Research Article

Efficacy of Modified Peanut Skin Decoction for Lung Cancer Myelosuppression

DOI:

10.3791/68880

⸱

September 16th, 2025

 ,  ,  ,  ,  , 
1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Hebei North University, 2Department of Cardiothoracic Surgery, The First Affiliated Hospital of Hebei North University, 3Department of Stomatology, The First Affiliated Hospital of Hebei North University, 4College of Traditional Chinese Medicine, Hebei North University, 5Department of Geriatrics, The First Affiliated Hospital of Hebei North University

In This Article

Summary

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This study evaluates the efficacy of modified Peanut Skin Decoction (PSD) in alleviating myelosuppression in patients with advanced lung squamous carcinoma receiving chemoimmunotherapy. Clinical outcomes and network pharmacology reveal PSD's mechanisms via phosphoinositide 3-kinase-protein kinase B/hypoxia-inducible factor-1 pathways.

Abstract

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This study conducted a randomized controlled trial to assess the efficacy and safety of modified Peanut Skin Decoction (PSD) for preventing myelosuppression in 60 patients with advanced squamous cell lung carcinoma receiving chemotherapy plus immunotherapy. Patients were randomised 1:1 to receive either standard supportive care granulocyte colony-stimulating factor (5 µg/kg) or supplemented by modified PSD as needed. Primary endpoints included white blood cell count, neutrophil count, haemoglobin level, platelet count, and World Health Organization Quality of Life Brief Version (WHOQOL-BREF) questionnaire scores measured on days 4, 8, 12, and 20. Secondary endpoints were onset time, duration, and recovery of grade III-IV myelosuppression, cumulative blood transfusion volumes, and adverse event rates. The results showed that PSD significantly delayed the onset of grade III-IV myelosuppression (5.63 ± 1.10 vs. 4.10 ± 1.24 days; p < 0.001) and shortened its duration (7.07 ± 1.72 vs. 9.97 ± 1.16 days; p < 0.001), while improving WHOQOL-BREF scores without increasing adverse event rates. Network pharmacology revealed that key active components target interleukin-6, tumour necrosis factor, and vascular endothelial growth factor A via the phosphoinositide 3-kinase-protein kinase B and hypoxia-inducible factor-1 signalling pathways, underpinning PSD's protective effects against myelosuppression. Overall, PSD effectively mitigates chemotherapy-induced myelosuppression and enhances patient quality of life.

Introduction

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Lung cancer ranks as the malignancy with the highest incidence and mortality rates in China. Projections suggest that by 2025, the number of patients with lung cancer in China is projected to exceed one million, positioning the nation as the global epicentre of lung cancer burden. Non-small cell lung cancer (NSCLC) constitutes 80%-85% of all lung cancer cases1, with squamous cell carcinoma of the lung accounting for 20%-30% of these instances2. In recent years, the advent of immune checkpoint inhibitors (ICIs) has significantly altered the treatment landscape for advanced squamous cell lung carcinoma, significantly altering clinical practice. The KEYNOTE-024 study was the first to reveal the potent efficacy of ICIs in advanced NSCLC with high programmed death-ligand 1 (PD-L1) expression (PD-L1 ≥50%), although only 18.4% of participants had squamous histology3. The EXPRESS II study established that among patients with advanced NSCLC in the real-world setting in China, just 21.5% of patients with advanced NSCLC exhibited PD-L1 ≥50%4.

Chemotherapy can synergise with ICIs by releasing tumour-associated antigens, remodelling the immune microenvironment, and modulating T-cell function. As a result, ICI-chemotherapy combinations are now the first-line standard for advanced squamous cell lung carcinoma. Although overall haematologic toxicity is lower with ICIs alone than with chemotherapy, myelosuppression remains a common chemotherapy-related adverse effect, disrupting bone marrow cell proliferation and maturation. In severe cases, this can lead to complications, such as infections, anaemia, and bleeding, necessitating dose reductions or impacting the treatment schedule, adversely affecting patient prognosis and even endangering lives5. Granulocyte colony-stimulating factor (G-CSF), commonly used to treat neutropenia, acts quickly but has a short duration of effect, and some patients may experience adverse reactions, such as fever, bone pain, and fatigue6. Severe anaemia or secondary thrombocytopenia necessitates the transfusion of costly and scarce blood products.

Traditional Chinese medicine (TCM) lacks a specific classification for myelosuppression; however, based on clinical manifestations, such as dizziness, fatigue, weakness in the lumbar and knees, palpitations, shortness of breath, bleeding, susceptibility to infections and fever, it can be classified under TCM syndromes such as 'blood deficiency', 'blood syndrome' or 'internal injury fever'7. Chemotherapy drugs, due to their noxious properties, tend to generate 'toxic heat', damaging organ functions and ultimately leading to bone marrow damage. The main pathological mechanisms are identified as spleen and kidney deficiency and insufficient Qi and blood8,9. Clinically, TCM treatment focuses on strengthening the spleen and kidneys and nourishing Qi and blood. As TCM's efficacy in alleviating chemotherapy-induced myelosuppression gains recognition, its role is increasingly valued. Peanut Skin Decoction (PSD), a formula derived from the hospital team's clinical experience in treating myelosuppression, contains peanut skin, Astragalus membranaceus, Herba Agrimoniae, Spatholobus suberectus, Codonopsis pilosula, Colla Corii Asini, Atractylodes macrocephala, Poria, Glycyrrhiza uralensis, Angelica sinensis, Forsythia suspensa, Psoralea corylifolia, Ligustrum lucidum, Eclipta prostrata, and Chinese dates. The peanut skin polyphenolic extract KK4-PSE, when combined with chemotherapy, can not only achieve greater tumour inhibition but also significantly mitigate hepatotoxicity induced by both cisplatin and 5-FU10, aligning with TCM theory and modern pharmacological research findings11. Ingredients such as Colla Corii Asini, peanut skin, Astragalus membranaceus, and Poria fortify the spleen, boost Qi, nourish blood, and consolidate the body's foundation, regulating immunity12. Ligustrum lucidum, Eclipta prostrata, and Chinese dates strengthen the kidney, replenish deficiency, and promote haematopoiesis. Current interventions rely on short-acting G-CSF injections and blood transfusions, which frequently cause medullary bone pain (reported in 20%-38% of patients) and may necessitate treatment delays or hospital admissions13,14. Bronze flavonoid-rich peanut skin polyphenols exhibit potent antioxidant and anti-inflammatory properties, suggesting that modified PSD may offer sustained haematopoietic support with fewer side effects and reduced healthcare burden11.

Therefore, this protocol focuses on stage IV squamous non-small cell lung carcinoma patients aged 18-75 years with Qi-blood deficiency undergoing four cycles of standard chemotherapy plus immunotherapy. Modified PSD (30 g peanut skin decocted in 500 mL water at 100 °C for 30 min, filtered through a 200-mesh sieve, administered warm in two divided doses 30 min post-meal) is assessed for its efficacy in mitigating chemotherapy-induced myelosuppression. Network pharmacology and molecular docking analyses are used to elucidate the formula's key active components and core molecular targets, providing mechanistic insight and clinical application guidance.

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Protocol

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This protocol was approved by the Ethics Committee of the First Affiliated Hospital of Hebei North University (No. W2021018) and adheres to the Declaration of Helsinki. All participants were informed and provided signed consent forms. The reagents, equipment, software, and database URLs used are listed in the Table of Materials.

1. Clinical study

  1. Study participants
    Using a convenience sampling approach, data were collected from 60 patients treated at the Traditional Chinese Medicine Oncology Department of the First Affiliated Hospital of Hebei North University between January 2021 and October 2022. These patients had completed four cycles of first-line treatment for advanced squamous cell carcinoma of the lung, consisting of sintilimab (200 mg on day 1), gemcitabine (1,000 mg/m2 on days 1 and 8), and cisplatin (75 mg/m2 on days 1 and 2). The patients were randomly divided into an observation group and a control group, with 30 patients in each group.
    The inclusion criteria were as follows: (1) Western medicine diagnosis based on the New Guidelines for the Diagnosis and Treatment of Common Malignant Tumors15, meeting the diagnostic criteria for primary lung cancer, with histological or cytological confirmation of squamous cell carcinoma of the lung, assessed as stage IV by imaging; (2) a TCM diagnosis in line with the Clinical Guiding Principles for New Traditional Chinese Medicine Drugs16, consistent with Qi and blood deficiency differentiation; (3) aged 18-75 years; (4) an estimated survival period >3 months; (5) voluntary participation in the study with signed informed consent; (6) Grade III-IV myelosuppression, defined according to the Common Terminology Criteria for Adverse Events v5.0 criteria as white blood cell (WBC) count < 2.0 × 109/L or ANC count < 1.0 × 109/L for grade III and WBC count <1.0 × 109/L or ANC <0.5 × 109/L for grade IV; and (7) last chemotherapy session completed within 3 days prior to enrolment.
    The exclusion criteria were as follows: (1) patients with mental disorders unable to cooperate with researchers or those with primary tumours at other sites; (2) allergies to any Chinese medicine ingredients used in this study; (3) uncontrollable infections or bleeding; or (4) severe cardiovascular or other organ dysfunctions.
  2. Preparation of decoction
    The ingredients of the modified PSD comprised peanut skin (30 g), Astragalus membranaceus (30 g), Herba Agrimoniae (30 g), Spatholobus suberectus (30 g), Codonopsis pilosula (24 g), Colla Corii Asini (10 g), Atractylodes macrocephala (15 g), Poria (15 g), Glycyrrhiza uralensis (10 g), Angelica sinensis (6 g), Forsythia suspensa (15 g), Psoralea corylifolia (10 g), Ligustrum lucidum (15 g), Eclipta prostrata (15 g) and Chinese dates (10 pieces).
    The preparation process began by soaking herbs in a ceramic decoction pot with 500 mL purified water for 30 min. This was heated to a rolling boil (100 °C) and maintained for 30 min, stirring every 10 min. The mixture was filtered through a 200-mesh sieve into a sterile container, and the residue was discarded.
  3. Study groups and treatment procedure
    Control group: received symptomatic supportive care. If fever was present, sensitive antibiotics were administered. If haemoglobin (Hb) was <60 g/L, suspended red blood cells were transfused. If the platelet (PLT) count was <30 × 109/L and there was a risk of spontaneous bleeding, PLT transfusions were given, continuing for 2 weeks.
    Observation group: all control-group treatments plus modified PSD (see step 1.2.1, Preparation of decoction'). The decoction was administered warm (≈40 °C) in two divided doses (250 mL each), 30 min after breakfast and dinner, with the patient seated upright. Patients were instructed to record each dose in an adherence log.
  4. Data collection
    For data collection, the following steps were followed: (1) General data: gender, age, and duration of illness; (2) Collection of post-treatment WBC count, NEU count, Hb level, and PLT count on days 4, 8, 12, and 20; (3) Documentation of the occurrence, duration, and recovery times of grade III-IV bone marrow suppression (defined by any of the following criteria: WBC count <2 × 109/L, NEU count < 1.0 × 109/L, Hb level <80 g/L, PLT count <50 × 109/L); (4) Collection of quality of life scores before treatment and at weeks 1 and 2 post-treatment. The World Health Organization Quality of Life Brief Version (WHOQOL-BREF) questionnaire was utilised to assess the quality of life scores of two groups of patients with advanced lung squamous carcinoma before and after the fourth cycle of chemotherapy combined with immunotherapy. This questionnaire comprises 26 items, 2 general items and 24 items across four domains (physical health, psychological health, social relationships, and environment), each scored on a 5-point Likert scale (total score range: 26-130). Higher scores indicate better quality of life17; (5) Collection of liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and renal function indicators (serum creatinine [CREA], Na+, K+ levels) before treatment and on day 8 post-treatment; (6) Adverse reactions during treatment, including liver function impairment (elevated ALT and/or AST), renal function impairment (elevated CREA), electrolyte disturbances (abnormal serum sodium, potassium, chloride levels) and electrocardiogram abnormalities (arrhythmias or new-onset myocardial ischaemia).
  5. Safety and waste disposal
    Adverse reactions were monitored at each visit, and decoction residues were disposed of as per hospital biohazard procedures.
  6. Statistical analysis
    All data were statistically analysed using the SPSS software. Normality testing was conducted using the Kolmogorov-Smirnov test. For measurement data conforming to a normal distribution, mean ± standard deviation was used for presentation, and independent sample t-tests were applied. Repeated measurement data were analysed using repeated measures analysis of variance (ANOVA). Enumeration data were expressed as frequency (n) or percentage (%) and analysed using the χ2 test. A two-tailed p-value of <0.05 was considered a statistically significant difference.

2. Network pharmacology

  1. Acquisition, screening, and target prediction of main active components
    The chemical components of modified PSD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and the Encyclopedia of Traditional Chinese Medicine (ETCM)18,19 database. Active components were screened based on their pharmacokinetic parameters. The two-dimensional structures and canonical SMILES of the active components were obtained from PubChem20, and potential targets were predicted using SwissTargetPrediction21. All predicted targets were validated against UniProt22.
  2. Disease target and drug-disease target prediction
    Disease targets related to 'myelosuppression' or 'bone marrow suppression' were identified via the GeneCards23 and Online Mendelian Inheritance in Man (OMIM)24databases, then validated using UniProt22. After deduplication, the disease targets related to myelosuppression/bone marrow suppression were obtained, and the intersection of these disease targets with the drug active component targets was identified as the potential therapeutic targets of modified PSD for treating bone marrow suppression.
  3. Construction of a drug component-target network
    The intersection targets of bone marrow suppression-related genes and the active components of modified PSD were analysed using the Venny 2.1 platform to identify potential therapeutic targets. The 'drug component-disease target' relationship network was visualised using Cytoscape 3.8.2 software.
  4. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis
    Potential therapeutic targets were subjected to gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Targets were imported into the DAVID database, with the species and background set to 'Homo sapiens'. The top 10 cellular components (CCs), biological processes (BPs), and molecular functions (MFs), and the top 20 key signalling pathways, ranked by p-value, were selected.
  5. Protein-protein interaction network construction
    To further elucidate the synergistic mechanisms of modified PSD targets and disease targets at the protein level, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database25 was used to predict the protein interaction relationships of core targets. Intersection target data were imported into the STRING database, setting the research species to 'Homo sapiens', the minimum required interaction score to 'highest confidence' (0.900), and discrete nodes were hidden to construct the protein-protein interaction (PPI) network diagram, identifying the core targets of modified PSD in treating bone marrow suppression.
  6. Molecular docking
    Molecular docking was performed between top-ranked drug components in the drug component-target network and top-ranked target proteins in the PPI network. Molecular structures of drug components were obtained in mol2 format from the TCMSP database, and three-dimensional molecular structures of target proteins in Protein Data Bank (PDB) format were obtained from the PDB database. The component and target gene structure files were processed using AutoDockTools and AutoDock Vina software for molecular docking.

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Results

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Clinical study section
General information
The results indicated that the observation group consisted of 30 patients, comprising 16 men and 14 women, averaging 59.10 ± 6.56 years of age; the control group also consisted of 30 patients, with 17 men and 13 women, averaging 58.97 ± 6.22 years of age. No statistically significant differences were observed between the two groups in terms of gender, age or duration of illness (p > 0.05), as shown in Table 1...

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Discussion

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In this randomised study of 60 patients with advanced-stage squamous lung carcinoma (stage IV), modified PSD demonstrated significant protective effects against severe haematological toxicity. Specifically, PSD administration prolonged the latency to grade III-IV myelosuppression onset and shortened its duration compared with standard supportive care. Concomitantly, patients receiving PSD exhibited clinically meaningful improvements in quality-of-life metrics (WHOQOL-BREF scores increased at Week 2), and elevated WBC, NE...

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Disclosures

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The authors have no conflicts of interest to declare.

Acknowledgements

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This work was supported by the Scientific Research Project of Hebei Provincial Administration of Traditional Chinese Medicine (2022423).

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
Angelica sinensisXiangxue Pharmaceutical Co., Ltd.
XSQ-AS-2021-10		-Dried, 6 g per dose
Astragalus membranaceusXiangxue Pharmaceutical Co., Ltd.
XSQ-AM-2021-02		-Dried, 30 g per dose
Atractylodes macrocephalaXiangxue Pharmaceutical Co., Ltd.
XSQ-AMa-2021-07		-Dried, 15 g per dose
AutoDock ToolsScripps Research Institutehttp://autodock.scripps.eduv1.5.6
AutoDock VinaScripps Research Institutehttp://vina.scripps.eduv1.1.2
Chinese datesXiangxue Pharmaceutical Co., Ltd.
XSQ-CZ-2021-15		-10 pieces per dose
Codonopsis pilosulaXiangxue Pharmaceutical Co., Ltd.
XSQ-CP-2021-05		-Dried, 24 g per dose
Colla Corii AsiniXiangxue Pharmaceutical Co., Ltd.
XSQ-CA-2021-06		-10 g per dose
CytoscapeCytoscape Consortiumhttps://cytoscape.orgv3.6.0
DAVIDNIAIDhttps://david.ncifcrf.gov-
Decoction apparatusCeramic pot-Capacity ≥1 L, used for herbal decoction
Eclipta prostrataXiangxue Pharmaceutical Co., Ltd.
XSQ-EP-2021-14		-Dried, 15 g per dose
ETCMTCMIPhttp://www.tcmip.cn/ETCM-
Forsythia suspensaXiangxue Pharmaceutical Co., Ltd.
XSQ-FS-2021-11		-Dried, 15 g per dose
GeneCardsWeizmann Institutehttps://www.genecards.org-
Glycyrrhiza uralensisXiangxue Pharmaceutical Co., Ltd.
XSQ-GU-2021-09		-Dried, 10 g per dose
Herba AgrimoniaeXiangxue Pharmaceutical Co., Ltd.
XSQ-HA-2021-03		-Dried, 30 g per dose
Ligustrum lucidumXiangxue Pharmaceutical Co., Ltd.
XSQ-LL-2021-13		-Dried, 15 g per dose
OMIMJohns Hopkins Universityhttps://omim.org-
PDBRCSBhttps://www.rcsb.org-
Peanut skinXiangxue Pharmaceutical Co., Ltd.
XSQ-PS-2021-01		-Dried, 30 g per dose
Platelet concentrateGeneric--
PoriaXiangxue Pharmaceutical Co., Ltd.
XSQ-P-2021-08		-Dried, 15 g per dose
Psoralea corylifoliaXiangxue Pharmaceutical Co., Ltd.
XSQ-PC-2021-12		-Dried, 10 g per dose
PubChemNCBIhttps://pubchem.ncbi.nlm.nih.gov-
Recombinant human G-CSFGeneric-5 μg/kg, subcutaneous injection
Sensitive antibioticsGeneric--
Spatholobus suberectusXiangxue Pharmaceutical Co.,
Ltd. XSQ-SS-2021-04		-Dried, 30 g per dose
SPSSIBMv26.0
STRINGELIXIRhttps://string-db.org-
Suspended red blood cellsGeneric--
Swiss Target PredictionSIBhttp://www.swisstargetprediction.ch-
TCMSPNWUhttp://lsp.nwu.edu.cn/tcmsp.php-
UniProtEMBL-EBIhttps://www.uniprot.org-
VennyBioInfoGPhttps://bioinfogp.cnb.csic.es/tools/venny/v2.1
WHOQOL-BREFWHOhttps://www.who.int/tools/whoqol-

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