Hepatocellular carcinoma (HCC) is at the focus of intense research efforts for the development of immune checkpoint inhibitors (ICI).1 Targeted inhibition of programmed cell death (PD-1) receptor/ligand (PD-1/PD-L1) interaction results in measurable anti-tumor responses in a fraction of patients with advanced HCC, a finding that led to the breakthrough approval of nivolumab2 and pembrolizumab3 by the Food and Drug Administration in light of the results of small, single-arm open-label studies. However, evidence of initial activity has not translated into statistically significant survival benefit in randomized controlled studies of anti-PD-1 monotherapy, a finding that has instigated the clinical development of immunotherapy combinations with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors4 and anti-angiogenics to further enhance the anti-tumor immunity.5

Evolving experience in the use of ICI suggests iatrogenic factors as important contributors in shaping clinical responses to immunotherapy.6 7 Corticosteroid therapy (CT) is often indicated in the management of cancer-related symptoms such as cachexia, anorexia, central nervous system edema or pain8 and is recommended by guidelines as first-line therapy for most immune-related adverse events (irAEs).9 CT exerts T-cell suppressive properties by reducing the proliferative potential of naïve T cells10 and stimulate regulatory T-cell development.11

Immunosuppressive CT may therefore adversely influence outcome in patients receiving ICI12 and in fact patients receiving chronic steroid therapy have been for this reason excluded from clinical trials of ICI. The effect of CT either at the moment of ICI commencement or during the course of ICI treatment remains undefined in HCC,13 a point of greater consequence in a disease where ICI monotherapy has struggled to demonstrate evidence of sustained clinical benefit. In this global observational study, we sought to document prevalence of and indications for CT use in patients with HCC being treated with ICI, and to examine the relationship between CT exposure and outcome.

We established a global dataset of 341 patients with HCC treated with ICI between 2016 and 2019 in nine tertiary referral centers in the USA (n=226), Europe (n=68) and Taiwan (n=47) (online supplemental table S1). Patients with a histological or radiologic diagnosis of HCC based on European Society for the Study of the Liver criteria14 and undergoing treatment with checkpoint inhibitors were identified from Oncology Pharmacy electronic records and entered into a prospectively maintained database. In total, we excluded 26 patients who were treated with PD-1/PD-L1 inhibitors in combination with kinase inhibitors and a further 11 patients that classified within Barcelona Clinic Liver Cancer (BCLC) stage D due to performance status 3 and/or Child-Pugh C cirrhosis. This resulted in 304 patients eligible for primary analyses (figure 1).

Evaluation of corticosteroid exposure was defined based on timing of administration in line with published literature on the topic.12 Patients were defined as receiving CT at baseline (bCT) if administered >10 mg of prednisone (or equivalent) for >24 hours within 30 days prior to ICI. Concomitant corticosteroid therapy (cCT) was defined as stated previously from the day of commencement of ICI until permanent cessation of immunotherapy.

Clinicopathologic variables including overall survival (OS) and progression-free survival (PFS) were derived from electronic medical records. OS was calculated from the date of ICI commencement until last follow-up or patients’ death. Response to ICI was evaluated according to RECIST criteria (version 1.1) and best responses to ICI were recorded for each evaluable patient. Electronic medical records were reviewed to identify prescription of oral or intravenous corticosteroid therapy (CT).

Patient characteristics are summarized as means or medians as appropriate. We conducted analysis of proportions across groups using Pearson χ² or Fisher’s exact tests. We represented group-specific OS and PFS using the Kaplan-Meier curve method and formally evaluated the difference in median survival times between pre-specified groups using the log-rank test. We performed univariable and multivariable analyses of survival using Cox regression models to evaluate the impact of CT on patients’ OS and PFS. To avoid collinearity bias, we evaluated features relating to corticosteroid therapy including overall CT exposure, timing and indication for CT therapy in separate multivariable models as outlined before.15 Post-landmark analysis was done in the subset of patients who received corticosteroid (prednisone >10 mg) during ICI treatment. This analysis compared the PFS and OS in patients with/without response with the ICI treatment with cortiscosteroid (CT). Kaplan-Meier analysis was used to estimate the PFS and OS from the time of ICI initiation in patients with (CR+PR) and without (SD+PD) response at 3, 6, 9 and 12 months. Patients who were not evaluable for response at a timepoint were excluded.

All statistical analyses were performed using SPSS V.25.0 and Stata V.16.1 (StataCorp LLC, College Station, TX, USA), and GraphPad Prism (GraphPad Software, La Jolla, CA, USA) with all estimates being reported with corresponding 95% CIs and a two-tailed level of significance of p<0.05.

We document for the first time that corticosteroid use alongside ICI is safe in patients with HCC, mirroring evidence in other indications.16 17 This is particularly reassuring for patients requiring cCT for irAE management, who, despite receiving higher doses of steroids for longer periods compared with other indications, had similar outcomes compared with steroid-unexposed patients. The low prevalence of bCT (5%), not predictive of outcome in our study, is perhaps unsurprising given that, unlike advanced lung cancer, unresectable HCC is a largely asymptomatic diagnosis and intracranial spread is rare.18 Interestingly, only patients with HCC receiving palliative CT had worse ORR, PFS and OS. This lends credence to the view that CT may correlate with prognosis by association with poor prognostic features (ie, cancer-related symptoms secondary to symptomatic or rapidly progressive disease) rather than blunting of ICI responsiveness.19

While limited by small sample size and lack of correlative analyses on peripheral immune cell responses following steroid treatment, the multi-center design of our study ensures adequate representation of the various etiologies of HCC and attempts to control for the diversity in clinical practice including corticosteroid prescribing. Given this study enrolled patients treated with ICI as part of routine clinical practice, our sample included patients with Child-Pugh B cirrhosis, largely excluded from clinical trials of ICI in HCC. While impaired liver function is a key prognostic determinant in HCC,20 this was unrelated to the provision of CT and supplementary analyses inclusive of Child-Pugh A patients only were concordant with main study outcomes (online supplemental figures S3–4). We could not ascertain the relationship between CT and comorbidities other than liver dysfunction, an aspect worth exploring in prospective studies.

To conclude, there is no sufficient evidence to suggest that CT exposure either prior to or during ICI therapy is associated with OS and PFS in patients with HCC; CT exposure does not associate with key clinicopathologic traits of HCC including stage, liver function, alpha-fetoprotein levels and line of therapy. CT for palliative indications identified patients with poorer response and survival from ICI and traces an interesting parallelism with evolving experience in lung cancer where association with adverse features rather than causality has emerged as a likely explanation of the detrimental role of CT.19 While mechanistic studies on the immune-modulatory effects of CT in ICI recipients are awaited, our clinical data are reassuring in suggesting that CT does not appear to worsen ORR and OS in HCC being treated with ICI. The relationship between CT and outcomes from combination regimens including ICI and anti-angiogenics should be further explored in prospective studies.