Novel LRTs are establishing their role in the management of HCC, necessitating the ability to accurately determine tumor response4, 5, 28
. For LRTs, standardization in methodology and evidence are lacking13
. In this analysis, we sought to test agreement between RECIST (uni-dimensional), WHO (bi-dimensional) and EASL (necrosis) guidelines, as well as to validate the clinical benefit imparted by observing response by correlating imaging response to TTP and survival. Lastly, the concept of the primary index lesion was introduced, potentially leading to a novel methodology of standardization of response and analyses of time to endpoint in patients with HCC who are receiving transarterial LRTs.
Although the pretreatment and post-treatment determinations of tumor volume (3-dimensional) are intuitively most representative of actual treatment effect, limitations in available technology prevent their routine use29
. Our data validate that the WHO (bidimensional) and RECIST (uni-dimensional) are similar in assessing change in size when applied to transarterial LRTs15
. The intermethod agreement was high (κ=0.86). Thus, given that tumors usually are not spherical and have irregular borders, we prefer using WHO over RECIST guidelines for transarterial LRTs, particularly when the patient sample size is small. On the other hand, there was minimal intermethod agreement between necrosis and size guidelines (EASL vs WHO, κ=0.28; EASL vs RECIST, κ=0.24). These findings are intuitive; a complete response by EASL could be be classified as a complete response, partial response, stable disease, or progressive disease by WHO or RECIST guidelines. Keppke et al.
confirmed this, reporting response rates of 23%, 26% and 57% with application of RECIST, WHO, and EASL guidelines, respectively11
. These findings were further confirmed by Forner et al10
. (κ=0.19 between EASL and RECIST guidelines)
The development of systemic biologic therapies in the management of HCCs, particularly those that are cytostatic rather than cytotoxic, necessitates the ability to measure response despite no change in tumor size3
. The imaging characteristics and response rates following LRTs can be heterogeneous at the lesional level; this is potentially related to anomalous blood supply to HCCs30
. Ablative techniques have been shown to cause necrosis without affecting tumor size10
. Complete response by EASL at 1 month following percutaneous therapies correlates with improved survival16
. The presence of residual tumor at 1month following ablation may indicate incomplete targeting of tumor. Thus, unlike complete response, a partial response by EASL guidelines (potentially representing treatment failure) may not necessarily indicate improved outcomes following thermal ablation16
. As seen in this study, transarterial LRTs have been shown to affect both size and necrosis as seen in this study, with both translating into favorable long-term outcomes31
Since EASL partial response is usually manifest at 1.6 months, one could postulate that EASL response may serve as an earlier surrogate for therapeutic benefit when compared with WHO response. Response by EASL also may have an important role in patients with HCC who are listed for liver transplantation because due: time from treatment to transplantation is variable and because EASL response is achieved earlier. The median time to WHO response was 7.7 months. A lesion that has decreased in size (WHO response) has stood the test of time, suggesting favorable tumor biology and the ability of the surrounding hepatic parenchyma to regenerate normally. The HRs for survival of responders vs. nonresponders by WHO and EASL were similar on multivariate analysis (0.55-0.54, respectively). These data suggest that EASL response (achieved early) and WHO response (achieved later and therefore time-tested) are both important parameters and are independent predictors of survival.
In patients with solitary HCC, the primary index lesion is clearly represented by the single tumor nodule that undergoes treatment. However, with multifocal disease, the ability to capture response and time-to-event endpoints becomes less evident given the multiplicity of tumors and staged treatment points.
Given these realities, can the concept of the primary index lesion be expanded to multifocal disease? There are 3 rationales for hypothesizing the potential clinical utility of the index lesion in multifocal disease. First, LRTs are performed as staged procedures and hence, as opposed to systemic therapies, not all lesions are treated at the same time, resulting in variable starting points for response and time-to-progression analyses. Second, not all patients being treated with LRTs undergo a complete treatment cycle (patients may progressive disease, experience adverse events, or be intolerant to further treatment). This would result in a confounding mathematical effect of overall response being dependent on the magnitude of the size changes of treated and untreated tumors, potentially erroneously leading to the reporting of stable or even progressive disease rather than response to therapy. Third, response assessment, TTP and survival are inherently flawed if they are measured from the end of the treatment cycle, because it may take 2 to 6 months to treat all disease. This would make comparison of LRTs with systemic agents (eg, TTP using sorafenib, 5.5 months) and hypothesis generation for future clinical trials, in which analyses of time to end point begin at the time of protocol enrollment or randomization, difficult3
Our analysis suggests that response seen in the primary index lesion following treatment, even in the presence of multifocal disease, showed a prognostic benefit following LRTs. In some sense, the primary index lesion was able to serve as a biomarker of long-term outcomes. The HRs using WHO and EASL were able to capture the significant TTP and survival benefit in responders vs non-responders in patients with solitary and multifocal HCC. Furthermore, responses by WHO (bidimensional) and EASL (necrosis) guidelines had independent effects on survival on multivariate analysis.
This study has limitations. The study includes patients treated with chemoembolization or with radioembolization using 90
Y. However, the baseline characteristics of the 2 treatment groups by Child-Pugh class, BCLC class, and UNOS stage were identical. In contradistinction to the data used to formulate the original RECIST guidelines (different malignancies, various systemic therapies), our analysis is more standardized, because it is based only on HCC. Few studies have compared size and enhancement guidelines for assessing tumor response10
. Although pathologic evaluation of the treated lesion represents the gold-standard for assessing response to treatment, this is available only in select cases following resection, transplantation, or autopsy31, 32
. The therapeutic benefit of imaging and other biomarkers must be studied33
. It would be interesting to investigate if the same concept of primary index lesion holds for ablative LRTs or systemic therapy. Survival between the 2 treatment groups was not significantly different.
In conclusion, WHO and RECIST guidelines had minimal agreement with EASL guidelines10
. The WHO and EASL responses were favorable and independent prognostic factors of survival. No imaging guidelines are currently considered the gold-standard for LRTs. The combined findings of response at the primary index lesion level being predictive of TTP and survival, the significant HR for TTP and survival in solitary and multifocal disease, and the significant HRs for survival maintained in the multivariate analyses all support the use of the primary index lesion as a biomarker to assess imaging response following transarterial LRTs. This may potentially lead to simplification, reproducibility and standardization of imaging assessment guidelines in LRTs. Measuring the primary index lesion and then starting analyses of time to endpoint at the time of first treatment (irrespective of completion of the treatment plan) is in keeping with the principles of intention-to-treat. It should be stressed that patients should continue to receive the planned treatment to target all disease, even in the presence of response in the primary index lesion. The findings presented herein will require further validation.