Original ArticleTreatment-associated Fatigue in Cancer Patients Treated with Immune Checkpoint Inhibitors; a Systematic Review and Meta-analysis
Introduction
Stimulating our self-immune system to combat cancer cells has been a daunting dream for cancer researchers for decades. Until recently, there was no effective method to achieve this [1]. However, in 2010 the first phase III study using a so-called immune checkpoint inhibitor showed survival advantage in patients with advanced metastatic melanoma. Checkpoint inhibitors work by inhibiting the internal regulatory checkpoints that prevent over-activation of cytotoxic T cells and thereby allowing therapeutic anti-tumour T-cell responses. Currently, the target checkpoints that are inhibited by monoclonal antibodies in clinical practice are CTLA-4 and PD-1. Ipilimumab and tremelimumab are two CTLA-4-targeting antibodies that have shown promising efficacy in treating advanced melanoma [2], [3], whereas PD-1-targeted agents include pembrolizumab and nivolumab, which have been approved in advanced melanoma and previously treated advanced non-small cell lung cancer (NSCLC) [4], [5]. Moreover, nivolumab has been approved in the treatment of previously treated advanced renal cell carcinoma (RCC) [6]. Evaluation of these agents in many other cancers, including lymphoma and gastrointestinal cancers, is ongoing.
However, due to the novelty of their mechanism of action, they have been accompanied by immune-related adverse events, which are unique to this category of drugs [7]. Immune-related adverse events include cutaneous, hepatic, endocrine, gastrointestinal, renal and pulmonary toxicities [8], [9], [10], [11], [12]. Moreover, an increased risk of fatigue has been observed. Fatigue is a well-known clinical problem in autoimmune diseases like lupus erythematosus and other connective tissue diseases. Therefore, it is not surprising to find fatigue as a potential immune-related adverse event reflecting some kind of induced autoimmunity. Consequently, there were concerns about the potential impact of checkpoint inhibitors on aggravating cancer-related fatigue. Therefore, this meta-analysis was conducted to determine the risk of treatment-associated fatigue in cancer patients who are being treated with inhibitors of the immune checkpoints.
Section snippets
Sourcing the Data
A thorough literature review of Medline and Google scholar was conducted. The search was carried out until December 2015 and it was confined to human studies, published in English and carried out on cancer patients. The search was additionally confined to randomised controlled trials. The search terms included: ‘nivolumab’[Supplementary Concept] OR ‘tremelimumab’[Supplementary Concept] OR “ipilimumab’[Supplementary Concept] OR ‘pembrolizumab’[Supplementary Concept]. Trials were evaluated
Search Results
The search strategy revealed 271 potentially suitable records on inhibitors of the immune checkpoints from Medline and Google scholar databases. The reasons for study exclusion are clarified in Figure 1. Accordingly, 17 clinical trials were considered eligible for the analysis; this included 14 phase III trials and three phase II trials [2], [3], [4], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. Six studies utilised ipilimumab, seven studies utilised
Discussion
Fatigue is one of the main side-effects of checkpoint inhibitors. As far as we know, this is the most up to date analysis to provide an assessment of treatment-associated fatigue in cancer patients receiving inhibitors of the immune checkpoints. This data analysis showed that CTLA-4 inhibitors (ipilimumab 10 mg/kg and tremelimumab) are linked to a higher risk of all- and high-grade fatigue compared with control regimens, whereas PD-1 inhibitors (nivolumab and pembrolizumab) are linked to a
Conclusions
This analysis of data showed that CTLA-4 inhibitors (ipilimumab 10 mg/kg and tremelimumab) are linked to a higher risk of all- and high-grade fatigue compared with control regimens, whereas PD-1 inhibitors (nivolumab and pembrolizumab) are linked to a lower risk of all- and high-grade fatigue compared with control regimens.
References (33)
- et al.
Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial
Lancet Oncol
(2014) - et al.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Lancet Oncol
(2014) - et al.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial
Lancet Oncol
(2015) - et al.
Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial
Ann Oncol
(2013) - et al.
Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
Lancet Oncol
(2015) - et al.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial
Lancet Oncol
(2015 Aug) - et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
(2016 Apr 9) - et al.
Cancer immunotherapy: moving beyond current vaccines
Nat Med
(2004) - et al.
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
(2010) - et al.
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma
N Engl J Med
(2011)
Pembrolizumab versus ipilimumab in advanced melanoma
N Engl J Med
Pembrolizumab for the treatment of non-small-cell lung cancer
N Engl J Med
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma
N Engl J Med
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
N Engl J Med
Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis
Future Oncol
Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis
Expert Opin Drug Saf
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