2023 Volume 143 Issue 7 Pages 617-620
Chemotherapy-induced myositis is a severe adverse event caused by chemotherapeutic agents such as immune checkpoint inhibitors (ICIs) or cytotoxic agents. We experienced a patient with gefitinib-induced myositis with symptoms of muscle cramps and stiffness in the limbs, and reported the treatment process. A 70-year-old woman received four courses of carboplatin (CBDCA)+pemetrexed (PEM)+gefitinib (intravenous CBDCA area under the curve (AUC) 5 and PEM 500 mg/m2, every 3 weeks, and oral gefitinib 250 mg daily), for epidermal growth factor receptor (EGFR) mutation-positive stage IV lung cancer treatment; followed by seven courses of PEM+gefitinib, and continued gefitinib monotherapy thereafter. Myositis occurred 5 months after the initiation of gefitinib monotherapy. She developed strong limb cramps despite regular oral administration of 400 mg acetaminophen three times a day and complained of pain on a numeric rating scale of 10/10. Her creatine kinase (CK) was elevated from the second course of CBDCA+PEM+gefitinib but was stable at grade 1–2 thereafter. However, the muscle symptoms disappeared with CK normalization within a few days of gefitinib discontinuation due to disease progression. The Naranjo Adverse Drug Reaction Scale score was 6, suggesting a probable association. Osimertinib (an EGFR tyrosine kinase inhibitor)-induced myositis has been reported, but similar events were first observed with gefitinib in this case. Consequently, when treating with gefitinib, myositis, including the CK variation, should be monitored and appropriately managed with multidirectional treatment.
Chemotherapy-induced myositis is a severe adverse event caused by chemotherapeutic agents such as immune checkpoint inhibitors (ICIs), cytotoxic agents, molecular target agents; gemcitabine, docetaxel, sunitinib, and osimertinib.1–7) Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has been shown to significantly prolong progression-free survival (PFS) in advanced non-small cell lung cancer with EGFR mutation.8) Although it is no longer the first-choice drug, it is sometimes used as monotherapy or in combination with cytotoxic agents when osimertinib is not available.9–11) EGFR-TKI-induced myositis is uncommon, but has been reported with osimertinib treatment.5–7) We experienced a case of gefitinib-induced myositis with symptoms of muscle cramps and stiffness in limbs with elevated creatinine kinase (CK) levels and report the treatment process below.
Statement of Ethics: Written informed consent was obtained from the patient for publication of the details of the medical case and any accompanying images. Case reports were granted exemption from requiring ethics approval at the Hokkaido University Hospital.
A 70-year-old woman was diagnosed with lung adenocarcinoma (stage IVb, EGFR exon 21 L858R mutation positive, programmed death-ligand 1 (PD-L1) of 40%). The primary tumor was located in the upper lobe of the right lung, with lymph node metastasis from the right pulmonary hilum to the mediastinum, with multiple intrapulmonary and bone metastases. She received osimertinib (80 mg daily) as the first-line treatment. A partial response was confirmed a month after initiation; however, heart failure, possibly due to osimertinib, resulted in its discontinuation. Hence, carboplatin (CBDCA)+pemetrexed (PEM)+gefitinib (intravenous CBDCA area under the curve (AUC) 5 and PEM 500 mg/m2 every 3 weeks, and oral gefitinib 250 mg daily), was initiated as second-line therapy. Denosumab treatment for bone metastases was initiated after the second course of treatment. In the first course, grade 3 nausea and grade 3 neutropenia were confirmed, and a dose reduction was undertaken (CBDCA AUC 4, PEM 400 mg/m2) from the second course. After the dose reduction, both nausea and neutropenia were attenuated, and three courses of treatment were administered at these same doses. Thereafter, maintenance therapy with PEM (400 mg/m2, every 3 weeks) and gefitinib (250 mg daily) was administered. Grade 2 paronychia occurred during the fifth course, resulting in a gefitinib dosage change to once every 2 d. After the seventh course, grade 2 paronychia recurred, and treatment was discontinued. Gefitinib monotherapy (250 mg once 2 d) was resumed approximately a month later with paronychia improvement, and the symptoms were well controlled after the restart.
The patient was an ex-smoker (Brinkman index, 200) but not a drinker, with normal liver and renal function at baseline. She received 1 g of Panvitan® (multivitamin including 5 mg of folic acid) once a day, 400 mg of acetaminophen three times a day, 100 mg of tocopherol nicotinate once a day, 5 mg of atorvastatin once a day, 2 tablets of Denotas® chewable combination tablets (calcium, magnesium, and natural form of vitamin D) once a day, 1 µg of alfacalcidol once a day, and 1 g of calcium lactate three times a day, at the restart of the gefitinib monotherapy. She had started acetaminophen before osimertinib initiation for back pain due to bone metastasis. Atorvastatin was started at another hospital where dyslipidemia was diagnosed, and she had been taking it prior to the osimertinib initiation. Atorvastatin was discontinued due to elevated CK during the seventh course of PEM+gefitinib.
The patient experienced grade 2 muscle cramps and stiffness of the limbs three months after resuming gefitinib monotherapy. She reported painful muscle cramps with a numeric rating scale (NRS) 10/10 in the right hand, and that frequent muscle cramps with an NRS 5/10 in the limbs occurred twice on day 393. Initially, we considered that hypocalcemia caused by the administration of denosumab induced the muscle cramps; however, hypocalcemia was not confirmed on the day of the visit (day 393, 9.2 mg/dL). Denosumab administration was suspended on the day, just in case; however, symptoms did not improve, and she had frequent muscle cramps with pain of NRS 5/10 for three months. Four months after the withdrawal of denosumab, tumor progression was observed, and treatment with gefitinib was discontinued. Muscle cramps and stiffness of the limbs disappeared a few days after the discontinuation. The CK variation is shown in Fig. 1. CK elevation was observed from the second course of CBDCA+PEM+gefitinib, without clinical symptoms, and was generally stable at grade 1. The dose of atorvastatin was reduced to 5 mg daily because of grade 2 CK elevation on day 253. Simultaneously, gefitinib was withdrawn for 1 month because of paronychia. After reducing atorvastatin and withdrawing gefitinib, the elevated CK level was reduced to grade 1. Thereafter, atorvastatin was discontinued even though CK was not reduced further. Although no specific CK elevation was observed during the onset of muscle cramps, it was quickly normalized after gefitinib discontinuation. The Naranjo adverse drug reaction scale in this case indicated a probable association between gefitinib and myositis (Naranjo Score 6). Therefore, we considered that the symptoms of muscle cramps and stiffness of limbs with CK elevation were derived from the myositis caused by gefitinib.
The patient had taken 10 mg of atorvastatin before gefitinib initiation. CK elevated on day 47. Gefitinib was changed to once every 2 d owing to grade 2 paronychia on day 190 (half line in the Figure). Atorvastatin was reduced to 5 mg daily due to elevated CK on day 253. At the same time, gefitinib was withdrawn for 1 month due to paronychia. Atorvastatin was discontinued due to no CK improvement on day 295. The myositis occurred on day 393, and the symptoms did not improve and remained frequent with muscle cramps with pain of NRS 5/10 for three months. When gefitinib was discontinued due to disease progression, CK normalized, and myositis disappeared after a few days.
The adverse events induced by EGFR-TKIs include skin disorders (rash, dry skin, and paronychia), mucositis, interstitial pneumonia, hepatotoxicity and pancytopenia.12) Although EGFR-TKI-induced myositis is uncommon, it has recently been reported with osimertinib.5–7) We speculate that EGFR-TKI-induced myositis was missed due to the lack of reports. We report a case of gefitinib-induced myositis, and this is the first report of its symptoms.
EGFR is involved in the proliferation of various cells.13) It is also expressed in muscle stem cells and plays an important role in the proliferation of skeletal muscle cells.13,14) Therefore, it is conceivable that EGFR-TKIs cause muscle damage by inhibiting EGFR expression in muscle stem cells. The patient received atorvastatin before starting gefitinib, but CK levels were elevated 1 month after CBDCA+PEM+gefitinib initiation, and myositis with muscle cramps occurred 3 months after atorvastatin discontinuation. When gefitinib was suspended because of paronychia, CK decreased markedly but did not normalize. However, when gefitinib was discontinued owing to disease progression, CK and myositis immediately normalized within a few days, and muscle cramps disappeared. In general, statin-induced myositis improves within a few weeks after discontinuation of statins,15) and if in the case of statin associated autoimmune myopathy needs immunosuppressive treatment like steroids for its improvement.16) Although atorvastatin probably did not directly induce myositis in this case, the combination of atorvastatin and gefitinib may have affected the results. Atorvastatin is weak inhibitor of CYP3A4,17) therefore gefitinib metabolism may have been delayed, resulting in the symptom development of symptoms. A similar process was confirmed in previous reports regarding osimertinib-induced symptoms,5–7) suggesting that elevated CK may be a predictor of myositis. Shusei et al. reported a case of CK elevation without any symptoms 10 d after osimertinib initiation, with stabilization at approximately 600 U/L.5) In their case, osimertinib was suspended due to the occurrence of muscle cramps and a further increase in CK (1238 U/L) 6 months later, leading to symptom disappearance with CK reducing. Powel et al. reported a case series in two patients who developed muscle cramps 17 d and 11 months, respectively, after osimertinib initiation with CK elevation.6) The symptoms disappeared, and CK levels decreased after osimertinib withdrawal in both patients. Fionnuala et al. reported a severe case in which the patient was unable to walk without assistance due to muscle soreness and weakness 12 d after osimertinib initiation, with CK elevation to 29680 U/L and liver dysfunction.7) Osimertinib was discontinued, and pulse-dose steroids and immunoglobulins were administered to treat the symptoms. These reports indicate that myositis appears within a range of a few days to several months.5–7) In our case, myositis appeared over a year after the start of gefitinib treatment, suggesting that symptom onset may vary depending on the patient. Although CK can be a capable indicator of myositis, onset time of symptoms from CK elevation differed in each case, therefore, we should monitor both CK and muscle symptoms simultaneously. In this case, regular oral acetaminophen administration was ineffective, indicating the need for other approaches. Syakuyaku Kanzo-To, an herbal medicine, is reportedly effective for muscle cramps and is frequently used for their management in Japan,18) although it was not used in this case. Moreover, other medications, such as non-steroidal anti-inflammatory drugs, for example, tramadol, and eperizone, may be effective, considering their mechanism of action. In addition, previous reports regarding osimertinib have shown that symptoms can be controlled by reducing its dose,5,6) and we consider that dose reduction of gefitinib, such as 250 mg once 2 or 3 d, could be a treatment option in cases of difficulty in symptom management by analgesics or grade 3 or higher CK elevation. A previous study has showed lung cancer with oncogenic drivers containing EGFR mutation should be treated with targeted drugs because of improvement of overall survivals.19) Therefore, we consider that gefitinib treatment should be continued in case of symptom control by supportive cares.
In conclusion, we reported gefitinib-induced myositis with elevated CK levels. When treating with EGFR-TKIs, patients should be carefully monitored for the possibility of this occurrence and symptoms should be appropriately managed.
Tatsuhiko Sakamoto contributed to the design of the report, collected the data, and drafted the manuscript. Yoshitaka Saito, Yoh Takekuma, Eiki Kikuchi and Mitsuru Sugawara revised the manuscript. All the authors have read and approved the final manuscript.
The authors declare no conflict of interest.
