temic corticosteroids, usually at an equivalent dose of prednisone 1-mg/kg daily. In such cases, treatment checkpoint inhibitor therapy should be interrupted until symptoms improve to baseline or grade 1 or lower before more treatment can be considered. In the event of severe rashes, not responsive to oral corticosteroids, clinicians should consider dermatology consultation and the addition of immunosuppressive medications such as infliximab, mycophenolate mofetil, or cyclophosphamide. Treatment with immune checkpoint inhibitors should be permanently discontinued if cutaneous symptoms fail to improve after 12 weeks of supportive management due to the risk of more severe symptoms. Diarrhea/colitis. Diarrhea/colitis with CTLA-4 blockade is more common than with PD-1/PD-L1 blockade. The rate of grade 3/4 diarrhea in patients treated with PD- 1/PD-L1 agents is very low across diseases, including RCC where treatment related diarrhea with nivolumab was reported in 12%, but only 1% grade ¾. For any patient with treatment-emergent diarrhea, clinicians should consider other etiologies that may be responsible, such as Clostridium diffıcile infection or other bacterial/viral pathogens. Patients should be counseled on the importance of maintaining oral hydration. Some clinicians fınd that the American Dietary Association’s colitis diet and antimotility agents (oral diphenoxylate HCl and atropine sulfate 4 times a day) can be helpful. For persistent mild diarrhea the use of oral budesonide can be considered (see below). For patients with symptoms refractory to these interventions, and for those with grade 3 diarrhea and negative infectious workup the use of oral or intravenous corticosteroids is required.8 When symptoms are refractory to oral corticosteroids, hospitalization for intravenous corticosteroids, hydration, and electrolyte management is required. Endoscopic workup can be reserved for situations when the diagnosis is unclear. If intravenous corticosteroids (up to 2 mg/kg methylprednisolone twice a day) do not lead to symptom resolution, infliximab (Remicade; Janssen Biotech, Horsham, PA) at a dose of 5 mg/kg, once every 2 weeks can be effective in patients with steroid-refractory colitis.9-11 The use of infliximab in this setting is based on its use in patients with inflammatory bowel diseases.12 In very rare cases, colitis can result in bowel perforation and require surgical intervention, and in some cases colostomy. In patients with low-grade events and those with prompt response to immunosuppressive therapy, anti-PD- 1 therapy may be resumed after glucocorticoid taper, which should be carried out over at least 1 month to prevent symptom rebound. In high-grade and steroid-refractory cases, therapy must be permanently discontinued. 12,13 Unfortunately, there are no proven treatments to prevent the occurrence of diarrhea. In one study, prophylactic use of the matrix-release corticosteroid budesonide was not found to be helpful.14 Hepatic events. Hepatitis, as determined by elevations in aspartate aminotransferase (AST), aminotransferase (ALT) and less commonly, total bilirubin, can develop in patients treated with checkpoint blockade. Although most episodes present only as asymptomatic laboratory abnormalities, some patients have an associated fever. Rates of AST and ALT elevations with CTLA-4 blockade vary among clinical trials, but they typically have been reported in less than 10% of patients.15 In large trials of PD- 1–blocking antibodies, the rates of hepatitis were lower(below 5%) and grade ¾ toxicity was even less common. 11,12 On the RCC registration trial the rate of immune related hepatitis was low (1.5%, and early in onset (median 7.3 weeks) reference.2 Radiographic fındings are not typical. In severe cases, however, fındings on CT scans may include mild hepatomegaly, periportal edema, or periportal lymphadenopathy. 14 Liver biopsies have described pathologic changes that include severe panlobular hepatitis with prominent perivenular infıltrate with endothelialitis or a primary biliary pattern with mild portal mononuclear infıltrate around bile ductules.14,16 Hepatic function (transaminases and bilirubin) should be monitored before each dose of checkpoint inhibitor therapy. In the setting of rising transaminases, viral and other drug-induced causes of hepatitis should be excluded. Patients with grade 1 elevations may not need treatment-interruption, but should we closely monitored for further enzyme rise, e.g. with once-twice weekly blood draws. For patients with grade ≥2 events treatment should be interrupted, alternative etiologies should be investigated, and prompt treatment with systemic corticosteroids is advised (e.g. starting dose prednisone 1mg/kg QD or equivalent) with close monitoring of liver function, ideally daily blood draws. Typically, responses are swift Once liver function tests have improved to within grade 1, steroids can be tapered, typically over a minimum of 3-4 weeks. In rare cases, elevations in AST and ALT are steroid-refractory and 500 mg every 12 hours of mycophenolate mofetil (CellCept; Genentech, South San Francisco, CA) may be helpful. The use of antithymocyte globulin therapy also was described in a case report.8 Unlike for patients with diarrhea/colitis, infliximab should not be given to patients with hepatitis because infliximab carries a risk of hepatotoxicity. Endocrinopathy. Immune-related adverse events that affect the pituitary, adrenal, and thyroid glands often present with nonspecifıc symptoms such as nausea, headache, and fatigue.8 Despite difficulties in determining the incidence of such AEs—due to the variable methods of assessment, diagnosis, and monitoring in each clinical trial, new data are emerging. For example, hypophysitis (pituitary inflammation) and hypothyroidism are the most common endocrinopathies and reportedly occur in up to 10% of patients treated with CTLA-4 blockade.8 The most frequent AE is thyroid dysfunction, which is seen in approximately 10% of RCC patients receiving Kidney Cancer Journal 41
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