In phase I and II trials taxane chemotherapeutic agents reported side effects, including myelosuppression, peripheral edema, and fluid retention. With further use of these agents, studies in the late 1980s and early 1990s began to report peripheral neuropathy and proximal muscle weakness as common complaints, the later with unexplained pathophysiology. We report a 65-year-old Hispanic woman with estrogen receptor (ER) and progesterone receptor (PR) positive invasive ductal breast carcinoma who presented with right thigh pain and swelling eight days after her third infusion of docetaxel (a taxane chemotherapeutic) and cyclophosphamide. Laboratory findings were notable for elevation in creatine phosphokinase (CPK), aldolase, and erythrocyte sedimentation rate (ESR); a magnetic resonance imaging (MRI) of her lower extremities showed evidence of bilateral muscle edema involving the anterior compartment muscles of the thighs. A workup to rule out other causes of myositis was negative. Docetaxel was not reintroduced and the patient improved with corticosteroids. Since 2005 this is, to our knowledge, the fifth reported case of docetaxel related inflammatory myositis. Taxanes have been noted to cause disabling but transient arthralgias and myalgias; it is important to consider the possibility of inflammatory myopathy as a possible complication in patients undergoing treatment with these agents.
Taxane drugs, paclitaxel and docetaxel, are chemotherapeutic agents which work by disrupting microtubule function to inhibit cell division. Docetaxel has become a frequently used agent, known for its efficacy in solid tumors, primarily breast cancer, metastatic prostate cancer, and non-small cell lung cancer. Breast cancer is the most common cancer and the second leading cause of cancer death in American women [
A 65-year-old Hispanic female presented to our Emergency Department with one week of right thigh pain and swelling. Her past medical history includes asthma, peripheral vascular disease, coronary artery disease, seizure disorder, hypertension, and hyperlipidemia. She was diagnosed with poorly differentiated invasive ductal carcinoma, with estrogen and progesterone receptor (ER and PR) positivity and human epidermal growth receptor 2 (HER2) negative, of her right breast in July 2013. She underwent a right breast lumpectomy and was started on adjuvant chemotherapy with a plan for 4 cycles of docetaxel 75 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 3 weeks. She completed 3 cycles and had tolerated the treatment well with no notable side effects, until she presented to the ED eight days after the last infusion complaining of right thigh pain. Her medications at the time of presentation are listed in Table
Home medications.
Medication | Dose |
---|---|
Amlodipine besylate | 5 mg daily |
Aspirin | 81 mg daily |
Nebivalol | 5 mg daily |
Dexamethasone | 4 mg (2 tablets BID, only for 3 days starting 1 day before chemotherapy) |
Docusate sodium | 100 mg daily PRN |
Ferrous sulfate | 325 mg BID |
Folic acid | 1 mg daily |
Hydrochlorothiazide | 12.5 mg daily |
Hydrocodone-acetaminophen | 5–500 mg daily PRN |
Levetiracetam | 750 mg q 12 hours |
Insulin glargine | 45 units at bedtime |
Linaclotide | 145 mcg daily |
Pregabalin | 25 mg daily |
Meclizine | 12.5 mg 2 tablets daily |
Memantine HCl | 5 mg daily |
Metoclopramide | 10 mg q 6 hours PRN |
Pegfilgrastim | 6 mg once SubQ per chemotherapy cycle, beginning 24–72 hours after completion of chemotherapy |
Esomeprazole | 40 mg daily |
Insulin aspart | 12 units TIDAC |
Ondansetron | 8 mg TID for 2 days after chemotherapy |
Prasugrel | 5 mg daily |
Ranitidine | 150 mg daily |
Rosuvastatin | 10 mg daily |
Trazodone | 50 mg at bedtime |
Vitamin C | 500 mg 2 tabs. daily |
The patient had begun to develop rapidly progressive pain and swelling of her right thigh, without complaints of weakness, eight days after her third infusion of docetaxel and cyclophosphamide. On examination, she was hemodynamically stable and afebrile. Her right thigh was erythematous and tender to light touch. She had decreased active range of motion of her right hip. There were no skin lesions. Her neurological examination was unremarkable; she had neither objective muscle weakness nor sensory deficit and had normal deep tendon reflexes. There was no fasciculation or muscle wasting. Her distal pulses were palpable.
Basic laboratory values demonstrated a leukocytosis of 12 × 109/L. There were no electrolyte abnormalities. Her creatinine phosphokinase (CPK) was elevated to 341 (normal range: 30–135 U/L), her aldolase was 13.3 (normal range: ≤ 8.1 U/L), and her erythrocyte sedimentation rate (ESR) was 38 (normal range: 0–24 mm/hr). Autoantibodies including antinuclear antibody, double stranded DNA, anti-Smith, rheumatoid factor, cyclic citrullinated peptide, anti-Ro (SSA) and anti-La (SSB), ribonucleoprotein, and Scl 70 were all negative.
Initially, the unilateral thigh pain and swelling in a patient undergoing chemotherapy and on oral steroids raised suspicion for cellulitis. The patient was commenced on a 7-day treatment of IV Vancomycin and Cefepime and transitioned to oral Clindamycin and Augmentin after the first week of antibiotics. The patient’s right thigh pain did not improve while on antibiotics. An MRI of the thighs was done (Figures
Axial T2-weighted FAT SAT image illustrating diffuse muscle edema involving the lower two-thirds of the anterior compartment muscles.
Coronal T2-weighted FAT SAT showing diffuse muscle edema involving the lower two-thirds of the anterior compartment muscles. The left thigh also shows muscle edema especially along the superior aspect of the rectus femoris and inferior aspect of the posterior compartment muscles.
Upon review of her diagnostic results, recent medications, and chemotherapy treatments, it was suspected that docetaxel was the offending agent causing the myositis. Antibiotics were discontinued and the patient was commenced on prednisone 20 mg orally for 9 days and tapered down to 10 mg orally for another 5 days. The patient’s symptoms improved significantly, including the erythema, tenderness, swelling, and range of motion. Her CPK normalized the day after prednisone was initiated.
Eight months after the last docetaxel treatment the patient remains asymptomatic without evidence of recurrent myositis. After her discharge the patient was treated with 4 months of radiation therapy. The patient is currently being treated with an aromatase inhibitor.
Our case describes a patient with ER and PR + invasive ductal carcinoma presenting with unilateral thigh pain and swelling after her third cycle of docetaxel. Due to the asymmetric presentation the patient was initially treated for cellulitis without improvement. Further evaluation by MRI showed evidence of bilateral myositis, despite the unilateral symptoms. The MRI results alongside elevated CPK levels suggested acute myositis. The patient improved with a prednisone taper and symptoms did not recur after cessation of docetaxel treatment. It is important to note the rapid resolution of CPK, which is unusual for myositis. In this case, the presumed offending agent, docetaxel, had been held for almost two weeks at the point of diagnosis and an element of spontaneous resolution is to be expected.
Docetaxel is a taxane chemotherapeutic agent, which promotes the polymerization and inhibits depolymerization of microtubules causing interference of cell division. Docetaxel has been used with efficacy, usually in combination with another chemotherapeutic agent, in breast, ovarian, refractory prostate, head and neck, gastric, and non-small cell lung cancers [
While Lipton et al. were the first to report taxane induced neuropathy in 1989 [
In 2005, two reports documented cases of acute inflammatory myositis developing in patients treated with docetaxel. Ardavanis et al. described the case of a 57-year-old man treated with a combination of gemcitabine and docetaxel for non-small cell lung cancer with positive results. After his fourth cycle of treatment the patient developed a symmetric proximal muscle weakness with elevations of CPK, lactate dehydrogenase (LDH), and aldolase. EMG and MRI investigation was not pursued due to the classic clinical picture and supportive lab results. The patient was treated with methylprednisolone and had resolution of muscle symptoms and normalization of enzymes within four weeks [
Hughes and Stuart-Harris described another case of docetaxel associated myositis in a 47-year-old woman with ER and PR + metastatic breast carcinoma. The patient experienced bilateral foot pain during her first cycle of treatment, which resolved between treatment cycles, and recurred after her second cycle with spontaneous resolution. After her third cycle of treatment the patient experienced a recurrence of her bilateral pain associated with weakness of her proximal lower extremities. The weakness progressed over 10 days to the point of difficulty with ambulation and transferring. The patient was found to have a markedly elevated CPK and was started on dexamethasone. After 6 days of treatment the patient was discharged home with strength sufficient to mobilize safely. Again, in this case, the clinical features and elevated CPK were taken as sufficient evidence of myositis and EMG; MRI and muscle biopsy were not performed [
Two other cases of docetaxel induced myositis were documented in separate clinical trials in 2006. Myositis was listed as a toxic side effect without details of the specific cases or description of workup for the diagnosis. Kalmadi et al. reported results from a phase II trial using docetaxel and gemcitabine as first-line therapy for non-small cell lung cancer. Of the 49 patients who were treated with this regimen one patient was noted to require dose adjustment for myositis [
In 2014, Winkelmann et al. described a case of a 64-year-old woman who was treated with paclitaxel and carboplatin for metastatic, poorly differentiated, serous adenocarcinoma. Between her second and third treatments the patient developed diffuse muscular weakness, as well as Raynaud’s phenomenon, skin tightness, and gastroesophageal reflux. Further investigation showed an elevation of ESR, liver function tests (LFTs), and a CPK of 1523 U/L. While her serum Scl70, ANA, and anticentromere were negative, a punch biopsy showed thickened collagen bundles consistent with sclerosis. After completion of chemotherapy and treatment with methotrexate and prednisone, the patient’s sclerosis improved and CPK trended downwards; however, muscle weakness persisted. A muscle biopsy was only done at this time, which showed nonspecific inflammation. This case exhibits two rare taxane induced symptoms, sclerosis and myositis [
Other interesting cases linking polymyositis with taxane agents have been described by Sasaki et al. and Gidron et al. (see Table
Documented case reports of taxane related myopathies.
Case | Demographics | Taxane |
Cancer type | Onset of muscle pathology | Treatment | Effect |
---|---|---|---|---|---|---|
Ardavanis et al. 2005 [ |
57, male | Docetaxel, gemcitabine | NSCLC | Day 7 after 4th cycle | Prednisone | Myositis of bilateral thighs |
|
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Hughes and Stuart-Harris, 2005 [ |
47, female | Docetaxel, epirubicin, and cyclophosphamide | Breast cancer, ER/PR+, HER2− | Day 11 after 2nd cycle | Prednisone | Myositis of bilateral thighs |
|
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Gidron et al., 2006 [ |
32, female | Paclitaxel, carboplatin | Hairy cell leukemia and thymoma | Day 7 after second cycle | IV corticosteroids, IVIG | Polymyositis and myocarditis (terminal) |
|
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Fardet et al., 2006 [ |
Unknown | Docetaxel or paclitaxel, agent unknown | Kaposi sarcoma | Unknown | Unknown | Unknown |
|
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Kalmadi et al., 2006 [ |
Unknown | Docetaxel and gemcitabine | NSCLC | Unknown | Unknown | Unknown |
|
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Sasaki et al., 2012 [ |
58, male | Paclitaxel, carboplatin | B cell thymoma | Day 18 after 2nd cycle | Not reported | Polymyositis, myocarditis (terminal) |
|
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Winkelmann et al., 2014 [ |
64, female | Paclitaxel, carboplatin | Ovarian adenocarcinoma | After second cycle | Methotrexate, prednisone | Polymyositis, scleroderma, Raynaud’s and GERD |
|
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Perel-Winkler and Derk, 2014 [ |
57, male | Paclitaxel and carboplatin | NSCLC | Months | Prednisone, plaquenil, methotrexate, and IVIG | Mucinous dermatomyositis |
|
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Current case: Perel-Winkler et al. | 65, female | Docetaxel and cyclophosphamide | Breast cancer (ER/PR+, HER2−) | Day 8 after 3rd cycle | Prednisone | Bilateral proximal thigh myositis R > L |
Perel-Winkler and Derk describe another case of diffuse cutaneous mucinosis and dermatomyositis in a 57-year-old man who was treated with paclitaxel and carboplatin for non-small cell lung cancer. The patient had good response to the treatment but developed a progressive, erythematous, pruritic rash four months after completion of his treatment. No active cancer was found on full body PET-CT; muscle enzymes were normal; however, MRI showed hyperenhancement of quadriceps muscles bilaterally. The patient did not respond to steroids or methotrexate and required IVIG for symptomatic resolution [
In our case and in many of the other published cases of docetaxel and paclitaxel induced myopathic toxicity (Table
In the setting of active malignancy, dermatomyositis (DM) and polymyositis (PM) should be considered in a patient presenting with muscle weakness, pain, and evidence of inflammation. Our patient did not have any of the classic cutaneous signs of DM, such as heliotropic rash, Gottron’s papules, shawl sign, and/or erythematous plaques. Furthermore, in both DM and PM, the presentation of muscle pathology usually occurs earlier in the course of the malignancy and improves with successful treatment [
Sensorimotor polyneuropathy can occur as a paraneoplastic syndrome or as a complication of chemotherapy treatments, including taxane agents as described above. With cases associated as side effects of treatment, the provider will likely note a progressive time course to presentation of symptoms. In the case of a paraneoplastic syndrome, neuropathic symptoms more often precede detection of malignancy. Paraneoplastic neurologic symptoms have varied presentations, including motor, sensory, and autonomic changes; muscle enzymes will remain in normal range and swelling is not a common presenting complaint [
Another rare cause of muscle pain and swelling which should be considered in an immunocompromised host is pyomyositis. In this pathology, a deep muscular infection exists and signs of infection are present including fevers and leukocytosis. On imaging one may note obvious abscesses within the thigh and gluteal muscles. Bacterial pyomyositis has been reported in association with both hematologic and solid organ malignancies. There have also been reports of toxicity-related pyomyositis in the setting of taxane agents. Two such cases have been described in the setting of paclitaxel treatment for endometrial cancer. Both patients presented classically with fever, pain, and decreased range of motion, but due to the rarity of the diagnosis appropriate treatment including drainage of the abscess collection was delayed [
Diabetes can also cause both neurologic and myopathic complications. Diabetic lumbosacral radiculoplexus neuropathy (DLRPN), also known as diabetic amyotrophy, is a rare complication of diabetes causing a debilitating proximal diabetic neuropathy leading to weakness and pain of the pelvic girdle and proximal muscles of the lower extremities. DLRPN affects less than 1% of diabetic patients, and the risk of developing this disorder is unrelated to glycemic control. The first presentation of this syndrome is usually unilateral thigh pain leading to weakness and atrophy and may progress to bilateral and more distal weakness. Autonomic involvement may occur leading to bladder, bowel, and sexual disorder; sensory involvement is also reported in advanced cases. DLRPN is diagnosed by EMG and is often associated with nonspecific markers of inflammation and immune mediated disease markers such as a positive antinuclear antibody test or rheumatoid factor [
Diabetic myonecrosis must also be considered as a differential. This disorder is a rare complication of poorly controlled diabetes, usually occurring in patients with preexisting microvascular disease. Acute onset of pain and swelling of the thigh is the most common presenting complaint [
Finally, drug-induced myopathy should also be considered in all cases of unexplained myalgias and weakness. Muscle toxicity can occur in association with many drugs. The large mass of muscle and its exposure to large amounts of blood flow make muscle a common source of adverse drug reactions. Drug-induced myopathy can be the cause of direct myotoxicity, most often associated with statins, colchicine, steroids, and antiretroviral agents [
Statin induced myopathy is a spectrum of disorders ranging from myalgias (muscle pain without CPK elevation) to myositis (muscle inflammation evidenced by CPK elevation) and rhabdomyolysis (debilitating muscle weakness with CPK > 10 times the normal range, often accompanied by kidney injury). While pain and muscle weakness are reported in 1–20% of patients taking statins, myositis and rhabdomyolysis reactions are rare and have been reported in less than 0.001% cases. Reactions to statins are related to dose but not time course, and drug-drug interactions are known to significantly affect the incidence of statin induced myopathies [
In our case a docetaxel induced inflammatory myositis was the best diagnosis, in consideration of all the differentials. Diabetic myonecrosis and statin induced myopathy cannot be definitely ruled out without further investigation with muscle biopsy. We believe that, in comparing our case to another docetaxel related myositis and in consideration of the temporal relationship, it is highly likely that our patient’s myositis was related to the taxane agent. Taxanes are known to cause disabling but transient arthralgias and myalgias in up to 75% of patients; these events typically occur 1 to 3 days after therapy and may significantly affect a patient’s quality of life for several days [
Neuromuscular side effects such as myalgia and neuropathy are now considered commonly known consequences of docetaxel treatment. Our case is the fifth documented case of inflammatory myositis in the setting of docetaxel treatment. A few other cases of myositis have been reported in association with the taxane agent, paclitaxel. Due to the small sample size, correlations between lengths of treatments, types of malignancy, or patient demographics cannot be made. It is important for clinicians to be aware that inflammatory myositis can be an adverse effect of docetaxel treatment. Myositis should be considered in the differential when managing a patient with muscle weakness after treatment with a taxane agent.
The authors declare that there is no conflict of interests regarding the publication of this paper.