Korean Journal of Pediatrics Vol. 52, No. 1, 2009 DOI : 10.3345/kjp.2009.52.1.119
Case report
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Hand-Foot syndrome induced by sorafenib, a multitargeted tyrosine kinase inhibitor, in a patient with advanced renal cell carcinoma Seung Hyun Lee, M.D., Sung Hun Noh, M.D., Sun Young Kim, Ph.D. Kyu Yun Jang, M.D.,* and Pyoung Han Hwang, M.D. *
Department of Pediatrics and Pathology , Research Institute of Clinical Medicine School of Medicine, Chonbuk National University, Jeonju, Korea = Abstract =
Renal cell carcinoma (RCC) arising from epithelial cells of the renal tubules is a highly aggressive and malignant tumor in all ages; however, it rarely occurs in children. the standard treatment for RCC is radical nephrectomy with lymph node dissection when the tumor is localized and can be completely resected. Adjuvant chemotherapy, radiotherapy, and immunotherapy are used for pediatric patients with advanced RCC involving lymph nodes or metastatic lesions. Sorafenib is an oral, multikinase inhibitor that has recently been approved for use in metastatic RCC. Common toxicities that have been reported include dermatologic changes such as rash or desquamation and hand-foot skin reaction, diarrhea, fatigue, alopecia, and hypertension. In particular, hand-foot syndrome (HFS) an erythematous skin lesion of the palms and solesis most often caused by cytostatic chemotherapeutic agents. In this report, we have studied a 1 4 -year-old female patient with hand-foot syndrome that occurred in association with sorafenib for the treatment of metastatic RCC. Furthermore, this case demonstrates that reversal of complications can be achieved by discontinuing the drug and intervention with topical steroids, vitamin E, and high-dose pyridoxine. (Kore an J Pe diatr 2 0 0 9 ;5 2 :1 1 9 -1 2 3 ) Key Words : Hand-Foot syndrome (HFS), Sorafenib, Renal cell carcinoma
1-week, treatment-free period. After this 1-week 'rest' period, the patient starts the next cycle of treatment. The
Introduction
2
normal recommended dosage is 400 mg/m twice daily. At Sorafenib is an oral, multikinase inhibitor that was recently
this dosage, sorafenib was generally well tolerated, with
approved for use in metastatic renal carcinoma. Sorafenib
manageable side effects including rash (34%), diarrhea (33
was initially developed as an inhibitor of Raf kinase; how-
%), fatigue (26%), and hypertension (11%) . However, a
ever, it has broad spectrum activity against multiple tyro-
dose reduction may be indicated at the onset of adverse
sine kinases, including angiogenic factors VEGFR (vascular
events. One of common adverse events associated with its
endothelial growth factor receptor) and PDGFR (plate de-
use in clinical practice is HFS, which is an erythematous
rived growth factor receptor) . Oral sorafenib is being in-
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skin lesion of the palma and sole, is most often caused by
creasingly accepted into clinical practice for advanced renal
cytostatic chemotherapeutic agents. The pathogenesis of the
cancer and in other tumor types as it permits convenient
HFS has not yet been sufficiently clarified and it is rarely
administration in a home-based setting. Sorafenib capsules
serious and never life-threatening. However, HFS can sig-
are taken orally twice daily approximately 12 hours apart
nificantly interfere with the activities of normal daily living .
(after breakfast and after dinner) for 3 weeks, followed by a
Renal cell carcinoma (RCC) arising from epithelial cells
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of the renal tubule is a highly aggressive and malignant Received :26 March 2008, Revised :30 June 2008 Accepted :15 October 2008 Address for correspondence :Pyoung Han Hwang, M.D. Department of Pediatrics, Chonbuk National University Hospital, 634-18, Keumam-dong, Jeonju, Jeonbuk 561-712, Korea Tel :82.63-250-1472, Fax :82.63-250-1464 E-mail :
[email protected]. The abbreviations used are: HFS, Hand-Foot syndrome, RCC, renal cell carcinoma, PPE, palmar plantar erythrodysaesthesia.
tumor in all ages. Although RCC accounts for 2% to 3% of 4)
all adult malignancies, it rarely occurs in children . The incidence of this tumor in childhood is estimated to be from 5)
0.1% to 0.3% of all childhood cancer , and from 2% to 6% 6)
of all malignant renal tumors . It is initially asymptomatic, but clinically overt symptoms such as an abdominal mass
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SH Lee, SH Noh, SY Kim, et al.
or hematuria may indicate late-stage disease and a poor
chyma of the right kidney with multiple lymph node involve-
prognosis. Standard treatment for RCC is radical nephrec-
ment at the regional retroperitoneal lymphatic chain (Fig.
tomy with lymph node dissection and results in cure when
1). On the parent's requests, the patient was transferred to
the tumor is localized and completely resected. However, the
another hospital for further evaluation. There, the patient
role of adjuvant chemotherapy, radiotherapy and immun-
underwent right radical nephrectomy and lymphadenectomy.
otherpy for pediatric patients with advanced RCC with
Histological evaluation of the renal tumor revealed a RCC
lymph node involvement or metastatic lesion has not been
(Fig. 2). Intramuscular interferon (INF) injections were in-
defined. Because approximately 20% to 50% of patients will
itiated after radiotherapy, consisting of 6 million IU/day of 5
eventually develop metastatic disease after nephrectomy,
times/2 weeks for 3 months, followed by INF injections of 5
patients with metastatic RCC face a dismal prognosis, with
times/2 weeks for another 6 months.
a median survival time of only 6 to 12 months and a 2-year 7)
survival rate of 10% to 20% .
One year after the surgery, the patient was readmitted to our hospital because of multiple bone pain. Routine tests
In this article, we report on a patient with HFS that
showed normal liver function, but a slight increase in C-
occurred in association with sorafenib for the treatment of
reactive protein (CRP), and elevated erythrocyte sedimenta-
metastatic RCC. And the review of current literature is
tion rate. A whole body bone scan and PET/CT demonst-
included.
rated hypermetabolic bony metastasis at the left shoulder, right proximal humerus, iliac bone and thoracic vertebrae (T9, 12) and pulmonary metastases.
Case report
In view of the fact that the metastatic lesions had failed A 14-year-old female was admitted to Chonbuk National
to respond to immunotherapy, the patient's parents elected
University hospital with 1 month-history of right flank pain
to have a sorafenib only treatment without other chemothe-
and macroscopic hematuria. Her past history was unremark-
rapy. Treatment was initiated, consisting of a with 28-day
able. There had been no weight loss, fever, or night sweats.
cycle of sorafenib at 400 mg orally twice daily, for 21 days
On physical examination, a large, firm, non tender mass
then the-7 days suspension of treatment to allow the patient
was palpated in right upper quadrant of the abdomen, and
to rest. Five days after the initial sorafenib administration,
there was a knocking tenderness of right flank area. No
she developed paresthesia in her palms and soles, which
evidence of lymph node enlargement was found. Urinalysis
became painful and erythematous. And well-demarcated
confirmed the hematuria. Blood and liver function tests
bullae were formed in the palms, toes and periungual zones
were normal except for low hemoglobin (6.6 g/dL) and high
of distal phalanges (Fig. 3). The bullae gradually resolved
lactate dehydrogenase (538 IU/L). The abdominal CT revealed a huge solid mass with the involvement of all paren-
Fig. 1. Abdominal computerized tomography showing huge mass in the right renal parenchyma and multiple lymphadenopathies.
Fig. 2. Pathological diagnosis of the renal mass revealed renal cell carcinoma with clear cell and rhabdoid cell components (Hematoxylin and eosin staining, ×400 magnification).
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Hand-Foot syndrome induced by sorafenib
Fig. 3. Acral erythema and hyperkeratosis in the hand and foot of a patient treated with sorafenib.
over the next 2-3 days, after which palmar and plantar cut-
the distal phalanges. It generally arises after 1-2 weeks of
aneous desquamation occurred. Based on clinical findings, a
treatment with EGFR inhibitors. With continued drug the-
diagnosis of HFS secondary to sorafenib therapy was made
rapy the swelling and erythema progresses and a central
and managed with topical steroid, vitamin E (300 mg/day)
pallor develops over the tufts of the distal phalanges. Most
and high dose pyridoxine (150 mg/day). The symptoms
reported case have resolved within 7 days of discontinuation
gradually resolved over two weeks.
of therapy , but tend to recur when therapy is re-instituted .
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Histologically, tissues affected by HFS show general inflammatory changes with white blood cell infiltration,
Discussin
which include dilated blood vessels, edema and increased The term 'hand-foot syndrome' has been used for de-
vascularity of the dermis, although nothing really stands
cades by hematologists to describe a painful swelling of the
out as a clear marker of the condition . Consequently there
hands and feet in very young patients (e.g., age
