{'fraction_non_alphanumeric': 0.030217474246470814, 'fraction_numerical': 0.016405951926745516, 'mean_word_length': 5.132896583996256, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Association of Anticancer Immune Checkpoint Inhibitors With Patient-Reported Outcomes Assessed in Randomized Clinical Trials

This systematic review and meta-analysis of randomized clinical trials involving patients with solid tumors assesses the association of immune checkpoint inhibitors with patient-reported quality of life.


Introduction
Immune checkpoint inhibitors (ICIs) have changed the paradigm of treatment of several cancer types. Currently, ICIs are administered as monotherapy or in combination with other immunotherapy drugs or other anticancer agents, such as targeted therapies or chemotherapies. 1,2 Both the efficacy and toxicity profiles of ICIs meaningfully differ from those of other classes of anticancer treatments. 3,4 The quality of life (QoL) of patients with metastatic cancer depends on multiple factors, some of which are independent of anticancer treatments, such as socioeconomic background, psychological condition, and concomitance of other chronic diseases, whereas other factors are strictly related to the cancer and its treatment, such as symptoms caused by the tumor that are in turn affected by the efficacy and toxicity of treatments. 5 Patient-reported outcomes (PROs) are able to capture QoL in a comprehensive way from the patient's point of view, taking into account all the different aspects that contribute to its definition. 6 In particular, the time to deterioration (TTD) of PRO score, defined as the time from patient randomization until the first deterioration of PRO score of clinical relevance, is a largely adopted measure to assess treatment effects on patient QoL during the entire trial follow-up, supported by international guidelines. 7 Although the efficacy of ICIs has been extensively investigated in the past few years, their association with patient QoL, compared with that of other available anticancer treatments, has been less explored. In this report, we detail the results of a systematic review and meta-analysis of PROs assessed in randomized clinical trials (RCTs) testing immunotherapy-based treatments vs anticancer treatments other than immunotherapy for patients with advanced solid tumors.

Search Strategy, Selection Criteria, and Data Extraction
We searched PubMed, MEDLINE, Embase, and Scopus for RCTs testing ICIs and reporting PROs, published from database inception to June 1, 2021. We also reviewed abstracts and presentations from all major conference proceedings, including the American Society of Clinical Oncology and the European Society for Medical Oncology, from January 1, 2010, to June 1, 2021. We followed recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium. 6,8 This study was exempted from ethics review by the European Institute of Oncology Institutional Review Board because it was a secondary synthesis of deidentified data.
We included RCTs that assessed programmed cell death receptor 1, programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors as monotherapy or in combination with another ICI and/or other anticancer drugs (ie, targeted therapy or chemotherapy) vs control groups not containing immunotherapy in patients with advanced solid tumors. We excluded single-group phase 1 and 2 trials and RCTs conducted in adjuvant and neoadjuvant settings or in hematologic tumors to avoid excessive heterogeneity. We included trials in which PROs were assessed through the Global Health Status (GHS) scale from the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) or the EuroQol Health-Related Quality of Life 5-Dimension, 3-Level (EQ-5D-3L) visual analog scale (VAS).
The GHS scale includes 2 items that explore the patients' overall health and quality of life. The raw scores are transformed to a linear scale that ranged from 0 to 100. Higher scores on the GHS scale indicate higher levels of health-related quality of life (HRQoL). [9][10][11] The EQ-5D-3L scale evaluates the patient's self-rated health state on a 100-point vertical VAS (ie, with 0 indicating worst imaginable health state and 100 indicating best imaginable health state). 12 We excluded trials reporting PROs only assessed through cancer-specific scales to ensure comparability across trials. [13][14][15][16] Full-text articles were reviewed independently by 2 authors (L.P. and F.C.). Inconsistencies were discussed by all authors to reach consensus. Reference lists of articles included in the final selection were reviewed to identify additional relevant articles. We included only the most recent and complete report when duplicate publications were identified. We extracted data on the following variables: study's name, first author and year of publication, study design and blinding, trial phase, underlying malignant neoplasm, number of patients, median follow-up time, treatment groups, line of therapy, PRO scale used, and PRO results.

Quality Assessment of Trials and PRO Reporting and Data Analysis
To ascertain risk of bias, we assessed the methodologic quality of each trial using the Cochrane Risk of Bias tool, version 5.1.0. 17,18 The coprimary aims of the meta-analysis were (1) to assess differences between treatment groups in the mean change of PRO score from baseline to 12 and 24 weeks of follow-up assessed through the QLQ-C30 GHS or EQ-5D-3L VAS and (2) to assess differences between treatment groups in the TTD of PRO score, defined as the time from patient randomization until the first deterioration of PRO score that met or exceeded the minimally important difference.
For each end point, trials have been analyzed according to the type of treatment administered in the experimental group: ICIs given as monotherapy, ICIs combined with chemotherapy, or ICIs in association with another ICI and/or with targeted therapies. A sensitivity analysis was performed excluding RCTs whose results were only available as congress abstracts.

JAMA Network Open | Oncology
Week 24 The between-groups differences in mean change of PROs assessed from baseline to 12 weeks or 24 weeks of follow-up are shown for patients assigned to intervention treatment (ie, immunotherapy-containing groups) compared with those assigned to control treatment (ie, groups not containing immunotherapy weeks (I 2 = 27.9%, P = .21), which became significant at 24 weeks of follow-up (I 2 = 62.1%, P = .02) ( Figure 1 and Figure 2).
In the group of 8 trials 49,51-57 testing other ICI-containing combinations, the mean change in PRO score from baseline to 12 and 24 weeks of follow-up was reported for both time points in 5 trials 49,51,52,54,57 and was assessed by the EORTC QLQ-C30 GHS in 2 trials 49,57 and by the EQ-5D-3L VAS in 3 trials. 51,52,54,57 All such RCTs were included in the analysis, for a total of 3243 individual PRO assessments   among single-study estimates of TTD (I 2 = 0.0%, P = .64). In the group of trials testing other ICI-containing combinations, the TTD was longer in the immunotherapy-containing groups compared with control groups in 5 of 7 RCTs 51-55 (pooled TTD HR, 0.78; 95% CI, 0.63-0.96) ( Figure 3). Significant heterogeneity was found among single-study estimates of TTD (I 2 = 79.0%, P < .001).

JAMA Network Open | Oncology
Finally, a sensitivity analysis was performed excluding RCTs whose results were only available as congress abstracts. Results did not materially change compared with those of the main analyses for both the mean change in PRO score at 12 and 24 weeks and the TTD (eTable 3 in the Supplement).

Discussion
We assessed the association of ICIs with the quality of life of more than 18 000 patients with solid tumors treated in 34 RCTs. Notably, even though few studies 58,59 have been conducted in this area, to our knowledge, this meta-analysis is the largest and includes only RCTs. Furthermore, we provided evidence on the association of recent ICI-containing treatments on PROs, especially of the combination of ICIs and chemotherapy, which is becoming a standard therapeutic approach for a large number of solid tumors.   The hazard ratios (HRs) of time to deterioration for patients assigned to intervention treatment (ie, immunotherapy-containing groups) compared with those assigned to control treatment (ie, groups not containing immunotherapy) are shown. Studies are grouped according to the experimental group type of treatment (ie, immune checkpoint inhibitor [ICI] monotherapy, ICI and chemotherapy, and other ICI-containing combinations). Squares indicate study specific HRs. Values less than 1 indicate that intervention was better than the control. Size of the square is proportional to the precision of the estimate (ie, the inverse of the variance). Horizontal lines indicate the 95% CIs. Diamonds indicate the metaanalytic pooled HRs, with their corresponding 95% CIs. The dashed vertical lines indicate the pooled HRs, and the dotted vertical line indicates an HR of 1, which is the null-hypothesis value (ie, no difference in time to deterioration between treatment groups).
Our results clearly show that differences in PROs over time favor immunotherapy in trials testing ICI monotherapy. However, in trials testing ICI-containing combinations, the degree of PRO improvement in favor of immunotherapy at 12 or 24 weeks was limited and under the clinically relevant cutoff. Although this result does not allow for the conclusion of better HRQoL in patients treated with an ICI combination, it supports the conclusion that none of the multidrug combinations worsened patient quality of life compared with control groups. This finding is noteworthy considering that in some RCTs, patients received up to 3 different classes of drugs. Several measures should be enacted to improve HRQoL assessment for immunotherapy. The assessment of HRQoL should be included within the primary objectives of RCTs testing immunotherapy. Furthermore, to achieve an unbiased assessment of the risk-benefit ratio of new therapeutic approaches, patient perception of how therapies impact their quality of life, elicited through PROs, should not be separated from the main analysis of trial results. In this regard, combined end points that jointly evaluate efficacy, toxicity, and HRQoL, such as Q-TWiST (Quality-Adjusted Time Without Symptoms or Toxicity), should be more broadly considered. 60 Moreover, in most cases, the HRQoL evaluations in RCTs stopped at 24 weeks of follow-up, leaving an important gap in the knowledge of HRQoL of patients surviving in the long term. Because the percentage of long-term survivors has been significantly increased by ICIs, a substantial time extension of HRQoL collection during the follow-up should be planned by trials testing ICIs. 61 Finally, a paramount limitation of instruments currently in use for assessing PROs is that these instruments have not been specifically developed and validated to evaluate HRQoL in trials testing immunotherapies.

Limitations
This work has several limitations. We analyzed published data rather than IPD. However, this weakness was substantially attenuated by the use of reconstructed IPD. 21 Furthermore, although we found no heterogeneity among single-study estimates in many analyses, there was heterogeneity in others. Such heterogeneity could be related to the different tumor histotypes in the patients enrolled in the RCTs analyzed. Indeed, some dimensions of quality of life may be specifically affected by tumor histotypes. For some cancer histotypes, only a few RCTs were available, which precluded the possibility of performing subgroup analyses. We addressed this issue by using random-effects models that took into account heterogeneity. However, potential differences among patients with different tumor histotypes should be more granularly investigated by future studies. Additionally, because results from only a few RCTs testing ICIs in the neoadjuvant or adjuvant setting have been reported to date, we decided not to include them in our analysis to avoid additional heterogeneity.

JAMA Network Open | Oncology
Thus, the conclusions of our work should be limited to patients treated with ICIs in the advanced disease setting.

Conclusions
The results of this meta-analysis demonstrate a favorable association of ICIs with patient quality of life compared with control groups that did not contain immunotherapy across a large spectrum of solid tumors. The benefit was particularly evident when ICIs were administered as monotherapy. In addition, this meta-analysis found that ICIs can be combined with several other classes of anticancer drugs, particularly chemotherapy, without worsening patient quality of life, which is a noteworthy finding considering that such combinations will be increasingly used in many solid tumors. Future research should incorporate PROs as a primary end point of RCTs testing immunotherapy to concretely develop a patient-centered model of care.