Yellow skin discoloration associated with sorafenib use for treatment of metastatic renal cell carcinoma.

Abstract: This report describes a patient with metastatic kidney cancer who developed a deep yellow skin discoloration while on therapy with the oral multitargeted tyrosine kinase inhibitor (TKI), sorafenib. A significant hand-foot syndrome, featuring acral skin desquamation and tender erythema at pressure points, was also present. A thorough clinicolaboratory investigation did not reveal any evidence of jaundice, [B.sub.12] deficiency, anemia, carotenemia, hypothyroidism, or any other disorder of endocrine or metabolic etiology.

Key Words: sorafenib, sunitinib, multitargeted tyrosine kinase inhibitors (TKIs), renal cell carcinoma, hand-foot syndrome

**********

Multiple mucocutaneous side effects have been described with the use of multitargeted tyrosine kinase inhibitors, including hand-foot syndrome, various rashes, pruritus, cheilitis, mucositis, eyelid edema, subungual splinter hemorrhages, hair depigmentation, alopecia, and dry skin. Although hand-foot syndrome and rash are well known adverse effects associated with sorafenib, we are not aware of any case reports in the English literature to date showing the association between yellow skin discoloration and sorafenib use. Yellow skin coloration has been previously documented with the use of a different multiple TKI, sunitinib.

Case Report

A 45-year-old Hispanic male presented for a follow-up visit three weeks after starting a new treatment for his kidney cancer. While completely asymptomatic before the start of his new medication, he presented with redness and a burning sensation at the level of his palms and soles. The burning would become worse while walking or standing for longer periods of time. He also noticed gradually increasing deep yellow skin discoloration that started one week into his new oral cancer therapy.

His medical history included metastatic renal cell carcinoma of papillary histology, diagnosed in February 2005. The diagnosis was made after left nephrectomy for two suspicious kidney masses that were less than 2 cm in size. At that time, the patient was also found to have multiple bilateral lung nodules. A follow-up computed tomography (CT) scan was done in April of the same year and showed new bilateral hilar masses. Combination therapy with recombinant interleukin-2 and interferon-alpha 2 was administered at that time. However, the disease progressed through the treatment and the patient presented with severe left back and leg pain in June 2005. An MRI showed evidence of osseous destruction at the level of L2 vertebra, caused by a 4-cm paraspinal mass, and newly discovered multiple liver metastases. Subsequently, he underwent palliative radiotherapy to the spine, with complete resolution of his pain.

In September of the same year, therapy with sorafenib (Nexavar), 400 mg orally twice daily was started. The baseline CT scan was showing a new left psoas mass at the level of L3, enlargement of his right hilar adenopathy, and an increase in the number and size of liver metastases. Besides sorafenib, the patient denied taking any other medication. He also denied using any vitamin or mineral supplements as well as any complementary medicine approaches for the treatment of his disease. On the review of systems, he also denied pruritus, dark urine, discolored stool, abdominal pain, fever, excessive alcohol intake, or diarrhea. He did not have any lightheadedness, dizziness or syncope.

His physical examination was significant for a deep yellow discoloration of the skin of his face (Fig. A), chest, abdomen, and extremities, without icteric sclerae or mucous membranes. He had moderate redness and tenderness in the periungual areas, involving all his fingers and toes. Bilateral palm and sole acral erythemas with various degrees of desquamation were also seen (Fig. B and C). Desquamation was most prominent on the lateral aspect of his fingers, palms and soles. Although moderate mucositis was present on the lateral aspect of his tongue, no perianal or penile erosions were seen. He did not present any evidence of eyelid edema, hair depigmentation, subungual splinter hemorrhages, or alopecia. His other important clinical finding was tender hepatomegaly, three fingerbreadths below the costal margin. No splenomegaly was appreciated. His vital signs were stable, with a blood pressure reading of 125/70 and no orthostatic changes. His deep tendon reflexes were well preserved and, when tested, he did not present any significant sensory abnormalities. His vibratory sense was intact.

Laboratory panel showed normal values for hemoglobin, white blood cell count, liver function tests (LFTs), creatinine, blood glucose, ferritin, and serum thyroid stimulating hormone (TSH). Furthermore, his morning cortisol, serum adrenal corticotropic hormone (ACTH), vitamin A, and carotene levels were within normal limits. When tested, his vitamin [B.sub.12] and folate levels were normal as well.

[FIGURE OMITTED]

Discussion

Yellow skin discoloration can be seen with the use of certain drugs or in the setting of a few systemic diseases. TKIs, used for treatment of various cancers, are well known to cause a large spectrum of skin lesions. (1) Yellow skin discoloration has been reported before with the use of a multi-targeted TKI sunitinib (Sutent), but not with sorafenib (Nexavar) use. The two medications have been recently approved by the US Food and Drug Administration for the treatment of advanced kidney cancer. Sunitinib was also granted approval as a second-line treatment for gastrointestinal stromal tumors.

A well-described phenomenon with sunitinib, yellow skin discoloration usually appears after the first week of treatment. (2,3) Color intensification may be seen at the skin level with continuation of treatment, but it spares entirely the sclerae and mucous membranes and is reversible with drug discontinuation within a few weeks. On occasion, transient intense yellow coloration of urine was reported to occur in patients treated with sunitinib. In one study, it paralleled the yellow skin coloration intensity and was thought to be due to the excretion of the drug and/or its metabolites. (3)

The hand-foot syndrome usually develops during the first 6 weeks of treatment with multitargeted kinase inhibitors. (3,4) It represents reversible palm and sole acral erythema, accompanied by various degrees of dysesthesia and epidermal desquamation at the pressure points, and is seen in approximately 30% of patients taking sorafenib. (4,5) A severe hand and foot skin reaction is seen in up to 13% of the patients on sorafenib. (4,6) Other manifestations of integumentary toxicity seen with TKIs are various types of rash and mucositis. Alopecia is more commonly encountered with sorafenib than with sunitinib, especially when the rash involves the scalp. (5) Asymptomatic subungual splinter hemorrhages, moderate eyelid edema, reversible hair depigmentation, perianal and penile erosions were described with sunitinib. (3)

Carotenemia, which is characterized by a yellowing of the skin (especially creases of the palms and soles), but not the sclerae, resembles the yellow skin discoloration in our patient and may be seen after ingestion of more than 30 mg of beta carotene on a daily basis. (7) However, our patient denied taking any vitamins or consuming large amounts of products containing carotene. When checked, his serum carotene level was found to be normal.

Our patient had been diagnosed with renal cell carcinoma metastatic to the liver, and jaundice is an important consideration in the differential diagnosis of his condition. Although his liver was found to be enlarged and tender, likely because of metastatic involvement, his sclerae and mucosal membranes were not icteric, and he did not have brown-colored urine. (8) Further, other clinical signs of jaundice such as light-colored stool, skin itching, and fever were also absent in our patient. His serum bilirubin levels, both direct and indirect, other LFTs, and lactate dehydrogenase were all within normal range, thus excluding jaundice from the differential diagnosis.

Hypothyroidism, which on rare occasions presents with pallor with a yellow tinge, was also ruled out due to the normal TSH level. (9) Cobalamin deficiency, presenting on occasion with deep yellow skin coloration, is also unlikely in our patient, in view of a normal hemoglobin level, cell counts, and lack of macrocytosis and typical neurologic findings. Because nearly 25% of cobalamin-deficient individuals have normal hemoglobin levels, we tested the vitamin [B.sub.12] level in our patient and found it to be normal. Furthermore, hereditary hemochromatosis, responsible for the occurrence of bronze diabetes, was ruled out by a normal ferritin level. (10) Stability of vital signs, as well as normal values for cortisol and ACTH, argued against Addison disease, Nelson syndrome, or ectopic ACTH syndrome as a cause for his skin discoloration. (11) There was no clinical laboratory evidence to suggest any other disorder of endocrine or metabolic etiology in the above setting. After drug discontinuation, the yellow pigmentation faded and then disappeared completely.

Thus, we conclude that the described yellow skin discoloration is likely to have been caused by sorafenib, in a fashion similar to the other multifaceted TKI, sunitinib. In our patient, just like in patients taking sunitinib, it spared the sclerae and mucous membranes, and disappeared upon drug discontinuation. According to Naranjo nomogram, the causality between the sorafenib and the described adverse outcome could be defined as at least probable, if not definite. (12) The observed skin discoloration may be related to the drug excretion via the skin, although direct skin toxicity of sorafenib or other unknown mechanisms are also possible. Physicians of various specialties should be familiar with yellow skin discoloration as a side effect of TKIs, and recognize it early to avoid a costly and often unnecessary diagnostic workup.

References

1. Robert C, Soria JC, Spats A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491-500.

2. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16-24.

3. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25-35.

4. Sorafenib Monograph. DrugDex in Micromedex Healthcare Series. Accessed July 2, 2006.

5. Ahmad T, Eisen T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 2004;10:6388S-6392S.

6. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505-2512.

7. Arya V, Grzybowski J, Schwartz RA. Carotenemia. Cutis 2003;71:441-442.

8. Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician 2004;69:299-304.

9. Aktuna D, Buchinger W, Lansteger W, et al. Beta-carotene, vitamin A and carrier proteins in thyroid diseases. Acta Med Austriaca 1993;20:17-20.

10. Chitturi S, Dakkak M, Campbell AP. Skin fragility and abnormal liver function tests. Postgrad Med J 1999;75:435-437.

11. Kong MF, Jeffcoate W. Eighty-six cases of Addison's disease. Clin Endocrinol (Oxf) 1994;41:757-761.

12. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

Constantin A. Dasanu, MD, PhD, Janice Dutcher, MD, and Doru T. Alexandrescu, MD

From New York Medical College, Our Lady of Mercy Cancer Center, Bronx, NY.

Reprint requests to Dr. Constantin A. Dasanu, Comprehensive Cancer Center, Our Lady of Mercy Medical Center, 600 East 233rd Street, Bronx, NY 10466. Email: [e-mail]

Accepted July 31, 2006.

RELATED ARTICLE: Key Points

* Yellow skin discoloration represents a probable side effect of sorafenib.

* With increasing use of multitargeted TKIs in the setting of various malignancies, physicians should be aware of this new entity.

* The awareness of sorafenib- and sunitinib-induced yellow skin discoloration is important for patient reassurance and avoidance of unnecessary diagnostic workup.