In recent years, biological and molecular targeted drugs have been developed and implemented for the treatment of malignant melanoma. These drugs include vemurafenib (a selective BRAF V600 kinase inhibitor) [7], ipilimumab (an antibody preparation that targets CTLA-4 and inhibits T-cell activation) [8], and nivolumab (a mAb to PD-1) [9]. PD-1 is an inhibitory and co-stimulatory factor that is expressed on activated T cells and was first identified by Ishida et al. in 1992 as a protein that is upregulated during T cell apoptosis [10]. In this context, PD-L1 and PD-L2 are expressed in cancer cells, where they bind to PD-1 and deliver inhibitory signals to T cells. Thus, nivolumab is a novel immune checkpoint inhibitor that exerts its anti-tumor effect by inducing PD-L1/PD-L2 binding and maintaining T cell function [11]. Clinical studies have confirmed that nivolumab is effective for treating malignant melanoma [12, 13], as it provides a 1-year survival rate of 72.9%, compared with 42.1% among patients who received dacarbazine monotherapy [4]. Currently, nivolumab therapy is indicated for patients who are refractory to conventional chemotherapy, which includes dacarbazine, and is typically administered intravenously at a dose of 2 mg/kg every 3 weeks. Treatment time with nivolumab is short because it does not require premedication to prevent the occurrence of nausea, and outpatient treatment is available, as no serious cytopenia occurs after treatment.
Nivolumab has several side effects, which are often considered relatively mild (e.g., malaise, pruritus, and nausea) [4, 5, 12, 13]. However, nivolumab is also associated with several severe side effects, which include interstitial pulmonary disease, liver dysfunction, thyroid deficiency, diarrhea, colitis, and infusion reactions [4, 13]. To the best of our knowledge, this is the first English report on a case of intestinal perforation after nivolumab therapy. The pathological mechanism of immunoreaction resulting in intestinal perforation is similar to that of an inflammatory reaction [14]. In a previous report on inflammatory colitis with metastatic melanoma, colonoscopic biopsy specimens demonstrated interstitial lymphoid infiltration after administration of anti-programmed death-1 antibody [15]. In the resected specimen obtained from our patient, we observed similar inflammatory findings (Fig. 3). An immunologic reaction may have a potential to influence intestinal perforation, and in the present case, we cannot deny that an immunologic reaction influenced the development of intestinal perforation. We consider that the perforation in our case was associated with the autoimmune mechanism of nivolumab, which would indicate that this drug has unique properties that differentiate it from other anti-tumor drugs. However, the mechanism of gastrointestinal perforation due to nivolumab is not understood, and there is no past evidence regarding this. While it has been previously reported that using nivolumab could cause colitis, there is also the risk that the gastrointestinal perforation could appear during treatment; therefore, physicians should be aware of the risk of gastrointestinal perforation when using nivolumab.
Nivolumab therapy has potential efficacy for malignant melanoma refractory to existing pharmaceutical therapies, such as in the present case. Moreover, nivolumab therapy could improve overall survival and quality of life among patients with malignant melanoma, and is expected to become a central or combination therapy for patients with unresectable malignant melanoma. However, nivolumab therapy can cause serious side effects (e.g., intestinal perforation in the present case), and patients who receive nivolumab therapy should be monitored for the onset of possible side effects. Nevertheless, the accumulation of additional cases or large-scale studies are needed to validate our findings.
