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Table of Contents
SYSTEMATIC REVIEW
Year : 2018  |  Volume : 17  |  Issue : 1  |  Page : 1-13

Immune checkpoint inhibitors and health-related quality of life: A systematic review of the current literature


Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Web Publication25-Jul-2018

Correspondence Address:
Mohamed H Elshahidi
Algomhorria Street, Mansoura, Dakahliya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MJ.MJ_19_18

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  Abstract 

Background: Over the past years, some immune checkpoint inhibitors (ICPIs) have been approved for clinical use in several malignancies. Examining the effects of ICPIs on the patients' health-related quality of life (HRQoL) may help clinicians in their decision-making process. Aim: The aim of this review is to summarize the current evidence about the effects of ICPIs on the patients' HRQoL. Methods: PubMed, Embase (via OvidSP), Web of Science, Scopus, and EBSCOhost were searched from their dates of inception to January 2018. Studies reporting the effects of ICPIs on the HRQoL using a valid questionnaire are included in the review. A narrative summary of the included studies was presented. Results: Sixteen studies met the specific inclusion criteria, which are as follows: seven about melanoma, three about renal cell carcinoma (RCC), one about metastatic Merkel-cell carcinoma (mMCC), two about squamous cell carcinoma of the head and neck, two about non-small-cell lung cancer (NSCLC), and one about colorectal cancer (CRC). In melanoma, more improvements in the global health status (GHS) were observed with pembrolizumab, ipilimumab 3 mg/kg, and pembrolizumab every 2 weeks than with ipilimumab, ipilimumab 10 mg/kg, and pembrolizumab every 3 weeks, respectively. However, no clinically significant differences were found when adding gp100 vaccine, using different doses of pembrolizumab or combining ICPIs. In RCC, the EQ-5D utility index and the time to deterioration were improved in the nivolumab groups than in everolimus groups. In squamous cell carcinoma of the head and neck, the GHS remained stable or improved with nivolumab. However, there was no significant difference in the time to deterioration between nivolumab and investigator's choice. In mMCC, a slight gain in the GHS was observed with avelumab. In NSCLC, improvements were observed in the symptoms scales and some of the functioning scales with pembrolizumab than chemotherapy. However, no difference was observed between them on emotional functioning. In CRC, some clinically meaningful improvements were observed in nivolumab plus ipilimumab. Conclusion: Due to the complexities in the longitudinal analysis of HRQoL data and some other concerns in the included studies designs, these results should be interpreted carefully.
PROSPERO registration number: CRD42018089311

Keywords: Cytotoxic T-lymphocyte-associated protein -4, health-related quality of life, immune checkpoint inhibitors, programmed death-1, programmed death-ligand 1, quality of life


How to cite this article:
Elshahidi MH. Immune checkpoint inhibitors and health-related quality of life: A systematic review of the current literature. Mustansiriya Med J 2018;17:1-13

How to cite this URL:
Elshahidi MH. Immune checkpoint inhibitors and health-related quality of life: A systematic review of the current literature. Mustansiriya Med J [serial online] 2018 [cited 2018 Aug 20];17:1-13. Available from: http://www.mmjonweb.org/text.asp?2018/17/1/1/237548


  Introduction Top


Rationale

Being the second leading cause of death worldwide, cancer accounts for 1 in 6 deaths with 8.8 million deaths in 2015.[1] Moreover, cancer occurrence negatively affects the physical and social functioning of the patients, with psychological distress being common among them.[2],[3],[4],[5] Health-related quality of life (HRQoL) is defined as individual's satisfaction or happiness with domains of life insofar as they affect or are affected by health.[6] HRQoL assessment includes the effect of diseases or treatments on the physical, social/role, emotional, and cognitive functioning domains.[7] Although clinical trials have principally considered overall survival and progress-free survival as their main endpoints, the importance of other patient-centered endpoints as HRQoL is increasingly being acknowledged.[8],[9] Incorporating HRQoL provides platform for shared clinical decision-making and personalize the treatment benefits from the patient's point of view.[10],[11] In 2006, the Food and Drug Administration (FDA) provided recommendations on the support of using HRQoL in the labeling claims.[12]

Immune checkpoint inhibitors (ICPIs) are a group of drugs able to block the interaction of the inhibitory signals between the cancer cells and the immune cells.[13] The cancer cell can deceive the immune system by expressing inhibitory molecules, for example, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2, that bind to T-cell receptor, for example, programmed death-1 (PD-1), and inhibit the immune response against it.[14] Blocking these restraints have shown to unleash the immune response against the cancer cells and prolonging the overall survival in a subset of patients with certain types of cancer.[15] In 2011, the FDA approved ipilimumab (Yervoy®), the first ICPI drug, targeting the inhibitor receptor cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), for the treatment of unresectable or metastatic melanoma.[16] Since then, several ICPIs have been approved for NSCLC, head-and-neck squamous cell carcinoma, breast cancer, colorectal cancer (CRC), and advanced urothelial carcinoma.[16] Despite their durable response, several immune-related adverse events (irAEs) including autoimmune colitis, hepatitis, endocrinopathies, arthralgia, and cutaneous adverse reactions were observed.[17],[18],[19],[20],[21] Given the high cost of ICPIs and their associated irAEs, investigating the effects of ICPIs on the patients' HRQoL may assist in the clinical decision-making process.[22],[23]

Objective

This review aims to systematically search the literature and to summarize current evidence regarding the effects of ICPIs on the HRQoL.


  Methods Top


Guidelines

The Preferred Reporting Items for Systematic reviews and Meta-Analyses statement was used in reporting this systematic review.[24]

Search strategy

The search process was carried out using the following search algorithm: ((((((((((((((((PD-1 inhibitor) OR Pembrolizumab) OR Keytruda) OR Nivolumab) OR Opdivo) OR PD-L1 inhibitor) OR Atezolizumab) OR Tecentriq) OR Avelumab) OR Bavencio) OR Durvalumab) OR Imfinzi) OR CTLA-4 inhibitor) OR Ipilimumab) OR Yervoy)) AND (((((((((“Quality of Life”[Mesh]) OR Quality of Life) OR Life quality) OR Health-Related Quality of Life) OR Health-Related Quality of Life) OR HRQOL) OR Qol) OR Hqol) OR Patient Reported Outcome).

Data sources

An electronic search of PubMed, Embase (via OvidSP), Scopus, Web of Science, and EBSCOhost was performed for articles published in them from their dates of inception to January 2018. Besides, the references of the included studies were also hand-searched for pertaining studies. No language filter was applied.

Criteria for selecting studies

Screening of the retrieved citations was in two phases

Title and abstract screening then full-text reviewing. Records were screened for meeting the following criteria: (1) peer-reviewed, published article, (2) included an ICPI, and (3) used a valid HRQoL questionnaire. Proposals, reviews, and editorials studies not involving ICPI or studies using quality-adjusted life years as a measure in cost-utility analyzes were excluded from the review. In addition, abstracts were excluded due to the difficulty in appraising the study design and in extracting the data.

Data extraction

A data extraction form was designed to collect the following data

Study ID ( first author, year of publication), type, population, interventions or arms, questionnaire, completion rate, analysis time-point, summary of the results, sensitivity analysis, and percentage of Grade 3–5 AEs.

Risk of bias and methodological quality assessments

The Cochrane risk of bias assessment tool was used in investigating the possible risk of bias in the included studies. It judges randomized trials based on random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete data, and selective reporting.[25] Furthermore, the methodological quality was appraised using a tool previously used in other systematic reviews of HRQoL.[26],[27] The criteria focus on aspects related to the study design were as follows: inclusion and exclusion, population characteristics, and statistical analyzes. Each study accesses a total of 14 points. Studies scoring ≥75% were of high quality, 75%–50% were of moderate quality, and ≤50% were of low quality.

Data synthesis

Due to the differences in the types of cancer that are included, no quantitative analysis was carried out. Summary of the included studies was presented in a narrative, qualitative method.


  Results Top


Study selection

The search algorithm reached 1493 citations. After duplicate removing, title and abstract screening, and full-text reviewing, 16 reports were included in the narrative synthesis by cancer type [Figure 1].
Figure 1: PRISMA flow diagram of the search process conducted on January 30th, 2018

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Melanoma

Seven studies were found pertaining to the effect of ICPIs on HRQoL in patients with melanoma [28],[29],[30],[31],[32],[33],[34] [Table 1] and [Table 2]. Two studies were open-label, and five studies were double-blind. HRQoL and patient-reported outcomes were considered secondary endpoints in three studies. Most studies included patients with Stage III or IV melanoma. One study included patients without BRAF mutation only, and another study included patients with BRAFV600 mutation. Most studies tested the effect of one ICPI against another ICPI, dacarbazine, placebo, or investigator's choice. One study investigated the effect of combining two ICPIs, nivolumab (a PD-1 inhibitor) plus ipilimumab (a CTLA-4 inhibitor) at different doses. All studies used the EORTC QLQ-C30 questionnaire, and four of them used the EQ-5D questionnaire. None of them included a melanoma-specific questionnaire. The total number of patients included in them was 5025. The completion rate at baseline differed among them; however, it decreased in all of them over time. The analysis of the mean change from baseline in the global health status (GHS) scale of the EORTC QLQ-C30 was calculated in most of them at week 12. The mean change in the GHS scale decreased more with ipilimumab than with pembrolizumab (a PD-1 inhibitor). In addition, the decrease in GHS score was more in the arm receiving pembrolizumab every 3 weeks than the group receiving it every 2 weeks. Similarly, high dose (10 mg/kg) of ipilimumab resulted in more decrease in the mean change of the GHS score than low dose (3 mg/kg). In addition, combining ipilimumab with Gp 100 peptide vaccine resulted in no or little improvements. Different doses of pembrolizumab showed no difference in the mean change in the GHS score. However, pembrolizumab showed less decrease in the mean change of GHS score than chemotherapy. In combining nivolumab plus ipilimumab, no clinical meaningful change was observed than monotherapy. No significant difference was observed in the functional scales between groups receiving different doses of pembrolizumab. Moreover, pembrolizumab was associated with improvement in the emotional functioning scale. Both dacarbazine and nivolumab were associated with stable function and symptoms. A small change was observed in the groups receiving pembrolizumab than the groups receiving chemotherapy. Furthermore, in the group receiving combination ICPIs, deterioration was observed in the fatigue, appetite, and symptoms scales than monotherapy. Using the EQ-5D scale, high dose of ipilimumab was associated with more decrease in the utility index. A significant difference in the utility index was neither observed between nivolumab and dacarbazine nor between combination ICPIs and monotherapy ICPI. However, the time to deterioration was shorter in the chemotherapy group than in the pembrolizumab group. In addition, high dose of ipilimumab and combination ICPIs were associated with high percentage of Grade 3–5 AEs than low dose of ipilimumab and monotherapy, respectively. Furthermore, more AEs were more in the dacarbazine group than the nivolumab group.
Table 1: Characteristics of the included studies about melanoma

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Table 2: Characteristics of the included studies about melanoma

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Renal cell carcinoma

Three studies examining the effects of ICPIs on HRQoL in patients with renal cell carcinoma were found [35],[36],[37] [Table 3]. Two studies were open-label, and one was single-arm, nonrandomized study. They included nivolumab either alone or versus everolimus (an inhibitor of mammalian target of rapamycin). All of them used the disease-specific questionnaire. None of them investigated the effect of combining ICPIs. The total number of the patients included in them was 1290. The time to deterioration was improved in the nivolumab groups. In addition, Grade 3–5 AEs were more among the nivolumab groups than everolimus.
Table 3: Characteristics of the included studies about renal cell carcinoma

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Squamous cell carcinoma of the head and neck

Two studies were identified [38],[39] [Table 4] and [Table 5]. Both reports were open-label and Phase III studies. They included nivolumab versus investigator's choice or standard of therapy. The total number of included patients was 722. GHS in the nivolumab groups remained stable or improved. The functional scales showed improvements favoring the nivolumab groups. The EQ-5D questionnaire showed improvements in the nivolumab groups. In addition, Grade 3–5 AEs were less among the nivolumab groups. However, there is no significant change in the time to deterioration.
Table 4: Characteristics of the included studies about squamous cell carcinoma of the head and neck, colorectal cancer, and Markel carcinoma

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Table 5: Characteristics of the included studies about squamous cell carcinoma of the head and neck, colorectal cancer, and Markel carcinoma

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Non-small cell lung cancer

Two studies were identified [40],[41] [Table 4] and [Table 5]. The two studies were reports from Phase III trials, one was double-blind trial, and the other was open-label. They investigated nivolumab or pembrolizumab versus docetaxel or investigator's choice. None of them includes combinations of ICPIs. Both of them used the disease-specific scale. The total number of included patients was 571. In the GHS scores, there were some improvements in the pembrolizumab group than investigator's choice. In addition, pembrolizumab improved some functional scores than chemotherapy including physical functioning, role functioning, and social functioning. However, there was minimal decrease in the cognitive functioning scale among the pembrolizumab group than chemotherapy. In addition, the effects of pembrolizumab and chemotherapy on emotional functioning were similar. In the symptoms scales, the pembrolizumab generally showed improvements than the investigator's choice group. In the utility index score, the mean change between ICPIs groups and docetaxel or investigator's choice was nearly similar. Regarding time to deterioration, the ICPIs arms showed improvements and prolonged the time to deterioration than the docetaxel or investigator's choice arms. Besides, the disease-specific scales favored ICPIs arm. Moreover, AEs were less among ICPIs groups.

Colorectal cancer

Only one study met the inclusion criteria [42] [Table 4] and [Table 5]. It was a single-arm study including 119 patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer mCRC. The study included the combination of nivolumab and ipilimumab for four doses then nivolumab every 2 weeks. It showed statistically and clinically significant mean change from baseline in the questionnaire scores. It considered a mean change ≥10 points to be clinically significant.

Merkel-cell carcinoma

After full-texting reviewing, a Phase II, single-arm study was included [43] [Table 4] and [Table 5]. It studied the effect of avelumab (a PD-L1 inhibitor) on HRQoL of 88 patients with metastatic Merkel-cell carcinoma. Small gain in the mean change from baseline in the HRQoL scale scores was observed.

Risk of bias and methodological quality assessment

According to the Cochrane risk of bias assessment tool, most of the included studies have low risk of bias in the following categories: random sequence generation, incomplete data reporting, and selecting reporting [Figure 2] and [Figure 3]. However, high risk of bias was observed in allocation concealment and blinding of participants and personnel, mostly due to the open-label design of some of the included studies. Moreover, according to the quality assessment tool, all of the included studies were of high quality, scoring ≥10 points [Table 2], [Table 3] and [Table 5].
Figure 2: Risk of bias summary: judgments about each risk of bias item for each included study

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Figure 3: Risk of bias graph: judgments about each risk of bias item presented as percentages across all included studies

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Questionnaire and sensitivity analysis

Out of the 16 included studies, eight studies used a disease-specific questionnaire. Summary of the included questionnaires is provided [Table 6].[44],[45],[46],[47],[48],[49],[50] The GHS scale uses a mean change ≥10 points in showing a clinically meaningful improvement. Only two included studies used a different mean change to demonstrate clinically meaningful improvement.
Table 6: Summary of the included questionnaires

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  Discussion Top


The evolution of ICPI have reconstructed the regimens of treatments of metastatic malignancies.[51] Reports from clinical trials presenting the improvements in progression-free survival and overall survival of these drugs are promising about the future of this remarkable treatment technique.[52] Despite these encouraging results, irAEs including dermatologic, endocrine, and hepatotoxic effects restraint enjoying their pros.[53] In the past, the most clinical trials in oncology have considered overall survival and progression-free survival as their traditional endpoints. However, as tools and methods have evolved, assessing HRQoL in oncology trials has been on the rise.[54],[55] This helps to advise the clinicians about the effectiveness of the treatments from the patients' perspectives and equips the patients with the information to personalize their treatment choices.[56] Despite their successful impact on the tumor, only certain groups of patients continued responding to them, and the others develop irAEs necessitating the discontinuation of the therapy.[57],[58],[59] This growing body of evidence shows the importance of selecting patients appropriately for receiving ICPIs.[60],[61] HRQoL may aid in investigating the groups most likely to respond well to ICPIs. Although the included studies generally have showed, when comparing with chemotherapy or investigator's choice, that HRQoL remained stable or improved, some concerns should be highlighted in interpreting these results. First, according to the risk of bias summary, most of the studies lack allocation concealment and blinding. This may predispose to selection and performance biases which may have affected the results of them. Second, some ICPIs' HRQoL reports are found in the form of abstracts during the screening process. Moreover, there are some ongoing ICPIs trials that have not reported their HRQoL results. Thus, the presented evidence of these included studies should be interpreted carefully.[62] Third, minimal clinically important differences (MCIDs) of ≥10 points used in some questionnaire has been reported years ago, and thus, using the same clinically meaningful threshold currently bears some limitations in interpreting these studies from a clinical point of view.[63] Only two studies have included a sensitivity analysis for using ≥ 15 points as their MCIDs. Finally, in some of the included studies, as the number of patients decrease, the remaining number of patients continuing the therapy showed improvements in their health status. This also may support the idea of patient selection for ICPI therapy.


  Conclusion Top


The review has summarized the present evidence regarding the HRQoL associated with immune-checkpoint inhibitors. The effects of therapy differ according to the type of tumor being involved. Considering their costly price and sometimes serious irAEs, this information may aid clinician in their decision-making process when considering ICPIs. However, due to the complexities associated with the longitudinal analyzes of HRQoL data, these results should be interpreted carefully. Moreover, future reports from ongoing trials are to be watched.

Limitation

The review results are limited by the limitations of the primary clinical trials included in it. Moreover, gray literature, for example, Google Scholar, has not been searched.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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