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Toxicities and outcomes: Do steroids matter?

Immune therapies, particularly those targeting programmed death-1/ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA-4), have transformed the treatment outlook for various cancer types. However, such therapies frequently trigger toxicities by inhibiting these key negative regulators of adaptive immunity. When mild, these toxic events are treated with expectant management and supportive care, but they require moderate-dose to high-dose systemic glucocorticoids (usually with prednisone 1 mg/kg or equivalent) when they are more severe. Therefore, steroid administration remains the keystone to reversing immune therapy toxicities. Glucocorticoids induce lymphopenia, inhibit gene transcription of proinflammatory genes, block the secretion of inflammatory cytokines, and have various other immunosuppressive mechanisms. Initially, clinicians feared that the lympholytic and immune-suppressive properties of steroids, when administered for toxicities, would blunt the antitumor immunity generated by immune checkpoint inhibitors. However, subsequent studies appeared to dismiss this fear. Several clinical trials and retrospective studies demonstrated that toxicities and their attendant steroids were associated with at least equivalent (if not superior) clinical outcomes (in terms of tumor response, progression-free survival, and overall survival). Thus, the hesitancy for using steroids to treat toxicities has diminished, and these agents remain the mainstay of treatment algorithms for severe toxicities across organ systems. In this issue of Cancer, Faje and colleagues report their experience treating 98 patients who had ipilimumab-induced hypophysitis. Patients with hypophysitis had superior clinical outcomes compared with those who do not have this toxicity, as reported previously in a smaller study. It is noteworthy that, in a subset of patients who received ipilimumab monotherapy, those who received low-dose steroids had superior clinical outcomes in terms of time to treatment failure (hazard ratio, 0.28; P 5 .001) and overall survival (hazard ratio, 0.24; P 5 .002) compared with those who received high-dose steroids. These findings persisted when integrated into multivariable models that included known prognostic factors, such as performance status and lactate dehydrogenase levels. This suggests that higher doses of steroids potentially may affect antitumor immunity and counteract the beneficial correlation between toxicity and response. The study by Faje et al adds several important insights into our understanding of immunotherapy and toxicities. First, in contrast to most other inflammatory toxicities, hypophysitis tends to be self-limited and can be treated safely with replacement-dose steroids alone instead of high-dose steroids. Indeed, in this study, patients who received low-dose versus high-dose steroids had equivalent rates and timing of resolution of their hypophysitis, in terms of both imaging findings and clinical symptoms. Thus, as the authors point out, this patient population provided a unique opportunity to dissect the impact of toxicity from the impact of steroid treatment on tumor-specific outcomes. Second, hypophysitis tends to occur during the first 4 doses of ipilimumab monotherapy. This avoids the confounding factor of many studies, which have linked toxicities (that may occur at any time during therapy) with response: toxicities occur at higher rates when patients continue to receive therapy, but they only continue to receive therapy if they are benefiting. Thus, the study provides further evidence that at least this particular toxicity (hypophysitis) is truly linked with improved outcomes. Third, still more evidence indicates that low-dose (rather than high-dose) steroids are sufficient to treat hypophysitis and should be considered the standard of care. Although the use of ipilimumab monotherapy likely will continue to decline moving forward, recent studies have demonstrated excellent activity of ipilimumab in combination with anti-PD-1 agents in renal cell carcinoma and lung cancer. Thus, hypophysitis, a condition nearly unique to ipilimumab therapy, will only continue to grow as a clinical problem for providers across disciplines. Although the findings are important, the study does present some limitations that preclude a widespread conclusion that steroids have an adverse impact on antitumor immunity. First (and most obviously), the low-dose group included