Delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen: a case report
© The Author(s). 2017
Received: 6 December 2016
Accepted: 21 March 2017
Published: 11 April 2017
High-dose chemotherapy with autologous stem cell rescue is commonly used for the treatment of relapsed germ cell tumors. We report the first case of delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen.
We report a case of a 21-year-old African-American man diagnosed with relapsed non-seminomatous germ cell tumor who received high-dose chemotherapy with carboplatin and etoposide following TIGER trial arm B off-protocol. His course was complicated by muscle pain and rhabdomyolysis after cycle 4 on day +12 after infusion of autologous stem cells. To the best of our knowledge, this complication has not been reported with this regimen. A differential diagnosis of sepsis and neutropenic fever along with side effects of high-dose chemotherapy were considered, but based on the timing of events, it was concluded that the etiology of rhabdomyolysis is high-dose chemotherapy. Rhabdomyolysis was successfully treated with hydration and did not recur during subsequent cycle 5.
Delayed rhabdomyolysis after high-dose chemotherapy with paclitaxel, ifosfamide, carboplatin, and etoposide regimen has not been previously reported and needs to be considered for preventive strategy and prompt diagnosis and treatment to avoid renal complications. Physicians should have a low threshold to check creatine kinase enzymes in patients with unexplained muscle pain or renal insufficiency after high-dose chemotherapy.
KeywordsRhabdomyolysis Testicular cancer TI-CE chemotherapy Carboplatin Etoposide
Germ cell tumor (GCT) even with metastatic disease responds well to initial chemotherapy. For patients who are appropriate for chemotherapy by staging, a cisplatin-based regimen such as cisplatin, bleomycin, and etoposide (BEP) is commonly used . Around 10% of the patients relapse after first complete remission .
Comparison between paclitaxel, ifosfamide, carboplatin, and etoposide regimen and Einhorn regimen
TI = 2 cycles
Einhorn cytoreduction 1–2 cycles
Number of high-dose cycles with stem cell rescue
400 mg/m2 (D 1–3)
750 mg/m2 (D 1–3)
AUC = 8 (D 1–3)
700 mg/m2 (D 1–3)
Rhabdomyolysis is a rare complication of HDCT for testicular cancer . We present a case of early relapse metastatic testicular cancer treated with HDCT TI-CE regimen complicated by rhabdomyolysis during cycle 4. This unusual adverse side effect has not been described in the literature using this regimen. It is important to keep in mind that rhabdomyolysis can be a possible complication in patients receiving HDCT with curative intent with autologous rescue for GCT in order to prevent renal failure.
Summary of paclitaxel, ifosfamide, carboplatin, and etoposide therapy cycles given to our patient
Every 14 days
D 1: paclitaxel 250 mg/m2 IV over 24 hours
D 2–4: ifosfamide 2000 mg/m2 IV + mesna support
D 4–14: GCSF 10 mcg/kg per day
D 11–14: stem cell collection (28×106/kg CD34+ cells collected)
Every 21 days
D 1–3: carboplatin AUC = 8 IV + etoposide 400 mg/m2 IV
D 5: stem cell infusion (9.65×106/kg CD34+ cells with each cycle)
D 3–21: GCSF 10mcg/kg per day
He tolerated the first cycle of CE-based HDCT (regimen cycle 3) without much difficulty except for culture-negative neutropenic fever despite prophylactic acyclovir 800 mg by mouth twice a day, fluconazole 200 mg by mouth daily, and ciprofloxacin 500 mg by mouth twice a day. Vancomycin 1250 mg administered intravenously twice a day and cefepime 2 gm administered intravenously daily were administered empirically for neutropenic fever. His neutropenic fever resolved and he was discharged on day +12.
Finally, regimen cycle 5 was tolerated without major complications. He developed diarrhea with stool positive for Clostridium difficile and was treated with oral metronidazole 500 mg every 8 hours for 10 days. He underwent restaging 3 months after completing HDCT and had no evidence of active malignancy. He continues to do well 4 months after completion of therapy and will remain in close follow-up.
The TIGER trial is a currently ongoing phase III trial designed to compare CDT (arm A, paclitaxel, ifosfamide, and cisplatin, TIP, × 4) and HDCT (arm B using TI-CE) as initial salvage treatment in relapsed and refractory GCTs. The result of this trial is currently pending . Development of stem cell autologous rescue after HDCT has decreased mortality from 20% to 2 to 3% . Nevertheless, HDCT still has major acute and chronic regimen-related toxicities (RRT). End organ damage depends on the number of cycles, time period between cycles, and specific chemotherapy drugs used in addition to underlying comorbidities. Common side effects of HDCT include bone marrow suppression (neutropenia, thrombocytopenia, and anemia), nausea, vomiting, fatigue, mucositis, and diarrhea. HDCT can also lead to secondary solid tumors or hematologic malignancies such as leukemias . Carboplatin-based therapy is also known to cause peripheral neuropathy and hearing loss.
Rhabdomyolysis is one of the established side effects of HDCT. Rhabdomyolysis is diagnosed when CK levels are five times above the normal range with no accompanying elevation of cardiac or brain fraction. It can present with muscle pain, weakness, vomiting, and confusion. Kidney damage by myoglobin leads to acute kidney injury (AKI). Rhabdomyolysis can be caused by exercise, crush injuries, muscle ischemia, hypothermia, hyperthermia, and by use of some drugs such as statins commonly used for lipid disorders. Some chemotherapy drugs are known to cause rhabdomyolysis and they include: ifosfamide, CE , trabectedin , gemcitabine/paclitaxel , cytarabine , doxorubicin, thioguanine, vincristine , mitoxantrone/cyclophosphamide , pemetrexed , high-dose cyclophosphamide (120 mg/kg) , and 5-azacytidine.
A patient with rhabdomyolysis should have close clinical monitoring including monitoring for serum creatinine and urine output monitoring because of the risk of developing oliguric AKI. Serial CK values are required to evaluate the response to treatment. Close electrolyte monitoring is needed as patients can develop hyperkalemia (in that case cardiac monitoring might be required) and low calcium. Patients are at risk of developing complications such as compartment syndrome and disseminated intravascular coagulation. The main treatment for rhabdomyolysis is aggressive hydration administered intravenously (6 to 12 liters over 24 hours). Bicarbonate if indicated for acidosis should be used with caution in patients with low calcium and high phosphate as it can precipitate calcium phosphate deposition. In severe cases, patients may require hemodialysis.
The exact mechanism of how chemotherapy agents cause rhabdomyolysis is variable and not always clear. Ifosfamide is thought to cause heart muscle damage more than skeletal muscular damage . Rhabdomyolysis usually develops on days 1 to 3 of chemotherapy . In our patient, rhabdomyolysis developed on day 13 of regimen cycle 4. He also had sepsis during this cycle, which could have contributed to the development of rhabdomyolysis. However, no other obvious causes of rhabdomyolysis (e.g. trauma, alcohol, seizures, myositis, ischemia) were identified. Without a high index of suspicion, serum CK levels are not checked during routine care of patients during HDCT/autologous rescue. Musculoskeletal aches and pains are common during HDCT regimens as patients are routinely getting GCSF to facilitate engraftment, hence rhabdomyolysis can go unrecognized resulting in severe renal injury. Delayed rhabdomyolysis with TI-CE regimen has not been reported in the literature.
Rhabdomyolysis is a recognized side effect of high-dose chemotherapy. A newly recognized side effect of delayed rhabdomyolysis with symptoms of bilateral leg muscle pain was documented in this case with TI-CE regimen. HDCT-induced rhabdomyolysis responded to aggressive hydration administered intravenously in our case. To prevent rhabdomyolysis as a complication of HDCT and promptly address it in a timely manner on presentation, physicians should have a low threshold to check CK levels in patients with unexplained muscle pain or new onset of renal insufficiency.
Acute kidney injury
Chemotherapy regimen, including cisplatin, bleomycin, and etoposide
Carboplatin and etoposide
Central nervous system
Granulocyte-colony stimulating factor
Germ cell tumor
Human chorionic gonadotropin
Paclitaxel and ifosfamide
Chemotherapy regimen, including paclitaxel (T), ifosfamide (I) carboplatin (C), etoposide (E)
Chemotherapy regimen, including paclitaxel (T), ifosfamide (I), cisplatin (C)
Chemotherapy regimen, including platinum, etoposide and ifosfamide
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Availability of data and materials
AS reviewed the literature, wrote the description of the clinical case, discussion, and introduction, and created the figures, edited the case report, and prepared the case report for publication. OC wrote the discussion, created the figures, edited the case report, and prepared the case report for publication. WU edited the case report. AH edited the case report. FA managed the patient clinically, edited the case report, and provided the final review of the case for publication. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
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- Daugaard G. Management of poor-prognosis or relapsed germ-cell cancer. BJU Int. 2009;104(9 Pt B):1392–7. doi:10.1111/j.1464-410X.2009.08865.x.View ArticlePubMedGoogle Scholar
- Einhorn LH. Curing metastatic testicular cancer. Proc Natl Acad Sci U S A. 2002;99(7):4592–5. doi:10.1073/pnas.072067999.View ArticlePubMedPubMed CentralGoogle Scholar
- Feldman DR, Huddart R, Hall E, Beyer J, Powles T. Is high dose therapy superior to conventional dose therapy as initial treatment for relapsed germ cell tumors? The TIGER Trial. J Cancer. 2011;2:374–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM, Abonour R. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357(4):340–8. doi:10.1056/NEJMoa067749.View ArticlePubMedGoogle Scholar
- Hoshi S, Itoh A, Kato S, Suzuki K, Kawamura S, Orikasa S. Severe rhabdomyolysis as a complication of high-dose chemotherapy in a patient with advanced testicular cancer. Int J Urol. 1999;6(1):56–8.View ArticlePubMedGoogle Scholar
- Lazarus HM, Reed MD, Spitzer TR, Rabaa MS, Blumer JL. High-dose i.v. thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat Rep. 1987;71(7-8):689–95.PubMedGoogle Scholar
- Kroger N, Zander AR, Martinelli G, Ferrante P, Moraleda JM, Da Prada GA, et al. Low incidence of secondary myelodysplasia and acute myeloid leukemia after high-dose chemotherapy as adjuvant therapy for breast cancer patients: a study by the Solid Tumors Working Party of the European Group for Blood and Marrow Transplantation. Ann Oncol. 2003;14(4):554–8.View ArticlePubMedGoogle Scholar
- Skorupa A, Beldner M, Kraft A, Montero AJ. Fatal rhabdomyolysis as a complication of ET-743 (Yondelis) chemotherapy for sarcoma. Cancer Biol Ther. 2007;6(7):1015–7.View ArticlePubMedGoogle Scholar
- Vicente E, Zafra M, Garcia-Martinez E, de la Pena FA. Acute rhabdomyolysis as a complication of paclitaxel-gemcitabine chemotherapy for ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):226. doi:10.1016/j.ejogrb.2009.04.029.View ArticlePubMedGoogle Scholar
- Truica CI, Frankel SR. Acute rhabdomyolysis as a complication of cytarabine chemotherapy for acute myeloid leukemia: case report and review of literature. Am J Hematol. 2002;70(4):320–3. doi:10.1002/ajh.10152.View ArticlePubMedGoogle Scholar
- Papakonstantinou C, Papanastasiou K, Kotsopoulou M, Mouratidou M, Sotiropoulos D, Kyrtsoni MC, et al. Chemotherapy-related acute rhabdomyolysis. J Natl Cancer Inst. 1992;84(7):536–7.View ArticlePubMedGoogle Scholar
- Levy RJ, Sparano JA, Khan G. Rhabdomyolysis: an unusual complication of cytotoxic chemotherapy. Med Oncol. 1995;12(4):219–22.View ArticlePubMedGoogle Scholar
- Ceribelli A, Cecere FL, Milella M, Facciolo F, Gelibter A, Cognetti F. Severe rhabdomyolysis associated with pemetrexed-based chemotherapy. Lancet Oncol. 2006;7(4):353. doi:10.1016/S1470-2045(06)70662-3.View ArticlePubMedGoogle Scholar
- Shima E, Hino M, Yamane T, Aoyama Y, Nakamae H, Yamamura R, et al. Acute rhabdomyolysis following administration of high-dose cyclophosphamide: case report. Ann Hematol. 2002;81(1):55–6. doi:10.1007/s00277-001-0399-2.View ArticlePubMedGoogle Scholar
- Feldman DR, Sheinfeld J, Bajorin DF, Fischer P, Turkula S, Ishill N, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol. 2010;28(10):1706–13. doi:10.1200/JCO.2009.25.1561.View ArticlePubMedPubMed CentralGoogle Scholar
- Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. 2006;118(5):2119–25. doi:10.1542/peds.2006-1352.View ArticlePubMedGoogle Scholar