Discussion
The patient in this case had no previous history of myopathy and immune disease. Liver function, renal function, electrolyte and urine routine were normal before chemotherapy. After intravenous infusion of etoposide-nedaplatin, the patient gradually developed a general feeling of fatigue, muscle pain and dark yellow urine. Laboratory tests showed that increased serum CK, Mb, ALT, AST, LDH, BUN, Scr and UA. After excluding trauma, strenuous activity, infections, hyperthermia, and immune factors, the patient was diagnosed with severe rhabdomyolysis induced by chemotherapy. After treatment with intravenous fluids and methylprednisolone, the patient’s symptoms were relieved and laboratory tests were significantly improved. Rhabdomyolysis induced by anti-cancer therapy, especially chemotherapy, is still rarely reported.
To further characterize this rare event, we reviewed the literature of rhabdomyolysis induced by anti-tumor drugs. The relevant articles published from 1965 to July 2022 were systematically searched using PubMed. Only 42 articles related to cases of rhabdomyolysis induced by anti-tumor drugs (Table 1). These drugs including cytotoxic agents (etoposide, doxorubicin, thioguanine, vincristine, mitoxantrone, trabectedin, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, cytarabine, gemcitabine, pemetrexed, paclitaxel, vincristine, pirarubicin), monoclonal antibody agents (bevacizumab,rituximab), molecule-targeting agents (dabrafenib, trametinib, imatinib, erlotinib, pazopanib, sorafenib, bortezomib), biological response modifiers (lenalidomide,interleukin-2,Interferon alfa-2b), hormonal agents(abiraterone, prednisone), immune checkpoint inhibitors (pembrolizumab, ipilimumab, nivolumab) and others (arsenic trioxide, denosumab). Among these cases, 6 cases died, 1 case worsened, and most of them were improved after treatment. Four cases were reported to be related to etoposide, carboplatin and nivolumab. ifosfamide, cyclophosphamide, paclitaxel, pemetrexed, pembrolizumab, vincristine, abiraterone, dabrafenib were reported in 3 cases. Doxorubicin, erlotinib, cytarabine, ipilimumab, gemcitabine, trametinib, cisplatin and interleukin-2 were reported in two cases. However,there are no reports related to etoposide-nedaplatin. As far as we know, this is the first case of etoposide-nedaplatin chemotherapy induced rhabdomyolysis ever reported.
Etoposide, an inhibitor of topoisomerase-II, exerts an anti-cancer effect by inhibiting DNA repair and cell mitosis. It is widely use in treatmenting lung cancer, germ cell tumor and refractory lymphoma. The main adverse reactions of etoposide include myelosuppression, gastrointestinal symptoms, allergy, alopecia, neurotoxicity, fever, and phlebitis [45]. Nedaplatin is the second generation of platinum drugs, which is an analog of cisplatin. The anti-cancer mechanism is similar to cisplatin, which can inhibit the growth of tumor cells by binding to DNA. It was approved in Japan for use in several cancers, including SCLC [46]. It has been allowed to be used in the treatment of esophageal cancer, lung cancer, gynecological cancer, head and neck tumors in China based on the results of many clinical trials, which showed that nedaplatin has similar anti-tumor therapeutic effects with a lower toxicity than cisplatin [47-50]. The common adverse effects of nedaplatin include bone marrow suppression, gastrointestinal symptoms, kidney dysfunction, ototoxicity, and alopecia, while allergic reaction and Adams-Stokes syndrome are rare complications [51].
In the literature review of this study, cases of rhabdomyolysis related to etoposide and platinum drugs including carboplatin, cisplatin and oxaliplatin were reported, but no report related to nedaplatin was found. In 1999, Hoshi et alreported that a 38-year-old man with choriocarcinoma in the left testis suffered from unconsciousness and hallucination after receiving high-dose chemotherapy (ifosfamide, carboplatin, etoposide), and died of respiratory failure [6]. Matsuzaki et al reported that a 15-year-old woman with alveolar rhabdomyosarcoma developed severe acute rhabdomyolysis shortly after the second multi-drug chemotherapy cycle, which consisted of etoposide, ifosfamide, actinomycin-D and vincristine. After mechanical ventilation and fluid replacement, the patient’s condition slowly improved [19]. Sokolova et al reported that a 21-year-old man with relapsed non-seminomatous germ cell tumor, who received high-dose chemotherapy with carboplatin and etoposide, presented with bilateral leg pain, and finally improved after treatment [27]. Etoposide combined with platinum drugs is the first-line chemotherapy for small cell lung cancer. To the best of our knowledge, this complication has not been reported with etoposide-nedaplatin regimen.
Another unexpected situation is that although the patient has rhabdomyolysis after first cycle of chemotherapy, the lung mass is obviously reduced by the lung CT scan. One possible hypothesis is that the patient is too sensitive to etoposide or nedaplatin, which leads to the simultaneous occurrence of tumor necrosis and muscle injury. However, whether rhabdomyolysis is associated with mass reduction remains uncertain, at least there is no evidence to support it at present. Certainly, we also consider the possibility of tumor lysis syndrome. Tumor lysis syndrome is characterized by a massive cytolysis with the release of intracellular electrolytes, nucleic acids, and metabolites into the circulation, resulting in hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia and even acute renal failure. However,the presented case developed chest tightness, weakness, asthma, palpitation after Day-2 chemotherapy. Laboratory examination showed that serum UA 369.0 umol/L, calcium (Ca) 2.22 mmol/L, potassium (K) 4.01 mmol/L and phosphate (P)1.24 mmol/L were within normal levels at that time. Serum UA (302.0 umol/L), Ca (2.20 mmol/L), K (4.33 mmol/L) and P (0.90 mmol/L) were also within normal levels on the 3rd day after chemotherapy. After discharge, the patient developed a progressive generalized muscle pain and weakness. Serum CK, Mb, ALT, AST and LDH levels were significantly increased, while serum UA(341.0 umol/L), Ca (2.34 mmol/L), and K (4.31 mmol/L) were still within normal levels on this admission. Therefore, it is impossible to diagnose tumour lysis syndrome.
In conclusion, severe rhabdomyolysis can lead to acute renal failure or even death. Rhabdomyolysis induced by anti-cancer drugs, especially chemotherapy drugs, is rarely reported and easily overlooked. Here, we report the first case of etoposide-nedaplatin chemotherapy-induced severe rhabdomyolysis. It is tempting to speculate that the patient is too sensitive to etoposide or nedaplatin, which leads to the simultaneous occurrence of tumor necrosis and muscle injury. However, the cause of etoposide-nedaplatin induced severe rhabdomyolysis is still unclear and more cases need to be collected for analysis in the future. Therefore, we think that physicians should be aware of this rare but potentially serious complication when using chemotherapy drugs. The possibility of acute rhabdomyolysis should be considered when patients receiving chemotherapy who developed progressive fatigue and muscle pain. Once the diagnosis were confirmed, the medication should be discontinued immediately and treatment should be carried out, especially to maintain kidney function.