Optimal timing of steroid initiation in response to CTLA-4 antibody in metastatic cancer: A mathematical model

Abstract

Immune checkpoint inhibitors, introduced in recent years, have revolutionized the treatment of many cancers. However, the toxicity associated with this therapy may cause severe adverse events. In the case of advanced lung cancer or metastatic melanoma, a significant number (10%) of patients treated with CTLA-4 inhibitor incur damage to the pituitary gland. In order to reduce the risk of hypophysitis and other severe adverse events, steroids may be combined with CTLA-4 inhibitor; they reduce toxicity, but they also diminish the anti-cancer effect of the immunotherapy. This trade-off between tumor reduction and the risk of severe adverse events poses the following question: What is the optimal time to initiate treatment with steroid. We address this question with a mathematical model from which we can also evaluate the comparative benefits of each schedule of steroid administration. In particular, we conclude that treatment with steroid should not begin too early, but also not very late, after immunotherapy began; more precisely, it should start as soon as tumor volume, under the effect of CTLA-4 inhibitor alone, begins to decrease. We can also compare the benefits of short term treatment of steroid at high doses to a longer term treatment with lower doses.

Endocrine toxicity of immune checkpoint inhibitors: a network meta-analysis of the current evidence

“…Previous studies have shown that CTLA-4 protein is expressed in the pituitary gland, which plays a key role in regulating hormone secretion [81,82]. Therefore, CTLA-4 inhibitors may interfere with the normal function of the pituitary gland and lead to a decrease in, or cessation of, anterior pituitary hormone secretion [83][84][85]. In addition, CTLA-4 inhibitors may cause expansion and activation of T cells, and consequently exacerbate the body's autoimmune response and aggravate the severity of hypophysitis.…”

Pituitary Enlargement and Hypopituitarism in Patients Treated with Immune Checkpoint Inhibitors: Two Sides of the Same Coin?

“…The European Society of Endocrinology clinical practice guidelines on hypophysitis emphasize that there is no clear evidence for the benefit of high-dose GC, with the possible exceptions of hypophysitis affecting the optic nerves [ 27 ]. Regarding the optimal timing of GC therapy initiation, a recent study developed a mathematical model to evaluate the comparative benefits of different GC administration schedules [ 28 ]. The authors suggested that the GCs treatment should be initiated precisely after the start of immunotherapy, as soon as the tumor volume begins to decrease under the effect of CTLA-4 inhibitors alone [ 28 ].…”

“…Regarding the optimal timing of GC therapy initiation, a recent study developed a mathematical model to evaluate the comparative benefits of different GC administration schedules [ 28 ]. The authors suggested that the GCs treatment should be initiated precisely after the start of immunotherapy, as soon as the tumor volume begins to decrease under the effect of CTLA-4 inhibitors alone [ 28 ].…”

Mathematical Modeling Support for Lung Cancer Therapy—A Short Review

“…One of the indirect proofs that such approach works can be seen in the context of metronomic chemotherapy, both curative [112] and palliative [17], and combined with other forms of treatment [79], which have recently been tested through modeling in the lung cancer context [113]. One of the most important issues in cancer treatment-its adverse effects-has also been modeled for NSCLC [114].…”

“…However, this is slowly beginning to change, as quantified data on these effects start to appear, also in the case of adverse effects in lung-cancer-targeted therapies [124]. In [114], mathematical models led to the formulation of guidelines concerning adjuvant steroid protocols that are used to support targeted therapy of metastatic lung cancer.…”