Hepatocellular carcinoma (HCC) is currently the 6th most common cancer and the 2nd leading cause of cancer-related deaths worldwide (1). The incidence of HCC around the globe follows the geographical distribution of the hepatitis B and C viruses, as infection with either virus is a significant risk factor of HCC (2-4). The management of HCC is multidisciplinary (3,5). However, patients with advanced HCC still have a dismal prognosis, with a 5-year overall survival (OS) of 31% for localized disease, 11% for regional disease, and 2% for metastatic disease (6).
Most patients with HCC are diagnosed at an advanced stage (7). Patients with advanced HCC who have progressed after 1st-line therapy have a poor prognosis. Sorafenib is a standard 1st-line systemic targeted therapy for advanced HCC (8). Unfortunately, patients who fail to respond to sorafenib have an OS of only 8 months without treatment (9-11).
Regorafenib can inhibit the activity of the protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity (12-14). The molecular structures of regorafenib and sorafenib are very similar, but regorafenib has a special molecular target and a more potent pharmacological activity than sorafenib. In 2017, the RESORCE trial released encouraging results (15-17). According to the results of the RESORCE trial, regorafenib improved OS with a hazard ratio (HR) of 0.63 [95% confidence interval (CI): 0.50–0.79; 1-sided P<0.0001], and patients treated regorafenib had a median OS of 10.6 months (95% CI: 9.1–12.1 months), while those who received a placebo had a median OS of 7.8 months (95% CI: 6.3–8.8 months) (15). Significant improvements were also found in relation to progression-free survival (PFS), time-to-progression (TTP), the disease control rate, and overall tumor response (15). In recent years, there has been increasing evidence that the application of regorafenib in combination with other adjuvant therapies, such as transarterial chemoembolization (TACE) and immune checkpoint inhibitors, may benefit some patients (18-20).
Regorafenib is a standard 2nd-line treatment for patients with advanced HCC, and the sequential therapy of regorafenib after progression to sorafenib has been adopted as an evidence-based treatment (3,5,21). However, patients in Asia, especially those in China, display different clinical characteristics to patients in the West (22-26). Previous studies have shown that Regorafenib-related adverse events were more frequent in Asian populations than in non-Asian populations, including hand-foot skin reaction (27-29) and liver function adverse events (30-32). These variances are possibly due to racial differences affecting drug absorption or pharmacokinetics or improved management of regorafenib-related toxicities. Beyond that, it remains unclear which clinical features would benefit patients from sequential therapy. Thus, our study was designed to assess the efficacy and safety and analyzed the prognostic factors of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China. We present the following article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-397/rc).
This is a two-center, retrospective, cohort research study. Patients with advanced HCC receiving sequential therapy at two large hospitals (Tianjin Medical University Cancer Institute and Hospital and Tianjin First Central Hospital) in China from October 2018 to April 2020 were included in the study. To be eligible for inclusion in the study, patients had to meet the following inclusion criteria: (I) be aged ≥18 years; (II) have Barcelona Clinic Liver Cancer (BCLC) stage B or C (2); (III) have previously undergone but failed to respond to treatment with sorafenib (i.e., had received sorafenib for ≥20 days and had documented radiological progression or had stopped taking the drug because of unbearable adverse reactions); (IV) had liver function status Child-Pugh A; (V) had adequate bone marrow, liver, and renal function; and (VI) had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–1. Patients were excluded from the study if they met any of the following exclusion criteria are (I) had received other treatments between the withdrawal of sorafenib and the start of regorafenib or had received other treatments during regorafenib treatment; (II) had a history of other tumors except for HCC; and/or (III) had severe cardiovascular or respiratory disease or human immunodeficiency virus infection. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Tianjin Medical University Cancer Institute and Hospital (No. bc2022135) and Tianjin First Central Hospital (No. 2022N256KY), with the requirement for informed consent waived. And this study complied with the Good Clinical Practice guidelines and applicable local laws. Any patient data that could identify individual patients were anonymized and de-identified before analysis.
The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. Based on previous trials, the starting dose was 160 mg of regorafenib once daily for 3 weeks, followed by 1 week of no treatment per cycle (15-17,33,34). A reduced starting dose of <160 mg/day regorafenib was allowed for some patients (15). The patients underwent evaluations every 4–6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results.
Data collection and definition
The following data were gathered from the patient charts: sex, age, history of hepatitis, history of chronic disease, unhealthy living habits, previous treatment (basic antiviral therapy and treatment before sorafenib), data on sorafenib treatment (tolerance and type of progression after sorafenib, enlargement of the original/new intrahepatic lesions, or new extrahepatic metastatic lesions), baseline data of regorafenib [ECOG-PS, Child-Pugh class, radiological evaluation, alpha-fetoprotein (AFP), and BCLC stage], data on regorafenib treatment [the start date of the regorafenib treatment, time of radiological progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and mRECIST, and adverse events of regorafenib treatment], and date of death or last follow-up. The patient data were anonymized and de-identified before the analysis.
Concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and AFP were assessed before each treatment cycle. A radiological evaluation, using computed tomography or magnetic resonance imaging scans, was conducted. OS was defined as the time from the initiation of regorafenib to death from any cause. PFS was defined as the time from the initiation of regorafenib to the date of disease progression or death from any cause before progression. Semiannual follow-up was based on telephone questionnaire, with additional follow-up procedures when needed. Safety was assessed by the frequency of treatment-emergent adverse events. Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03.
All the statistical analyses were conducted using SPSS 23 (IBM, Armonk, NY, USA). The normally distributed continuous data were tested using the Kolmogorov-Smirnov test and are expressed as the mean ± standard deviation. The non-normally distributed continuous data are expressed as the median (range). Loss to follow-up and missing values were excluded from the study. The PFS of regorafenib treatment patients was estimated using Kaplan-Meier plots of medians with 95% CIs. A univariable analysis was conducted using the Kaplan-Meier method, and differences were evaluated using the log-rank test. The univariable Cox proportional-hazards model was fitted to each variable. Next, all variables with a two-sided P value <0.05 and other significant factors identified in previous studies were included in the multivariable analysis using a stepwise Cox hazard-regression model to evaluate their value as independent predictors of PFS and OS. P values <0.05 were considered statistically significant.
A total of 55 patients with advanced HCC received sequential therapy from October 2018 to April 2020. However, 5 patients were lost to follow-up, and 7 were excluded for not receiving regular reviews or missing critical clinical information. Table 1 sets out the baseline characteristics of the 43 patients included in the study. Patients had a mean age of 60.4±9.1 years, and 39 (90.7%) patients were male. Of the patients, 35 (81.4%) had a history of hepatitis B, and 60% had received previous antiviral therapy. Of the patients, 14 (32.6%) patients had AFP levels ≥400 ng/mL before 2nd-line treatment. All patients had Child-Pugh class A cirrhosis and ECOG 0–1, and 60.5% and 39.5% of the patients were classified as BCLC stage B and C, respectively. All 43 patients were confirmed to show radiological progression during sorafenib therapy. Additionally, 5 (11.6%) patients had a macrovascular invasion. Further, 8 (18.6%) patients had extrahepatic metastasis, with the most common metastatic site being the lungs (n=8, 18.6%), followed by the bones (n=5, 11.6%). In relation to the patterns of progression during sorafenib treatment, 18 (41.9%), 11 (25.6%), 10 (23.3%), and 4 (9.3%) patients were classified as having growth of intrahepatic or extrahepatic lesions or both, a new extrahepatic lesion, a new intrahepatic lesion, or unknown, respectively. Almost all the patients underwent pre-treatment before regorafenib. During the sorafenib administration, 40 patients displayed a tolerance to sorafenib.
|Age, years, mean ± SD||60.4±9.1|
|Male, n (%)||39 (90.7)|
|History of diabetes, n (%)||12 (27.9)|
|History of hypertension, n (%)||20 (46.5)|
|Smoking history, n (%)||20 (46.5)|
|History of alcoholism, n (%)||9 (20.9)|
|Etiology, n (%)|
|Hepatitis B||35 (81.4)|
|Standard antiviral therapy, n (%)||21/35 (60.0)|
|AFP (ng/mL), median (interquartile range)||32.4 (4.4, 821.7)|
|AFP ≥400 ng/mL, n (%)||14 (32.6)|
|Child-Pugh class A, n (%)||43 (100.0)|
|ECOG-PS ≤1, n (%)||43 (100.0)|
|ALT (U/L), median (interquartile range)||31.0 (16.0, 53.5)|
|ALT >60 U/L, n (%)||10 (23.3)|
|AST (U/L), median (interquartile range)||37.0 (22.5, 65.0)|
|AST >60 U/L, n (%)||11 (25.6)|
|ALB (g/L), median (interquartile range)||40.3 (36.3, 45.1)|
|Barcelona Clinic Liver Cancer stage, n (%)|
|Macrovascular invasion, n (%)||5 (11.6)|
|Extrahepatic metastasis, n (%)||8 (18.6)|
|Lung, n (%)||8 (18.6)|
|Bone, n (%)||5 (11.6)|
|Adrenal, n (%)||2 (4.7)|
|Macrovascular invasion and/or extrahepatic disease, n (%)||13 (30.2)|
|Pattern of progression on previous sorafenib treatment, n (%)|
|Growth of intrahepatic or extrahepatic lesions, or both||18 (41.9)|
|New extrahepatic lesion||11 (25.6)|
|New intrahepatic lesion||10 (23.3)|
|Pretreatment, n (%)||35 (81.4)|
|Pre-resection, n (%)||28 (65.1)|
|Pre-local ablation, n (%)||6 (14.0)|
|Pre-TACE, n (%)||31 (72.1)|
|Pre-liver transplantation, n (%)||7 (16.3)|
|Pre-radiotherapy, n (%)||4 (9.3)|
|Tolerance of sorafenib, tolerance, n (%)||40 (93.0)|
HCC, hepatocellular carcinoma; AFP, alpha-fetoprotein; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; ALT, alanine transaminase; AST, aspartate aminotransferase; ALB, albumin; TACE, transarterial chemoembolization.
Effectiveness of regorafenib
The starting dose of regorafenib was determined according to each patient’s basic condition (80–160 mg). With a median follow-up period of 8 months (95% CI: 11.3–11.4 months), the median PFS and OS (see Figure 1) were 11.0 months (95% CI: 5.8–16.2 months) and 17.0 months (95% CI: 12.8–21.2 months), respectively. We confirmed that 14 patients had radiological progression after regorafenib administration.
Factors associated with PFS
Among the variables, AFP, alanine transaminase (ALT), and aspartate aminotransferase (AST) before 2nd-line treatment were significant risk factors for PFS in the univariable analyses (see Table 2). The Kaplan-Meier curves of the PFS of HCC patients treated with regorafenib after sorafenib for the before 2nd-line treatment AFP <400 and ≥400 ng/mL groups showed significant differences (see Figure 2A). Additionally, significant differences were also found between normal (≤60 U/L) and abnormal (>60 U/L) ALT (P=0.003) and AST (P=0.009) before 2nd-line treatment (see Figure 2B,2C). The multivariable Cox proportional-hazards regression analysis showed that AFP (HR =0.225; 95% CI: 0.073–0.688; P=0.009), ALT (HR =0.195; 95% CI: 0.051–0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063–0.697; P=0.011), and extrahepatic metastasis (HR =0.074; 95% CI: 0.009–0.608; P=0.015) before 2nd-line treatment were independently associated with PFS (see Table 2). No factors were found to be associated with OS (see Table 3).
|HR||95% CI||P||HR||95% CI||P|
|History of diabetes||0.408||0.163–1.022||0.056|
|History of hypertension||0.626||0.245–1.602||0.328|
|History of alcoholism||1.495||0.435–5.142||0.524|
|Tolerance of sorafenib||1.452||0.333–6.338||0.62|
|AFP ≥400 vs. <400 ng/mL||0.319||0.125–0.811||0.016*||0.225||0.073–0.688||0.009*|
|ALT >60 vs. ≤60 U/L||0.27||0.105–0.694||0.007*||0.195||0.051–0.741||0.016*|
|AST >60 vs. ≤60 U/L||0.323||0.129–0.809||0.016*||0.209||0.063–0.697||0.011*|
|ALB before 2nd-line treatment||0.958||0.894–1.027||0.23|
|Pattern of progression on previous sorafenib treatment|
|Growth of intrahepatic or extrahepatic lesions, or both||1|
|New extrahepatic lesion||4.141||0.518–33.103||0.18|
|New intrahepatic lesion||1.198||0.124–11.599||0.876|
|Macrovascular invasion and/or extrahepatic disease||0.465||0.185–1.170||0.104||–||–||–|
*, P values <0.05 were considered statistically significant. PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; TACE, transarterial chemoembolization; AFP, α-fetoprotein; AST, aspartate transaminase; ALT, alanine transaminase; BCLC, Barcelona Clinic Liver Cancer.
|History of diabetes||4.048||0.501–32.732||0.19|
|History of hypertension||4.15||0.795–21.633||0.091|
|History of alcoholism||34.27||0.033–35,300.905||0.318|
|Tolerance of sorafenib||1.908||0.233–15.606||0.547|
|AFP ≥400 vs. <400 ng/mL||0.43||0.112–1.645||0.217|
|ALT >60 vs. ≤60 U/L||0.387||0.086–1.736||0.215|
|AST >60 vs. ≤60 U/L||0.269||0.066–1.099||0.067|
|ALB before 2nd-line treatment||0.944||0.845–1.054||0.302|
|Pattern of progression on previous sorafenib treatment|
|Growth of intrahepatic or extrahepatic lesions, or both||1|
|New extrahepatic lesion||24,528.378||0–4.863E+147||0.952|
|New intrahepatic lesion||28,019.74338||0–5.5567E+147||0.951|
|Macrovascular invasion and/or extrahepatic disease||0.795||0.186–3.397||0.757|
OS, overall survival; HR, hazard ratio; CI, confidence interval; AFP, α-fetoprotein; AST, aspartate transaminase; ALT, alanine transaminase; ALB, albumin; BCLC, Barcelona Clinic Liver Cancer.
Safety and tolerability
The regorafenib-related adverse events are summarized in Table 4. A total of 31 (72.1%) patients experienced at least 1 treatment-related adverse event. Most of adverse events were able to be managed by dose modifications and appropriate supportive care. The most common toxicities were hand-foot skin reactions (n=21, 48.8%), diarrhea (n=14, 32.6%), and hypertension (n=6, 14%). The most common grade 3–4 toxicities were hypoalbuminemia (n=2, 4.7%), anemia (n=2, 4.7%), and thrombocytopenia (n=2, 4.7%). Most of the adverse reactions were < grade 3.
|Variable||Any grade (N=43), n (%)||Grades 3–4 (N=43), n (%)|
|Any adverse event||31 (72.1)||3 (7.0)|
|Hand-foot skin reaction||21 (48.8)||0|
|Elevated serum AST/ALT||6 (14.0)||1 (2.3)|
|Hypoalbuminemia||5 (11.6)||2 (4.7)|
|Thrombocytopenia||3 (7.0)||2 (4.7)|
|Elevated serum blood bilirubin||3 (7.0)||1 (2.3)|
|Anemia||2 (4.7)||2 (4.7)|
|Gastrointestinal bleeding||1 (2.3)||1 (2.3)|
|Fatigue and decreased appetite||1 (2.3)||1 (2.3)|
HCC, hepatocellular carcinoma; AST, aspartate transaminase; ALT, alanine transaminase.
A total of 19 patients discontinued regorafenib due to disease progression, adverse events, or death during the observation period. No patient stopped taking the drug permanently because of serious adverse events. There were 9 deaths during the observation period. Of the 9 deaths, 1 patient died from liver failure caused by regorafenib treatment, and 5 patients died from non-tumor–related causes.
The efficacy of regorafenib was confirmed by the RESORCE trial in advanced HCC patients who showed progression after treatment with sorafenib (15-17). This study sought to verify the efficacy and safety of sorafenib sequential to regorafenib in the treatment of advanced HCC patients based on real-world data from China. The results strongly suggest that sequential treatment with sorafenib and regorafenib is well-tolerated and effective in patients with advanced HCC. Further, wine identified some pre-treatment clinical indicators that can be used to screen patients with a good prognosis.
Our results complement those of the RESORCE trial, which excluded many more patients with complex clinical conditions. Indeed, the RESORCE trial excluded patients intolerant to sorafenib due to adverse events and those who required a sorafenib dose reduction to <400 mg/d. Due to the impressive physique of the Chinese patients, such patients were not excluded in the present study. Our study’s median PFS and OS were comparable to those of the RESORCE trial and those in other reports from Japan and Korea (15,34,35), which further confirms the efficacy of sequential treatment in patients with advanced HCC even in real-world therapy settings.
In previous studies and this study, while palmar-plantar erythrodysesthesia, diarrhea, fatigue, decreased appetite, elevated AST, and hypertension were the most common adverse events, most of these events were < grade 3, and could be controlled by adjusting the dose and providing optimal supportive care (15,34,35). Further, in our cohort, no patient stopped taking the drug permanently because of severe adverse reactions.
Research on the mechanism of sequential therapy of the two targeted drugs is still underway. A previous in vitro experiment showed that samples treated with regorafenib and sorafenib differed in protein expression compared to those treated with a placebo (36). The pattern of protein upregulation by the two drugs was similar, indicating that the rapidly accelerated fibrosarcoma (RAF)/Mitogen-activated protein kinase kinase (MAPKK)/extracellular-signal-regulated kinases (ERK) pathway was activated, but sorafenib downregulated more proteins than regorafenib. Both regorafenib and sorafenib were effective in a mouse liver cancer model, but several cases showed better regorafenib activity, which may explain the significant efficacy of regorafenib in patients with sorafenib resistance (36).
The outstanding results of sequential therapy could play a very positive role in guiding clinical treatment (37). This study found no significant associations between pre-treatment, sorafenib tolerance, the pattern of progression on previous sorafenib treatment, BCLC stage, or macrovascular invasion before 2nd-line treatment and the PFS or OS of 2nd-line treatment. The RESORCE trial also found that regorafenib improved the outcomes of patients with HCC with a good liver function reserve (15). Regardless of the previous pattern of progression of sorafenib and regardless of the last dose of sorafenib, regorafenib produced a definite effect (17). A further report suggests that therapy with sequential sorafenib followed by regorafenib might result in an unprecedented median OS of 26 months (16). We verified these findings in our research.
The present study showed that AFP ≥400 ng/mL, ALT ≥60 IU/L, and AST ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The multivariable Cox proportional-hazards regression analysis also showed that AFP ≥400 ng/mL, ALT ≥60 IU/L, and AST ≥60 IU/L before 2nd-line treatment were independently associated with PFS. It may be that patients with a good liver function reserve before 2nd-line treatment are more likely to benefit from the sequential treatment. Further, AFP might be used as a clinical indicator for screening people who are likely to benefit from sequential therapy.
Previous studies had found that patients with a Child-Pugh score of 5 before sorafenib treatment had a significantly better prognosis than patients with a score of 6 (15,38,39). This is because patients with a score of 5 can be switched early from TACE to sorafenib if TACE is not effective and they can then be switched from sorafenib to regorafenib if they are refractory to sorafenib (15,16,33). This may be an essential strategy for improving survival in the future. The long survival time of 26 months achieved by timely sequential therapy is almost comparable to trae4ditional TACE in the treatment of intermediate-stage HCC (33,40). A recent study of patients with recurrent HCC after liver transplantation demonstrated that sequential therapy with sorafenib and regorafenib significantly prolonged OS (28.8 months), and was an independent predictor of OS (41). In recent years, some studies have found that nivolumab, cabozantinib, or regorafenib produce excellent treatment effects after sorafenib treatment failure in advanced HCC patients, but the difference was not statistically significant (42,43). Now that the potential of sorafenib-regorafenib sequential therapy to significantly improve patient prognosis is more pronounced, it may be necessary to re-evaluate the appropriate time at which to start sorafenib. With the help of some efficient and commonly used clinical indicators, patients eligible for sorafenib therapy can receive it promptly and thus benefit from all currently available therapies.
Currently, it is not apparent which patients will benefit from sequential treatment. A previous study has shown that multiple proteins and micro ribonucleic acids might be predictive of OS in HCC patients treated with regorafenib, and the analysis of the association between baseline plasma levels of 266 proteins and responses to regorafenib treatment identified 5 biomarkers, including Angiopoietin-1 (ANG-1), cystatin B, Latency associated peptide transforming growth factor beta-1 (LAP TGF-b1), Lectin-like oxidized LDL receptor-1 (LOX-1), and Macrophage inflammatory protein-1a (MIP-1a) as possible predictors of OS, and 47 biomarkers, including the 5 predictive for OS, as possible predictors of TTP (44). A previous study highlighted the predictive role of AFP, the neutrophil-to-lymphocyte ratio, and extrahepatic spread in predicting the efficacy of sequential therapy (45). In our study, the Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073–0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051–0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063–0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009–0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. Based on these clinical characteristics it may be possible to distinguish patients who would benefit from sequential therapy. However, these findings need to be validated.
The present study had some limitations. This study was only conducted at 2 hospitals, which led to a small sample size. Patients were informed of the possible adverse reactions before they took the drug. However, some patients still did not pay enough attention to drug-related adverse reactions, which led to a lack of monitoring of critical adverse reactions (such as proteinuria). There was no comparator group. In addition, the analyses were limited to the data available in the patient charts. Other studies have also proposed to predict the prognosis of sorafenib and regorafenib sequential therapy based on clinical indicators (46,47), but there is still no accepted method for predicting the potential population likely to benefit from sequential therapy.
In conclusion, sequential therapy with sorafenib and regorafenib is well-tolerated and effective in patients with advanced HCC. Additionally, patients with a good liver function reserve and a high level of AFP before 2nd-line treatment may benefit more from sequential treatment. This evidence supports the results of the clinical trials (15-17,35).
Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 82173317), the National Science and Technology Major Project of China (Grant No. 2018ZX10302205), and the Science and Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No. 2017KJ199).
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-397/rc
Data Sharing Statement: available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-397/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-397/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). This study was approved by the ethics committee of Tianjin Medical University Cancer Institute and Hospital (No. bc2022135) and Tianjin First Central Hospital (No. 2022N256KY), with the requirement for informed consent waived. And this study complied with the Good Clinical Practice guidelines and applicable local laws. Any patient data that could identify individual patients were anonymized and de-identified before analysis.
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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