|Year : 2020 | Volume
| Issue : 2 | Page : 301-308
Time to untreatable progression is an appropriate surrogate endpoint for overall survival in patients with hepatocellular carcinoma after transarterial chemoembolization
Hongyu Wang1, Bin Li2, Yu Wang1, Jiang Zhang3, Yanqin Wu1, Wenzhe Fan1, Jiaping Li1
1 Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
2 Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
3 Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
|Date of Submission||21-Oct-2019|
|Date of Decision||09-Jan-2020|
|Date of Acceptance||06-Apr-2020|
|Date of Web Publication||28-May-2020|
Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan 2 Road, Guangzhou 510080
Source of Support: None, Conflict of Interest: None
Aims: The aim of the study was to determine whether the time to progression (TTP) or time to untreatable progression (TTUP) is an appropriate surrogate endpoint for overall survival (OS) in patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE).
Materials and Methods: Eighty-four patients with Barcelona clinic liver cancer (BCLC) stage B or C HCC underwent TACE. The correlations of TTP and TTUP with OS were evaluated after a log transformation of the indicated values. After identifying independent prognostic factors of TTP, TTUP, and OS, the partial correlations of TTP and TTUP with OS were analyzed in all patients and subgroups. Subsequently, the prognostic value of TTP and TTUP was compared by the multivariate survival analysis of OS.
Results: Both the BCLC stage and tumor number were correlated with TTP and TTUP. In addition, the BCLC stage, initial treatment failure, and sorafenib administration were associated with OS. In all patients, the correlation coefficients of TTP and TTUP with OS were 0.559 and 0.789, respectively. Adjustment for independent prognostic factors yielded partial correlation coefficients which were 0.433 and 0.697, respectively. Furthermore, OS was found to be associated with TTUP (P = 0.003; hazard ratio: 0.253; 95% confidence interval: 0.10–0.63) but not with TTP.
Conclusion: Untreatable progression is more representative of clinical progression in patients with HCC who underwent TACE. In the current study, TTUP is a more appropriate surrogate endpoint for OS than TTP. Future studies should explore whether untreatable progression is a valuable endpoint event in clinical trials or an indicator of the need for second-line therapy.
Keywords: Hepatocellular carcinoma, overall survival, surrogate endpoint, time to untreatable progression, transarterial chemoembolization
|How to cite this article:|
Wang H, Li B, Wang Y, Zhang J, Wu Y, Fan W, Li J. Time to untreatable progression is an appropriate surrogate endpoint for overall survival in patients with hepatocellular carcinoma after transarterial chemoembolization. J Can Res Ther 2020;16:301-8
|How to cite this URL:|
Wang H, Li B, Wang Y, Zhang J, Wu Y, Fan W, Li J. Time to untreatable progression is an appropriate surrogate endpoint for overall survival in patients with hepatocellular carcinoma after transarterial chemoembolization. J Can Res Ther [serial online] 2020 [cited 2020 Jul 5];16:301-8. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/301/285203
FNx01Hongyu Wang and Bin Li contributed equally to this work
| > Introduction|| |
Most patients present with stage B or C hepatocellular carcinoma (HCC) according to the Barcelona clinic liver cancer (BCLC) classification system at the time of diagnosis. As these patients are not eligible for surgical resection, transarterial chemoembolization (TACE) and sorafenib administration are considered asfirst-line treatment options. After TACE, the patient's tumor response, residual tumor characteristics, Child–Pugh score, and performance status are important factors that must be considered when making decisions about TACE retreatment and alternative therapies in clinical practice. Currently, several scoring systems have been developed to identify whether patients would benefit from repeated TACE and to determine candidates for alternative therapies.,,, However, these systems have a limited predictive value and cannot be used to make definitive clinical decisions.
In addition to the above limitations, the definitions of disease progression in these evaluation systems, which are based on the Modified Response Evaluation Criteria in Solid Tumors, may not accurately reflect the actual response of HCC to TACE. Untreatable progression, which includes a refractory response after two or more consecutive TACE procedures, major progression (e.g., massive liver involvement, extrahepatic metastasis, or vascular invasion), and minor intrahepatic progression with impaired liver function and a performance status indicating contraindication to treatment, has been proposed as an alternative endpoint.,
Given the above findings, we hypothesized that untreatable progression may be more representative of clinical progression in HCC patients who have undergone TACE. The time to progression (TTP) is typically used as a secondary or surrogate endpoint in early clinical trials. However, the strength of the correlation of the TTP with survival has not been confirmed. Recently, several studies have reported moderate or strong correlations between the time to untreatable progression (TTUP) and overall survival (OS). Accordingly, the TTUP has been proposed as a useful parameter for treatment guidance and a promising surrogate endpoint for OS in patients treated with TACE.,, To validate whether TTUP is a more appropriate alternative endpoint for OS than TTP, we compared the correlations of both the TTUP and TTP with OS in patients with BCLC stage B and C HCC who were treated with TACE.
| > Materials and Methods|| |
This retrospective study was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, as reflected by the provision of approval by the ethical committee of our hospital. HCC was diagnosed according to the pathology or imaging criteria included in the guidelines of the European Association for the Study of the Liver. The study included 84 consecutive HCC patients treated from August 2015 to July 2018 who met the following criteria: (a) BCLC stage B or C HCC, (b) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, (c) Child–Pugh class A or B liver disease, and (d) a history of regular follow-up and retreatment as needed. Patients were excluded from our study if they met the following criteria: (a) missing baseline imaging information; (b) metastasis of HCC to the main portal vein (tumor thrombus) or an extrahepatic site; (c) a history of surgery, ablation, or radiotherapy after initial TACE; (d) loss to follow-up within 6 months; or (e) severe medical comorbidities, including severe heart or kidney dysfunction, coagulation disorders (i.e., prothrombin activity <40% or platelet count <30 × 109/L), or other malignancies [Figure 1].
|Figure 1: Flow diagram of the exclusion criteria applied to patients with HCC. HCC = Hepatocellular carcinoma, BCLC = Barcelona clinic liver cancer, TACE = Transarterial chemoembolization, ECOG = Eastern Cooperative Oncology Group|
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Patients who present with branch vascular invasion but have preserved liver function can benefit from TACE., However, those with main portal vein invasion are not commonly treated with TACE at our institution. As TACE is generally effective for intrahepatic lesions, patients with extrahepatic metastases were not included to minimize heterogeneity.
Transarterial chemoembolization procedures
All patients were treated with superselective TACE administered by a senior interventional radiologist with 12 years of experience. The procedure was performed as previously described. First, 20–50 mg of lobaplatin solution was initially infused into the tumor-feeding vessels. Next, a mixture of 20–60 mg of doxorubicin hydrochloride and 5–20 mL of lipiodol (Lipiodol Ultrafluide; Guerbet, Aulnay Sous Bois, France) was administered into the feeder vessels. Finally, polyvinyl alcohol particles of 300 μm in diameter (Polyvinyl Alcohol Foam Embolization; Cook) were administered into the tumor-feeding vessels. Follow-up computed tomography scans were performed after 1 month to evaluate the tumor responses. Residual viable lesions were retreated with TACE. All patients were followed up every 1–3 months via clinical examinations, including imaging, liver function, and α-fetoprotein tests. Subsequent treatments were performed as needed or were combined with sorafenib according to the European Association for the Study of the Liver Clinical Practice Guidelines.
Evaluation of tumor responses and outcomes
Two senior radiologists independently assessed the images to evaluate the tumor responses according to the Modified Response Evaluation Criteria in Solid Tumors. Any disagreements were resolved via consensus. Untreatable progression was assessed using the previously described methods,, and was defined by the fulfillment of any one of the following conditions: (1) nonresponsiveness (i.e., stable or progressive disease) of target lesions after ≥2 consecutive TACE sessions, (2) multiple intrahepatic metastases or an increase in the number of lesions, (3) extrahepatic metastasis, (4) macrovascular invasion in patients with BCLC stage B HCC or an enlarged tumor thrombus in patients with BCLC stage C HCC, or (5) liver decompensation or a severe physical decline as represented by a Child–Pugh score ≥10 and/or an ECOG performance status score ≥2.
TTP was defined as the elapsed time from thefirst TACE treatment to disease progression, whereas TTUP was defined as the elapsed time from thefirst TACE treatment to untreatable progression. OS was defined as the interval between the date of thefirst TACE treatment and death from any cause or the last follow-up. Postprogression survival (PPS) was defined as the time from disease progression to the date of death or the last follow-up, while untreatable postprogression survival (UPPS) was defined as the time from untreatable progression to the date of death or the last follow-up.
In addition to the baseline characteristics, other variables that might affect the prognosis of HCC patients were defined according to the tumor response after the initial TACE, the tumor characteristics associated with untreatable progression, and the status of sorafenib treatment after progression. During our study, we also defined the following intermediate variables: (1) initial TACE failure, defined as a consecutive lack of response after two initial TACE treatments; (2) the pattern of untreatable progression with intrahepatic target lesions alone versus multiple causes of progression, including vascular invasion, extrahepatic metastasis, and a Child–Pugh score ≥10 and/or ECOG score >2; and (3) treatment with TACE monotherapy versus TACE combined with sorafenib. We note that different progression patterns affect the duration of PPS and would subsequently impact the design and analysis of a trial of second-line treatment.,,
Categorical variables were presented as numbers and percentages, while continuous variables were presented as means and standard deviations. Categorical variables were compared using the Chi-square test. Factors influencing the TTP, TTUP, PPS, UPPS, and OS were identified through Cox regression analyses. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each factor. The multivariate model included each variable that received P < 0.10 in the univariate analysis. The relationships of TTP and TTUP with OS were identified using scatter plots and Spearman coefficients. After subjecting the TTP, TTUP, and OS values to logarithmic transformation to achieve a normal distribution, the relationships of log(TTP) and log(TTUP) with log(OS) were identified using scatter plots and Pearson's correlation coefficients in all patients and between different subgroups. Partial correlation of log(TTP) and log(TTUP) with log(OS) was also performed after adjusting for the associated prognostic factors. Moreover, the prognostic value of TTP and TTUP was compared by multivariate survival analysis.
All statistical tests were performed using Stata/MP version 14.0 (Stata Corporation LP, College Station, TX, USA). Two-sided P < 0.05 was considered statistically significant.
| > Results|| |
Characteristics of the patients
A total of 312 patients with BCLC stage B or C HCC underwent TACE during the study period. As indicated in [Figure 1], 84 patients met the eligibility criteria and were included in the study cohort. The baseline characteristics and intermediate variables of these patients are depicted in [Table 1]. A total of 42 (50%) BCLC B stage and 42 (50%) BCLC C stage patients with HCC were included. Of these, 23 had been previously treated with TACE, ablation, or surgical resection.
|Table 1: Baseline characteristics of the patients and intermediate variables|
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Treatments and outcomes
All patients developed untreatable progression after one or more treatment sessions, and 37 of them were assessed as initial TACE failure. There were significant differences in BCLC stage (B or C) and tumor number (≤5 or >5) betweent initial TACE failure group and initial TACE non-failure group (P < 0.001 for both). Moreover, 29 patients with progressive or TACE-uncontrolled HCC were treated with sorafenib. According to the classification of progression patterns, 20 cases were classified as intrahepatic target lesion progression alone, whereas 64 were classified as having multiple causes of progression.
Sixty-one (72.6%) patients died after a median follow-up and duration of 30.20 months (95% CI: 20.33–40.07). The median TTP, TTUP, and OS were 3.23 (95% CI: 2.73–4.10), 5.16 (95% CI: 3.70–7.93), and 17.36 months (95% CI: 15.36–19.37), respectively [Table 2]. The median PPS and UPPS were 11.93 (95% CI: 9.73–13.63) and 8.37 months (95% CI: 7.53–10.17), respectively.
|Table 2: Median time to progression, time to untreatable progression, and overall survival in all patients and subgroups|
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Prognostic factors for time to progression, postprogression survival, time to untreatable progression, untreatable postprogression survival, and overall survival
The univariate analysis identified the BCLC stage, tumor number, and vascular invasion as significant predictors of both TTP and TTUP. Moreover, the prognostic factors for TTP were included among the prognostic factors of PPS, which included the BCLC stage, tumor number, vascular invasion, sorafenib administration, and progression pattern. However, the prognostic factors of UPPS were sorafenib administration and progression pattern, which did not overlap with the predictive factors for TTUP.
A multivariate analysis identified the BCLC stage (P = 0.007; HR: 1.93; 95% CI: 1.20–3.09) and tumor number (P = 0.006; HR: 2.36; 95% CI: 1.28–4.35) as independent predictors of TTP. Moreover, the BCLC stage (P = 0.031; HR: 1.92; 95% CI: 1.06–3.46) and sorafenib administration (P = 0.011; HR: 0.45; 95% CI: 0.24–0.83) were identified as independent predictors of PPS. The BCLC stage (P < 0.001; HR: 2.77; 95% CI: 1.72–4.47) and tumor number (P = 0.001; HR: 2.94; 95% CI: 1.55–5.60) were identified as independent predictors of TTUP. However, only sorafenib administration (P = 0.010; HR: 0.44; 95% CI: 0.24–0.82) was identified as an independent predictor of UPPS. Finally, the BCLC stage (P = 0.010; HR: 2.28; 95% CI: 1.22–4.25), initial treatment failure (P = 0.024; HR: 2.27; 95% CI: 1.12–4.62), and sorafenib administration (P = 0.003; HR: 0.38; 95% CI: 0.20–0.71) were identified as independent predictors of OS [Table 3].
|Table 3: Multivariate cox regression analysis of time to progression, postprogression survival, time to untreatable progression, untreatable post-progression survival, and overall survival|
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Correlations of time to progression and time to untreatable progression with overall survival
In all patients, the correlations of TTP and TTUP with OS yielded coefficients of 0.559 and 0.789, respectively [Spearman correlation test, both P < 0.001; [Figure 2]. After log transformation, the corresponding correlation coefficients were 0.611 and 0.811. After adjusting for the BCLC stage, tumor number, initial treatment failure, and sorafenib administration, the respective partial correlation coefficients were 0.433 and 0.697 [Pearson correlation test, both P < 0.001; [Figure 3].
|Figure 2: Scatter plots and correlations of TTP and TTUP with OS. A weak correlation was observed between TTP and OS, while a strong correlation was noted between TTUP and OS. TTP = Time to progression, TTUP = Time to untreatable progression, OS = Overall survival|
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|Figure 3: Scatter plots and correlations of log (TTP) and log (TTUP) with log (OS). A moderate correlation was observed between log (TTP) and log (OS), while a strong correlation was determined between log (TTUP) and log (OS). After adjusting for the BCLC stage, tumor number, initial treatment failure, and sorafenib administration, partial correlations of 0.433 and 0.697 were determined for log (TTP) and log (TTUP) with log (OS), respectively. TTP = Time to progression, TTUP = Time to untreatable progression, OS = Overall survival, BCLC = Barcelona clinic liver cancer|
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Stronger correlations were observed between TTUP and OS than between TTP and OS in all subgroups except that of patients with >5 tumors. Meanwhile, moderate-to-strong correlations were observed between TTUP and OS in patients with BCLC stage B HCC, ≤5 tumors, treatment nonfailure, and TACE monotherapy [Pearson correlation test, r = 0.729, 0.810, 0.851, and 0.856, respectively; [Table 4].
|Table 4: Correlation analysis of time to progression and time to untreatable progression with overall survival for the subgroups†|
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Further survival analysis of time to progression and time to untreatable progression
To more directly compare the prognostic values of TTP and TTUP, we conducted a Cox regression analysis that included the TTP, TTUP, BCLC stage, tumor number, initial treatment failure, and sorafenib administration. Notably, we identified a statistically significant difference in BCLC staging (P = 0.006; HR: 2.46; 95% CI: 1.29–4.69), sorafenib administration (P < 0.001; HR: 0.28; 95% CI: 0.14–0.56), and TTUP (P < 0.001; HR: 0.82; 95% CI: 0.74–0.91) but not in TTP (P = 0.47; HR: 1.04; 95% CI: 0.93–1.16). In addition, patients were divided into two groups according to the median values of TTP and TTUP. A subsequent Cox regression analysis revealed that the significant association between TTUP (P = 0.003; HR: 0.253; 95% CI: 0.10–0.63) and OS was retained [Figure 4].
|Figure 4: Multivariate survival analysis curves of patients in the TTUP group. Patients were divided into two groups according to the median duration of TTUP (>5.16 vs. ≤5.16). A multivariate survival analysis revealed that TTUP was correlated significantly with OS (hazard ratio = 0.253, P = 0.003). TTUP = Time to untreatable progression, OS = Overall survival|
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| > Discussion|| |
Generally, patients with HCC require multiple TACE treatments. In a recent study, a predictive model for TACE resistance in BCLC B and C HCC was established to accurately predict the efficacy of TACE, as multiple rounds of TACE could lead to treatment resistance and the progression of refractory disease. Accordingly, we propose that untreatable progression may be a more accurate indicator of treatment failure or clinical progression, which also means that TTUP is more suitable as surrogate endpoint for OS than TTP. To verify our hypothesis, we compared the correlation of TTP and TTUP with OS in HCC patients after TACE. Notably, we demonstrated that TTUP was most strongly correlated with OS in all patients and in most subgroups. Furthermore, TTUP, rather than TTP, was significantly associated with OS in the multivariate analysis.
As shown in [Figure 2], the coefficients of the correlations of TTP and TTUP with OS in all patients were 0.559 and 0.789, respectively, indicating a moderate correlation between TTUP and OS. In an earlier retrospective study of 192 patients with BCLC stage B HCC treated with TACE, a moderate correlation between TTUP and OS (r = 0.527) was similarly observed. In addition, a TTUP ≥ 10 months was considered an independent prognostic factor for an improved OS. In another study of 592 patients with BCLC stage B HCC, a strong correlation was observed between TTUP and OS (r = 0.810), while a study of 165 patients with BCLC stages A, B, and C revealed a strong correlation between TTUP and OS (r = 0.816). Although these studies all demonstrated a significant correlation of TTUP with OS, none considered the associated prognostic factors.
The true nature of the surrogate endpoint cannot be understood sufficiently from a basic comparison of correlations. According to the IQWiG framework and Fleming criteria, a study of a credible surrogate should not only present an acceptable correlation between the candidate surrogate and the final endpoints but should also demonstrate the rationality and reliability of the surrogate endpoint., Accordingly, we also conducted a survival analysis of TTP, PPS, TTUP, UPPS, and OS and identified the BCLC stage and tumor number as independent prognostic factors of TTP and TTUP. In addition, we identified the BCLC stage as an independent prognostic factor of both TTP and PPS but did not identify any overlap between the independent prognostic factors of TTUP and UPPS. This result may indicate that untreatable progression is a valuable clinical event that marks a shift from the prognostic effects of baseline characteristics to those of subsequent treatment. In addition, as HCC is a heterogeneous disease, the correlations of TTP and TTUP with OS may be attributed to a combination of multiple prognostic factors. Therefore, we performed a partial correlation comparison. After adjusting for the BCLC stage, tumor number, initial treatment failure, and sorafenib administration, the partial correlation between TTUP and OS remained stronger than that between TTP and OS. Furthermore, we performed a Cox regression analysis that included the TTP, TTUP, and independent prognostic factors. Our results demonstrated that TTUP, rather than TTP, was significantly associated with OS. All these results indicate the reliability and rationality of TTUP as an alternative endpoint for OS.
Two previous simulation studies demonstrated the effects of the proportion of progression-free survival to OS on their correlation; moreover, the reliability of progression-free survival as a surrogate endpoint would be largely diluted by the PPS., The greater proportion of surrogate events to OS may enhance the reliability of its use as a surrogate endpoint. As shown in [Table 2], the TTUP was longer than the TTP in all patients and in most subgroups. In addition, in patients with BCLC stage B HCC, ≤5 tumors, and a history of initial TACE non-failure and TACE monotherapy, the proportion of TTUP to OS was greater than that of their counterpart groups. Therefore, in these patients and their subgroups, the correlation between TTUP and OS was significantly greater than that of the TTP. On the contrary, patients treated with sorafenib had a longer PPS, which relatively diminished the contribution of the TTUP to OS. Therefore, it showed a strong correlation between PPS and OS in patients with advanced HCC treated with sorafenib. Taken together, the surrogate markers for OS are inherently limited to the tumor type, tumor staging, line of therapy, type of agent, and specific surrogate–outcome pairings.
Our study had several limitations of note. First, the study design was retrospective and the included sample of patients was small. Therefore, the data may be heterogeneous. However, this bias was minimized by the independent assessment of all consecutive HCC patients. Second, our cases might not be generally representative because the median TTP and TTUP were relatively shorter than those of previous studies.,, We attribute this difference to the inclusion of 23 (27.4%) patients who received antitumor therapy before enrollment in our study. However, this difference did not affect the interpretation of our results. Third, 23 (27.4%) patients remained alive on the final follow-up date, resulting in a relatively large TTUP-to-OS ratio. Therefore, our data would be strengthened by a larger sample size and a longer follow-up period.
| > Conclusion|| |
Our results support the hypothesis that untreatable progression, rather than progression alone, may be more representative of clinical progression. Moreover, our findings highlight TTUP as a more favorable surrogate endpoint for OS than TTP. Future studies must assess whether untreatable progression is a valuable endpoint event in clinical trials or a marker event for second-line therapy.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (No. 81671797 and 81971719), major scientific and technological project of Guangdong Province (No. 2017B030308006), and the major program for tackling key problems of Guangzhou City, China (No. 201704020144).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]