Abstract
Background/Aim: Patients with non-small-cell lung cancer treated with immune checkpoint inhibitors (ICI) might be forced to discontinue treatment for various reasons. We conducted a retrospective study to evaluate the impact of discontinuation of ICI treatment on patient prognosis. Patients and Methods: We performed a retrospective study that reviewed the medical charts of 86 patients treated with ICI monotherapy and 34 patients treated with a combination of ICI and chemotherapy during the period from February 2016 to February 2022 at our two hospitals. ‘Discontinuation’ was defined as a cessation of ICI treatment for more than two cycles for any reason. Results: The two most common reasons for discontinuation were immune-related adverse events and at the request of the patient. Nineteen patients who had discontinued ICI, resumed ICI or another therapy. Discontinuation of ICI treatment was a favorable factor in overall survival in 84 patients with ICI monotherapy as well as in 34 patients treated with chemotherapy combined with ICI. Conclusion: This analysis found discontinuation of ICI treatment did not adversely affect prognosis. This suggests that when treating patients with non-small-cell lung cancer with ICI, chest physicians should respond flexibly, and, with careful monitoring, consider discontinuation of ICI.
Immune checkpoint inhibitors (ICI) have significantly changed the way we treat advanced non-small cell lung cancer (NSCLC) (1, 2). Patients receiving ICI therapy can exhibit long survival, with a cure being achieved for a considerable number of patients with advanced NSCLC (1, 2). As ICI treatment for NSCLC has become more common, attention has focused on predicting the effects of ICIs and the survival of patients treated with them (3-5). Attention has also been paid to how chemotherapy given prior to ICI treatment affects subsequent treatment (6). Conventional cytotoxic antitumor drug dosing intervals have been set based on pharmacokinetic and pharmacodynamic theories, such as drug half-life and changes in blood drug levels (7). If for some reason therapeutic drugs are discontinued, a diminished therapeutic effect would be expected. Yet follow-up results of clinical trial patients after the conclusion of their ICI administration and patients who discontinued ICI due to immune-related adverse events (irAEs) found that in some patients there was not a diminished therapeutic effect with ICI discontinuation. This adds to the challenge around decisions to allow discontinuation of ICI treatment at the patient’s request. In recent years, attention has been focused on the prognosis of patients who have discontinued ICI therapy (8-18). Many studies have reported that the development of an irAE is a favorable prognostic factor (19-21), except for patients with life-threatening irAEs, such as pulmonary irAEs. However, it is difficult to determine whether to allow ICI discontinuation when an irAE develops.
Now that ICI monotherapy and combination therapy have become routine, we conducted a retrospective study to clarify the effect of discontinuation of ICI on the prognosis of patients treated with these ICI therapies.
Patients and Methods
Patients. This study examined the medical records of all patients diagnosed with NSCLC between February 2016 and February 2022 at two tertiary hospitals in Japan (Mito Medical Center, University of Tsukuba-Mito Kyodo General Hospital, and Ryugasaki Saiseikai Hospital). NSCLC was diagnosed using the World Health Organization classification with tumor node metastasis staging (TNM Classification, eighth Edition) (22) performed prior to the initiation of ICI therapy. All patients with NSCLC treated with ICI monotherapy or a combination of ICI and chemotherapy during this period were included in the study. However, patients with a driver mutation were excluded from this study, since their response to ICI differs from that of patients without a driver mutation (23, 24). Staging was performed from computed tomography/magnetic resonance imaging of the head, ultrasonography/computed tomography of the abdomen, and bone scans. Patient demographics including age, sex, Eastern Cooperative Oncology Group score for performance status (PS), histopathology, disease stage, programmed death ligand 1 (PD-L1) expression, objective tumor response and survival were extracted from their medical records. Tumor response was categorized as complete response, partial response, stable disease or progressive disease, as per the Response Evaluation Criteria in Solid Tumors (Version 1.1) (25). irAEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (26).
Discontinuation of ICI. In this study, we tried to understand the actual circumstances of discontinuation of treatment in clinical practice as much as possible. Therefore, regardless of the reason, ‘discontinuation’ was defined as the discontinuation of two or more courses of ICI treatment. When the patient requested discontinuation ICI treatment, only those with stable disease, partial response, or complete response state were considering as undergoing ‘discontinuation’ those with a progressive disease state of lung cancer were not considered as discontinuation. The reason for discontinuation was extracted from patients’ medical records.
Statistical analysis. Nominal variables were compared using a chi-squared test and values with an unknown population variance were compared using a nonparametric Mann–Whitney test. Progression-free survival (PFS), commonly used in cancer treatment, was defined as the length of time during and after the treatment of a disease that a patient lived with their disease but it did not worsen. PFS was calculated with a Kaplan–Meier analysis and compared using a log-rank test. Cox proportional hazards modeling with the forward-backward stepwise method was used to identify the independent variables to be included in the final model, with PFS as the dependent variable. Multivariable analyses included only variables with a p-value of less than 0.2 in univariate analysis. All statistical analyses were conducted using SPSS version 23 (IBM Corporation, Armonk, NY, USA). A p-value of less than 0.05 was considered significant.
Ethics. This study complied with the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labor, and Welfare of Japan. Written informed consent to participate in a non-interventional retrospective study was obtained from each patient. The Mito Medical Center-University of Tsukuba Hospital Ethics Committee approved the examination of medical records for the purpose of this study (no. 20-57).
Results
Patients who underwent discontinuation of ICI. During the study period, there were 130 patients who were treated with ICI therapy. Of these 130 patients, 84 were treated with ICI monotherapy and 46 were treated with a combination of ICI therapy and chemotherapy. Eighteen out of the 84 patients (21.4%) treated with ICI monotherapy discontinued ICI treatment, while 18 out of the 46 patients (39.1%) treated with chemotherapy and ICI combination discontinued ICI treatment. The frequency of discontinuation was significantly higher in patients who received chemotherapy combined with ICI than that in patients treated with ICI monotherapy (p=0.041). The characteristics of these patients are shown in Table I. In both treatment groups, there was no significant difference in the background of patients between those who did or did not discontinue ICI therapy. After discontinuation, some form of treatment was resumed in 11 out of 18 patients who received the ICI monotherapy and eight out of 18 patients who received the combination of ICI and chemotherapy.
Characteristics of patients with and without discontinuation of immune checkpoint inhibitor (ICI).
Reason for discontinuation of ICI. In the 18 patients who discontinued ICI monotherapy, there were three reasons for discontinuation: (i) irAEs (n=10); (ii) at the request of the patient (n=6); and (iii) at the discretion of the doctor considering the long-term response (n=2). The median (range) duration of administration of ICI until discontinuation and survival after ICI discontinuation in these three groups of patients were 9 (3-120) and 60 (29-182), 7 (2-32) and 57 (12-100), and 135 (4-265) and 76 (1-152) months, respectively. There was no significant difference in survival after discontinuation among these three patient groups with different reasons for discontinuation. Similarly, in the 18 patients who discontinued their chemotherapy and ICI therapy combination, there were four reasons for discontinuation: (i) Side-effects (n=12); (ii) at the request of the patient (n=5); (iii) at the discretion of the doctor considering the long-term response (n=2); and (iv) the detection of Mycobacterium tuberculosis in a sputum culture (n=1). The median (range) duration of administration of ICI until discontinuation and survival after ICI discontinuation in these groups were 27 (10-69) and 37 (6-18), 57 (18-65) and 45 (14-42), and 25 and 76 months, respectively. There was no significant difference in survival after discontinuation of ICI therapy between the first two patient groups (discontinuation due to side-effects and at the patient’s request).
Treatment content and clinical course of each patient. Figure 1A shows the treatment details and clinical course of the 84 patients who received ICI monotherapy, and Figure 1B shows the treatment details and clinical course of the 24 patients who received chemotherapy and ICI combination therapy. These panels shows that clinical courses in the group with discontinuation of ICI were longer than those in the group without discontinuation, both in patients who received ICI monotherapy and in patients who received chemotherapy and ICI combination therapy.
Treatment content and clinical course of each patient treated with immune checkpoint inhibitor (ICI) monotherapy (A) and ICI in combination with chemotherapy (B). The upper rows show treatment periods for patients with discontinuation of therapy (n=18 and n=18 patients, respectively) and the lower rows show treatment periods for patients without discontinuation (n=66 and n=28, respectively). *Patient alive at last follow-up.
Contribution of ICI discontinuation to survival in patients treated with ICI monotherapy. Since there was no difference in patient background between patients with and without ICI discontinuation, factor analysis for PFS and OS was performed. Both in patients who received ICI monotherapy and in those who received chemotherapy and ICI combination therapy, discontinuation of ICI was a favorable factor in OS, although it was not a favorable factor in PFS.
Contribution of ICI discontinuation to survival in patients treated with chemotherapy and ICI combination. Only stage IIIA-C was a favorable factor for PFS, while discontinuation was a favorable factor along with adenocarcinoma for OS, as shown in Table II.
Univariate and multivariate analysis of progression-free (PFS) and overall survival (OS) in patients treated with immune checkpoint inhibitor (ICI) as monotherapy or in combination with chemotherapy, with and without discontinuation of ICI.
Discussion
There were five major findings from this study. Firstly, that around 20% to 30% of patients discontinued ICI, either as monotherapy or in combination with chemotherapy. Secondly, the frequency of discontinuation was significantly higher in patients who received chemotherapy combined with ICI than that in those treated with ICI monotherapy. Thirdly, discontinuation due to side-effects, and at the patient’s request were frequent reasons for discontinuation of both monotherapy and combination therapy. Fourthly, around half of the patients resumed some form of treatment after discontinuation or received supportive care, but the remaining patients did not receive additional treatment. Finally, discontinuation of ICI did not have an impact on PFS. However, it was a significant favorable factor for OS in patients treated with ICI monotherapy, as well as in those treated with chemotherapy combined with ICI.
The following three aspects were key considerations in this study. Firstly, the intent was to reflect clinical practice as much as possible, therefore, patients in clinical trials were not included, and all the patients received ICI in clinical practice. Secondly, patients treated with ICI monotherapy and patients treated with ICI combined with chemotherapy were studied separately when investigating the effects of discontinuation. Thirdly, as the response to ICI in relation to both PFS and OS might differ between patients with and without driver mutations (23, 24), this study excluded patients with a known driver mutation in their NSCLC. In addition, we examined whether ICI discontinuation was related to PFS and OS in patients treated with ICI.
In many previous studies, ICI was discontinued due to irAEs or because the maximum treatment duration was reached in clinical trials (8-11, 20). Most studies investigated discontinuation of ICI monotherapy (4-14), while a few reported ICI discontinuation in patients treated with chemotherapy combined with ICI (15). Some studies also included patients with carcinoma other than NSCLC (11, 12, 16) and others included patients whose tumors harbored known driver mutations (17, 18). Several studies even reported a good prognosis for patients with irAEs other than grade 5 (27). Various types and severities of irAEs, from minor, such as itching, to serious, such as respiratory failure that was saved by administration of prednisolone (27). If an endocrine irAE occurs, ICI might be continued under replacement therapy (27). However, when serious side-effects occur, it might be difficult to decide whether to withdraw or discontinue ICI. In particular, it is difficult to make an evaluation in patients seen in clinical practice who are not participants in clinical trials, as no clear guidelines exist. In addition, when patients request the discontinuation of ICI, it may be difficult to determine whether to continue ICI treatment, especially in those who are responding to it. The results of this study provide some guidance on whether to instigate ICI discontinuation in such situations. Among those who discontinued ICI therapy in this study, many patients discontinued at their own request, not because of irAEs. Importantly, survival after discontinuation did not differ between these two discontinuation groups. Therefore, we conclude that survival after discontinuation was affected by causes other than irAEs.
There were some limitations in this study. It was a retrospective study with a small number of patients. While not a statistically powered prospective controlled trial, the study was an analysis of several ICI treatments administered to patients with various clinical backgrounds. Lastly, as ICI discontinuation included discontinuation at the request of the patient, as well as discontinuation due to irAEs, consideration must be given to the confounding nature of these factors.
Conclusion
Based on the results of this study, we cannot recommend discontinuation of ICI. It was feared that discontinuation of conventional lung cancer treatment would have an adverse effect on prognosis but that the situation might be different with ICI treatment, and it might not be necessary to hesitate to discontinue ICI in the case of non-progressive disease. With the exception of a severe irAE, such as a pulmonary irAE, discontinuation of ICI therapy and subsequent resumption of treatment might be a treatment option. Needless to say, even if ICI discontinuation is selected, it is necessary to pay attention to the potential for tumor recurrence.
Footnotes
Authors’ Contributions
SH, SO, YS, GO, KM, SS, TK, TS, HS, and NH had full access to all of the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. SH, HS and NH contributed substantially to the study design, data analysis and interpretation, and writing the article.
Conflicts of Interest
None declared.
- Received June 2, 2022.
- Revision received June 29, 2022.
- Accepted July 12, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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