The Real World Report on Immunotherapy is out! Efficacy and quality of life are equally important

*For medical professionals only

In today's world where immunotherapy combined with chemotherapy is becoming the standard treatment regimen, how immunotherapy affects the quality of life of cancer patients, a high-quality systematic review and meta-analysis gives you answers

Highlights:
1.
The use of immune checkpoint inhibitors (ICIs) was associated with improved patient-reported outcome (PROs) scores
.
2.
Multi-drug combination therapy containing ICIs did not show improvement in health-related quality of life (HRQoL) associated with it, but did not lead to deterioration
in patient quality of life.
3.
Immunotherapy helps to improve the quality
of life of patients.

ICIs have changed the way
tumors are treated.

Although the therapeutic efficacy of ICIs has been extensively studied over the past few years, their relationship to patient quality of life has been rarely reported compared to other anti-cancer treatments
.
In a systematic review and meta-analysis published on August 16, 2022 in JAMA Network Open, based on multiple randomized clinical trials (RCTs) that included patients with advanced solid tumors receiving or not receiving immunotherapy, investigators analyzed patient-reported outcomes (PROs) assessed in detail to explore the relationship between
ICIs and quality of life in patients with solid tumors.
The
researchers searched all RCT studies related to ICIs and PROs in the PubMed, MEDLINE, Embase, and Scopus databases, with a deadline of June 1, 2021, and a total of 2259 studies
were retrieved.

The investigators specified the experimental group as: solid tumor patients using ICIs as monotherapy or combination chemotherapy or in combination with another ICIs and/or targeted therapy; The control group is defined as patients with advanced solid tumors that do not include immunotherapy
.

The study methodology
study included 34 immunotherapy-related study literature, including a total of 18,709 patients, and the ICIs involved in the study included PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors
.

PROs are
evaluated according to the Global Health Status (GHS) Scale of the European Organization for Cancer Research and Treatment (EORTC) Core Quality of Life Questionnaire (QLQ-C30), or the EuroQol Health-Related Quality of Life 5-3 Level (EQ-5D-3L) Visual Simulation Scale (VAS).

The investigators reported a quality assessment
of the trial using the Cochrane Bias Risk Tool.

Differences in the average change in PRO scores assessed by QLQ-C30 GHS or EQ-5D-3L VAS from baseline to 12 and 24 week follow-up between treatment groups at study endpoint
(1);
(2) Differences in the timing of pro score exacerbation (TTD) between treatment groups, defined as the time from patient randomization to the first deterioration of clinically relevant PRO scores, is a major measure
to assess the effectiveness of patient quality of life (QoL) treatment throughout trial follow-up.

In
the 19 RCTs using ICIs as monotherapy, the mean change in PROs score from baseline to 12 weeks of follow-up was 4.
6 (95% CI, 2.
8 to 6.
4) and the average change from baseline to 24 weeks was 6.
1 (95% CI, 4.
2 to 8.
1), and the change results of PROs significantly supported icIs to improve quality of life
.
In the eight RCTs with ICIs combined with chemotherapy, the overall difference in PROs scores at 12 and 24 weeks was 1.
4 (95% CI: −0.
4 to 3.
2) and 2.
5 (95% CI: −0.
8 to 5.
9),
respectively.
In the eight RCTs treated with other combinations of ICIs, the overall difference in PROs scores at 12 and 24 weeks was 2.
1 (95% CI: −0.
8 to 5.
0) and 2.
1 (95% CI, −0.
4 to 4.
5),
respectively.
In all 3 groups of RCTs evaluated, the treatment group containing ICIs had a significantly longer deterioration time compared with the control group [the risk ratio of ICIs as monotherapy was 0.
80 (95% CI: 0.
70 to 0.
91), the risk ratio of ICIs combined with chemotherapy was 0.
89 (95% CI: 0.
78 to 1.
00), and the risk ratio of other combinations containing ICIs was 0.
78 (95% ) CI：0.
63~0.
96）]
。 Figure 1 Intergroup differences in mean changes in PROs from baseline to 12 and 24 weeks Figure 2 Intergroup differences
in mean changes in PROs over time Trend Plot
3 Risk ratio
of time of exacerbation The results of the study show that in ICIs monotherapy RCTs, over time, Differences in PROs support immunotherapy to improve patient quality of life
.

However, in RCTs where ICIs are applied in combination with other drugs, the degree of PRO improvement is limited at 12 or 24 weeks and below
the clinically relevant cut-off.

While this result does not lead to the conclusion that there is better health-associated survival therapy (HRQoL) in patients receiving combination icis, it supports the conclusion that the multi-drug combination did not worsen the quality of life of
patients compared to the control group.

Considering that in some randomized controlled trials, patients received up to 3 different classes of drugs, this finding is noteworthy
.

The findings of
the study ICIs as monotherapy appear to have a good correlation with patient-reported quality of life and can be used in combination with other classes of anticancer drugs without reducing improvement
in quality of life.
As immunotherapy combined with chemotherapy is becoming the standard of care for multiple solid tumors, this meta-analysis evaluating the effects of multiple solid tumor treatment regimens, including immunotherapy, on PROs shows far-reaching clinical implications
.
However, the researchers note that an important observation that emerged during the completion of this systematic review was that none of the included RCTs had HRQoL as the primary endpoint, while PROs
were usually only mentioned in secondary endpoint and delay reports.

This observation shows that the importance of HRQoL in the field of anti-cancer immunotherapy is underestimated
.
In this regard, the researchers have made some suggestions
.

First, the evaluation of HRQoL should be included in the main objectives of RCT detection immunotherapy
.

Second, the combined endpoints of joint assessment of efficacy, toxicity, and HRQoL, such as quality-of-life-adjusted time to disease or toxic symptoms (Q-TWiST), should be considered more broadly, and PROs should be included in the primary analysis of trial results to achieve an unbiased assessment
of the risk-benefit ratio of new treatments.

In addition, in most cases, HRQoL evaluation in randomized controlled trials is discontinued after 24 weeks, and since ICIs significantly increase the percentage of long-term survival patients, the planned follow-up time for ICIs trials should be extended to refine HRQoL collection
.

Finally, the current tools used to evaluate PRO have limitations that may not be able to fully capture the tolerability characteristics
of a new therapy due to a lack of specialized development and validation.

Therefore, the researchers suggest that relevant scientific associations focusing on quality of life should accelerate the development, validation and rollout
of new HRQoL assessment tools for immunotherapy trials.
In addition, the researchers pointed out some limitations
of this study.

First, this analysis included only published studies and not a meta-analysis
of individual case data (IPD).

Second, although the researchers have found heterogeneity that may be associated with different tumor tissue types in patients who are included in RCTs
.

The potential differences between patients with different tumor tissue types deserve more detailed study
in the future.

Third, because only a handful of RCTs have reported results from testing ICIs in neoadjuvant or adjuvant environments so far, the investigators did not include these studies in this analysis
.
Research expansion
At present, with the application of immunotherapy in the field of tumor treatment more and more attention by the majority of clinicians and researchers, immunotherapy drugs have long been a hot spot in drug research and development and clinical trials, and related RCTs are emerging in an endless stream, accompanied by the continuous emergence
of immunotherapy-related meta-analysis.
Among them, in addition to the efficacy of immunotherapy in different cancer types, it has been widely concerned by researchers, and the number of related studies published is the safety of immunotherapy (including drug toxicity, immune-related adverse reactions
, etc.
).
A 2018 meta-analysis evaluating the fatal toxic effects associated with immune checkpoint inhibitors showed that the fatal toxic effects of immune checkpoint inhibitors were rare, occurring in about 0.
3% to 1.
3%, and that fatal toxic effects usually occurred early in treatment [2
].

In the same year, other investigators turned their attention to the problem of endocrine dysfunction associated with immune checkpoint inhibitors, and this meta-analysis reported an increased risk of thyroid dysfunction and pititis in patients treated with PD-1 plus CTLA-4 inhibitors [3
].
A 2021 meta-analysis evaluating immune checkpoint inhibitor-associated cardiotoxicity noted that despite the low incidence of cardiac immune-related adverse events (irAEs), the high mortality rate is noteworthy [4].


Another meta-analysis of the same year also focused on cardiovascular (CV)-related irAEs, and found that the use of ICI was associated with an increased risk of six CV-irAEs, including myocarditis, pericardial disease, heart failure, dyslipidemia, myocardial infarction, and cerebral artery ischemia [5
].
A 2021 meta-analysis showed a positive correlation between irAEs and the development of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in patients treated with ICI, regardless of disease site, ICIs type, and irAEs
.

Toxicity of grade 3 or higher results in a more ideal ORR, but a worse OS [6].

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JAMA network open,5(8),e2226252.
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org/10.
1001/jamanetworkopen.
2022.
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Y.
Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors:A Systematic Review and Meta-analysis.
JAMA oncology,4(12),1721–1728.
https://doi.
org/10.
1001/jamaoncol.
2018.
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Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens:A Systematic Review and Meta-analysis.
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https://doi.
org/10.
1001/jamaoncol.
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Cardiotoxicity associated with immune checkpoint inhibitor therapy:a meta-analysis.
European journal of heart failure,23(10),1739–1747.
https://doi.
org/10.
1002/ejhf.
2289[5]Dolladille,C.
Cardiovascular immunotoxicities associated with immune checkpoint inhibitors :a safety meta-analysis.
European heart journal,42(48),4964–4977.
https://doi.
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1093/eurheartj/ehab618[6]Hussaini,S.
Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors-A systematic review and meta-analysis.
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