Introduction
Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide (1). Small cell LC (SCLC), accounting for ~15% of all LCs (2), is classified into limited-stage and extensive-stage (ES-SCLC) according to the VALSG staging system. The five-year relative survival rate for SCLC is ~6.4% (3), most patients are diagnosed at the extensive stage (4). For over 30 years, platinum plus etoposide has been the standard first-line treatment (5). In the latest NCCN guidelines (6), atezolizumab and durvalumab, as immune checkpoint inhibitors (ICIs) combined with platinum-etoposide, have been officially established as the preferred first-line treatment options for ES-SCLC.
During chemotherapy for patients with LC, various adverse reactions often occur. Glucocorticoids, such as dexamethasone, have anti-inflammatory, immunosuppression and anti-allergic effects (7) and may help reduce chemotherapy-related adverse reactions, thus being widely used in chemotherapy regimens for patients with LC (8). Although dexamethasone is routinely used for antiemesis, the optimal timing-prophylactic versus symptom-triggered-remains undefined. In clinical practice, there are two main strategies: One is prophylactic use, where dexamethasone is routinely administered before the initiation of chemotherapy or prior to the onset of adverse reactions, with the expectation that early intervention will reduce the incidence and severity of adverse reactions; the other is episodic use, where symptomatic treatment is only provided after patients develop clear symptoms of adverse reactions (such as severe nausea and vomiting and drug allergic reactions). Each of these strategies has its own considerations: Prophylactic use may reduce the suffering caused by adverse reactions, but long-term or excessive use may increase the risk of infections, blood glucose fluctuations and other side effects; while episodic use can avoid unnecessary drug exposure, it may lead to the aggravation of adverse reactions due to delayed intervention, and even affect the progress of chemotherapy. It is precisely due to the uncertainty in the timing of dexamethasone administration and the controversies surrounding the balance between efficacy and safety of different administration strategies (8,9) that the present study intended to adopt the prophylactic dexamethasone administration regimen. By systematically observing its efficacy in controlling adverse reactions, patient tolerance and related safety indicators during platinum-etoposide chemotherapy, the present study aimed to provide clinical evidence for clarifying the optimal timing of dexamethasone administration in LC chemotherapy.
Discussion
Glucocorticoids can alleviate chemotherapy-induced adverse reactions through various mechanisms (12). Their anti-inflammatory effects can inhibit the release of inflammatory mediators, reducing tissue inflammation and relieving symptoms such as vomiting and constipation (13). Additionally, they can stabilize mast cell and lysosomal membranes, reducing the occurrence of allergic and toxic reactions (14), which may have a positive impact on preventing severe adverse reactions. However, long-term use of glucocorticoids may lead to a series of side effects, such as metabolic disorders (15). This dilemma places clinicians in the challenging position of continuously weighing therapeutic benefit against potential harm. In the context of LC chemotherapy, a pivotal and still unresolved question is whether dexamethasone should be administered only after adverse events have manifested, or whether prophylactic use is more likely to maximize net clinical benefit. Consequently, optimizing the strategic deployment of dexamethasone remains an urgent unmet need.
To address this central controversy, the present study specifically interrogates the prophylactic dexamethasone paradigm. The results showed that compared with the control group, the hormone group had a significantly lower incidence of nausea/vomiting, confirming the effectiveness of prophylactic glucocorticoid use in reducing chemotherapy-related nausea/vomiting and after adjusting for age, sex and ECOG performance status in a multivariable logistic regression model, the incidence of vomiting remained significantly lower in the prophylactic dexamethasone group than in the non-prophylactic group (Table SII), consistent with the pharmacological actions of glucocorticoids (7). Nausea/vomiting is a common adverse reaction to chemotherapy and glucocorticoids can alleviate vomiting symptoms by inhibiting neurotransmitter release and regulating gastrointestinal function (16). In patients treated with etoposide plus platinum and all patients, the hormone group had a significantly lower incidence of constipation. Glucocorticoids can improve intestinal motility, promote water absorption in the intestines and make stools softer and easier to pass (17). In patients treated with etoposide plus platinum combined with ICIs and all patients, the hormone group had a significantly lower incidence of leukopenia. Glucocorticoids may regulate the immune system and hematopoietic function of the body, reducing the inhibitory effects of chemotherapy drugs on bone marrow hematopoietic cells and thereby lowering the risk of leukopenia (18). Moreover, in patients receiving etoposide plus platinum combined with ICIs, the hormone group had significantly less renal dysfunction, suggesting a potential kidney-protective effect of prophylactic dexamethasone in this chemo-immunotherapy subset (19). Glucocorticoids can reduce renal tubular injury, inflammation and improve renal microcirculation caused by chemotherapy drugs, thus reducing the risk of renal dysfunction (20), which is of significant clinical importance for patients with ES-SCLC receiving chemotherapy. Renal dysfunction not only affects the quality of life of patients but may also limit the dosage and course of subsequent chemotherapy drugs (21). Although this renal benefit is intriguing, it was observed exclusively in the chemo-immunotherapy subgroup and needs prospective validation. Notably, all analyses adhered to the intention-to-treat principle, rescue dexamethasone was administered only after documented nausea/vomiting or other breakthrough toxicities and therefore could not bias the primary endpoint assessment (incidence of nausea/vomiting). Nevertheless, such rescue therapy constitutes a potential confounder in survival analyses. To address this, both univariate and multivariate Cox regression analyses were performed after excluding patients who received any systemic glucocorticoid. The results remained consistent, showing that prophylactic versus no prophylactic dexamethasone did not significantly affect overall survival either before or after this exclusion (Table SI).
Concerns have been raised that sustained systemic glucocorticoids (≥10 mg prednisone-equivalent daily) can attenuate the efficacy of immune-checkpoint inhibitors (22). In the present cohort study, however, short-term chemotherapy-linked dexamethasone (4.5 mg orally for 3 days) did not adversely affect ORR, DCR or OS in patients receiving ICIs. These findings align with prospective data showing that brief steroid pulses for anti-emesis do not significantly diminish efficacy of ICIs (23). Until further randomized evidence is available, the lowest effective dose and shortest feasible duration of dexamethasone should be preferred.
However, in terms of hypertension, the hormone group showed a higher incidence compared with the control group, although the difference was not statistically significant. This trend suggests that prophylactic glucocorticoid use may increase the risk of hypertension, possibly related to the physiological effects of glucocorticoids in promoting sodium and water retention (24). However, due to limitations such as sample size, no significant difference was observed. For patients with a history of hypertension or other cardiovascular risk factors, it is recommended to closely monitor blood pressure changes during treatment and take appropriate measures to avoid potential adverse effects, such as administering antihypertensive therapy if necessary. Additionally, glucocorticoids can lead to increased blood glucose levels by promoting gluconeogenesis and reducing peripheral tissue glucose uptake (25). Although there was no direct data supporting this in the present study, based on previous research (26,27), long-term or high-dose use of glucocorticoids may increase the risk of hyperglycemia. In the present study, glucocorticoids were used prophylactically for a short term, therefore no hyperglycemia events were observed. However, based on previous research results, patients with diabetes or abnormal glucose regulation should have their blood glucose monitored during treatment, and any abnormalities should be promptly addressed. Regarding other adverse reactions, such as anemia, thrombocytopenia, hypoalbuminemia, AST elevation, ALT elevation and electrolyte disturbances, no significant differences were observed between the two groups. It should be noted that, although subgroup analyzes were attempted, the limited sample size rendered most of these subgroups underpowered. Residual confounding cannot be fully excluded and needs to be validated in larger-scale or pooled datasets. In conclusion, prophylactic glucocorticoid use has certain benefits for patients with ES-SCLC on platinum-based doublet therapy. It can alleviate nausea and vomiting, reduce the risk of leukopenia, and decrease the incidence of constipation, thereby improving patients' treatment experience and boosting adherence. The present study found no significant adverse events linked to prophylactic glucocorticoid use. Additionally, no significant differences in ORR, DCR, or median survival were observed between the two groups, indicating that prophylactic glucocorticoid use does not affect treatment efficacy. In clinical practice, recognizing the dual-edged nature of glucocorticoids and using them appropriately can optimize treatment and enhance patients' quality of life.