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Dramatic improvement of palmar plantar erythrodysesthesia (PPE) with oral prednisone
- Raja Jaber, Whitney Dessio, MD and Shenhong Wu, MD (11 April 2007)
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Raja Jaber, MD, Dept of Preventive Medicine Stony Brook University Hospital,Stony Brook, NY 11794, Whitney Dessio, MD and Shenhong Wu, MD
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To the Editor: We read with great interest the outstanding review article by Lorusso et al. on the pegylated liposomal doxorubicin-related palmar plantar erythrodysesthesia (PPE). We here report a case of liposomal doxorubicin-related persistent grade 3 PPE which was refractory to the reported treatments but dramatically responded to a short course of systemic treatment with oral prednisone. Our 56 year-old white female patient has stage IV breast cancer metastatic to the liver and lungs and had previously suffered from severe neuropathy secondary to taxanes and clinical trials of Epothilone and Halichondron-B. She was maintained successfully on Doxil 45mg/m² since September 2005 with regression of liver metastasis and stabilization of the lungs metastasis. In February 2006 she consulted her oncologist for foot ulcers who diagnosed possible PPE and prescribed Biafine topically (preparation used for treatment of radiodermatitis). When she did not respond, the dose of Doxil was reduced to 40mg/m² ( Feb 22nd) and she consulted her primary care physician who prescribed pyridoxine 100mg po twice a day and Dimethylsulfoxide (DMSO) 70% gel to be applied to the feet. Both Pyridoxine 150-200mg and DMSO 99% have been cited as possibly beneficial for PPE in uncontrolled studies1,2,3. Without relief, she visited a dermatologist who treated her lesions as burns and prescribed Silvadene and Bactroban. Desperate, she also consulted her podiatrist who opened one of the blisters on her right heel without any relief. Her oncologist therefore decided to hold the Doxil dose scheduled for March 22nd. Despite holding the chemotherapy, she continued to worsen and returned to us on March 30, frustrated and in considerable pain. General appearance showed a woman who was clearly uncomfortable reporting moderate to severe pain with the slightest contact or pressure, hardly able to walk and wearing flip flops despite the cold weather. Physical exam revealed erythema of the hands and feet and blistering of both feet, left worse than right. She had opened blisters of the second, fourth, and fifth toes bilaterally, of the left third toe as well as the sole of the right medial heel and the skin above the right lateral malleolus. Some of the blisters were bleeding. In addition to the ulcers, superficial desquamation was noted on the heels and soles, greater on the left than the right. Overall, the skin on both hands and feet was a very shiny red with violaceous areas. While a case report had recently been published about using Vitamin E, 300 mg/day p.o daily for PPE associated with docetaxel-capecitabine4, we elected against the use of antioxidants for fear of interfering with Doxil’s mechanism of action, and decided to treat PPE as an inflammatory disorder. The patient was tried on Medrol dosepak consisting of 21-four milligram tablets of methylprednisone to be administered according to the following instructions: six tablets on day 1, five on day 2, four on day 3, three on day 4, two on day 5, and the remaining one on day 6. After three days, the patient phoned to report dramatic recovery in appearance and function. On April 5 she attended a previously scheduled dermatology visit, all ulcers had healed and her physical findings were described as consistent with post inflammatory changes. Patient was so well that she was able to tolerate another course of PLD at the same reduced dose on April 6 without complications. She subsequently tolerated another reduced course in May but unfortunately her disease progressed and Doxil had to be discontinued. Oral dexamethasone has been reported to have preventive effects in the recurrence of PPE5 but there are no published reports of treating established PPE with prednisone. As summarized by the Lorusso review6, the only treatments so far are anecdotal and rely on topical agents with unclear benefits. Typically, the patients end up receiving a lowered dosage or have their treatments delayed. While as pointed out in the Lorusso review, dosage reduction and schedule lengthening may decrease the incidence and ameliorate symptoms of PPE, there are no studies demonstrating that these altered schedules are equally effective in treating patients with metastatic breast cancer. The histology of PPE shows an inflammatory cell infiltrate along with hyperkeratosis and increased dermal vascularity7. We, therefore, reasoned that an anti-inflammatory agent such as prednisone would be beneficial. The rapid, dramatic response to the Medrol Pack suggests a true response although we recognize several confounding factors such as usage of pyridoxine, DMSO, and Biafine and the delay and subsequent skipping of chemotherapy. However, despite all these interventions, patient continued to experience severe discomfort at 5 weeks after treatment even though PPE is thought to heal at about that time8. In conclusion, PPE is a debilitating complication of PLD that can lead to delay, reduction, or discontinuation of chemotherapy. In addition, PPE will be an increasing problem due to a high incidence associated with new biologic multikinase inhibitors such as sorafenib and sunitinib. We propose oral prednisone as a safe treatment modality worth trying if PPE occurs despite preventive dosages of dexamethasone, pyridoxine and cooling of extremities6. Definite conclusions as to the efficacy of oral prednisone in the treatment of PPE will require formal controlled clinical trials. Whitney Dessio, MD Stony Brook University School of Medicine Stony Brook, NY Raja Jaber, MD Department of Preventive Medicine Stony Brook University Stony Brook, NY Shenhong Wu, MD, PhD Assistant Professor Division of Medical Oncology Department of Medicine Stony Brook University Cancer Center REFERENCES 1. Fabian CJ, Molina R, Slavik M et al. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5- fluorouracil infusion. Invest New Drugs 1990; 8(1): 57-63. 2. Eng C, Mauer AM, Fleming GF et al. Phase I study of pegylated liposomal doxorubicin, paclitaxel, and cisplatin in patients with advanced solid tumors. Ann Oncol 2001; 12: 1743–1747. 3. Lopez AM, Wallace L, Dorr RT et al. Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantarerythrodysesthesia. Cancer Chemother Pharmacol 1999; 44(4): 303-6. 4. Kara IO, Sahin B, Erkisi M. Palmar-plantar erythrodysesthesia due to docetaxel-capecitabine therapy is treated with vitamin E without dose reduction. Breast 2006; 15(3): 414-24. 5. Drake RD, Lin WM, King M et al. Oral dexamethasone attenuates Doxil-induced palmar-plantar erythrodysesthersias in patients with recurrent gynecologic malignancies. Gyn Oncol 2004; 94(2): 320-324. 6. Lorusso D, Di Stefano A, Carone V et al. Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia(‘hand-foot’ syndrome). Ann Oncol Adv Access. January 17, 2007. (dol:10.1093/annonc/mdl1477) 7. Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar management. Am J Clin Dermatol 2000; 1(4): 225-34. 8. Lotem M, Hubert A, Lyass O et al. Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 2000; 136: 1475-1480. Conflict of Interest:None declared |
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