Rhabdomyolysis Occurred Again after Changing Chemotherapy Regimens in Ovarian Cancer: A Case Report

Rhabdomyolysis (RM) is the release of enzymes such as creatine kinase (CK), myoglobin, ions and small molecule toxic substances into the circulation after muscle destruction. The syndrome is caused by biochemical disorders and organ function impairment. The clinical manifestations are myalgia, myasthenia, dark urine, elevated CK, and severe cases may develop acute renal failure. Most cases of nontraumatic RM are due to alcohol and drugs. Other uncommon causes include infections, seizures, electrolyte imbalances (potassium, phosphorus, and magnesium depletion), and rare hereditary enzyme deficiencies [1]. The incidence of chemotherapy-induced RM is rare, but it is a syndrome that may cause death and clinical oncologists should pay more attention to it. Here, we report a case of RM in an ovarian cancer patient after chemotherapy. After the symptoms were relieved, the chemotherapy regimen was changed, and RM occurred again.

The patient was a 60-year-old woman with an elevated Ca125 in February 2023. PET-CT examination showed: bilateral adnexal soft tissue density shadow, with uneven glucose metabolism increased focus, considering the possibility of malignant tumor from the reproductive system; with extensive metastasis of peritoneal and pelvic mesangium; suspicious high metabolic focus in the right lobe envelope of liver and possible metastasis; multiple lymph node metastases occurred in the mesentery, retroperitoneum, mediastinum, bilateral internal milk region, supraclavicular bone, right supraphrenic pericardium, and bilateral iliac vessels. Puncture pathology indicated high-grade serous carcinoma. TP (albumin-paclitaxel 400 mg + carboplatin 500 mg) was administered from March 17 for 4 cycles (bevacizumab 400 mg was added to the first 2 cycles). May 22 Cancer Prevention and Control Center of Sun Yat-sen University examined CA15-3: 37.8 U/mL↑; CA125: 274.0 U/mL; Human epididymal protein 4: 12,000 pmol/L; CT was evaluated as PR. On June 15, 2023, total hysterectomy and double adnexa were performed under general anesthesia. Postoperative pathology: high-grade serous carcinoma (right external superior iliac lymph node) 3, 1/3 showed metastasis (left internal iliac lymph node) 1, showing metastasis (right upper abdominal aorta lymph node) 3, 1/3 showed metastasis (upper left abdominal aorta lymph node) 3, 1/3 showed metastasis (appendix). Under microscope: carcinoma infiltration was found in the serous layer, subserous layer and musculi propria of the appendix. Immunohistochemical: # 991141-221: CK7 (+), Pax - 8 (+), WTI (+), p53 (+90%) and p16 (diffuse+) and ER (+90%), PR (−), Napsin A (−) P504S (A+), HNF1 beta (partial weak+), Ki-67(50%+). A fifth cycle of TP (albumin-paclitaxel 400 mg + carboplatin 500 mg) was given after surgery. The patient’s CA125 was higher than before. On August 2, the treatment was replaced with Taxol 260 mg + carboplatin 500 mg + bevacizumab 400 mg. In about 1 week, the patient developed double upper limb soreness, which was not taken seriously. On August 23, CK: 7,444.5 U/L, high-sensitive troponin I (hsTnI): 47 pg/mL, myoglobin: 779.2 ng/mL, which was considered as RM. The symptoms improved after symptomatic treatment such as fluid rehydration. On October 1, CK was 135.2 U/L.

On September 6, she went to the Cancer Prevention and Control Center of Sun Yat-sen University to check CA125 (207 U/mL), which was higher than before. Gene test: TP53 gene mutation: p.S241F; tumor mutation load: 2.99 mutations/Mb (tumor mutation load-L); microsatellite instability: microsatellite stabilization type; pathogenic/suspected pathogenic germ line variation: not detected. The treatment was changed to Doxorubicin hydrochloride liposome 40 mg + bevacizumab 500 mg d1 for 3 cycles. No RM occurred, but CA125 was elevated again after 3 cycles of chemotherapy. The patient went to Hong Kong Sanatorium and Hospital and received chemotherapy on November 29: gemcitabine 1,000 mg (d1 d8) + albumin-paclitaxel 100 mg (d1 d8) + remolumab 100 mg (d1). About 1 week after chemotherapy, the patient developed pain in both upper limbs again, facial edema, and right eye strabismus. On December 18, the patient examined CK was 6,754.4 U/L, hsTnI was 22.3 pg/mL, myoglobin was 1,161.4 ng/mL, CA125 was 156 u/mL. HE4 was 132 pmol/L (lower than before). Symptoms were improved after treatment; CK was 282.2 U/L on December 28. Changes of CK in the patient are in Figure 1.

The clinical occurrence of chemotherapy-induced RM is rare. Some chemotherapy drugs known to cause RM include gemcitabine/paclitaxel [2], cytarabine, doxorubicin, vincristine [3], mitoxantrone/cyclophosphamide [4], pemetrexide [5], high-dose cyclophosphamide (120 mg/kg) [6], oxaliplatin/S1 [7]. The specific mechanism of chemotherapy-induced RM is still unclear. Truica CI and Frankel SR hypothesize that the muscle damage seen in patients treated with cytarabine could be a consequence of the uncoupling of oxidative phoshorylation triggered by the cytochrome c release, with subsequent depletion of the ATP reserves at the level of the skeletal muscle. This, in turn, would lead to a loss of integrity of the cell membrane and spillage of cell contents into the interstitial space and plasma [1]. The main treatment for transmyolysis is intravenous hydration (6–12 L in 24 h). Bicarbonate, if used for acidosis, should be used with caution in patients with low calcium and high phosphorus because it can precipitate calcium phosphate deposits. In severe cases, patients may require hemodialysis.

Can chemotherapy be repeated after chemotherapy-induced RM occurs? Will the syndrome recur after chemotherapy? This should be discussed in the context of the patient’s condition. If the patient has returned to normal since his last RM, some experts believe he may receive cytotoxic agents belonging to the same or different classes of agents without recurrence of the syndrome. Pissarra [8] reported a case of a 52-year-old man, with a resected stage III colon cancer that started postoperative adjuvant chemotherapy with capecitabine plus oxaliplatin. After the second cycle, the patient developed distal muscle pain and weakness, with a total inability to walk. Blood tests showed an elevated CK and renal injury. Severe drug-related RM was diagnosed. When the patient recovered, he completed adjuvant chemotherapy with capecitabine alone for six cycles more, with no toxicity. Chemotherapy should be treated with caution if a patient develops severe RM, which in some cases can lead to death.

In our cases, the patient received TP (albumin-paclitaxel + carboplatin) for the first 5 cycles, and after PD chemotherapy was changed to paclitaxel + carboplatin + bevacizumab. RM occurred in about 1 week after chemo, which was considered to be caused by paclitaxel. After tumor reprogression, chemotherapy was changed to Doxorubicin hydrochloride liposome 40 mg + Bevacizumab 500 mg d1 for 3 cycles, and no RM occurred. The patient’s CA125 was elevated again, and the chemotherapy regimen was changed to gemcitabine 1,000 mg (d1 d8) + albumin-paclitaxel 100 mg (d1 d8) + remolumab 100 mg (d1), and the patient developed RM again. In terms of the chemotherapy drugs used by the patient and the occurrence of the syndrome, the first occurrence of RM in the patient was considered to be caused by paclitaxel drugs, and the second occurrence was considered to be caused by gemcitabine drugs. The syndrome has previously been reported as a result of high-dose chemotherapy, but combining our case with other case reports, it should not be related to the dose of chemotherapy. In addition, RM should be associated with certain chemotherapy agents in our patient, who was treated with different chemotherapy agents and antivascular regimens, but the drugs considered to cause RM were paclitaxel and gemcitabine, and both were routine doses.

According to our case report, the occurrence of RM is mainly caused by certain specific chemotherapy drugs such as gemcitabine and paclitaxel and is not closely related to other factors such as the patient’s constitution or genetic factors. And the occurrence of RM is not caused by high-dose chemotherapy drugs as reported in previous literature, it can be caused by conventional doses of drugs. If RM occurs and is completely relieved, chemotherapy may be considered again depending on the patient’s condition and physical condition. However, caution should be exercised in selecting drugs to avoid recurrence of RM, and the condition should be closely monitored.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000542103).

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Data curation and resources: Shaocong Cao. Writing and editing: Tao Peng.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author upon reasonable request.