Decreased overall survival in patients with hepatocellular carcinoma during the COVID-19 pandemic

Introduction

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies with a rising incidence worldwide, but wide disparities among regions (1). In Germany, incidence ranges between s 7.2/100,000 in men and 1.9/100,000 in women, with an average age of onset of 71 years in men and 74 years in women (2). The majority of patients with HCC suffer from underlying chronic liver disease, i.e., liver cirrhosis due to excess alcohol consumption, viral hepatitis, or metabolic dysfunction-associated steatotic liver disease (MASLD) (1). Therefore, regular biannual surveillance for HCC by ultrasound is recommended in patients with liver cirrhosis (3). The aim of HCC surveillance is to detect HCC at early stages, as therapy and prognosis are stage-dependent. As a standard of care, staging and therapy of HCC are classified according to the Barcelona Clinic Liver Cancer (BCLC) classification in the Western world (4), according to which the most important factors determining prognosis of HCC are size and number of tumor lesions, vascular invasion and extrahepatic manifestations, alongside liver function stratified by Child-Pugh-Score (5). While median survival at very early and early stage HCC (BCLC 0 and BCLC A) is >5 years, survival declines to a little more than 2 years in advanced stage HCC (BCLC C), underscoring the importance of early diagnosis and treatment of HCC (4).

In March 2020, coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO) (6) and led to an overload of national health care systems worldwide, resulting in limited access to health care services for patients. Access was particularly restricted for patients with non-emergency issues, such as patients presenting for surveillance and screening of malignant tumors. Along these lines, it was shown that colorectal cancer screening via colonoscopy decreased during the COVID-19 pandemic (7) and that fewer diagnoses of gastrointestinal (GI) cancers were made (8-10). Moreover, having observed a decline in urgent referrals and chemotherapy attendance in cancer patients in England in early 2020, an increase of deaths in cancer patients was mathematically predicted (8). For patients at risk for HCC development, a reduction in the number of surveillance visits during the COVID-19 pandemic was reported which was associated with a reduction of HCC diagnoses during the early phase of the pandemic (11,12). As these findings are indicative of delayed HCC diagnosis, we aimed to investigate whether diagnosis in HCC patients was associated with a more advanced disease stage at the time of diagnosis during the COVID-19 pandemic and if this resulted in differences in overall survival (OS) of HCC patients. We present this article in accordance with the TREND reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-54/rc).

Methods

Patient cohort

All patients with initial diagnosis of HCC between March 2018 and February 2022, who presented at the Clinical Department for Internal Medicine II or the Comprehensive Cancer Center at the University Medical Center of the Technical University of Munich (TUM), Germany, were included into this study. Diagnosis of HCC was established by histology or imaging characteristics according to international guidelines (13). Tumor recurrence after ≥2 years from initial diagnosis was regarded as de novo HCC. Data were recorded and analyzed in a pseudonymized manner. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was reviewed and approved by the local ethics committee (TUM Ethics Committee, TUM School of Medicine and Health, Munich; No. 2022-509-S-KH). According to local ethics committees, there is no informed consent required. There was no industry support or involvement in the present study. The study was designed as an open, retrospective, single-center longitudinal survey. Patients’ age, sex, date of diagnosis, BCLC stage at initial diagnosis, etiology of underlying liver disease, alpha-fetoprotein (AFP) at time of diagnosis, and survival data were analyzed. Patients were grouped according to initial diagnosis before and after March 2020, i.e., before and after the COVID-19 pandemic as declared by the WHO. HCC treatment was determined by a multidisciplinary tumor board according to international guidelines.

Statistical analysis

All data were analyzed using Microsoft excel (version 16) and SPSS (version 29). Statistics were based on an intention to treat analysis. Mann-Whitney and t-test as well as Pearson’s Chi-squared test were used for comparisons of variables between or among groups where appropriate. Survival analysis was performed via Kaplan-Meier curves and log-rank test. The OS and the survival rates were provided with the median and the 95% confidence interval (CI). P values <0.05 were considered statistically significant. Continuous data were provided as mean and range. Categorical were presented in absolute numbers and percentages.

Results

Between March 2018 and February 2022, 175 patients diagnosed with HCC at our center were included. Mean patient age at time of diagnosis was 68 years (range, 26 to 91 years), 78% (n=137) of patients were male and the majority of patients suffered from liver fibrosis or cirrhosis (n=137, 78%). Major risk factors for HCC development in the overall patient cohort were alcoholic liver disease (n=58, 33%), chronic viral hepatitis (n=55, 31%), and MASLD (n=19, 11%). Before the COVID-19 pandemic (March 2018 to February 2020; pre-COVID-19) 79 patients were diagnosed with HCC, while 96 patients were diagnosed during the pandemic (March 2020 to February 2022; during COVID-19). There were no significant differences in age, sex, presence of liver fibrosis or cirrhosis, or etiology of liver disease between the pre-COVID-19 and during COVID-19 groups (Table 1). Median AFP at diagnosis was 12.2 ng/mL with a maximum of 491,000 ng/mL. There were no statistically significant differences in AFP levels between groups (Table 1). Whereas a decrease in surveillance visits and HCC diagnoses during the COVID-19 pandemic was reported in other publications (11,12), our data showed no evidence of a reduction in HCC diagnoses during the early phase of the pandemic. After the first year of the pandemic, we even observed an increase in HCC diagnoses with 34 cases of HCC diagnosed in the twelve months prior to the pandemic (March 2019 to February 2020) compared to 44 HCC cases during the first year of the COVID-19 pandemic (March 2020 to February 2021) (Figure S1).

Discussion

Key findings

HCC was diagnosed at more advanced BCLC stages during the COVID-19 pandemic

HCC stage at first diagnosis was classified according to the BCLC system (4) in our patient cohort of 175 patients. Within the whole study cohort, 67 patients (38.3%) were diagnosed with HCC at very early or early stages (BCLC 0 and A), while 50 (28.6%) were diagnosed with intermediate stage (BCLC B), 51 (29.1%) with advanced stage (BCLC C), and 7 (4.0%) with end-stage (BCLC D) HCC (Table 2). Importantly, when comparing BCLC stages at the time of diagnosis, we observed that during the COVID-19 pandemic, a significantly lower absolute number and percentage of patients were diagnosed with HCC at early, potentially curative stages (BCLC 0 and A), compared to the pre-COVID-19 group (n=28, 29%), during COVID-19 vs. 39 patients (49%) pre-COVID-19; P=0.03, Table 2, Figure 1).

Figure 1 BCLC stage at the time of diagnosis. Charts display the number (A) and percentage (B) of patients diagnosed per BCLC stage prior to the COVID-19 pandemic (left) and during the COVID-19 pandemic (right); P=0.03 (trend test for ordinal variables). BCLC, Barcelona Clinic Liver Cancer; COVID-19, coronavirus disease 2019.

HCC diagnosis during the early pandemic was associated with reduced OS

We next analyzed OS of patients diagnosed with HCC in our patient cohort. The overall median survival of all HCC patients was 25.03 months (95% CI: 16.9–33.2). Among all HCC patients, the median survival rate of patients with BCLC 0/A HCC (55.87 months, 95% CI: 45.3–66.4) was superior to those of patients with HCC in stages BCLC B (28.06 months, 95% CI: 17.2–38.9), BCLC C (8.13 months, 95% CI: 5.3–11.0), and BCLC D (9.81 months, 95% CI: 0.0–21.3). This is in line with estimated survival rates of HCC patients as outlined in the BCLC classification for early and intermediate stage HCC (4); however, the survival rate of patients with advanced stage HCC was slightly lower in this real-world setting (Figure S2, Table 3). We next compared OS between patients diagnosed with HCC prior to and during the COVID-19 pandemic. Among those patients diagnosed with HCC prior to the COVID-19 pandemic, median survival was 32.65 months (95% CI: 14.6–50.7), compared to 21.57 months (95% CI: 14.3–28.8) in patients diagnosed with HCC during the COVID-19 pandemic (P=0.06) (Figure S3). Importantly, we observed a significantly lower median OS in patients diagnosed with HCC during the first 12 months of the pandemic, compared to those diagnosed with HCC prior to the COVID-19 pandemic (median OS 23.9 months: 17.23 months first year of COVID-19 pandemic (March 2020 to February 2021) vs. 32.65 months pre-COVID-19 (March 2018 to February 2020; P=0.02) (Figure 2), but not in the second year of the pandemic (Figure S4), indicating that the survival of newly diagnosed HCC patients was most severely affected during the early pandemic.

Figure 2 Survival probability and median OS in months after initial diagnosis according to time of diagnosis for patients diagnosed within the first 12 months of the pandemic (March 2020 through February 2021; number at risk). Vertical ticks represent censored observations. OS, overall survival; CI, confidence interval; COVID-19, coronavirus disease 2019.

It is highly likely that presentation at a more advanced tumor stage during the pandemic (Figure 1) contributes to reduced OS during the first year of the COVID-19 pandemic (Figure 2) our center. However, reports of delayed or insufficient oncologic treatment during the pandemic might also play a role (14). We therefore analyzed BCLC stage-dependent survival rates in the pre-COVID-19 and during-COVID-19 cohorts. Importantly, there was no difference in OS as well as 12-months survival rate when patients were stratified according to BCLC stage (P=0.58) (Figure 3, Table 3): while median OS was not reached for (very) early-stage HCC (BCLC 0/A) and intermediate stage HCC (BCLC B) at the time of analysis, there were no significant differences in median OS for advanced stage HCC (BCLC C, pre-COVID-19 4.7 months vs. COVID-19 8.13 months). Similarly, no significant differences were observed for 12-months survival rates for all BCLC stages analyzed from our cohort (BCLC 0/A through C, Table 3).

Figure 3 Survival probability in months after initial diagnosis according to time of diagnosis distributed into BCLC stage. Overall survival according to BCLC stage was not significantly different between groups, P=0.58. (A) Patients with (very) early HCC (BCLC 0/A). (B) Patients with intermediate stage HCC (BCLC B). (C) Patients with advanced stage HCC (BCLC C). (D) Patients with terminal stage HCC (BCLC D). BCLC, Barcelona Clinic Liver Cancer; COVID-19, coronavirus disease 2019; HCC, hepatocellular carcinoma.

Taken together, our results show the HCC was diagnosed at more advanced stages during the COVID-19 pandemic which was associated with a reduced OS of patients diagnosed with HCC during the first year of the COVID-19 pandemic.

Strengths and limitations

Our study has several limitations. Firstly, analysis is limited to a single center cohort at a tertiary care facility. Therefore, limitations in access to diagnosis and treatment might differ from smaller hospitals and primary care facilities that had severely limited capacities for non-COVID-19 patients. One of the greatest strengths of our study undoubtedly lies in the extended follow-up period and the high quality of patient data. As our study focused on patients with first diagnosis of HCC, patient numbers were limited and did not allow for in-depth analysis of patient subgroups according to tumor stage or HCC etiology. However, even considering the comparatively small patient cohort, significant differences in tumor stage and survival were evident at our center and are in line with findings and models in other cancer entities (15,16).

Comparison with similar researches

Indeed, several retrospective studies reported a reduced number of patients diagnosed with HCC during the COVID-19 pandemic (12,17-19). Interestingly, findings from our center did not show a decline in HCC diagnoses during the pandemic but rather an increase which was more pronounced during the second year of the pandemic. While these findings were surprising, a simple explanation for the observed increase might be a higher number of patient referrals to tertiary centers at a time when primary and secondary care facilities had limited capacities for non-emergency cases. During the pandemic, our center was indeed largely able to maintain its overall healthcare infrastructure in oncology and prioritized appointments for newly diagnosed cancer patients. Thereby, the observed increase in HCC diagnoses most likely represents a shift of patients to hospitals with a comparatively high capacity for diagnosis and treatment of non-COVID-19 patients during the pandemic.

A number of studies investigated the influence of the COVID-19 pandemic on HCC diagnosis and outcome (12,19). No effect on BCLC stage at the time of diagnosis was reported during the first four months of the pandemic in the Asia-Pacific region (20) or in a report comprising two years of the pandemic in a study from Japan (21). Nevertheless, a compensatory increase of HCC cases at later time points was already presumed by Ribaldone et al. (12) In overall GI cancer, tumors were detected at a more advanced stages, though the increase was not significant considering HCC alone in a Japanese cohort of 413 patients (9). In a multicenter cohort from Scotland comprising the first 7 months of the COVID-19 pandemic in 2020, a significant increase in BCLC stage and also Child-Pugh-Score was reported in comparison to the same time period of the pre-pandemic era in 2019—and these were associated with a significantly decreased survival (22), comparable to our findings.

Explanation of findings

During the COVID-19-pandemic, overload of national healthcare systems not only had a profound impact on the care of cancer patients, but specifically on non-urgent cancer screening procedures. At our center, surveillance by ultrasound is offered to all outpatients in hepatology who are at risk for development of HCC according to international guidelines (13,23). During the early phase of the COVID-19-pandemic, regular surveillance visits at our hepatology outpatient clinic were cancelled for all patients with asymptomatic liver disease, and telephone-only visits were offered. This measure was necessary to re-allocate medical staff for the treatment of patients with severe SARS-CoV2 infection and to avoid the spread of SARS-CoV2 in outpatient clinics. This approach was comparable to measures taken by hospitals worldwide (24), as consensus statements of European and American associations suggested deferring HCC surveillance by two months or more (25). Patients were advised to get in-person appointments once the situation stabilized and recommendations to self-isolate were lifted. Even after HCC surveillance was resumed at outpatient clinics in summer 2020, many patients were hesitant to attend appointments for concerns of contracting SARS-CoV2 infection. Although details on the percentual decline in HCC surveillance visits was not documented at our center, this observation matches studies reporting a decreased rate of HCC screening visits especially during the earlier phase of the pandemic (17,18). In addition to reduced surveillance, several patients diagnosed with HCC at our center during the COVID-19 pandemic reported that they had postponed medical visits despite symptoms such as abdominal discomfort, development of ascites or weight loss, due to difficulties in getting medical appointments with their primary care physician, fear of infection, or not taking the symptoms serious enough to justify medical presentation during the pandemic.

Reduced early survival during the COVID-19 pandemic might not only depend on tumor stage at the time of diagnosis but could also be attributed to treatment delay due to overload of the health care system (20,26). In our cohort however, there was no difference in stage-dependent survival rates between pre-COVID-19 and COVID-19 cohorts. While we were not able to estimate stage-dependent survival rates for different time spans during the pandemic due to the limited number of patients in our single center cohort, a multicenter analysis of the first 4 months of the pandemic from UK and German hospitals did not detect an influence of mildly delayed treatment on OS (26). Whereas data from our center did not show a difference in BCLC-dependent survival between the pre-COVID-19 and the COVID-19 era, a French multicenter cohort showed a reduced 12-month survival rate not only in the overall cohort, but also in BCLC A and BCLC C patients (14). However, the study population in this analysis differed considerably from our cohort, as they included all HCC patients with treatment recommendations and not only first presentations. Additionally, only the first 6 weeks of the pandemic were analyzed and where treatment delays were reported in more than 25% of cases. Therefore, patients with delayed presentation were likely to be missed in the French cohort. On the other hand, treatment delays during the first 6 weeks of the pandemic could not be analyzed in our cohort that only included patients with first diagnoses of HCC and therefore only a small number of patients during the first six weeks. While the French and our study both showed a reduced OS during the COVID-19 pandemic, it is highly likely that different factors contributed to this observation, including treatment delays in the very early phase of the pandemic and delayed presentation (14) as well as diagnosis at more advanced tumor stages during the first year of the pandemic.

Implications and actions needed

Our data indicate that limited resources can lead to a delay in tumor diagnoses with implications for OS. Screening of patients at risk for HCC and low-threshold access to health care facilities should be implemented whenever possible to avoid late diagnosis and dismal prognosis.

Conclusions

In summary, we showed that the COVID-19 pandemic led to an increase in patients diagnosed at later tumor stages in comparison to the pre-COVID-19 era. This increase in patients with more advanced tumor stages translated in reduced survival during the first year of the pandemic–highlighting the importance of early diagnosis in HCC and advocating for close monitoring of at-risk patients especially in conditions of reduced health care access.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-54/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-54/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-54/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-54/coif). The 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 protocol was reviewed and approved by the local ethics committee (TUM Ethics Committee, TUM School of Medicine and Health, Munich; No. 2022-509-S-KH). According to local ethics committees, there is no informed consent required.

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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