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Table of Contents
REAL WORLD DATA
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 204-208

Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with solid neoplasms: A real-world experience from a tertiary cancer center


Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel West, Mumbai - 400 012, Maharashtra; Homi Bhabha National Institute (HBNI), Mumbai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_88_19

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  Abstract 


Introduction: Checkpoint inhibitors (CPIs) are rapidly becoming the standard of care in solid tumors for multiple indications. Steroids due to their immunosuppressive nature might decrease the efficacy of these agents. To test this hypothesis, we performed an audit of our patients who had received CPI and concomitant steroids.
Patients and Methods: This was a retrospective audit of a prospectively maintained database at Tata Memorial Hospital, Mumbai, between August 2015 and November 2018. Patients who received CPI for palliative indication were included. Overall survival (OS) was calculated from the date of the start of immunotherapy to the date of death. Data regarding the use of steroids and cumulative number of days of use were noted. Time-to-event analysis was done using Kaplan–Meier estimator, and hazard ratio (HR) was calculated using Cox proportional model.
Results: A total of 155 patients were identified to have received CPI during the study period, of which 38 (24.5%) patients received steroids with prednisolone equivalent of ≥10 mg/day. The median age of the patients receiving steroids was 58.7 years (range, 22–85), and 31 (81.6%) patients were male. The median duration of steroid use was 7 (range, 2–30) days. The median OS for patients who received steroids was 3.9 months (95% confidence interval [CI], 1.8–11.4) versus 5.47 months (95% CI, 1.3–9.6) in patients who did not receive steroids (P = 0.23). The median progression-free survival for patients who received steroids for <10 days was 1.4 months (95% CI, 0.9–1.9) versus 3.8 months (95% CI, 0–8.6) for patients who received steroids for 10 or more days (P = 0.009). Using duration of steroid use as a continuous variable, HR for death was 1.0 (95% CI, 0.90–1.04, P = 0.991). There was a statistically significant better OS in patients who did not receive antibiotics (median OS, 11.4 months [95% CI, 8.5–14.3] vs. 2.8 months [95% CI, 1.5–4.1], P = 0.047).
Conclusions: There was no statistical difference in OS in patients on immunotherapy with or without the use of steroids supporting the notion that steroids can be judiciously used along with CPI.

Keywords: Antibiotics, checkpoint inhibitors, steroids, survival outcomes, immunotherapy, ICI


How to cite this article:
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Abraham G, Talreja V, D'Souza H, Prabhash K. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with solid neoplasms: A real-world experience from a tertiary cancer center. Cancer Res Stat Treat 2019;2:204-8

How to cite this URL:
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Abraham G, Talreja V, D'Souza H, Prabhash K. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with solid neoplasms: A real-world experience from a tertiary cancer center. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Apr 3];2:204-8. Available from: http://www.crstonline.com/text.asp?2019/2/2/204/273703




  Introduction Top


Checkpoint inhibitors (CPI) are rapidly becoming the standard of care in solid tumors for multiple indications.[1] Corticosteroids are used routinely in oncology for their analgesic, antiemetic, and anti-inflammatory properties, and important uses include the palliation of metastatic disease to the central nervous system (CNS) and management of immune-related adverse effects (irAE). Since CPI have varying response rates among cancers and within cohorts with the same malignancy, the factors that influence the efficacy of CPI are of critical interest in current oncology practice.[2] Presently, a large number of clinical trials studying CPI exclude cancer patients who are on corticosteroids; this is based on the biological hypothesis that corticosteroids may antagonize the therapeutic effects of immunotherapy.[3] However, there are both positive and negative data on the impact of concomitant use of steroids and CPI on survival. Arbour et al. showed that the use of ≥10 mg of prednisone before starting CPI negatively affects clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC) receiving programmed death-1 (PD-1) inhibitors.[4] On the other side of the coin, the systematic review by Garant et al. suggested that the concomitant administration of corticosteroids and CPI may not necessarily lead to poorer clinical outcomes.[3] To add data from real-world settings to this controversial subject, we performed a retrospective audit of outcomes of our patients who received CPI along with concomitant use of corticosteroids for any indication.


  Patients and Methods Top


Study population

This study is a retrospective audit of a prospectively maintained database of patients who received CPI alone for palliative indication for solid tumors in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, Maharashtra, India. The patients' management was discussed in a multidisciplinary joint clinic. The information about the use of steroids and cumulative number of days of use was obtained from the electronic medical records. Steroid use was considered significant if patients received prednisolone equivalent of ≥10 mg/day for any duration. This particular threshold was taken as it was an exclusion criterion for most of the pivotal immunotherapy clinical trials.[5],[6] Using a retrospective chart review, the reasons for corticosteroid administration were grouped as either management of irAE or any other indication. While performing this study, various ethical guidelines such as the Declaration of Helsinki, the International Council for Harmonization-Good Clinical Practice, and the Indian Council of Medical Research guidelines were followed.

Clinical outcomes

Response assessment was performed using radiological assessment according to the Response Evaluation Criteria in Solid Tumors version 1.1. Response assessment was done 2 months after the commencement of CPI or at any symptoms/signs of clinical progression whichever was earlier. Adverse events during immunotherapy were documented and graded using the Common Terminology Criteria for Adverse Events version 4.02. Data collected included the date of the start of immunotherapy, date of stopping immunotherapy, reason for stopping immunotherapy, date of progressive disease, and date of death. Progression-free survival (PFS) was defined as the interval from the date of starting CPI till the date of progression or death due to any cause if it occurred before disease progression or the last follow-up date whichever was earlier. Overall survival (OS) was calculated from the date of the start of CPI to the date of death. Patients who were still alive were censored at the date of the last contact.

Statistical analysis

All statistical calculations were performed using SPSS statistical software for windows version 20.0 (Armonk, New York, USA, IBM Corp.). Categorical and continuous variables were summarized using descriptive statistics. Time-to-event analysis was done using Kaplan–Meier estimator,[7] and hazard ratio (HR) was calculated using Cox proportional model.[8],[9] All P values were based on a two-sided hypothesis with a confidence interval (CI) at the 95% level, and P < 0.05 was considered statistically significant.


  Results Top


A total of 155 patients were identified to have received CPI (151 patients received nivolumab and 4 received pembrolizumab) during the study period, of which 38 (24.5%) patients received steroids with prednisolone equivalent of ≥10 mg/day. [Figure 1] shows the patient flowchart diagram of the study. All patients receiving steroids were on nivolumab in this study. The median age of the patients receiving steroids was 58.7 years (range, 22–85), and 31 (81.6%) patients were male. CPI was used as first- or second-line therapy in 23 (60.5%) patients, and 6 (15.8%) patients had brain metastasis at the time of initiating CPI. Eastern Cooperative Oncology Group Performance Status was 0–1 in 23 (60.5%) patients while antibiotics were required in 27 (71.1%) patients. The primary site was lung in 63% of the patients followed by head and neck in 16% of the patients.
Figure 1: Patient flowchart diagram of the study patients receiving checkpoint inhibitors according to the consumption of steroids. Steroids were required as a part of management of immune-related adverse events in 12 (31.6%) patients which included pneumonitis and hepatitis, both in 3 (7.9%), nephritis, encephalitis, and hypophysitis each in 1 (2.6%) patient. Various combinations of immune-related adverse events occurred in 5 (13%) patients. Steroids were used as a continuous therapeutic measure for preexisting conditions (like rheumatoid arthritis and exacerbations of chronic obstructive pulmonary disease) in 5 (13%) patients

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The median duration of steroid use was 7 days (range, 2–30). Steroids were required as a part of the management of immune-related adverse events in 12 (31.6%) patients which included pneumonitis and hepatitis, both in 3 (7.9%), nephritis, encephalitis and hypophysitis each in 1 (2.6%) patient. Various combinations of adrenal insufficiency, pneumonitis, nephritis, and hypophysitis occurred in 5 (13%) patients. Steroids were used as a continuous therapeutic measure for preexisting conditions (rheumatoid arthritis and exacerbations of chronic obstructive pulmonary disease) in 5 (13%) patients while palliation of symptoms such as CNS metastasis, pain, and dyspnea was the indication in 21 (55.2%) patients.

The median PFS for patients who received steroids was 1.5 months (95% CI, 1.2–1.9) versus 3.1 months (95% CI, 1.8–4.4) in patients who did not receive steroids, P = 0.28. The corresponding one-year survival was 29.5% (±9) versus 40.6% (±5.4). The median OS for patients who received steroids was 3.9 months (95% CI, 1.8–11.4) versus 5.47 months (95% CI, 1.3–9.6) in patients who did not receive steroids, P = 0.23. Using duration of steroid use as a continuous variable, the HR for death was 1.0 (95% CI, 0.90–1.04; P = 0.991). The median PFS for patients who received steroids for <10 days was 1.4 months (95% CI, 0.9–1.9) versus 3.8 months (95% CI, 0–8.6) for patients who received steroids for 10 or more days [P = 0.009, [Figure 2] (HR, 2.6; 95% CI, 1.2–5.6). However, there was no statistically significant difference in OS (median 1.48 months vs. 8.8 months, respectively, P = 0.114). Furthermore, there was no difference in PFS or OS depending on the indication for the use of steroids [irAE versus others, [Table 1]. There was a statistically significant better OS in patients who did not receive antibiotics (median OS, 11.4 months; 95% CI, 8.5–14.3) compared to patients who received antibiotics (median OS, 2.8 months; 95% CI, 1.5–4.1), P = 0.047 [Figure 3].
Figure 2: Kaplan–Meier curve of progression-free survival of patients on checkpoint inhibitors who received steroids for the duration of <10 days (blue) versus who received for ≥10 days (green)

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Table 1: Characteristics of the patients who received steroids along with immunotherapy

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Figure 3: Kaplan–Meier curve of overall survival of patients on checkpoint inhibitors concomitant with steroids who did not receive antibiotics (blue) versus who received (green)

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  Discussion Top


Corticosteroids are known to exert an immunosuppressive effect through their pleiotropic effects on immune cell apoptosis, cytokine release, differentiation, migration, and clonal expansion.[10] This property of steroids is used in the management of irAE that may result from CPI therapy. However, at the same time, this has raised concern that the efficacy of immunotherapy may be abrogated by the use of corticosteroids at the time of CPI initiation. In our study, we found no statistical difference in median PFS and OS for patients on immunotherapy with or without the concomitant use of steroids. This finding is in agreement with the systematic review by Garant et al. which concluded that the concomitant administration of corticosteroids and CPI may not necessarily lead to poorer clinical outcomes.[3] However, in a study by Fucà et al.,[11] in patients with metastatic NSCLC (mNSCLC), the early use of steroids was found to be associated with poor disease control (odds ratio, 0.32; P = 0.006), PFS (HR, 1.80; P = 0.003), and OS (HR, 2.60; P < 0.001). Similarly, in a study by Arbour et al.,[4] baseline corticosteroid use was significantly associated with decreased PFS (HR, 1.3; P = 0.03), and OS (HR, 1.7; P < 0.001) in mNSCLC. Both these studies were focused on mNSCLC which comprised 63% of the patients in our study, and this may be one of the reasons for differences in results.

We found that the duration of the use of steroids significantly impacted the PFS with inferior survival noted in patients who received steroids for <10 days. This may stem from the use of longer duration of steroids in more compelling indications such as irAE or preexisting but controlled autoimmune diseases. In a recent study by Ricciuti et al.,[12] although patients with NSCLC treated with ≥10 mg of prednisone at the time of immunotherapy initiation were found to have worse outcomes than patients who received between 0 and 10 mg of prednisone, the authors concluded that this difference appeared to be driven by a poor-prognosis subgroup of patients who received corticosteroids for palliative indications, primarily brain metastases (57.6%), cancer-related dyspnea (18.2%), and cancer-related bone pain (16.7%). In our study, there was no difference in PFS or OS depending on the indication of the use of steroids (irAE versus others). However, the smaller number of patients in our study precludes any definite results.

Another important finding in our study was the statistically significant better OS in patients who did not receive antibiotics compared to those who did. There have been previous reports of negative association of antibiotics on clinical activity of CPI in patients with advanced renal and NSCLC both in terms of PFS and OS.[13] To our knowledge, no previous study has reported results on the use of antibiotics in patients who received steroids while receiving CPI. Thus, our study adds important data on the interplay of the use of both steroids and antibiotics in patients receiving CPI.

There are some important drawbacks of our study which should be kept in mind while applying the results of this study in clinical practice. Apart from the retrospective nature of the study and inherent drawbacks, this study included principally patients of NSCLC and head-and-neck cancers. Furthermore, dissecting the data into subgroups might have failed to give significant results due to smaller number of patients in various subgroups making interpretation difficult. However, this study adds real-world data on the issue of the use of steroids concomitant with CPI in low-middle-income countries.[14]


  Conclusions Top


In our study, we found no statistical difference in median PFS and OS for patients on immunotherapy for solid tumors with or without concomitant use of steroids supporting the notion that steroids can be judiciously used along with CPI without compromising the outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018;36:2872-8.  Back to cited text no. 4
    
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Fucà G, Galli G, Poggi M, Lo Russo G, Proto C, Imbimbo M, et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 2019;4:e000457.  Back to cited text no. 11
    
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Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018;29:1437-44.  Back to cited text no. 13
    
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