- © 2013 by American Society of Clinical Oncology
Severe Liver and Skin Toxicity After Radiation and Vemurafenib in Metastatic Melanoma
- Christopher J. Anker,
- Antoni Ribas,
- Allie H. Grossmann,
- Xinjian Chen,
- Krishna K. Narra,
- Wallace Akerley,
- Robert H. I. Andtbacka,
- Robert Dirk Noyes,
- Dennis C. Shrieve and
- Kenneth F. Grossmann⇑
- Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
- Intermountain Healthcare, Salt Lake City, UT
- Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
- Corresponding author: Kenneth F. Grossmann, MD, PhD, Medical Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Rm 2124, Salt Lake City, UT 84112; e-mail: kenneth.grossmann{at}hci.utah.edu.
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, post-treatment 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.
Discussion
Both vemurafenib and RT are active agents in the treatment of melanoma. In a phase I/II study of vemurafenib, an impressive overall response rate of greater than 50% was achieved, with symptomatic relief possible within 1 to 2 weeks.1 The median progression-free survival was 7 months. Despite early in vitro data that led to the belief that melanoma is radioresistant, thus requiring hypofractionation,2 more recent studies have disproved this.3,4 Clinical response rates to RT range from 49% to 97%, and significant symptom relief is experienced by 39% to 84% of patients.3–6
For many systemic agents, damage is augmented, sometimes synergistically, when combined with RT. If systemic treatment is administered concurrently or within 7 days of finishing RT, the amplified reaction is defined as RT enhancement.7 Toxicity from this combination separated by more than 7 days is referred to as RT recall. In humans, the safety of combining RT and vemurafenib is not well understood because clinical studies with vemurafenib have excluded concomitant or closely scheduled RT. In vitro data suggest that vemurafenib sensitizes BRAF-mutated melanoma cells to RT but not BRAF wild-type melanoma cells.8 Inhibition of the Ras/Raf/MEK/extracellular signal–regulated kinase pathway in other cancer cell lines with MEK inhibition has resulted in radiosensitization, possibly by abrogation of an early G2 cell cycle checkpoint leading to mitotic catastrophe.9 It is possible that the reintroduction of vemurafenib after only 2 days following RT in our patient prevented appropriate repair of normal cells and led to markedly enhanced dermatalogic and hepatic toxicity. This case also suggests a dose dependence of radiation sensitization, given that the L2 to L5 treatment field experienced less skin toxicity than the T1 to 7, T10 to L1, and acetabular fields, either as a result of a longer washout (8 v 2 days), a lower restarting dose of the drug (480 mg twice per day for 3 days followed by an increase to full dose v 960 mg twice per day), a lower dose of radiation (8 Gy over one fraction v 20 Gy over five fractions), or a combination of all three factors.
Clinically, both RT enhancement and recall present similarly to RT dermatitis with erythema, edema, vesiculation, bullae, and erosions. In more severe reactions, necrosis and ulceration may occur.10 The reaction is typically confined to the RT portal, but it may extend locally. Long-term sequelae often involve skin atrophy, telangiectasias, fibrosis, and pigmentation changes. Reactions may last days to months, and are typically self-limiting. Corticosteroids and cold compresses may alleviate discomfort, and local wound care may prevent infection. The avoidance of trauma, heat, and ultraviolet light can help expedite healing.7
Liver toxicity from concurrent RT and dactinomycin (AMD) has been reported in the treatment of Wilms disease, but no deaths have been described with this combination. Patients have recovered from marked liver enlargement and hypoalbuminemia with only supportive treatment.11–13 In the International Society of Pediatric Oncology (SIOP) nephroblastoma trial SIOP-9, RT was given concurrently with AMD.13 The rate of overall hepatotoxicity was 2.6 times higher (95% CI, 1.5 to 4.5; P < .003) in those patients whose field of RT included the liver than in those with no or left side–only RT. A reduced AMD dose or postponing AMD treatment after RT completion is recommended. Hepatic toxicity has also been seen when AMD is restarted after an initial concurrent course of AMD and RT.12 After RT, the liver undergoes an acute stage of injury that results in hepatic congestion and, in turn, in portal bed pressure elevation, hypersplenism, and thrombocytopenia. Liver regeneration and recovery from this may take up to 6 months.13 During regeneration, the liver is mitotically active and therefore hypersensitive to systemic agents. AMD has been administered without incidence after liver regeneration is complete. Interestingly, to the authors' knowledge, no concomitant dermatitis has been reported with RT/AMD–induced hepatic injury. Conversely, all published reports of dermatologic RT enhancement or recall in a port overlying the liver have not been associated with hepatic toxicity.14–16 Recent data suggests that amifostine may be an effective normal liver radioprotector; therefore, this agent might be useful in future studies in which RT toxicity is of concern.17
To our knowledge, this is the first report of synergistic toxicity from the combination of RT and vemurafenib. The described toxicity was likely dependent on our patient's individual biology; we would not expect such severe reactions to be universal. It is notable that this patient did not experience any other vemurafenib-related adverse events, such as photosensitivity, that would have suggested heightened sensitivity to radiation before her radiation treatments. The severity of the complication described here underscores the importance of prospective studies investigating the safety of RT combined with a BRAF inhibitor. Until these studies are completed, we recommend withholding vemurafenib for 7 days before and after RT.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Antoni Ribas, Roche (C); Kenneth F. Grossman, Roche (U) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
