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.