Discussion
SJS and TEN present as widespread erythema, erosion, blisters, mucosal rash, and fever. Frequently, they are caused by drugs, but can also be caused by infections from mycoplasma or certain viruses2. Apoptosis of epidermal and mucosal epithelial cells induced by CD8 + T cells is considered as the etiology of both SJS and TEN. However, the detailed mechanism of development of SJS and TEN has not been elucidated. These diseases are rare but serious. In particular, the mortality rate associated with the most severe form of TEN is as high as 30%. Most cases of TEN develop from SJS. According to the Japanese diagnostic criteria for SJS and TEN, SJS is diagnosed if erosion involves less than 10% body surface area, and TEN is diagnosed if it involves 10% or more. Our patient was initially diagnosed with SJS and subsequently with TEN after worsening of skin symptoms.
When SJS or TEN are caused by a drug, they develop within 1-2 weeks from the beginning of drug therapy. In our patient, skin symptoms appeared on the 27th day after administration of the first dose of nivolumab. A relatively long time had passed from the administration of nivolumab until the appearance of skin symptoms. However, as no new drug therapy, apart from nivolumab, was ongoing, nivolumab was determined to be the causative drug for the onset of TEN. In ALDEN, an algorithm developed for determining the drug causality in SJS and TEN, a period of onset of 5 to 28 days after the drug administration is “suggestive”, which is consistent with the course of this patient 3. However, we must understand that severe skin adverse events can occur even 4 weeks after drug administration.
In the RegiSCAR study, the mortality rate of acute SJS and TEN was determined to be 23% 4. The acute cause of death is sepsis, which occurs due to secondary bacterial and fungal infections in the skin and mucous membrane lesions. Pneumonia is a major complication of SJS and TEN, with approximately half of the patients requiring a ventilator, which is often associated with a poor prognosis5.
Our patient showed improvement in skin symptoms, but died due to worsening of the respiratory function. Increase in lung metastatic lesions and associated pleural effusion were the principal causes of respiratory deterioration. Furthermore, it was determined that respiratory function was further deteriorated due to pneumonia caused by SJS or TEN. However, it is difficult to arrange ventilators for patients with cancer that cannot be cured.
SJS and TEN caused by nivolumab has been reported in patients with melanoma, hepatocellular carcinoma, non-small cell lung cancer, and lymphoma, but this is the first reported case of SJS or TEN associated with head and neck cancer 6-9. SJS or TEN were not observed in adverse event reports in the CheckMate-141 study1. In addition, only 2 cases of grade 3 or grade 4 skin adverse events were reported in the international randomized phase 3 study (n = 945) with nivolumab and ipilimumab for advanced melanoma10. Deaths caused by TEN have been reported with nivolumab use for metastatic melanoma and lymphoma 6, 8. The mechanism by which immune-checkpoint inhibitors such as anti-PD-1 antibody and anti-cytotoxic T lymphocyte-associated-4 antibody cause SJS and TEN has not been elucidated. Several drugs such as antibacterial, anti-epileptic, and nonsteroidal anti-inflammatory drugs, and allopurinol are listed as high-risk drugs for the development of SJS and TEN. Currently, molecular-targeting drugs and immune-checkpoint inhibitors used for cancer treatment are not classified as risk drugs, but are expected to be assessed for risk after the documentation of adequate cases treated with these anticancer agents in the future.
In head and neck cancer, nivolumab is approved as a treatment modality for patients with platinum-resistant recurrence/metastasis. Several patients show distant metastasis or local recurrence with a compromised general medical condition. Prior chemotherapy is also a factor that can affect the general condition. If SJS or TEN develops in such patients, it will be fatal. In addition, treatment guidelines for SJS and TEN recommend plasma-exchange therapy in cases of resistance to steroid pulse therapy. However, plasma-exchange therapy should be carefully used in patients with cancer. In our patient, steroid pulse therapy was not effective immediately, and hence, plasma-exchange therapy was considered. However, due to the increase in lung metastatic lesions and worsening of the respiratory condition, plasma-exchange therapy was not initiated, and intravenous immunoglobulin was administered. Infliximab, an anti-tumor necrosis factor-α antibody, may be administered for severe skin adverse events, but no reports on its use in patients with adverse skin events caused by nivolumab have been documented10. It is necessary to determine a suitable treatment modality for TEN considering the prognosis and disease control status of each case.
With the progress of immunotherapy for cancer, many patients are treated with immunotherapeutic agents worldwide. In the future, the number of patients developing severe skin adverse events, such as SJS or TEN, is expected to increase. For immunotherapy, the patient’s general medical condition should be evaluated to manage the adverse events by early detection and appropriate treatment planning.