Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit

Gemcitabine-induced myopathy Lionel Spielmanna,n, Laurent Messer, MDb, Paul Moreau, MDb, Elodie Etienne, MDc, Carole Meyer, MDd, Jean Sibilia, MD, PhDa, Jacques-Eric Gottenberg, MD, PhDa, Bernard Geny, MD, PhDe, Béatrice Lannes, MD, PhDf, Alain Meyer, MDa,e,n a

Service de Rhumatologie, Centre de Référence des Maladies Auto-immunes Rares, Hôpitaux Universitaires, CHRU de Strasbourg, Cedex, France Service de Rhumatologie, Hôpitaux de Colmar, Colmar, France c Service de Biochimie, Hôpitaux de Colmar, Colmar, France d Service de Chirurgie Générale Digestive et Thoracique, Hôpitaux de Colmar, Colmar, France e Pôle de Pathologie Thoracique, Hôpitaux Universitaire de Strasbourg, Service de Physiologie et d'Explorations Fonctionnelles, Cedex, France f Service de Pathologie, Hôpitaux Universitaires de Strasbourg, Cedex, France b

a r t i c l e in fo

Keywords: Myopathy Vasculopathy Gemcitabine

a b s t r a c t Background: There have been few studies on muscle injury caused by cytotoxic agents used in cancer. In particular, only four cases of muscle manifestations have been reported in patients who received gemcitabine as single chemotherapy without adjuvant radiotherapy. In only one of these observations gemcitabine was considered to be the causative agent. Methods: We report the case of a patient without comorbidity treated with gemcitabine monotherapy for 2 months for pancreatic adenocarcinoma, who developed a proximal motor deficiency of the lower limbs and myolysis (creatinine kinase 1858 IU/L) associated with an erythema of both thighs. Results: Muscle MRI revealed the presence of edema on both the quadriceps muscles. A muscle biopsy showed post-necrotic regeneration and significant vascular proliferation. Only three small inflammatory infiltrates were observed, while expression of the major histocompatibility complex class I in muscle fibers was normal. There was no recurrence of cancer, anti-TIF-1γ antibodies tested negative, and discontinuation of gemcitabine, without further treatment, resulted in complete disappearance of symptoms. Conclusions: The present observation suggests that gemcitabine monotherapy without adjuvant radiotherapy can cause myopathy through vascular lesions, a mechanism which also underlies the more common side effects of this treatment. These findings have obvious therapeutic implications. & 2013 Elsevier Inc. All rights reserved.

Introduction Muscle injury caused by cytotoxic agents has been poorly studied. Nevertheless, recognition of this side effect is crucial as it has important therapeutic implications. We report the case of a patient treated with gemcitabine (a nucleoside analog) for pancreatic adenocarcinoma, who developed painful proximal muscle weakness of the lower limbs and myolysis. The characterization of this myopathy by recent diagnostic tools, particularly anti-TIF-1γ antibodies testing, magnetic resonance imaging (MRI), and muscle histology including major histocompatibility complex class I (MHC-I) and membrane attack complex (C5b-9) staining, allowed to suspect the causative involvement of gemcitabine, given the presence of an original vasculopathy within the quadriceps

n Corresponding authors at: Service de Rhumatologie, Centre de Référence des Maladies Auto-immunes Rares, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1 Ave Molière, Strasbourg 67200, France. E-mail addresses: [email protected] (L. Spielmann), alain. [email protected] (A. Meyer).

0049-0172/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.11.009

muscle. The discontinuation of gemcitabine without further treatment resulted in complete disappearance of symptoms. Case report A 69-year-old patient was admitted because of myalgia of the anterior aspect of both thighs with erythema. This patient had a history of adenocarcinoma of the pancreatic uncus (pT3N1M0), which had been treated by cephalic duodeno–pancreatectomy 6 months prior to admission. Chemotherapy with gemcitabine (1000 mg/m2/week) was ongoing, and the last infusion (2nd cycle, 3rd infusion) had been performed 1 day before the onset of symptoms. There was no other treatment aside from taking 75,000 IU of pancreatin (CREONs) per day. The patient consumed neither alcohol nor tobacco. On admission, temperature was 371C. There was an erythema of the anteromedial aspect of both the thighs. Palpation of the anterior compartments of the thighs was painful. There was evidence of motor deficiency, graded 4/5, at the level of both the quadriceps, along with difficulty in rising from a squatting

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L. Spielmann et al. / Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

Fig. 1. STIR-weighted (echo time ¼ 60 ms) (A) and gadolinium-enhanced T1-weighted (B) MRI images of the thighs showing a high signal intensity in the rectus femoris muscles and right vastus medialis muscle. These muscles also displayed abnormally low signal intensity on non-gadolinium enhanced T1 images (data not shown). STIRweighted (echo time ¼ 60 ms) (C) and gadolinium-enhanced T1-weighted (D) MRI images performed 9 weeks later showing significant improvement of these abnormalities.

position. Deep tendon reflexes were present and symmetrical. The remainder of the clinical examination was unremarkable. C-reactive protein was 13.8 mg/dL [normal (N) o 0.4] and blood count was normal. Creatinine kinase was 1858 IU/L (N ¼ 40–180). Blood cultures were sterile, while test results for HIV serology, Trichinella spiralis, and Toxocara canis were negative. Tests for Toxoplasma gondii serology, EBV, and CMV showed prior immunization. There were no antinuclear antibodies. The patient tested negative for anti-TIF-1γ antibodies (D-tek, Belgium) and for the other autoantibodies associated with inflammatory myopathies (anti-Mi2, anti-Jo-1, anti-PL-7, anti-PL12, anti-SRP, anti-PM-Scl, and anti-Ku). ANCAs were also negative. STIR-weighted and gadolinium-enhanced T1-weighted MR images of the thighs showed high signal intensity in the rectus femoris muscles and right vastus medialis muscle (Fig. 1A and B). Electromyogram did not show any myogenic signs. Muscle biopsy results of the rectus femoris muscle are described in Figure 2. The abdominopelvic scan did not reveal any recurrence of the pancreatic tumor. Chemotherapy with gemcitabine was suspended and the symptoms gradually regressed. CK levels returned to normal after 3 weeks of treatment discontinuation. Nine weeks after admission, skin erythema was no longer present, myalgia had disappeared, and muscle strength had returned to normal. The control MRI scan performed at this time showed significant improvement of the lesions (Fig. 1C and D). After 9 months of follow-up, there was no recurrence of muscle symptoms, the carcinoembryonic antigen assay was at 4.3 ng/mL (N o 5), and the thoraco–abdomino–pelvic CT scan showed no sign of tumor recurrence.

Discussion Muscle side effects with gemcitabine have been the most commonly reported in patients co-treated with radiotherapy [1–13] (Table 1). These cases were mainly characterized by muscle lesions and skin rash confined to previously irradiated areas,

corresponding to a so-called “radiation recall” [14]. However, this side effect is not specific to gemcitabine, reported reaction with other cytotoxic agents has been mostly limited to dermatitis, about two-thirds of radiation recall under gemcitabine-involved internal tissues and organs, including muscle [5]. In more rare instances, muscle toxicity has been reported with gemcitabine in association with other antimetabolites without previous radiotherapy [15–17] (Table 2). In association with docetaxel, occurrence was one out of 42 patients [17], and the myopathy was described as bilateral pain and weakness of the pelvic girdle, along with mild myolysis and peripheral edema [16]. No data on MRI or muscle biopsy were available. Under gemcitabine and fluouracile, a patient was reported having developed pain, impaired movement of the upper arms and upper leg, and swelling, along with myolysis. Vasculitis and muscle fiber necrosis were found on muscle biopsy [15]. Although in these cases, combinations make it difficult to attribute the myotoxicity to either agent, we did not find any report of myopathy with docetaxel or fluouracile as a single therapy or with an antimetabolite other than gemcitabine. To our knowledge, four cases of muscle manifestations have been described in patients who received gemcitabine as a single chemotherapy without adjuvant radiotherapy [13,18–20] (Table 3). These observations displayed striking similarities between them and resemble those reported herein: all patients had undergone pancreatic resection and the lower limbs were affected in all cases, especially the thighs [13,19,20]. Two patients exhibited a skin rash on the thighs [13,20]. MRI, available in one patient, showed T2 fatsaturation hypersignals in both thigh muscles, especially in the rectus femoris [13]. Quadriceps muscle biopsy, performed in three patients, systematically showed muscle fiber necrosis and inflammatory infiltrate. Pentsova et al. [13] also reported replacement of muscle fibers by vascular proliferation. Nonetheless, the authors' interpretation of the symptoms differed, illustrating the diagnostic difficulties of this clinical situation. Vacta et al. [19] concluded to diabetic muscular ischemia, Syrios et al. [20] to a paraneoplastic inflammatory myopathy,

L. Spielmann et al. / Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

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Fig. 2. Muscle biopsy performed on the rectus femoris muscle. Hematoxylin–eosin staining shows important variation of fiber size (A), numerous internal myonuclei (B and C), and some regenerating muscle fibers (C, arrows). Endomysial and perimysial fibrosis (A), with significant vascular proliferation (B, arrow heads), is prominent. Gomori trichrome staining shows a perimysial and focal lymphocytic infiltrate (D and n), comprised predominantly of CD4þ lymphocytes, some CD8 þ lymphocytes, and no CD20þ lymphocytes (data not shown). Two other similar foci were identified. Immunolabeling of MHC-I shows no expression of this protein by muscle fiber sarcolemma, while intense immunostaining of the vascular endothelium serves as positive control for the reaction (E). Immunolabeling of the membrane attack complex (C5b-9) demonstrates a deposit of complement across the vascular endothelium (F).

and Geffen and Horowitz [18] and Pentsova et al. [13] to gemcitabine-induced “muscle contracture” and “myositis,” respectively. In the present case, the imputability of gemcitabine in the observed muscle manifestations is significant since six of the eight attribution elements proposed by Miller at al. [21] for defining the causal relationship between an environmental exposure and a clinical syndrome were present. In particular, unlike the aforementioned cases, our observation included two important diagnostic tools: Firstly, MHC-I immunostaining was absent in muscle fibers, which is a strong argument against the diagnosis of inflammatory myopathy, including paraneoplastic dermatomyositis [22,23], despite the presence of small mononuclear infiltrates. Secondly, anti-TIF-1γ, which has a negative predictive value of 95% for the diagnosis of cancer-associated myositis [24], was not detected in our patient. Concordantly, there was no recurrence of cancer and evolution was satisfactory without introduction of new immunomodulatory agents or new chemotherapy.

Interestingly, Syrios et al. [20] and Geffen and Horowitz [18] were able to continue gemcitabine treatment with coadministration of corticosteroids, which may be a therapeutic option for physicians to be aware of. Thrombosis, endothelial wall thickening, and vascular proliferation found in muscle biopsy (13, present case) strongly indicate that the mechanism of muscle damage in gemcitabine-treated patients may involve vascular mechanisms. This is consistent with the various vascular events previously described with this drug, including thromboembolic events, thrombotic microangiopathy, digital ischemia, vasculitis, capillary leak syndrome, and liver veno–occlusive disease [25]. In vitro, gemcitabine was found to increase apoptosis of endothelial cells in a dose-dependent manner along with enhanced cell surface activity of tissue factor, a major initiator of thrombosis and angiogenesis, as well as decreased activity of tissue factor pathway inhibitor, an inhibitor of coagulation [26]. Accordingly, increased thrombin generation

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Author

Welsh et al. [1]

Sex/age Gemcitabine Co-treatment Radiotherapy Cancer/ (years) weekly dose/ dose/time frame site/dose/time surgery time frame between start of frame between between start oftreatment and end of treatment treatment and muscle and symptoms muscle symptoms symptoms M/68 NR/4 months

Ganem F/59 et al. [2] Fogarty F/65 et al. [3]

Cisplatin/ Pelvis/45 NR/4 months Gy/5 months

1000 mg/m2/3 Cisplatin/ Pelvis/33 Gy/3 months months 100 mg/m2/3 months 1000 mg/m2/6 Carboplatin/ Chest/36 Gy/4 weeks AUC 5/6 months weeks

Clinical muscle injury site/myalgia/ weakness

Cutaneous signs

CK (IU/L)

CRP (mg/Myogenic dL) signs EMG

Muscle imaging/ muscles/lesion

Muscle histology

Discontinuation of gemcitabine/ delay diagnosis discontinuation

Treatment for Evolution muscle disease/ molecule/dose

Final diagnostic

Bladder TCC/ Buttocks, cystectomy symmetric/ yes/NR

NR

NR

NR

NR

MRI/gluteal muscles/ hyper-T2

NR

Yes/at diagnosis

NSAI, prednisone/ NR/1 week

Radiation myositis

Right lung SCC/yes

Cellulomyositis NR of the right buttock Posterior neck 214 and upper back erythema

NR

NR

NR

NR

NR

NR

NR

Yes/3 week

Steroids, antibiotics/ NR/NR NSAI, dexamethasone/NR/6 weeks

NR

NR

NR

NR

No

Ibuprofen

Recovery

Radiation recall

NR

NR

MRI/gluteal muscle/ hyper-T2 MRI/chest wall musculature/ inflammatory change CT/rectus abdominus/ decreased density MRI/rectus abdominus/ hyper-gado, hyper-T2 fatsat

NR

NR

Corticosteroids

Recovery

Radiation recall

NR

NR

Radiation recall

1129

NR

NR

NR

NR

NR

Right buttock/ yes/NR

Lung SCC/No Left posterior chest wall, pectoral muscles/yes/ NR Pancreas Abdominal wall/ Abdomen ADK/No yes erythema

Jeter et al. F/52 [4]

750–1000 mg/ 5-FU/NR/ m2/9 weeks concurrent with RT

Abdomen/ 50.4 Gy/3 months

Friedlan- M/62 der et al. [5]

1000 mg/m2/2 None months

Abdomen/ 50.4 Gy/3 months

Pancreas ADK/No

Fakih [6]

1000 mg/m2/4.5 5-FU/200 months mg/m²/ concurrent with RT

Abdomen/ 50.4 Gy/5 months

Pancreas/ ADK/No

Squire F/54 et al. [7]

1000 mg/m2/2 None months

Horan M/58 et al. [8]

1000 mg/m2/3.5 None months

Left hip, left Lung ADK/NoLeft hip and No acetabulum, buttock/yes/ and left ribs/ NR 50 Gy//3 months Chest/24 Gy/5.5 Right lung Right upper No months SCC/No chest wall/yes/ NR

M/52

Abdominal wall/ Anterior and 207 yes/yes posterior radiation portals erythema and loss of hair Abdominal wall/ Epigastric NR yes/NR erythema

Improvement, gluteal muscle atrophy Recovery

Radiation myositis

Recovery, Radiation subcutaneous recall fibrosis

CT/rectus NR abdominus/ enlargement and heterogeneity MRI/left gluteal NR muscle/hyperSTIR

Yes/at diagnosis None

Recovery

No

Correlated with Radiation changes in recall prednisone dosage

CT/right pectoralis major/ thickening

Yes/at diagnosis None

Necrosis

Prednisone

Recovery

Radiation recall

L. Spielmann et al. / Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

Table 1 Characteristics of patients having presented muscle manifestations under gemcitabine and radiotherapy reported literaturea

Alco et al. F/42 [9]

1250 mg/m2/4 5-FU/NR/ months concurrent with RT

Abdomen/45 Gy/ Pancreas 4 months ADK/PS

Abdominal wall/ Abdominal wall NR yes/NR swelling

NR

NR

Left lung Left chest wall/ Left breast and NR NSCLC/No yes/NR chest wall swelling

NR

NR

Upper anterior 278 chest swelling

NR

NR

CT/pectoral muscles bilaterally/ hypodense swelling,

No

4758

NR

Yes

None

Right forearm/ yes/NR

Swelling of the right forearm

NR

NR

NR

MRI/right RF, S, Normal (1 Yes/at VM; right and week after diagnosis left VL/hypergemcitabine T2 fat-sat discontinuation) MRI/flexor NR Yes/5 weeks muscle/hyperT2 fat-sat

DexameRecovery thasone/6 mg

Radiation recall

Thighs, symmetric/ yes/yes

Torso and extremities lacy

51

5.54

Yes

MRI/thighs and NR calves muscles/ hyper-T1 fat-sat, hypergado, and hyper-T2 fat-sat

Corticosteroids Recovery (dexamethasone 4 mg per day)

Gemcitabineinduced myositis

800–1200 mg/ Carboplatin/AUC Chest/62 Gy/4 m2/3.5 5.5/3.5 months months months

M/30

NR/3 months

M/55

1000 mg/m2/6 None weeks

Eckardt et al. [12]

F/14

Pentsova et al. [13]

F/55

900 mg/m2/35 Docetaxel/ Right forearm/ Right days 100 mg/m²/35 48 Gy/40 days forearm days synovial sarcoma/ yes 80 mg/m2/4.5 Docetaxel/NR/ Abdomen/NR/2 Pancreatic months NR. weeks (after ADK/NR Capecitabine/ initiation) NR/NR

O'Regan et al. [10]

Radiation recall Wong et al. [11]

Vinorelbine and Chest/39.6 Gy/5 Hodgkin Chest doxorubicin/ months lymphoma wall/yes/ NR/3 months NR

Abdomen/NR/NRDuodenum Thighs, ADK/DPC symmetric/ yes/NR

Necrosis and

Yes/at diagnosis NSAI, steroids/ NR/1 week

Recovery

Radiation recall

Yes/at diagnosis NSAI, steroids, Improved antihistaminics, superoxide dismutase, pentoxifylline, Vitamin E, and selenium/NR/ NR inflammation Yes/at diagnosis None

Radiation recall

Yes/NR

Recovery

Recovery

Gemcitabineinduced myositis

ADK ¼ adenocarcinoma; CK ¼ creatinine kinase; CDP ¼ cephalic duodeno–pancreatectomy; CRP ¼ C-reactive protein; EMG ¼ electromyogram; Hyper-gado ¼ hypersignal on gadolinium-enhanced T1-weighted MR images; HyperSTIR ¼ hypersignal on STIR-weighted MR images; Hyper-T1 ¼ hypersignal on T1-weighted MR images; Hyper-T2 ¼ hypersignal on T2-weighted MR images; Fat-Sat ¼ fat-saturation; MRI ¼ magnetic resonance imaging; NSCLC ¼ nonsmall cell lung cancer; NR ¼ not reported; PS ¼ pancreatosplenectomy; RF ¼ rectus femoris muscle; RT ¼ radiotherapy; SM ¼ semi-membranous muscle; ST ¼ semi-tendinous muscle; TCC ¼ transitional cell carcinoma; VM ¼ vastus medialis muscle. a

Written in English.

L. Spielmann et al. / Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

F/67

MRI/ NR Abdominal muscles/ hyper-gado MRI/left pectoral NR and dorsal muscles/ hyper-gado

5

6

Table 2 Characteristics of patients having presented muscle manifestations under gemcitabine in association with other antimetabolites without previous or concurrent radiotherapy reported in the literature Author

Sex/age (years)

Kalmadi et al. [17]

Voorburg et al. [15]

Co-treatment Cancer/ surgery dose/time frame between start of treatment and muscle symptoms

42 patients, 600 mg/m2/ Docetaxel/ 22 males/ NR 36 mg/m2/ 63 years NR (range: 40–81) M/45 1000 mg/m2/2 Cisplatin/2 months months

CRP (mg/dL)

Myogenic signs EMG

MRI of the thighs Muscles/ Signal

Muscle histology

Discontinuation of gemcitabine/ delay diagnosis discontinuation

Treatment for muscle disease/ molecule/ dose

Pelvic Bilateral girdle, lower symmetric/ extremity yes/yes edema

2 times upper normal limit

10

NR

NR

NR

Yes/at diagnosis

NR

1 patient (2%)

NR

NR

NR

NR

NR

NR

MethylRecovery prednisolone/ 24 mg per day NR NR

NR

Right Swelling of 1847 quadriceps; both leg triceps and left arm brachii, symmetric/ yes/yes

NR

NR

NR

Muscle Yes/3 weeks fibers necrosis, vessel walls leukocytic infiltrate with fibrinoid necrosis, focal thrombosis.

Clinical muscle injury site/ myalgia/ weakness

Hypertension and diabetes

NSCLC/No

Right lung NSCLC/No

1100 mg/m2/ Docetaxel/ Right lung 13 weeks 100 mg/m2/ ADK/No 13 weeks

Evolution

CK (IU/L)

Comorbidities

Cutaneous signs

Peripheral edema in 2 patients (5%)

Recovery Prednisone/ 1 mg/kg per day/ 10 days colchicine/ 1.5 mg per day/ 10 days

Final diagnosis

Druginduced acute myopathy Druginduced myositis

Druginduced vasculitis

ADK ¼ adenocarcinoma; CK ¼ creatinine kinase; CDP ¼ cephalic duodeno–pancreatectomy; CRP ¼ C-reactive protein; EMG ¼ electromyogram; MRI ¼ magnetic resonance imaging; NSCLC ¼ non-small cell lung cancer; NR ¼ not reported.

L. Spielmann et al. / Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

Ardavanis M/57 et al. [16]

Gemcitabine weekly dose/time frame between start of treatment and muscle symptoms

Table 3 Characteristics of patients having presented muscle manifestations under gemcitabine monotherapy reported in English literature Author

Cancer/surgery CoClinical muscle Cutaneous CK signs (IU/L) morbidities injury site/ myalgia/ weakness

Geffen and M/46 Horowitz [18]

1000 mg/m2/1 Pancreas month ADK/CDP

Vatca et al. F/57 [19] Pentsova et al. [13]

CRP (mg/L)

Myogenic signs EMG

MRI of the thighs muscles/ signal

Muscle histology Fibers necrosis or regeneration/MHC-I expression

Vascular Mononucchange lear infiltrates immunophenotyping

Discontinuation of gemcitabine/delay diagnosis discontinuation

Immuno modulator molecule/ dose

Evolution

Edema in 440 “muscle contracture”/ the hand and feet knees and right elbow

NR

NR

NR

NR

NR

NR

At Prednisone Recovery diagnosis

1000 mg/m2/4 Cholangiocarci- Diabetes months noma/CDP

Right thigh/ yes/NR

NR

NR

NR

Yes/NR

Yes/NR

NR

NR

M/60

1000 mg/m2/3 Pancreas months ADK/CDP

Thighs, symmetric/ yes/yes

69.7

Yes

RF, ST, and Yes/NR SM/hyperT2 fat-sat, necrosis

Yes/NR

Syrios et al. [20]

M/52

58.80

Yes

NR

Yes/CD8 þ

Present case

M/69

NR 595 1000 mg/m2/6 Pancreas Diabetes, Upper and smoking lower girdles, months ADK/distal symmetric/ pancreatectyes/yes/ omy þ splenectomy 2 1000 mg/m /6 Pancreas ADK/ None Erythema 1858 Thighs, thighs weeks CDP symmetric/ yes/yes

138

No

RF and VM/ Yes/No hyper-T2 fat-sat, necrosis

DexameRecovery Thrombo- At diagnosis thasone/ sis, wall 4 mg thickening, and proliferation Recovery NR 6 months Methylprednisolone/ 16 mg per day No Recovery Prolifera- At diagnosis tion and endothelial deposit of C5b-9

NR

NR

Erythema NR right thigh Erythema 432 thighs and L hemithorax

Yes/NR

Yes/CD4 þ , CD8þ

NR

NR

Final diagnosis

Gemcitabineinduced severe extremity edema with muscle contracture Diabetic muscular ischemia Gemcitabineinduced “myositis”

Paraneoplastic inflammatory myopathy Gemcitabineinduced vascular myopathy

L. Spielmann et al. / Seminars in Arthritis and Rheumatism ] (2013) ]]]–]]]

Sex/age Gemcitabine, (years) weekly dose/ time frame between start of treatment and muscle symptoms

ADK ¼ adenocarcinoma; CK ¼ creatinine kinase; CDP ¼ cephalic duodeno–pancreatectomy; CRP ¼ C-reactive protein; EMG ¼ electromyogram; MHC ¼ major histocompatibility complex; MRI ¼ magnetic resonance imaging; NR ¼ Not reported; RF ¼ rectus femoris muscle; SM ¼ semi-membranous muscle; ST ¼ semi-tendinous muscle; VM ¼ vastus medialis muscle.

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was observed in patients treated with gemcitabine and cisplatin [27]. Interestingly, thrombin was recently found to directly promote activation of complement by cleaving C5 [28]. The demonstration of deposit of C5b-9 across the vascular endothelium in the muscle of our patient suggests that complement-induced damages of the vessels may also be involved in the muscular toxicity of gemcitabine. In conclusion, the present observation demonstrates that gemcitabine monotherapy can provoke myopathy with features suggestive of an underlying vascular mechanism. Knowledge of this side effect is important in order to avoid erroneously interpreting these events for a paraneoplastic inflammatory myopathy. References [1] Welsh JS, Torre TG, DeWeese TL, O'Reilly S. Radiation myositis. Ann Oncol 1999;10:1105–8. [2] Ganem G, Solal-Celigny P, Joffroy A, Tassy D, Delpon A, Dupuis O. Radiation myositis: the possible role of gemcitabine. Ann Oncol 2000;11:1615–6. [3] Fogarty G, Ball D, Rischin D. Radiation recall reaction following gemcitabine. Lung Cancer 2001;33:299–302. [4] Jeter MD, Jänne PA, Brooks S, Burstein HJ, Wen P, Fuchs CS, et al. Gemcitabineinduced radiation recall. Int J Radiat Oncol Biol Phys 2002;53:394–400. [5] Friedlander PA, Bansal R, Schwartz L, Wagman R, Posner J, Kemeny N. Gemcitabine-related radiation recall preferentially involves internal tissue and organs. Cancer 2004;100:1793–9. [6] Fakih MG. Gemcitabine-induced rectus abdominus radiation recall. JOP 2006;7:306–10. [7] Squire S, Chan M, Feller E, Mega A, Gold R. An unusual case of gemcitabineinduced radiation recall. Am J Clin Oncol 2006;29:636. [8] Horan G, Smith SL, Podd TJ. Gemcitabine-induced radiation necrosis of the pectoralis major muscle. Clin Oncol (R Coll Radiol) 2006;18:85. [9] Alco G, Igdem S, Dincer M, Tecimer C, Senturk R, Vural M, et al. Gemcitabine induced radiation recall myositis: report of two cases. Uhod-Uluslar Hematol 2009;19:249–53. [10] O'Regan KN, Nishino M, Armand P, Kelly PJ, DG-I Hwang, Di Salvo D. Sonographic features of pectoralis muscle necrosis secondary to gemcitabineinduced radiation recall: case report and review of current literature. J Ultrasound Med 2010;29:1499–502. [11] Wong KM, Khanna M, Wu RC, Hedley DW. Gemcitabine-induced acute myositis in a patient with duodenal cancer. Clin Oncol (R Coll Radiol) 2011;23:492–3. [12] Eckardt MA, Bean A, Selch MT, Federman N. A child with gemcitabine-induced severe radiation recall myositis resulting in a compartment syndrome. J Pediatr Hematol Oncol 2013;35:156–61.

[13] Pentsova E, Liu A, Rosenblum M, O'Reilly E, Chen X, Hormigo A. Gemcitabine induced myositis in patients with pancreatic cancer: case reports and topic review. J Neurooncol 2012;106:15–21. [14] Burris HA 3rd, Hurtig J. Radiation recall with anticancer agents. Oncologist 2010;15:1227–37. [15] Voorburg AMCJ, van Beek FT, Slee PHTJ, Seldenrijk CA, Schramel FMNH. Vasculitis due to gemcitabine. Lung Cancer 2002;36:203–5. [16] Ardavanis AS, Ioannidis GN, Rigatos GA. Acute myopathy in a patient with lung adenocarcinoma treated with gemcitabine and docetaxel. Anticancer Res 2005;25:523–5. [17] Kalmadi S, McNeill G, Davis M, Peereboom D, Adelstein D, Mekhail T. Phase II trial of weekly docetaxel and gemcitabine as first-line therapy for patients with advanced non-small cell lung cancer. Med Oncol 2006;23:507–13. [18] Geffen DB, Horowitz J. Gemcitabine-induced severe extremity edema with muscle contractures and subsequent prevention with prednisone. Isr Med Assoc J 2000;2:552–3. [19] Vatca M-A, Tejwani sheela, Yates todd. Ischemic myositis in a diabetic patient receiving chemotherapy. Community Oncol 2009;6:69–79. [20] Syrios J, Kechagias G, Xynos ID, Gamaletsou MN, Papageorgiou A, Agrogiannis G, et al. Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report. BMC Gastroenterol 2011;11:33. [21] Miller FW, Hess EV, Clauw DJ, Hertzman PA, Pincus T, Silver RM, et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum 2000;43:243–9. [22] Jain A, Sharma MC, Sarkar C, Bhatia R, Singh S, Handa R. Major histocompatibility complex class I and II detection as a diagnostic tool in idiopathic inflammatory myopathies. Arch Pathol Lab Med 2007;131:1070–6. [23] Van der Pas J, Hengstman GJD, ter Laak HJ, Borm GF, van Engelen BGM. Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies. J Neurol Neurosurg Psychiatr 2004;75:136–9. [24] Trallero-Araguás E, Rodrigo-Pendás JÁ, Selva-O'Callaghan A, Martínez-Gómez X, Bosch X, Labrador-Horrillo M, et al. Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum 2012;64:523–32. [25] Dasanu CA. Gemcitabine: vascular toxicity and prothrombotic potential. Expert Opin Drug Saf 2008;7:703–16. [26] Ma L, Francia G, Viloria-Petit A, Hicklin DJ, du Manoir J, Rak J, et al. In vitro procoagulant activity induced in endothelial cells by chemotherapy and antiangiogenic drug combinations: modulation by lower-dose chemotherapy. Cancer Res 2005;65:5365–73. [27] Kuenen BC, Levi M, Meijers JCM, van Hinsbergh VWM, Berkhof J, Kakkar AK, et al. Potential role of platelets in endothelial damage observed during treatment with cisplatin, gemcitabine, and the angiogenesis inhibitor SU5416. J Clin Oncol 2003;21:2192–8. [28] Krisinger MJ, Goebeler V, Lu Z, Meixner SC, Myles T, Pryzdial ELG, et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood 2012;120:1717–25.

Gemcitabine-induced myopathy.

There have been few studies on muscle injury caused by cytotoxic agents used in cancer. In particular, only four cases of muscle manifestations have b...
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