-100.00). In addition, we administered to our patients the EQ-5D 5-level test (EQ-5D-5L); this short questionnaire, created to improve sensitivity while reducing ceiling effects compared to the EQ-5D-3L, was developed in 2009 by the EuroQol Group. It consists of an EQ-5D descriptive system and an EQ visual analogue scale (EQ VAS). The first includes five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) of which each has 5 levels (no problems, mild problems, moderate problems, severe problems and extreme problems). The patient indicates his or her health status by checking the box next to the most appropriate statement in each of the five dimensions and it translates into a 1-digit number indicating the level selected for that dimension. The numbers for the five dimensions can be combined into a 5-digit number describing the patient's health status.

The visual analogue scale (VAS), on the other hand, assesses the patient's health on a vertical visual scale where the endpoints represent "The best health you can imagine" and "The worst health you can imagine". The VAS has a good validity, good anchor-based responsiveness compared to multi-item questionnaires and it has an excellent reliability; it is used as a quantitative measure of health outcome that reflects the patient's own judgment.

The EQ5D questionnaires we collected did not show significant changes in quality of life (p value = 0.198) between baseline and restaging (median 1.99 and median 2 vs 3.25 and median 3).

Results from QoL VAS were slightly better at the moment of reassessment than they were at baseline (median at baseline 50, range 20.00-90.00, vs median at reassessment = 60, range 00.00-90.00) although not clinically significant (p-value = 0.3993). Additionally, since all patients in this collection had cerebral secondaries, the (EORTC) QLQ-BN20 was also applied. This test was validated in 1961, with a further phase IV validation in 2010. The focus of this test is the assessment of the effects of tumor and its treatment on symptoms, function and health-related quality of life (HRQoL) in patients with brain tumors. It is used in both clinical trials and in clinical practice.

In our case series, no evident change in symptoms was documented according to the QLQ-BN20 test and only a minimal trend in worsening of symptoms occurred with a median BN20 of 20 (1.67-66.67) at baseline and 26.67 (range 0.00-85.00) at the restaging evaluation), without a statistically significant difference (p = 0.279. Results from collected questionnaires are reported in Table 2 & Figures 3 & 4.

DISCUSSION AND CONCLUSIONS

Recent studies document that most of the pathogenic processes involved in oncogenesis, neoplastic progression, aging and increased toxicity are related to inflammatory features. This subject is currently of paramount interest in oncological field and evidences are emerging that molecules with an effectiveness on the management of inflammatory mechanisms can be adjuvant to standard therapies.

Silibinin is giving promising results as an adjuvant in current therapies, showing documented antitumor activity: it interacts with different phases of carcinogenesis including the inhibition of proliferation and regulation of the cell cycle, the induction of cell apoptosis, inhibition of angiogenesis, and the inhibition of migration that then gives rise to metastases.

In our study we included CNS metastatic lung cancer patients based on the evidence provided by the literature, which has already demonstrated that Silibinin has significant effects on growth inhibition and induction of apoptotic cell death in both SCLC and NSCLC cells.

In our study, Silibinin has been well tolerated, showing no relevant side effects. Only one among our patients reported diarrhea, which led to treatment discontinuation; however, relationship with Silibinin is unclear, since the patient was assuming an oral TKI that may cause diarrhea as common side effect.

Despite not achieving statistical significance, analysis of different EORTC QLQ sub-scales results and their evolution show that the perception of symptoms in patients affected by lung cancer with CNS involvement, tends to increase overtime notwithstanding Silibinin treatment; on the other hand, the overall subjective QoL appears to be improved. This seeming contradiction may actually represent the capability of Silibinin to limit and slow the worsening of neurological symptoms enough to improve the perception of quality of life, despite the natural progression of tumoral disease.

Future studies will be needed to better understand the antitumor properties of Silibinin, identify the most effective administration method and specific dosages for different types of cancer. All this will be useful to fully exploit the potential of Silibinin also in the oncology field.

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  Table 1
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  Table 2