Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma.

Case Report A 15-year-old girl underwent wide local excision and sentinel lymphadenectomy of a thin, nonulcerated melanoma. One of 16 lymph nodes contained a focus of microscopic metastasis. Staging imaging showed no other disease. After the first of 12 planned months of adjuvant interferon alfa, the medication was discontinued early because of significant fatigue. New lung nodules were detected on surveillance computed tomography (CT) imaging 3 years after diagnosis, and a biopsy confirmed melanoma. Magnetic resonance imaging (MRI) of the brain also showed a new metastasis to the right parietal bone. The patient was started on high-dose interleukin-2. Follow-up MRI showed local progression of the skull lesion, so stereotactic radiation (RT) involving 25 Gy over five treatments was given after her second interleukin-2 cycle. Adverse effects of RT included alopecia and faint erythema in the radiated area. The patient developed back pain, and surveillance CT scans 2 weeks later showed new bone metastases in the axial skeleton, liver and spleen metastases, and progression in her lungs. BRAF mutation testing of a subcutaneous metastasis that was excised from the back showed a V600E mutation. The patient was enrolled onto a phase II study investigating vemurafenib in metastatic melanoma that was approved by the institutional review board of the University of California, Los Angeles. Her initial vemurafenib dose was 960 mg twice per day. Within 14 days, her performance status improved, with a substantial decrease in her spinal pain. No photosensitivity was observed. After 1 month, CT scans showed progression of bone metastases, but the disease in her liver, lungs, and spleen was either stable or decreased. After withholding vemurafenib for 4 days, 20 Gy of RT was administered over five fractions to the painful bone metastases. A posterior-anterior (PA) beam was used for T1 to T7 and T10 to L1, and her bilateral acetabula were treated with an AP/PA arrangement. Vemurafenib was restarted 2 days after the completion of RT. Two weeks after RT, the patient developed a tender, raised rash with well-delineated borders that matched her RT portals (Fig 1, portals are indicated in yellow; Fig 2, portals are indicated in cyan). Dry desquamation and then resolution of the skin changes occurred within 4 weeks. Imaging performed 3 weeks after RT showed overall stability of non-CNS disease, but 12 new brain metastases were detected. Although whole-brain therapy would be standard treatment in this scenario, because of significant concerns about skin toxicity, stereotactic radiosurgery (SRS) to each brain metastasis was recommended. Two weeks later the patient developed lower extremity weakness, and a lumbar spine MRI showed cauda equina compression at L4. She received 8 Gy of RT to L2 to L5 using a PA field, but vemurafenib was only withheld for 2 days because of the emergent nature of the treatment. Three days later, 20-Gy SRS was performed on each of the brain metastases. Vemurafenib was restarted 4 days after SRS, beginning at 480 mg for 3 days before moving to a full dose. Approximately 1 week after RT, she developed only mild erythema that matched the L2 to L5 portal. CT scans performed 10 weeks after the completion of her second course of RT showed interval pulmonary progression, with mixed responses elsewhere. Of concern was the development of innumerable, tightly packed, hypodense lesions in the liver that matched her previous RT portal (Fig 3A, pretreatment scan, black arrows indicate examples of liver metastases outside the RT portal; Fig 3B, posttreatment scan with RT isodose overlay [100 cGy 1 Gy]). Days later the patient developed severe chest discomfort and was admitted for pain control. The following 3 days she developed worsening abdominal pain and an acute drop in hematocrit. Interval accumulation of a large subcapsular hepatic hematoma and hemoperitoneum consistent with hepatic hemorrhage were detected on CT imaging (Fig 3C, white arrows). The patient died 2 days later. An autopsy showed an enlarged liver with multicystic change that was mostly limited to the central liver. Microscopically, these cysts were hemorrhagic and lined with melanoma cells (Fig 4A, 20 magnification of subcapsular cyst lined by melanoma. Organizing clot was seen emerging through ruptured cysts, explaining the sudden drop in hematocrit. Fig 4B, 40 magnification of multiple cysts lined by melanoma [arrow]; Fig 4C, 400 magnification). The intervening liver parenchyma showed severe zone III necrosis and scattered venous thrombi that were consistent with radiation-induced liver toxicity. However, outside of the radiation field, the liver also showed zone III necrosis, although it was less severe and without venous thrombi. This was suggestive of an additional source of liver damage subsequent to the initial insult, such as global ischemia. The late-occurring ischemic injury was likely the combined result of blood loss from a ruptured hematoma found at autopsy and multiorgan failure near the time of death.