- Email: [email protected]
Gemcitabine-associated scleroderma-like changes of the lower extremities
Gemcitabine-associated scleroderma-like changes of the lower extremities Didier Bessis, MD,a Bernard Guillot, MD,a Eric Legouffe, MD,b and Jean-Jacques Guilhou, MDa Montpellier, France Gemcitabine is a nucleosid analog approved for use in the treatment of metastatic urothelial carcinoma of the bladder. We describe an unusual case of scleroderma-like changes of the lower extremities after treatment by gemcitabine for metastatic carcinoma of the bladder. The patient developed initial inflammatory edema (3 kg) restricted to the lower extremities and subsequent scleroderma-like changes after 2 cycles of gemcitabine. Cutaneous biopsy specimen revealed diffuse sclerosis without involvment of the fascia or muscle. Discontinuation of gemcitabine resulted in dramatic removal of the edema, softening of the skin, and partial reversibility of the fibrotic process. This is the first case report of a scleroderma-like reaction associated with gemcitabine. This antineoplastic agent must be added to the very limited number of cytostatic agents capable of giving rise to scleroderma-like features. (J Am Acad Dermatol 2004;51:S73-6.)
G
emcitabine (Gemzar; 2929-difluoro-29deoxycytidine) is a new nucleoside analog with structural similarities to cytarabine. This drug acts by inhibition of ribonucleotide reductase, of deoxycytidine monophosphate deaminase, and by intracellular activation to biphosphate and triphosphate derivatives, which are incorporated into DNA and then inhibit DNA synthesis.1,2 This antineoplastic agent has been licensed for the treatment of pancreatic and nonsmall-cell lung cancer, but also has shown significant efficacy as a single agent across a variety of others solid tumors, such as those of breast, ovarian, and bladder cancer.3-5 The recommended dose of gemcitabine is 800 to 1200 mg/m2, given intravenously weekly 3 3 weeks every 4 weeks. It is well tolerated and has a mild toxicity profile.6 Hematologic toxicity is mild and myelosuppression is rarely of clinical significance. Other
This supplement is made possible through the generous support of Stiefel Laboratories for the American Academy of Dermatology. From the Department of DermatologyePhle´bology, Centre Hospitalier et Universitaire de Montpellier, Hoˆpital Saint-Eloi,a and Department of He´matology and Medical Oncology, Centre Hospitalier et Universitaire de Montpellier, Hoˆpital Lapeyronie.b Funding sources: None. Conflicts of interests: None identified. Reprint requests: Didier Bessis, MD, Department of DermatologyePhle´bology, Centre Hospitalier et Universitaire de Montpellier, Hoˆpital Saint-Eloi, 80, avenue Augustin-Fliche, 34295 Montpellier Cedex 5, France. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2001.07.001
common reported side effects included transient and mild rise in transaminases, fever, and transient flu-like symptoms. Cutaneous reactions are well described and include mild skin rash, and rare mucositis and alopecia. Peripheral edema is reported to occur in 20.3% of patients in the absence of cardiac, hepatic, or renal failure.6 In this report, we describe, to our knowledge, the first case of scleroderma-like changes of the lower extremities, occuring in dependent areas after pronouced inflammatory edema, in a patient receiving gemcitabine therapy.
CASE REPORT A 50-year-old white man was given the diagnosis of pulmonary metastasis of a transitional cell carcinoma of the bladder. He failed to respond to radical cystectomy followed by 4 cyclic (every 4 weeks) courses of a chemotherapeutic regimen combining methotrexate, vinblastine, doxorubicin, and cisplatin. Six months later, sacroiliac bone metastases were documented. Treatment was then initiated with gemcitabine intravenous infusion at a dose of 1200 g/m2. Before initiation of therapy, renal, hepatic, cardiac, and endocrine functions were normal. Albuminemia was decreased to 18.8 g/L (normal: 37-53 g/L). Treatment including amitriptyline, clonazepam, morphine, and paracetamol remained unchanged. On day 7, the patient experienced moderate edema of the lower limbs, predominantly on the legs and the backs of the feet. No other side effect was observed. Physical examination and laboratory tests showed no evidence of renal, hepatic, or cardiac failure. On day 8, gemcitabine was given at S73
S74 Bessis et al
J AM ACAD DERMATOL AUGUST 2004
Fig 1. A and B, Diffuse bilateral and symmetric edema and purpuric red-brown discoloration of lower limbs sparing toes.
Fig 2. A and B, Diffuse brown coloration of skin corresponding to thickened and secondary sclerosis of skin.
the same dose. Two days later, edema progressed to the level of the knees, associated with a 4-kg weight gain. Concomitantly, diffuse erythema of the legs and the backs of the feet was noted, sparing the toes and the plantar face. Physical examination revealed severe bilateral and symmetric indurated edema of the lower limbs and feet. The skin in these area was purpuric with a red-brown discoloration (Fig 1), warm, and painful to touch. No synovitis, tender friction rubs, telangiectasia, calcific deposits, or other signs of systemic scleroderma were noted. The leukocyte count was 4.7 3 103, hemoglobin was 10.5 g/dL, and the platelet count was 56.103. Serum chemistries and creatinine phosphokinase were normal. Albuminemia remained unchanged. A 4-mm
punch biopsy specimen of the right leg showed moderate perivascular lymphocytic infiltrate of the papillary dermis and marked lipoatrophy of the hypodermis. Ultrasonographic and Doppler studies of the leg vessels excluded venous thrombosis. Gemcitabine was discontinued and, empirically, antibiotic therapy (oral pristinamycin, 2 g/d) was institued. No skin changes were observed 2 weeks later and the antibiotic was stopped. Within the next 3 weeks, dramatic improvement of the edema was noted with a decrease of pain and erythema but persistance of induration and the development of a progressive cutaneous sclerosis and hyperpigmentation of the lower aspects of the legs (Fig 2). Moderate flexion and extension restrictions were
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
Bessis et al S75
Fig 3. A, Biopsy specimen from left leg revealed sclerosis of dermal collagen and fibrous septae of subcutaneous fat with moderate perivascular lymphocytic infiltrate of dermis and hypodermis. B, Close-up view of sclerosis. (A and B, Hematoxylin-eosin stain; original magnifications: A, 34; B, 325.)
found bilaterally in the ankles. Incisional, full-thickness, skin-to-muscle biopsy specimen from the left leg revealed diffuse sclerosis of the dermal collagen and fibrous septae of the subcutaneous fat (Fig 3). Moderate perivascular lymphocytic infiltrate of the dermis and hypodermis was also noted. No histologic abnormality of the fascia or muscle was observed. Antinuclear antibody, extractable nuclear antigen, antitopoisomerase, anticentromere, and anticardiolipin antibodies were absent. Nailfold capillaroscopy was normal. Magnetic resonance imaging of the lower limbs confirmed nonspecific thickening of the subcutaneous fat and fasciae without muscle involvment. Although no new treatment was institued, softening of the cutaneous tissues was progressively noted the next month. The patient died of progressive pulmonary and bone metastasis 1 month later. No postmortem examination was performed.
DISCUSSION To our knowledge, this is the first report of a scleroderma-like condition related to gemcitabine therapy. Differential diagnosis with idiopathic or paraneoplastic systemic sclerosis, Shulman fasciitis, or other primary condition of scleroderma could be ruled out by the absence of visceral involvment, eosinophilia, and autoantibodies (particularly anti-
centromere or antitopoisomerase). Arguments that support a direct correlation between the skin changes and a potential drug toxicity induced by gemcitabine include (1) rapid development after the onset of the treatment; and (2) rapid reversibility, although partial, of the fibrotic process after early discontinuation of the drug. Gemcitabine has been reported associated with a limited number of cutaneous reactions (24.8%): rash (20.3%); alopecia (14.1%); mucositis (8.4%); urticaria; generalized desquamation; and pruritus including pruritus ani.6,7 These side effects are usually mild and transient, rarely resulting in adjustment of the dose or early discontinuation of the drug. Peripheral edema is a frequent side effect, reported in 20.3% of patients treated with gemcitabine.6 However, the edema is mild or moderate, reversible after stopping treatment, and rarely results in discontinuation of the medication (0.6%). In absence of cardiac, hepatic, or renal failure, the mechanism of this toxicity remains unknown. Prevention with prednisone has recently been noted in one case.8 Erysipeloid rash confined to areas of pre-existing lymphedema have recently been described during gemcitabine therapy. This skin reaction was timeand dose-limited, repeatedly observed on the same body areas 40 to 48 hours after intravenous administration and fading slowly after 14 days without
S76 Bessis et al
specific treatment. No scleroderma-like changes were noted, but no histology of the skin lesion was mentioned.9 Various scleroderma-like conditions induced by chemotherapeutic drugs have been reported.10 Progressive systemic scleroderma-like presentation including sclerodactyly with swelling; induration of the hands and forearms; tightening and thickening of the skin of hands, forearms, arms, thighs, legs, and feet; hyperpigmentation; and inconstant Raynaud phenomenom have been repeatedly reported with bleomycin11 and more recently with uraciltegafur.12,13 In the cases of bleomycin-induced scleroderma, the skin lesions were clearly dosedependant, and resolved or improved several weeks or months after discontinuation of the drug. Rare observations of scleroderma induced by bleomycin and limited to areas of skin previously treated by radiotherapy have been reported.14 To date, 4 observations of scleroderma changes of the lower limbs have been reported, exclusively induced by docetaxel.15,16 In one case, the scleroderma changes extended to the lower aspect of the trunk and the distal upper extremities.16 The clinical presentation was very similar to our observation with 3 phases of skin involvement: (1) an initial inflammatory and indurated edematous phase of the lower limbs followed by; (2) scleroderma changes and pigmentation of the skin; and (3) a softening phase. Although the exact pathophysiologic mechanism is unknown, the exclusive and circumscribed localization of the scleroderma-like changes in dependant areas suggest a locoregional toxicity by an accumulation of the drug or its metabolites in the subcutaneous tissue. We believe that gemcitabine should be added to the list of drugs inducing scleroderma.
J AM ACAD DERMATOL AUGUST 2004
REFERENCES 1. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumor activity of gemcitabine. Cancer Res 1990;50:4417-22. 2. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of gemcitabine on DNA synthesis. Cancer Res 1991;51:6110-7. 3. Carmichael J. The role of gemcitabine in the treatment of other tumours. Br J Cancer 1998;78:21-5. 4. Moore MJ, Tannock IF, Ernst DS, Huan S, Murray N. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 1977;15:3441-5. 5. Sternberg CN. Gemcitabine in bladder cancer. Semin Oncol 2000;27:31-9. 6. Aapro MS, Martin C, Hatty S. Gemcitabineea safety review. Anticancer Drugs 1998;9:191-201. 7. Hejna M, Valencak J, Raderer M. Anal pruritus after cancer chemotherapy with gemcitabine. N Engl J Med 1999;340: 655-6. 8. Geffen D, Horowitz J. Gemcitabine-induced severe extremity edema with muscle contractures and subsequent prevention with prednisone. Isr Med Assoc J 2000;2:552-3. 9. Brandes A, Reichmann U, Plasswilm L, Bamberg M. Timeand dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabineea report of three cases. Anticancer Drugs 2000;11:15-7. 10. Haustein UF, Haupt B. Drug-induced scleroderma and sclerodermiform conditions. Clin Dermatol 1998;16:353-66. 11. Kerr LD, Spiera H. Scleroderma in association with the use of bleomycin: a report of 3 cases. J Rheumatol 1992;19:294-6. 12. Kono T, Ishii M, Negoro N, Taniguchi S. Scleroderma-like reaction induced by uracil-tegafur (UFT), a second-generation anticancer agent. J Am Acad Dermatol 2000;42:519-20. 13. Sheishima M, Izumi T, Kanoh H. Raynaud’s phenomenon possibly induced by a compound drug of tegafur and uracil. Eur J Dermatol 1999;9:55-8. 14. Marck Y, Meunier L, Barne´on G, Meynadier J. Scleroderma of the shoulders after treatment with combined bleomycin and radiotherapy. Ann Dermatol Venereol 1994;121:712-4. 15. Battafarano DF, Zimmerman GC, Older SAZ, Keeling JH, Burris HA. Docetaxel (Taxotere) associated scleroderma-like changes of the lower extremities. Cancer 1995;76:110-5. 16. Cleveland MG, Ajaikumar BS, Reganti R. Cutaneous fibrosis induced by docetaxel: a case report. Cancer 2000;88:1078-81.
G
emcitabine (Gemzar; 2929-difluoro-29deoxycytidine) is a new nucleoside analog with structural similarities to cytarabine. This drug acts by inhibition of ribonucleotide reductase, of deoxycytidine monophosphate deaminase, and by intracellular activation to biphosphate and triphosphate derivatives, which are incorporated into DNA and then inhibit DNA synthesis.1,2 This antineoplastic agent has been licensed for the treatment of pancreatic and nonsmall-cell lung cancer, but also has shown significant efficacy as a single agent across a variety of others solid tumors, such as those of breast, ovarian, and bladder cancer.3-5 The recommended dose of gemcitabine is 800 to 1200 mg/m2, given intravenously weekly 3 3 weeks every 4 weeks. It is well tolerated and has a mild toxicity profile.6 Hematologic toxicity is mild and myelosuppression is rarely of clinical significance. Other
This supplement is made possible through the generous support of Stiefel Laboratories for the American Academy of Dermatology. From the Department of DermatologyePhle´bology, Centre Hospitalier et Universitaire de Montpellier, Hoˆpital Saint-Eloi,a and Department of He´matology and Medical Oncology, Centre Hospitalier et Universitaire de Montpellier, Hoˆpital Lapeyronie.b Funding sources: None. Conflicts of interests: None identified. Reprint requests: Didier Bessis, MD, Department of DermatologyePhle´bology, Centre Hospitalier et Universitaire de Montpellier, Hoˆpital Saint-Eloi, 80, avenue Augustin-Fliche, 34295 Montpellier Cedex 5, France. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2001.07.001
common reported side effects included transient and mild rise in transaminases, fever, and transient flu-like symptoms. Cutaneous reactions are well described and include mild skin rash, and rare mucositis and alopecia. Peripheral edema is reported to occur in 20.3% of patients in the absence of cardiac, hepatic, or renal failure.6 In this report, we describe, to our knowledge, the first case of scleroderma-like changes of the lower extremities, occuring in dependent areas after pronouced inflammatory edema, in a patient receiving gemcitabine therapy.
CASE REPORT A 50-year-old white man was given the diagnosis of pulmonary metastasis of a transitional cell carcinoma of the bladder. He failed to respond to radical cystectomy followed by 4 cyclic (every 4 weeks) courses of a chemotherapeutic regimen combining methotrexate, vinblastine, doxorubicin, and cisplatin. Six months later, sacroiliac bone metastases were documented. Treatment was then initiated with gemcitabine intravenous infusion at a dose of 1200 g/m2. Before initiation of therapy, renal, hepatic, cardiac, and endocrine functions were normal. Albuminemia was decreased to 18.8 g/L (normal: 37-53 g/L). Treatment including amitriptyline, clonazepam, morphine, and paracetamol remained unchanged. On day 7, the patient experienced moderate edema of the lower limbs, predominantly on the legs and the backs of the feet. No other side effect was observed. Physical examination and laboratory tests showed no evidence of renal, hepatic, or cardiac failure. On day 8, gemcitabine was given at S73
S74 Bessis et al
J AM ACAD DERMATOL AUGUST 2004
Fig 1. A and B, Diffuse bilateral and symmetric edema and purpuric red-brown discoloration of lower limbs sparing toes.
Fig 2. A and B, Diffuse brown coloration of skin corresponding to thickened and secondary sclerosis of skin.
the same dose. Two days later, edema progressed to the level of the knees, associated with a 4-kg weight gain. Concomitantly, diffuse erythema of the legs and the backs of the feet was noted, sparing the toes and the plantar face. Physical examination revealed severe bilateral and symmetric indurated edema of the lower limbs and feet. The skin in these area was purpuric with a red-brown discoloration (Fig 1), warm, and painful to touch. No synovitis, tender friction rubs, telangiectasia, calcific deposits, or other signs of systemic scleroderma were noted. The leukocyte count was 4.7 3 103, hemoglobin was 10.5 g/dL, and the platelet count was 56.103. Serum chemistries and creatinine phosphokinase were normal. Albuminemia remained unchanged. A 4-mm
punch biopsy specimen of the right leg showed moderate perivascular lymphocytic infiltrate of the papillary dermis and marked lipoatrophy of the hypodermis. Ultrasonographic and Doppler studies of the leg vessels excluded venous thrombosis. Gemcitabine was discontinued and, empirically, antibiotic therapy (oral pristinamycin, 2 g/d) was institued. No skin changes were observed 2 weeks later and the antibiotic was stopped. Within the next 3 weeks, dramatic improvement of the edema was noted with a decrease of pain and erythema but persistance of induration and the development of a progressive cutaneous sclerosis and hyperpigmentation of the lower aspects of the legs (Fig 2). Moderate flexion and extension restrictions were
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
Bessis et al S75
Fig 3. A, Biopsy specimen from left leg revealed sclerosis of dermal collagen and fibrous septae of subcutaneous fat with moderate perivascular lymphocytic infiltrate of dermis and hypodermis. B, Close-up view of sclerosis. (A and B, Hematoxylin-eosin stain; original magnifications: A, 34; B, 325.)
found bilaterally in the ankles. Incisional, full-thickness, skin-to-muscle biopsy specimen from the left leg revealed diffuse sclerosis of the dermal collagen and fibrous septae of the subcutaneous fat (Fig 3). Moderate perivascular lymphocytic infiltrate of the dermis and hypodermis was also noted. No histologic abnormality of the fascia or muscle was observed. Antinuclear antibody, extractable nuclear antigen, antitopoisomerase, anticentromere, and anticardiolipin antibodies were absent. Nailfold capillaroscopy was normal. Magnetic resonance imaging of the lower limbs confirmed nonspecific thickening of the subcutaneous fat and fasciae without muscle involvment. Although no new treatment was institued, softening of the cutaneous tissues was progressively noted the next month. The patient died of progressive pulmonary and bone metastasis 1 month later. No postmortem examination was performed.
DISCUSSION To our knowledge, this is the first report of a scleroderma-like condition related to gemcitabine therapy. Differential diagnosis with idiopathic or paraneoplastic systemic sclerosis, Shulman fasciitis, or other primary condition of scleroderma could be ruled out by the absence of visceral involvment, eosinophilia, and autoantibodies (particularly anti-
centromere or antitopoisomerase). Arguments that support a direct correlation between the skin changes and a potential drug toxicity induced by gemcitabine include (1) rapid development after the onset of the treatment; and (2) rapid reversibility, although partial, of the fibrotic process after early discontinuation of the drug. Gemcitabine has been reported associated with a limited number of cutaneous reactions (24.8%): rash (20.3%); alopecia (14.1%); mucositis (8.4%); urticaria; generalized desquamation; and pruritus including pruritus ani.6,7 These side effects are usually mild and transient, rarely resulting in adjustment of the dose or early discontinuation of the drug. Peripheral edema is a frequent side effect, reported in 20.3% of patients treated with gemcitabine.6 However, the edema is mild or moderate, reversible after stopping treatment, and rarely results in discontinuation of the medication (0.6%). In absence of cardiac, hepatic, or renal failure, the mechanism of this toxicity remains unknown. Prevention with prednisone has recently been noted in one case.8 Erysipeloid rash confined to areas of pre-existing lymphedema have recently been described during gemcitabine therapy. This skin reaction was timeand dose-limited, repeatedly observed on the same body areas 40 to 48 hours after intravenous administration and fading slowly after 14 days without
S76 Bessis et al
specific treatment. No scleroderma-like changes were noted, but no histology of the skin lesion was mentioned.9 Various scleroderma-like conditions induced by chemotherapeutic drugs have been reported.10 Progressive systemic scleroderma-like presentation including sclerodactyly with swelling; induration of the hands and forearms; tightening and thickening of the skin of hands, forearms, arms, thighs, legs, and feet; hyperpigmentation; and inconstant Raynaud phenomenom have been repeatedly reported with bleomycin11 and more recently with uraciltegafur.12,13 In the cases of bleomycin-induced scleroderma, the skin lesions were clearly dosedependant, and resolved or improved several weeks or months after discontinuation of the drug. Rare observations of scleroderma induced by bleomycin and limited to areas of skin previously treated by radiotherapy have been reported.14 To date, 4 observations of scleroderma changes of the lower limbs have been reported, exclusively induced by docetaxel.15,16 In one case, the scleroderma changes extended to the lower aspect of the trunk and the distal upper extremities.16 The clinical presentation was very similar to our observation with 3 phases of skin involvement: (1) an initial inflammatory and indurated edematous phase of the lower limbs followed by; (2) scleroderma changes and pigmentation of the skin; and (3) a softening phase. Although the exact pathophysiologic mechanism is unknown, the exclusive and circumscribed localization of the scleroderma-like changes in dependant areas suggest a locoregional toxicity by an accumulation of the drug or its metabolites in the subcutaneous tissue. We believe that gemcitabine should be added to the list of drugs inducing scleroderma.
J AM ACAD DERMATOL AUGUST 2004
REFERENCES 1. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumor activity of gemcitabine. Cancer Res 1990;50:4417-22. 2. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of gemcitabine on DNA synthesis. Cancer Res 1991;51:6110-7. 3. Carmichael J. The role of gemcitabine in the treatment of other tumours. Br J Cancer 1998;78:21-5. 4. Moore MJ, Tannock IF, Ernst DS, Huan S, Murray N. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 1977;15:3441-5. 5. Sternberg CN. Gemcitabine in bladder cancer. Semin Oncol 2000;27:31-9. 6. Aapro MS, Martin C, Hatty S. Gemcitabineea safety review. Anticancer Drugs 1998;9:191-201. 7. Hejna M, Valencak J, Raderer M. Anal pruritus after cancer chemotherapy with gemcitabine. N Engl J Med 1999;340: 655-6. 8. Geffen D, Horowitz J. Gemcitabine-induced severe extremity edema with muscle contractures and subsequent prevention with prednisone. Isr Med Assoc J 2000;2:552-3. 9. Brandes A, Reichmann U, Plasswilm L, Bamberg M. Timeand dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabineea report of three cases. Anticancer Drugs 2000;11:15-7. 10. Haustein UF, Haupt B. Drug-induced scleroderma and sclerodermiform conditions. Clin Dermatol 1998;16:353-66. 11. Kerr LD, Spiera H. Scleroderma in association with the use of bleomycin: a report of 3 cases. J Rheumatol 1992;19:294-6. 12. Kono T, Ishii M, Negoro N, Taniguchi S. Scleroderma-like reaction induced by uracil-tegafur (UFT), a second-generation anticancer agent. J Am Acad Dermatol 2000;42:519-20. 13. Sheishima M, Izumi T, Kanoh H. Raynaud’s phenomenon possibly induced by a compound drug of tegafur and uracil. Eur J Dermatol 1999;9:55-8. 14. Marck Y, Meunier L, Barne´on G, Meynadier J. Scleroderma of the shoulders after treatment with combined bleomycin and radiotherapy. Ann Dermatol Venereol 1994;121:712-4. 15. Battafarano DF, Zimmerman GC, Older SAZ, Keeling JH, Burris HA. Docetaxel (Taxotere) associated scleroderma-like changes of the lower extremities. Cancer 1995;76:110-5. 16. Cleveland MG, Ajaikumar BS, Reganti R. Cutaneous fibrosis induced by docetaxel: a case report. Cancer 2000;88:1078-81.