Oral administration of osimertinib mesylate induced multiple peripheral neuropathy of a non-small-cell lung cancer patient and treated with traditional Chinese medicine - A case report.

1
Introduction
According to GLOBOCAN 2022, lung cancer is the most commonly diagnosed malignant tumor and the leading cause of cancer related death, accounting for 12.4 % of all cancer diagnoses and 18.7 % of cancer deaths [1]. NSCLC comprises approximately 85 % of all lung cancer cases [2]. Relevant studies show that the mutation rate of EGFR genes for adenocarcinoma patients in the Asia-Pacific region is 49.2 %, and as high as 14.1 % for non-adenocarcinoma patients, which is similar with that for adenocarcinoma patients in Europe and the United States [3]. OM (Osimertinib mesylate) is a third-generation EGFR-TKI that can efficiently inhibit cells with EGFR-sensitive mutations and EGFR T790M resistance mutations. It is widely used as the first-line treatment for stage IB-IIIA postoperative, locally advanced, or metastatic NSCLC adult patients with EGFR exon 19 deletion or exon 21 (L858R) substitution mutations, as well as for locally advanced or metastatic NSCLC adult patients who have developed disease progression during or after previous EGFR-TKI treatment and have tested positive for EGFR T790M mutation [[4], [5], [6]]. Common adverse reactions induced by OM include interstitial pneumonia, hematological toxicity, hepatotoxicity, cutaneous toxicity, and gastrointestinal reactions [7]. The management principles of above common adverse effects have now been recognized and accepted [8]. After reviewing the literature, some adverse effects of OM have been reported, including diarrhea, paronychia, oral mucositis, acne-like skin rashes, and myositis; however, there is no report of OM-induced MPN [9,10]. Here we present a case involving the oral administration of OM, which induced MPN in an advanced NSCLC male patient, and the successful treatment using a TCM (Traditional Chinese Medicine) approach (i.e., dialectical Chinese herbal decoctions). The TCM prescription was selected from TCM Great Master Professor Jiaxiang Liu's ‘Jin-Fu-Kang prescription’ (金复康方) a pioneering treatment for lung cancer, and combined with the modified ‘Du-Huo-Ji-Sheng decoction’ (独活寄生汤) coming from ‘Thousand-Golden-Prescriptions’. The preliminary pharmacological researches of these two prescriptions in previous literatures confirmed their wide range of pharmacological activities in the treatment of lung cancers and inflammations [[11], [12], [13], [14]].

2
Patient information
A 70-year-old male postoperative NSCLC patient, 170 cm tall and weighing 69 kg, first visited our hospital outpatient department with the following symptoms: nearly 1 year after resection of the left lung mass, he developed persistent weakness in both lower limbs for about 3 months.
2.1
History of present illness
The patient with lung adenocarcinoma underwent a left upper lobectomy and lymph node dissection on September 29, 2020. The postoperative pathological results (B20-10519) indicated the following: 90 % invasive alveolar adenocarcinoma with 10 % micropapillary component, measuring 2.2 × 2 × 1.8 cm3, with vascular invasion, airway dissemination (STAS), and tumor invasion of the visceral pleural elastic lamina (PL1) confirmed by elastic tissue staining. Immunohistochemistry: TTF-1 (+), NapsiA (+), P40 (−), CK5/6 (−). No tumor involvement was found at the bronchial incision margin (F20-18429). Lymph node 2+/6 demonstrated tumor metastasis (1/1 in ‘Group 5 infra-aortic arch’ and 1/1 in ‘Group 6 para-aortic group’). The postoperative staging was T2aN2M0 IIIa. Second-generation sequencing revealed an in-frame deletion mutation c.2236_2250del (p.E746_A750del) in exon 19 of the EGFR gene (NM_005228.3), with an abundance of 3.25 %. The patient recovered as expected after the surgery. One month after surgery, he underwent standard regimen chemotherapy 4 cycles (pemetrexed 900 mg + carboplatin 550 mg q3w). One and a half months after completing the standard chemotherapy regimen, he was prescribed oral administration of OM (Tagrisso, AstraZeneca, UK) at 80 mg qd for targeted therapy. Only one month later, he began experiencing numbness in his hands and feet, weakness in both lower limbs, and limited mobility. In the following two months of OM treatment, his symptoms gradually worsened until he could no longer stand or walk. He immediately stopped the oral administration of OM as per his doctor's advice, but his symptoms did not improve significantly.

2.2
Past medical history
The patient was previously in good health with no history of peripheral neuropathy, hereditary peripheral neuropathy, or paraneoplastic peripheral neuropathy. He had no history of hypertension, diabetes, liver or kidney dysfunction, Guillain-Barré syndrome, and malnutrition. Additionally, he had not been treated with relevant medications, such as metronidazole, colchicine, sulfasalazine, tacrolimus, or nucleoside analogues.

2.3
Personal and family history
The patient was retired. He had no history of smoking, drinking, obesity, or exposure to toxic and harmful substances. He also had no history of engaging in prostitution or human immunodeficiency virus infection. There was no family history of diabetes or other hereditary diseases.

3
Clinical findings
The patient was in a conscious state. Dialogue and communication were normal. His pupils responded normally to light. His forehead wrinkles, nasolabial folds, and mouth corners were symmetrical. His voice was not hoarse, and he did not cough or choke when drinking water. Upon tongue examination his tongue was found centered. The muscle strength in double upper limbs was at grade V, while that in double lower limbs was at grade IV. The muscle tone was normal, and no involuntary movements were observed. All ataxia-related examinations were negative. His physiological signs were within normal limits, and no pathological signs were elicited. Meningeal stimulation signs were negative.

4
Timeline
The Table 1 presentd a timeline of the case.

5
Diagnostic assessment
5.1
Laboratory investigations
Skull-enhanced magnetic resonance imaging (MRI): A few ischemic foci in the bilateral frontal and parietal lobes.
Lumbar vertebra MRI: Degenerative changes in the lumbar spine including lumbar disc herniation at L3-4, L4-5, and L5-S1.
Emission Computed Tomography: No signs of tumor recurrence or metastasis were observed.
Electromyography: Increased insertion potential, fibrillation, and positive spikes were observed in some examined muscles. With slight contraction, the motor unit action potentials became abnormally wide or partially widened, and recruitment was reduced.
Nerve conduction velocity: The examined motor nerve conduction velocity slowed down and some nerves were accompanied with the conduction block. Some sensory nerve conduction velocities slowed down and accompanied by a reduction in the amplitude of sensory nerve action potentials, with or without a slight decrease in velocity. The latency of motor nerve F wave was prolonged or not elicited. The tibial nerve H reflex was absent.
The condition was diagnosed as MPN, as well as motor and sensory nerve myelin damage with axonal changes.

5.2
TCM diagnosis
According to the initial TCM symptoms of the patient at the first visit, including a more reddish tongue with thin white fur and a thin, weak pulse, he was diagnosed with lung cancer and leg wilting, which were attributed to Qi Yin deficiency and liver and kidney deficiency.

6
Therapeutic intervention
Since Aug. 5, 2021, the patient has been treated by TCM decoctions orally (180 mL bid) based on TCM treatment principles (invigorating Qi, nourishing Yin, and tonifying the liver and kidney) in the oncology outpatient department of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. The prescription was selected from TCM Great Master Professor Jiaxiang Liu's ‘Jin-Fu-Kang prescription’, a pioneering treatment for lung cancer, and the modified ‘Du-Huo-Ji-Sheng decoction’ coming from ‘Thousand-Golden-Prescriptions’. All ingredients in the prescription are listed in Table 1.
All ingredients in the prescription were decocted with water, and the resulting decoction was administered orally for seven days. [The TCM decoction pieces were provided by Shanghai Wanshicheng Chinese Medicine Products Co., Ltd.]
During the second visit: The patient's lower limb weakness had improved slightly compared to the previous condition. He was able to walk 5–10 m with the assistance of a walker. The numbness was almost the same as before. He occasionally experienced pain in both lower limbs. Physical examinations revealed that his tongue was more reddish with a thin, greasy coating. His pulse was faint and feeble. Therefore, Hujisheng [Visci Herba] 15 g, Luoshiteng [Trachelospermi Caulis et Folium] 30 g, Guanghuoxiang [Pogostemonis Herba] 12 g, and Peilan [Eupatorii Herba] 12 g were added to the original prescription. All ingredients in the above prescription were decocted with water, and the resulting decoction was administered orally for 14 days.
During the third visit: The weakness and numbness in the patient's both lower limbs had significantly improved. He was able to walk continuously for over 30 m with the assistance of a walker. Meanwhile the patient experienced mild diarrhea, occurring 2–3 times daily. After the examination, he had a pale-red tongue with a thin, greasy coating and a fine pulse. Therefore, Houpo [Magnoliae Officinalis Cortex] 9 g, and Cangzhu [Atractylodis Rhizoma] 9 g were added to the previous prescription. All ingredients in the above prescription were decocted with water, and the resulting decoction was administered orally for 14 days. The adjusted ingredients added to the original prescription were shown in Table 2.
After that, the patient insisted on taking the above TCM decoction with regular follow-ups. As the treatment progressed, his MPN symptoms gradually subsided, and his walking distance was incrementally increased with the aid of a walker. Eventually, he was able to walk unassisted.

7
Follow-up and outcomes
The patient has been able to walk normally in March 2025. The MPN symptoms have almost disappeared. No signs of recurrence and metastasis of lung cancer were detected in various imaging reexaminations. Based on his key assessments of electromyography reports before/after treatment (SI 1 and 2), combining with TNS table (SI Table S1), we evaluated his recovery status of peripheral nerve function [15]. As shown in Fig. 1, his TNS was decreased markedly from 21 before treatment to 8 after TCM treatment. The significant decrease of TNS confirms his good recovery of peripheral nerve function.

8
Discussion
OM is a third-generation EGFR-TKI developed by AstraZeneca Pharmaceutical Company and introduced to the market in the United States in 2015 [4]. With the increasing use of this drug in clinical treatment, its adverse reactions have gradually attracted more attention. In this case, the patient was diagnosed with lung cancer, which involves an in-frame deletion mutation in exon 19 of the EGFR gene. One and a half months after completing the standard chemotherapy regimen, he started receiving targeted therapy with OM. The dosage and administration method of OM were based on the recommendations provided in the instructions. The subsequent examinations confirmed the absence of nerve involvement, bone metastasis, and other complications. In addition, there were no additional disease factors contributing to peripheral nerve damage either. The patient received a postoperative adjuvant chemotherapy plan consisting of Pemetrexed plus Carboplatin. Among these, platinum drugs may cause nerve damage to varying degrees, primarily including peripheral neurotoxicity, hearing loss, and central neurotoxicity [16]. However, the incidence and types of nerve damage caused by various platinum drugs differ. The neurotoxicity of oxaliplatin and cisplatin is most common, but it is very rare with carboplatin at standard dosages [[17], [18], [19], [20], [21]]. After reviewing the literature, no cases of its effect on motor nerves had been reported to date [22]. In addition, the interval between the last time of carboplatin administration and the onset of symptoms for the patient exceeded 6 weeks. Therefore, the likelihood of MPN being induced by carboplatin can be ruled out in this case. In summary, the patient's MPN was diagnosed following the oral administration of OM after ruling out other diseases and drug interventions that could cause peripheral neuropathy. According to the Naranjo adverse drug reaction (ADR) evaluation scale [23], the causal relationship between OM and MPN was evaluated, yielding an ADR score of 6 points. This indicated a probable link between the patient's MPN and the oral administration of OM. Based on the evaluation criteria for common adverse events established by the National Institutes of Health, this adverse event was classified as level 3 (i.e., serious or medically important but not immediately life-threatening; resulting in hospitalization or prolonging the duration of hospitalization; causing disability and limiting self-care activities of daily life) [24]. Therefore, this case holds significant implications for clinical drug use.
Currently, most reported cases of cancer-related peripheral neuropathy are mainly induced by chemotherapy drugs, which exhibit dose-dependence and cumulative effects. Most patients experience sensory symptoms rather than motor symptoms [25]. During chemotherapy, the function of motor nerves typically remains unchanged. After discontinuing chemotherapy, the cancer-related peripheral neuropathy gradually improved over time. However, MPN induced by targeted drugs has been rarely reported. The adverse reactions listed in the package insert for OM include interstitial lung disease (3.9 %), diarrhea (49 %), stomatitis (20 %), rash (47 %), leukopenia (60 %), and QTc interval prolongation (0.9 %) [4,26]. Some hepatic and renal impairments, as well as hematological events, were reported in the literature [8,27]. Death would occur in the most severe cases [3]. To our knowledge, there are no reports about MPN caused by OM in previous literature except for one case of epilepsy induced by it. Therefore, this represents a novel adverse drug reaction. Compared with the first- and second-generation EGFR-TKIs, OM has a superior ability to penetrate the blood-brain barrier and demonstrates excellent efficacy in patients with central nervous system metastases. This was unsurprisingly confirmed by the international randomized, placebo-controlled, double-blind, phase III ADAURA trials [28]. However, it needs to be confirmed in further studies whether this feature increases the potential risk of OM-induced damage to the nervous system.
Explanation of the patient's TCM prescription (including herb functions and compatibility principles) at the first visit: Neijing (Canon of Internal Medicine) states: ‘Adequate healthy Qi within the body can prevent invasion of pathogenic factors. The areas where pathogenic factors invade are often deficient in Qi.’ Inspired by the pathogenesis principle of Zhengqi in TCM and drawing on his extensive clinical experience, TCM Great Master Professor Jiaxiang Liu first created the system of academic thoughts on ‘Fuzheng treatment of cancer’ [29]. The TCM prescription used in this case is based on the ‘Jin-Fu-Kang prescription’ [30], pioneered by Professor Liu for lung cancer treatment, and combined with the classic prescription ‘Du-Huo-Ji-Sheng decoction’ from the ‘Thousand-Golden-Prescription’ for the treatment of peripheral neuropathy. In addition, the use of TCM decoction for treating peripheral neuropathy, which caused by diabetes or some certain chemotherapeutic drugs, has been reported for a long time and there was a substantial amount of clinical research data to support their effectiveness [[31], [32], [33]].
In the ‘Jin-Fu-Kang prescription’, Beishashen [Glehniae Radix] serves as the monarch herb with sweetness and bitterness, slightly cold in nature, and its attribution to the lung and spleen meridians. It has the functions of nourishing Yin and producing fluids, moisturizing the lung and relieving coughs. Tiandong [Asparagi Radix] and Maidong [Ophiopogonis Radix] serve as the ministerial herbs, which are used to nourish Yin, enhance body fluids, moisturize the lungs, nourish the stomach and kidneys. They are paired with the monarch herb Beishashen [Glehniae Radix] to enhance the effects of invigorating Qi and nourishing Yin. Other herbs are used as adjuvant drugs, including Yinyanghuo [Epimedii Folium], Shanzhuyu [Corni Fructus], Tusizi [Cuscutae Semen], Jiaogulan [Gynostemma Pentaphyllum], Shishangbai [Selaginella Doederleinii], Shijianchuan [Salvia Chinensis], Baihuasheshecao [Hedyotis Diffusa], Shancigu [Cremastrae Pseudobulbus], Dilong [Pheretima], Jiangcan [Bombyx Batryticatus], and so on. Yinyanghuo [Epimedii Folium] is spicy, sweet, and warm in nature, and it is attributed to the liver and kidney meridians. It has the effect of reinforcing kidneys to enhance Yang and strengthen tendons and bones. ‘Compendium of Materia Medica (Great Pharmacopoeia)’ also states ‘Yinyanghuo [Epimedii Folium] is warm but not dry, and can benefit the vital spirit.’ It is added to the prescription for nourishing Qi and Yin as an adjuvant drug, which exerts its effects on warming kidney's and spleen's Yang. By combining the liver- and kidney-tonifying properties of Shanzhuyu [Corni Fructus] and Tusizi [Cuscutae Semen] with the Qi-replenishing and spleen-invigorating effects of Jiaogulan [Gynostemma Pentaphyllum], the overall efficacy can be significantly enhanced. Shishangbai [Selaginella Doederleinii], Shijianchuan [Salvia Chinensis], Baihuasheshecao [Hedyotis Diffusa], and Shancigu [Cremastrae Pseudobulbus], among others, are heat-clearing and detoxifying herbal medicines, which are selected to treat lung cancer caused by evil toxins as the pathogenic factors. Jiangcan [Bombyx Batryticatus] can dispel phlegm and dissipate nodules, while Dilong [Pheretima] can relieve cough and asthma, thereby enhancing the efficacy of the monarch and ministerial herbs in dispelling evil toxins. Combining the modified ‘Du-Huo-Ji-Sheng decoction’, whose composition is adjusted according to the patients' conditions, Duhuo [Angelicae Pubescentis Radix] and Qianghuo [Notopterygii Rhizoma et Radix] are used to relieve spasm, dispel wind, dispel cold and, remove dampness. Niuxi [Achyranthis Bidentatae Radix] is used to warm and promote the blood circulation, subsequently guiding drugs downward. Sangjisheng [Taxilli Herba] can tonify the liver and kidneys, and strengthen muscles and bones. The combined use of above four herbs can have the effect of tonifying the liver and kidneys, as well as replenishing Qi and blood. They not only enhance the body's resistance and eliminate internal evil toxins, but also prevent the external evil toxins from re-infecting the body. Finally, Jineijin [Endothelium Corneum Gigeriae Galli] was used as a messenger drug to harmonize the spleen and stomach.
Explanation of the patient's adjusted prescription of TCM at the second visit: During the second consultation, the patient showed reduced weakness in both lower limbs, though numbness improved only slightly with occasional pain. The tongue coating appeared thin and greasy. To address these symptoms, Hujisheng [Visci Herba] was added to enhance liver and kidney nourishment for alleviating numbness, while Luoshiteng [Trachelospermi Caulis et Folium] was included for pain relief. Additionally, Guanghuoxiang [Pogostemonis Herba] and Peilan [Eupatorii Herba] were incorporated to resolve dampness through their aromatic properties, helping to improve the greasy tongue coating.
Explanation of the patient's adjusted prescription of TCM at the third visit: During the third consultation, the patient's peripheral neuropathy symptoms showed significant improvement. However, mild diarrhea emerged as a new concern. To address this, Houpo [Magnoliae Officinalis Cortex] and Cangzhu [Atractylodis Rhizoma] were added to the treatment regimen to resolve dampness, strengthen the spleen, and alleviate diarrhea.
As a result, the combined use of all the above drugs can achieve the treatment of both symptoms and root causes for MPN induced by the oral administration of OM in NSCLC postoperative patients.

9
Conclusion
In summary, a rare case about oral administration of OM-induced MPN in a NSCLC patient was reported here. The patient received daily oral TCM decoction based on syndrome differentiation. One month later, his symptoms of MPN were obviously relieved with the significantly reduced TNS. He can stand and ambulate with the assistance of a walker. The use of dialectical TCM decoction is a feasible treatment protocol to alleviate and even eliminate MPN symptoms. As a treasure trove of the Chinese nation, TCM plays a crucial role in preventing tumor recurrence and metastasis, as well as alleviating side effects associated with antitumor drugs. By prioritizing the enhancement of healthy energy alongside syndrome differentiation as the treatment principle, while also emphasizing the maintenance of the healthy Qi of human body as a foundation, and dispelling evil toxins to restore the balance of Yin and Yang as the treatment method, the body's functions are comprehensively regulated to achieve improvements in symptoms, quality of life, and patient survival.

Informed consent
The patient has given the written consent for publishing his case report in the journal. He is also aware that his name and personal data will not be published and due efforts will be made to conceal the identity.

Patient perspectives
During the follow-up visit on Oct. 31, 2024, the NSCLC postoperative patient reported being satisfied with the TCM treatment for his MPN, which was induced by the oral administration of OM. After the course of our treatment, he was able to walk normally, and all the symptoms of MPN were significantly alleviated. Meanwhile, no signs of recurrence and metastasis of lung cancer were found in various imaging reexaminations. He felt better, and his quality of life improved as well. He expressed heartfelt gratitude to the doctors for giving him the best care.

Author contributions
All research done by the authors. HXG and YYL conceptualized and designed the study, drafted the initial manuscript, and obtained the patient consent form; LHG and LZM helped with the resolution of the clinical case, and reviewed the manuscript. All authors approved the final manuscript.

Declaration of generative AI in scientific writing
During the preparation of this work, the authors did not use any generative AI in scientific writing and take full responsibility for the content of the publication.

Funding sources
National Administration of Traditional Chinese Medicine (ZYYZDXK-2023063); Shanghai Clinical Research Center for Traditional Chinese Medicine Oncology (21MC1930500); Shanghai famous old Chinese Medicine academic experience research studio of Hegen Li (SHGZS-202215).

Conflict of interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yilin Yao reports financial support was provided by Shanghai famous old Chinese Medicine academic experience research studio (No. SHGZS-202215). Hegen Li reports financial support was provided by National Administration of Traditional Chinese Medicine (ZYYZDXK-2023063). Hegen Li reports financial support was provided by 10.13039/501100016983Shanghai Clinical Research Center for Traditional Chinese Medicine Oncology (No. 21MC1930500).