Lung metastasis and lymph node metastasis are risk factors for hyperprogressive disease in primary liver cancer patients treated with immune checkpoint inhibitors

Introduction

Primary liver cancer (PLC) is a common malignant tumor of the digestive system. It mainly includes three different pathological categories: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and HCC-ICC. HCC is the most common type, accounting for 85% to 90% of all PLCs, followed by ICC, which accounts for 15% of all PLCs (1). Globally, liver cancer ranks seventh among malignant tumors regarding the annual number of new cases, and third regarding the number of deaths (2). Approximately 70% to 80% of liver cancer patients present with advanced-stage disease at diagnosis. By this time, such patients are unable to undergo radical surgery and can only receive palliative treatment, such as systemic treatment, and their prognosis is notably poor (3). Since 2017, lenvatinib has been approved as the first-line treatment for liver cancer, and regorafenib, cabozantinib, and ramucirumab have been approved as second-line treatment for liver cancer in clinical application, marking a new era of targeted therapy for liver cancer. Although the objective remission rate of patients with advanced liver cancer has significantly improved, their overall survival time has not been effectively extended (4).

In recent years, immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) antibody, programmed death ligand-1 (PD-L1) antibody, and cytotoxic T lymphocyte antigen (CTLA4) antibody, have been used for the treatment of liver cancer, with promising curative effects seen in clinical practice (5). With the widespread use of ICIs in clinical practice, increasing evidence has shown that some patients demonstrate a rapid increase in the tumor burden within a short period of time after receiving ICIs, resulting in a significant reduction in survival time. This phenomenon is known as hyperprogressive disease (HPD) (6). According to reports, the incidence of HPD in patients with non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma is approximately 13.8% and 29%, respectively (7,8). It has also been reported that tumors grow rapidly in patients with advanced liver cancer receiving PD-1/PD-L1 inhibitor therapy, occurring in approximately 9% and 8% of the treatment cohort, respectively (9,10). In most previous studies, some patients receiving immunotherapy experienced higher disease progression and mortality rates during the early stages of treatment, which seriously affected disease prognosis and survival outcomes (11-13). Therefore, it is important to identify the risk factors for HPD to guide treatment decisions. Many previous reports have attempted to identify the risk factors of HPD, which include advanced age, female sex, worse performance status score, and higher metastases prior to treatment (14-17). However, the association of HPD with these risk factors in patients with PLC remains to be explored. Therefore, in this study, we aimed to analyze the relationship between clinical variables and HPD in patients with PLC treated with PD-1/PD-L1 inhibitor, and to explore the risk factors for HPD. We constructed a risk model to assess the risk of HPD in patients with PLC prior to the commencement of PD-1/PD-L1 inhibitor treatment and described the treatment of patients with HPD in detail. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/apm-21-2023).

Methods

Patients and data collection

This was a retrospective study that included patients who received PD-1/PD-L1 inhibitor treatment after a histological or clinical diagnosis of PLC in Nanfang Hospital, between August 2018 and October 2020. The inclusion criteria were as follows: (I) patient information on PD-1/PD-L1 inhibitor infusion in the electronic medical records and in the doctor’s orders; (II) Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2 points; and (III) Child-Pugh score A/B stage. The exclusion criteria were as follows: (I) missing baseline data; (II) without target lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; (III) lack of the required imaging examination before and after treatment; and (IV) presence of other tumors apart from PLC. The flowchart of the patient selection process is shown in Figure 1. We retrospectively collected the following data: age, sex, alcohol consumption, smoking history, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, ECOG PS, Child-Pugh score, circulating markers (neutrophil and lymphocyte counts), blood biochemistry (alanine aminotransferase, aspartate aminotransferase, total bilirubin, and albumin), organs with metastasis before PD-1/PD-L1 inhibitor treatment, number of organs with metastasis, portal vein tumor thrombus (PVTT), type of PVTT, and type of treatment undergone before PD-1/PD-L1 inhibitor treatment. As mentioned in previous studies, PVTT was divided into four types (18). All patients underwent enhanced computed tomography (CT) or magnetic resonance imaging before and after immunotherapy, and all target lesions underwent baseline and post-immunotherapy imaging examinations for evaluation. The pre-baseline scan was performed between 3 months before treatment and at baseline. The first scan for evaluation was performed approximately 2 months after the initial administration of immunotherapy. CT scans were used to assess the treatment response based on the RECIST 1.1 (19). The primary endpoint was the onset of HPD, which was defined as HPD from the date of the first administration of PD-1/PD-L1 inhibitor treatment to the first imaging evaluation based on the RECIST 1.1. The secondary endpoint was progression-free survival (PFS), which was defined as the time between the first immunosuppressive treatment and progression. RECIST 1.1 was used to evaluate the efficacy of the patient at the first imaging evaluation and to calculate the rates of partial response/stable disease (PR/SD), progressive disease (PD) without HPD, and HPD at the first imaging evaluation. This study was approved by the Medical Ethics Committee of Nanfang Hospital, Southern Medical University (NFEC-2021-048). The requirement for informed consent from the patients was waived because of the retrospective nature of the study. This study was performed in accordance with the ethical standards of the Declaration of Helsinki (as revised in 2013).

Figure 1 Flowchart of the patients included in the study. PLC, primary liver cancer; ICI, immune checkpoint inhibitor; PR, partial response; SD, stable disease; PD, progressive disease; HPD, hyperprogressive disease.

Definition of HPD

According to a previous study, we defined HPD as PD within approximately 2 months after the initiation of treatment according to the RECIST 1.1, with a measurable lesion increase of ≥10 mm. The criteria for HPD were as follows: (I) the total diameter of the target lesion increased by ≥40% compared with baseline and/or (II) the total diameter of the target lesion increased by ≥20% compared with baseline and new lesions appeared in at least two different organs (20).

Statistical analysis

We divided patients into the non-HPD (PR, SD, and PD without HPD) and HPD (PD with HPD) groups based on the patients’ response to treatment. The independent sample t-test, chi-squared test, or Mann-Whitney U test were used to assess the correlation between HPD and categorical variables or continuous variables, as appropriate. RECIST 1.1 was used to evaluate the efficacy of the treatment. We used univariate and multivariate logistic regression analyses to determine the clinical variables related to HPD. Logistic regression was used to establish a risk model based on the clinical variables that had predictive significance for HPD. We calculated the area under the curve (AUC) to evaluate the predictive ability of the model. Kaplan-Meier survival curves were used to compare PFS of the HPD, non-HPD, and PR/SD groups. All tests were two-sided, and a P value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 26.0 software (IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

A total of 129 patients treated with PD-1/PD-L1 inhibitor were included in the analysis. The baseline clinical characteristics of the HPD and non-HPD groups are shown in Table 1. There were significant differences between the two groups in the number of organ metastases, lung metastases, lymph node metastases, and liver resection prior to immunotherapy (P<0.05). Most patients were below 65 years of age (n=108, 83.7%), were men (n=107, 82.9%), had Child-Pugh A (n=105, 81.4%), had Barcelona-Clinic Liver Cancer (BCLC) stage C (n=96, 74.4%), had a good ECOG PS (0 or 1: n=119, 92.2%), and had HBV infection (n=114, 88.4%). Forty-nine patients had extrahepatic metastasis; 35 patients had lung metastasis and 54 had lymph node metastasis. Fifty-eight patients had PVTT. We used the RECIST 1.1 to evaluate the 129 included patients. According to the RECIST 1.1, 84 (65.1%) patients had PR/SD, 32 (24.8%) had PD without HPD, and 13 (10.1%) had HPD. Basic information and the treatment details of HPD patients are shown in Table S1.

Assessment of HPD

We evaluated HPD according to the RECIST 1.1. We first assessed the percentage of tumor growth in patients treated with PD-1/PD-L1 inhibitor. The baseline tumor diameter of each patient was evaluated based on the imaging results obtained within 3 months prior to the first use of PD-1/PD-L1 inhibitor, and those results were compared to the imaging results obtained approximately 2 months after the patient’s first immunotherapy session to evaluate the tumor growth percentage. The average tumor growth ratio of all patients was 4.98%. Seventeen patients (13.1%) had a tumor growth percentage of ≥20%, and 6 patients (4.7%) had a tumor growth percentage of ≥40%. Second, we evaluated the status of new metastases occurring within approximately 2 months after the initiation of immunotherapy. Regarding metastases, thirty-one patients (24.0%) developed new metastases in two or more different organs, whereas 50 patients had no new metastases. 48 patients had one new metastasis. Finally, according to the RECIST 1.1, we identified 13 (13/129, 10.1%) patients with HPD. Among these, 5 patients (38.5%) had a tumor growth percentage of ≥40%, and 8 (61.5%) had that of ≥20% with new metastases in more than two different organs. Based on the RECIST 1.1, 84 patients with PR/SD accounted for 65.1% of the study population, and 32 patients who had PD without HPD accounted for 24.8% of the study population.

PFS survival analysis and clinical variables related to HPD

We conducted a survival analysis of PFS in all patients, and the results are shown in Figure 2. Our results showed that patients with HPD had worse PFS as compared with non-HPD patients (P<0.001). Univariate and multivariate analyses were used to study the clinical variables associated with HPD. Univariate regression analysis revealed that lung metastasis, lymph node metastasis, and liver resection were significantly associated with HPD (Table 2). Variables with a P value of <0.2 in the univariate regression analysis [lung metastasis, lymph node metastasis, liver resection, neutrophil-lymphocyte ratio (NLR), total bilirubin, PVTT, and number of organs with extrahepatic metastasis] ECOG PS, albumin, and BCLC were included in the multivariate regression analysis (21). Among these, lymph node metastasis and lung metastasis were found to be significantly associated with HPD (Table 3). We included lymph node metastasis, lung metastasis, NLR, albumin, and PS in the logistic regression analysis and established a risk model to assess the risk of HPD. The receiver operating characteristic curve is shown in Figure 3, with an AUC of 0.801 (P<0.001).

Figure 2 Kaplan-Meier curves for HPD in patients with primary liver cancer treated with PD-1/PD-L1 inhibitor. (A) Survival analysis comparing PFS between the HPD and non-HPD groups; (B) Kaplan-Meier curves comparing PFS between patients with PR/SD, PD without HPD, and HPD. HPD, hyperprogressive disease; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Figure 3 The receiver operating characteristic curves of a risk model for HPD in patients with primary liver cancer treated with PD-1/PD-L1 inhibitor. AUC, area under the curve; HPD, hyperprogressive disease; ROC, receiver operating characteristic.

Discussion

It is well known that immunotherapy changes the treatment patterns in liver cancer. However, a small number of patients receiving immunotherapy experience rapid tumor progression, and the median survival time for these patients is shorter than that of patients without HPD. In this study, 10.1% of patients with PLC who were administered immunosuppressive therapy experienced HPD. Kim et al. used the ratio of tumor growth kinetics to tumor growth rate to assess HPD and found that 12.7% of patients treated with nivolumab developed HPD (22). The incidence of HPD in our study was similar to that reported in theirs. In addition, the study by Champiat et al. included 20 solid tumors involving NSCLC, and HPD reportedly occurred in 12 (9.1%) of 131 patients receiving PD-1/PD-L1 inhibitor treatment (14). A report of head and neck squamous cell carcinoma indicated that the use of PD-1/PD-L1 inhibitors resulted in a 29% incidence of HPD. Ferrara et al. included patients with advanced NSCLC and found that the HPD rate of the PD-1/PD-L1 inhibitor group was 13.8% (7). This may be because the probability of hyperprogression after ICI treatment varies based on different types of tumors and the research conducted.

In our study, multivariate analysis indicated that lymph node and lung metastases are risk factors for HPD in patients with PLC treated with ICIs and were positively associated with HPD. Lymph node metastasis is an important factor for poor survival in liver cancer patients, and according to reports, patients with lymph node metastases have worse survival outcomes compared to those without. It has been reported that lung metastasis is also an important factor for poor survival in liver cancer patients. Moreover, prognostic analysis shows that overall survival and cause-specific survival are both worse in liver cancer patients with lung metastasis than in those without distant metastasis (23).

Other clinical factors related to HPD have been reported in the literature, such as age, sex, local recurrence, poor ECOG PS, number of metastatic lesions, NLR, and C-reactive protein levels. Our research showed that NLR was not associated with HPD in the univariate or multivariate analysis, which may be due to differences in the sample size. The current study did not find a significant association between advanced age and HPD. However, a study published in 2017 by Champiat et al. (14) showed that elderly patients were more likely to develop HPD. It was found that patients over 65 years of age were more likely to develop HPD (22). However, this conclusion is not consistent across all retrospective studies and requires confirmation. Kanjanapan et al. found that HPD is more likely to occur in female patients after ICI monotherapy (15). However, the present study shows that sex is not associated with HPD. Our univariate and multivariate logistics regression analyses also revealed that the number of metastatic organs was not significantly associated with HPD. In addition, liver function classification and PVTT have been found to be related to HPD in previous reports; however, in this study, liver function classification and PVTT were not associated with HPD (24). Previous studies have reported that NLR may be a risk factor for HPD (22,25). A poor PS has been reported to be significantly related to the occurrence of HPD (17). Albumin is an important indicator of the efficacy of immunotherapy (26). We incorporated lymph node metastasis, lung metastasis, NLR, albumin, and PS scores into the logistic regression analysis and established a risk model. The receiver operating characteristic curve indicated that this model had moderate predictive power.

In our univariate analysis, there was a significant difference in HPD rates between patients who had undergone liver resection and those who had not undergone partial hepatectomy. One patient underwent palliative liver resection, and one patient underwent partial hepatectomy for gallstones removal. The remaining patients had tumor remnant, recurrence of intrahepatic tumor, or distant metastasis after partial hepatectomy. Other treatments such as transarterial chemoembolization, hepatic arterial infusion chemotherapy, liver tumor ablation, and targeted drugs were not significantly related to HPD.

This study has some limitations. First, this was a retrospective study, and potential biases were inevitable; the data was obtained from a single center and only included a population of PLC in China. Owing to the differences in race, region, etiology, and the environment of liver cancer, these results may not be generalizable. Therefore, further research including large samples of data from various countries is required to verify our findings. In addition, because some patients do not have any measurable tumor lesions before or after treatment or do not have proper CT scans, some HPDs may be missed. In addition, chemotherapy or targeted therapy do not preclude the occurrence of hyperprogressive phenomena in a variety of preclinical and clinical research models; thus, the same analysis should be performed in a control group receiving non-immunotherapy drugs. Finally, because some patients were lost to follow-up, we were unable to conduct further analysis of overall survival to explore the survival outcome of patients. Previous reports have confirmed that patients with HPD have a significantly lower median overall survival than those with natural progression of the disease.

Conclusions

In our cohort, the HPD rate was 10.1% in patients with PLC receiving ICI therapy. Compared with non-HPD patients, HPD patients had worse PFS. Lung metastasis and lymph node metastasis were independent risk factors of HPD, and our HPD risk model had moderate predictive power. Considering our findings, a larger sample of prospective data is required to explore HPD-related risk factors and establish related risk assessment tools to guide clinical diagnosis and treatment.

Acknowledgments

We would like to thank all the data collectors for their support of this study. We would like to thank Editage (www.editage.cn) for the English language editing.

Funding: This work was supported by the National Nature Science Foundation of China (Grant Nos. 81773008, 81972897) and by the Clinical Research Startup Program of Southern Medical University via the High-level University Construction Funding of the Guangdong Provincial Department of Education (LC2019ZD003).

Footnote

Reporting Checklist: The authors have completed the STROBE Statement reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-2023

Data Sharing Statement: Available at https://dx.doi.org/10.21037/apm-21-2023

Peer Review File: Available at https://dx.doi.org/10.21037/apm-21-2023

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-2023). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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. This study was approved by the Medical Ethics Committee of Nanfang Hospital, Southern Medical University (NFEC-2021-048). The requirement for informed consent from the patients was waived because of the retrospective nature of the study. This study was performed in accordance with the ethical standards of the Declaration of Helsinki (as revised in 2013).

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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