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Late presentation of sorafenib-associated rash: a case report
© Sarkodie and Ross; licensee BioMed Central Ltd. 2010
Received: 8 December 2009
Accepted: 25 October 2010
Published: 25 October 2010
Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is licensed for the treatment of hepatocellular carcinoma. Rash is one of the most common side effects of its use, generally appearing within days to a few weeks of commencing treatment. We report the first case of rash appearing nine months after starting treatment with sorafenib.
A 75-year-old Caucasian man initially presented with asymptomatic transient jaundice. He was diagnosed with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma after extensive investigation. He tolerated sorafenib 400 mg twice a day before presenting nine months later with a rash, confirmed to be drug-induced.
Sorafenib is a drug of choice in Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. It can cause protracted rash quite late into treatment. Successful management of the rash could contribute to achieving stable disease in hepatocellular carcinoma over a significant period of time.
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world and the third most frequent cause of cancer death worldwide . The incidence of HCC is 500,000 to one million cases per year.
HCC is closely associated with hepatic cirrhosis in the western world, being found in about 70% of all cases. Treatment of HCC is effective in improving survival only when diagnosed at an early stage of the disease.
The BCLC staging
Stage A: early
Single, <5 cm
No portal HT, normal bilirubin
Single, <5 cm
Portal HT, normal bilirubin
Single, <5 cm
Portal HT, normal bilirubin
3 tumors, <3 cm
Stage C: advanced
Vascular invasion/extrahepatic spread
Stage D: end stage
Okuda Staging System.
Using the BCLC staging stage A can be managed with radical therapies, such as resection, transplantation or percutaneous treatments. Stages B and C are managed with new agents in clinical trials or palliative care. Transarterial chemoembolization (TACE) is beneficial but is limited by patient suitability and maximum dose of chemotherapy agent used [3, 4]. Stage D is for symptomatic treatment .
Sorafenib is an oral multitargeted tyrosine kinase inhibitor. It inhibits the receptor tyrosine receptors (RTKs), VEGFR 1-3 (vascular endothelial growth factor receptor), FLT-3 (fms-like tyrosine kinase receptor-3), PDGFR (platelet-derived growth factor receptor ) and the non-receptor serine threonine kinases BRAF (B-Raf proto-oncogene serine/threonine-protein kinase) and (C-Raf proto-oncogene serine/threonine-protein kinase) CRAF. The BRAF and CRAF kinases are members of the RAF/(mitogen-activated protein kinase) MEK/(extracellular-signal-regulated kinases) ERK signaling cascade, which is involved in the survival and proliferation of tumor cells and is a therapeutic target in cancer [3–16].
Phase I trials of sorafenib demonstrated, in addition to safety, promising efficacy in HCC. It was well tolerated; most adverse events were mild to moderate in severity, with most reported side effects at any grade being fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%) and hand-foot skin reaction (25%) [4, 6, 11].
Phase II trials evaluated efficacy and pharmacokinetics of sorafenib in HCC and demonstrated anti-tumor activity in HCC. In one trial of 137 patients, 2.2% of patients achieved a partial response and 33.6% had stable disease over 16 weeks . A subsequent multi-center phase III, double blind, placebo-controlled trial (SHARP trial) involving 602 patients with advanced HCC was conducted. The median survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (P ≤ 0.001) .
Fourteen months after commencing treatment (November 2006) our patient presented with a further rash of common toxicity criteria (CTC) grade 2 over his trunk and limbs. Study medication was stopped at that point. Four weeks later the rash had resolved so the trial medication was recommenced at a reduced dose of 400 mg daily. Our patient remained stable on monthly reviews. Four months later he developed a similar rash as previously; pruritic, mainly on the trunk, but worse on the back. Dermovate (clobetasol propionate 0.05%), diprobase creams and Piriton (chlorphenamine) provided little relief so the trial drug was suspended. Within two months the rash resolved but our patient was not recommenced on trial medication. In spite of that, he again presented a new rash two months later (four months after stopping trial medication). A dermatologist suspected nodular prurigo. Biopsies were taken of the new rash. Histological findings were consistent with nodular prurigo. This was managed with 1% menthol in aqueous cream and 1:4 betnovate ointments and the rash improved to CTC grade 1.
Sorafenib (Nexavar, Bayer) is a molecular inhibitor of several tyrosine kinases. It targets the Raf/Mek/Erk pathway [3–16]. Its efficacy has been demonstrated in clinical trials [4, 6, 7, 11, 16]. Dermatological side effects including rash/desquamation (27%), hand-foot skin reaction (HFSR, 27%), pruritus (18%) and dry skin (10%) are well documented. Other side effects include fatigue (40%), anorexia (35%), diarrhea (40%) hypertension and elevated amylase.
The skin rash usually appears within a few weeks of commencing sorafenib [8–11, 17]. The mechanism of the rash is poorly understood. There appears to be a relationship between the eccrine activity of the skin, resulting in higher drug concentration in the areas of the rash or desquamation . Inhibition of HER-1/EGFR in the skin is also thought to play a role in the development of the rash . Some studies found a relationship between the Child-Pugh score prior to commencement of medication and the severity of the adverse drug reaction .
The late presentation of the rash in our patient appears to be the first reported of its kind in the literature to date. It first appeared nine months into treatment; it was mild to moderate in severity but was protracted and recurring. Management included moisturizing creams and topical steroids, the latter being of limited use . Further improvements in our understanding of the pathogenesis underlying the side effects are needed in the management of these patients.
Sorafenib, a multitargeted tyrosine kinase inhibitor, is a drug of choice in patients with BCLC stage B HCC. Skin rash is a common adverse drug reaction, occurring within weeks of commencement of the drug. It is, however, important to note that the rash can present quite late into treatment. Prompt recognition and management of the rash remains vital to patients' outcome.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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