Effect of baseline cancer pain on the efficacy of immunotherapy in lung cancer patients

Introduction

Cancer pain is one of the most prevalent signs of the disease and one of the consequences that patients fear the most (1). There is growing evidence in oncology that quality of life and survival are associated with early and effective palliative care, including pain management (2). The incidence of pain in patients with newly diagnosed and advanced cancer is approximately 24% to 60% and approximately 62% to 86%, respectively. The pain is severe in one-third of the patients (1,3-5). Previous studies (6,7) stated that 90% of individuals with lung cancer will experience cancer pain during the illness, which will reduce immunity (8).

Recently, immune checkpoint inhibitors (ICIs) have been rapidly developed. ICIs can activate the anti-cancer function of depleted T cells and have substantial survival benefits in a variety of malignant tumor patients (9,10), with a significant effect in treating lung cancer. Widely used ICIs mainly include inhibitors of cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death-ligand 1 (PD-L1) (11). ICIs are promising immunotherapy drugs that can achieve satisfactory efficacy for different tumor types, different treatment pathways, different drug combinations, and different treatment regimens (12). However, only 20% to 30% of patients benefit from ICI monotherapy (13,14). Even in melanoma patients, who display the highest response rates to ICI, only a few patients achieve lasting remission, and 60% to 70% of patients do not have any discernible response to anti-PD-1 therapy, which has the effect of immune tolerance. In addition, other factors affect immunotherapy, such as toxic superposition of non-small cell lung cancer (NSCLC), drug toxicity, special population, and other problems (9,10,15,16). The efficacy of ICIs in studies of the Eastern Cooperative Oncology Group (ECOG) is reportedly affected by a variety of factors, such as PD-L1 expression, smoking history, radiotherapy, ECOG performance status (PS) (17-20), and concomitant medications (21). However, no reports have assessed whether baseline cancer pain has an effect on survival outcomes among patients with lung cancer who received ICIs.

The aim of this retrospective study was to determine the effect of baseline cancer pain on the prognosis of individuals with lung cancer who were treated with ICIs. In addition, we explored the impact of breakthrough pain on prognosis. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-375/rc).

Methods

Patients

The medical records of patients with persistent lung cancer who received ICI treatment in Zhejiang Cancer Hospital from January 1, 2000, to December 31, 2022, were retrospectively evaluated. We included 280 lung cancer patients. All patients met the following criteria: (I) 18 years of age or older; (II) tumor stage IIIB or IV lung cancer according to the American Joint Committee on Cancer (AJCC) eighth edition of tumor-node-metastasis (TNM) staging of lung cancer; (III) baseline cancer pain in cancer pain group and no baseline cancer pain in non-cancer pain group; and (V) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, having at least one lesion that could be radiographically measured. Patients with non-advanced lung cancer and those with incomplete information were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Committee at Zhejiang Cancer Hospital (No. IRB-2023-120) and individual consent for this retrospective analysis was waived.

Assessments

Baseline cancer pain was defined as a type of tumor-related pain present in the initiation phase of immunotherapy. The pain intensity of patients was assessed on a digital rating scale [i.e., Numerical Rating Scale (NRS) 0–10]. We provided each patient with a digital rating scale at each visit to help us understand when and how far their pain occurred. Cancer pain was divided into three categories: somatic pain (37.5%), neuropathic pain (31.3%), visceral pain (8.3%), and mixed pain (22.9%) (Table S1).

RECIST version 1.1 criteria were used to determine progression-free survival (PFS) (defined as the duration between initiation of immunotherapy and disease progression or all-cause mortality) and overall survival (OS) (measured from the onset of diagnosis of advanced cancer to death, loss to follow-up, or the date of last follow-up, whichever occurred first). Secondary endpoints included overall response rate (ORR), frequency of patients who obtained partial response (PR) or complete response (CR) at two consecutive evaluations at least 4 weeks apart. The responses to immunotherapy were also determined using RECIST version 1.1. Patients were followed up until December 31, 2022.

Statistical analyses

The analyses were performed using Solutions Statistical Package for the Social Sciences software (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 9 (GraphPad Software, Inc., San Diego, CA, USA). Propensity score matching (PSM) was performed to limit potential selection bias. A logistic regression model was established based on the following covariates to calculate the propensity score: age, sex, ECOG PS, presence or absence of lung-related surgery, histological type, smoking history, PD-L1 expression, combined medication, line of treatments with ICIs, adverse reactions, and types of ICIs. Patients with baseline cancer pain were matched with patients without baseline cancer pain using a 1:1 Greedy algorithm (caliper =0.2). Differences in continuous and categorical variables were evaluated with the Wilcoxon rank-sum and Fisher’s exact test, respectively. Survival curves were estimated using the Kaplan-Meier method. Cox regression analysis was employed to compute the hazard ratio (HR) and 95% confidence interval (CI) for PFS and OS. A P value of <0.05 was considered statistically significant.

Results

Patient characteristics

The 280 patients identified in this research included 133 with baseline cancer pain and 147 without baseline cancer pain. In the cancer pain group, this pain was mild (NRS: 1–3) in 47 patients (35.3%) and moderate to severe (NRS ≥4) in 86 patients (64.7%). After PSM, 48 patients with baseline cancer pain and 48 patients without baseline cancer pain were selected. Before matching, in the group with baseline cancer pain, fewer patients were positive for PD-L1 (17.3% vs. 31.3%; P=0.011), PS was worse (PS ≥2 patients: 21.8% vs. 2.7%; P<0.001), and fewer patients had undergone lung-related surgery (20.3% vs. 64.6%; P<0.001), compared to patients without baseline cancer pain. Immunotherapy regimens also differed in these patients (immunochemotherapy, 38.3% vs. 53.7%; immunotherapy plus targeted therapy, 13.6% vs. 15.0%; immune monotherapy, 48.1% vs. 31.3%). PSM was performed to balance confounding covariates between the two groups. The resulting two groups of patients were matched age, sex, ECOG PS, presence or absence of lung-related surgery, histological type, smoking history, PD-L1 expression, combined medication, lines of ICI treatments, types of ICIs, and adverse reactions (Table 1).

Of the 133 patients with baseline cancer pain, 61 developed breakthrough pain during immunotherapy. PSM was used to match patients with breakthrough pain. After matching, 27 patients with breakthrough pain and 27 patients without breakthrough pain were selected. Most patients with baseline cancer pain had ≤2 pain sites (93.8%), a small number of patients felt pain at a level ≥3 (6.3%), and 19 patients (39.6%) experienced breakthrough pain during cancer pain (Table S1).

Relationship between pain and efficacy

CR was achieved in none of the 48 patients with baseline cancer pain and in one (2.1%) of the patients without baseline cancer pain. PR was achieved in seven (14.6%) of the 48 patients with baseline cancer pain and 15 (31.3%) of the patients without baseline cancer pain. The ORR of lung cancer patients with baseline cancer pain was significantly shorter than that of lung cancer patients without baseline cancer pain (14.6% vs. 33.3%; P=0.031; Table S2).

The median PFS of lung cancer patients with baseline cancer pain was significantly shorter than that of lung cancer patients without baseline cancer pain (3.1, 95% CI: 2.14–3.85 vs. 6.5, 95% CI: 3.10–8.90 months; P=0.001; Figure 1A). The median OS of lung cancer patients with baseline cancer pain was significantly shorter than that of lung cancer patients without baseline cancer pain (16.5, 95% CI: 13.45–18.54 vs. 31.2, 95% CI: 24.45–43.54 months; P<0.001; Figure 1B).

Figure 1 Survival analysis of 96 patients with lung carcinoma treated with immunotherapy after propensity score matching. (A) PFS curves of patients with or without baseline cancer pain. (B) OS curves of patients with or without baseline cancer pain. CI, confidence interval; mPFS, median progression-free survival; mOS, median overall survival.

The median PFS of patients with baseline cancer pain who presented with breakthrough pain was significantly shorter than that of patients with baseline cancer pain without breakthrough pain (1.9, 95% CI: 1.31–2.63 vs. 4.2, 95% CI: 2.60–5.79 months; P=0.001; Figure 2A).

Figure 2 Survival analysis of 27 patients with lung carcinoma with breakthrough pain after propensity score matching. (A) PFS curves of patients with or without breakthrough pain. (B) OS curves of patients with or without breakthrough pain. CI, confidence interval; mPFS, median progression-free survival; mOS, median overall survival.

The median OS of patients with baseline cancer pain who presented with breakthrough pain was significantly shorter than that of patients with cancer pain without breakthrough pain (9.9, 95% CI: 6.85–11.14 vs. 18.7, 95% CI: 11.21–24.78 months; P=0.012; Figure 2B).

Survival outcomes according to patient characteristics

In univariable analyses, several features displayed meaningful P values. These included age, PS value, lung surgery, EGFR/ALK mutation positive, PD-L1 expression, lines of ICI treatments, medication with combined ICIs, and breakthrough pain (Table 2). Multivariate analysis performed on these data revealed that breakthrough pain, age, and lines of ICI treatments are independent prognostic factor for OS (HR =2.296, 95% CI: 1.215–4.336, P=0.010; HR =0.533, 95% CI: 0.289–0.984, P=0.044; HR =0.165, 95% CI: 0.073–0.372, P<0.001, respectively; Figure 3), but not with PFS.

Figure 3 HR and 95% CI for PFS and OS in all patients. PFS, progression-free survival; PS, performance status; HR, hazard ratio; CI, confidence interval; ICIs, immune checkpoint inhibitors; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; OS, overall survival.

Discussion

Our results demonstrate that baseline cancer pain is a negative prognostic factor for lung cancer patients receiving immunotherapy. Patients with baseline cancer pain may have a worse survival prognosis if they develop breakthrough pain. As far as we know, this is the first research to assess the result of baseline cancer pain on survival in lung cancer patients treated with ICIs. Furthermore, this is also the initial investigation of the impact of breakthrough cancer pain on survival among patients with lung cancer who received ICIs.

People with cancer pain often use opioids and nonsteroidal drugs for pain relief. According to the treatment guidelines for cancer pain, the drugs used to relieve mild cancer pain are non-steroidal anti-inflammatory drugs (NSAIDs), with opioids used to treat moderate to severe cancer pain (22). It has been reported that opioid users respond less to ICI treatment than non-opioid users [odds ratio (OR) =0.49, 95% CI: 0.37–0.65; P<0.001] (23). Taniguchi et al. reported that patients with opioid use displayed significantly shorter median PFS (1.17 vs. 2.07 months, P=0.002) and OS (4.20 vs. 9.57 months, P=0.018) than patients without opioid use (24). Miura et al. (25) further investigated the effect of concomitant drugs on clinical outcomes in patients with advanced NSCLC with ICIs. The authors identified opioid use as an independent risk factor (time-to-treatment failure: HR =1.39, P=0.021, OS: HR =1.54; P=0.007), and described that patient who used opioids had a shorter median OS (5.7 vs. 15.9 months; P<0.001). NSAIDs were shown to have an impact on OS and PFS of patients who received ICI treatment in one study (26), while other studies did not discover a meaningful connection between NSAIDs and ICIs concerning OS and PFS (23,27). Our study featured a slight difference in survival time; the OS we observed was longer than in other studies. The difference is mainly due to two factors. First, our OS was defined as the time from the onset of late diagnosis to the time of death, while OS was previously defined as the time from the start of initiation of the immune drug to the death of the patient. Second, our study included a variety of immunotherapy regimens, including immunotherapy combinations. Cancer pain has an immunosuppressive effect (8,28). Animal studies provide direct evidence that natural killer (NK) cells play a key role in controlling metastasis (29), conclusive evidence from humans suggests that low perioperative NK activity is associated with higher rates of cancer recurrence and mortality in lung cancer patients (30), taking into account acute pain also inhibits NK activity, Cancer pain suppresses immune function by reducing the activity of NK cells (31). ICIs enhance the anti-tumor activity of immune cells by inhibiting immune checkpoints. They have opposite effects on the immune system, so cancer pain may have a negative impact on immunotherapy efficacy. However, there has been a lack of previous studies that directly examine the relationship between baseline cancer pain and ICIs. Our findings reveal that patients with baseline cancer pain had shorter median PFS and median OS than those without baseline cancer pain (3.1 vs. 6.5 months, P=0.001; 16.5 vs. 31.2 months, P<0.001). These findings indicate that patients who receive ICIs with baseline cancer pain may have a worse survival.

Breakthrough pain is a distinct pain state and common in patients with cancer pain (32). After PSM, survival curve analysis of 54 patients with breakthrough pain revealed worse survival outcomes of patients with breakthrough pain. Patients with breakthrough pain had shorter median PFS and median OS than patients without breakthrough pain (1.9 vs. 4.2 months, P=0.001; 9.9 vs. 18.7 months, P=0.012). In addition, multivariable analyses revealed that breakthrough pain was an independent prognostic factor (HR =2.296, 95% CI: 1.215–4.336, P=0.010).

Our study has some limitations. First, the study was retrospective and the information provided by medical records is limited. Although we performed PSM analysis to balance confounders, our sample size was also small. Therefore, this PSM analysis may not be optimal. In addition, our study included lung carcinoma with small cells. Small cell lung cancer is not sensitive to immunotherapy in this situation. In addition, more disease may have more pain, and patients with cancer pain may have a higher tumor burden. We did not conduct PSM for comorbidities and underlying conditions, which may also be factors affecting patient efficacy and survival, and need to be further explored in the future (33). This may have affected the findings.

Conclusions

Patients with baseline cancer pain have worse survival. Patients with baseline cancer pain who develop breakthrough pain have a worse response to immunotherapy. Breakthrough pain is an independent prognostic factor of immunotherapy.

Acknowledgments

We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding: This study was funded by the Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-375/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-375/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-375/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-375/coif). ZS reports that this study was funded by the Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653). ZS was sponsored by Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Committee at Zhejiang Cancer Hospital (No. IRB-2023-120) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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