2). Thus, a mere reduction in enhancement just reflects a hypovascular HCC profile and should not be wrongly registered

as partial response or CR. As mentioned above, tumor progression is a critical event. Despite all limitations, it has become the recommended endpoint for the early assessment of novel agents.28 Hence, proper criteria to register its occurrence are mandatory for optimal practice and research. Conventional RECIST is not fully reliable for this purpose in HCC patients. The imaging follow-up protocol of the sorafenib phase III trials already incorporated Dorsomorphin order several amendments. Ascites or pleural effusion should not be registered as disease progression unless malignant origin was proven by pathology. Presence of slightly enlarged lymph nodes can be observed in cirrhosis of any etiology.42, 43 Thus, malignant involvement would not be declared until growth beyond 2 cm. Modified RECIST (mRECIST) was developed to take into account tumor necrosis such as that which occurs during chemoembolization and radiofrequency ablation. However, whether mRECIST can be extrapolated to targeted therapy or not has not been X-396 mw validated. Changes in arterial perfusion of HCC target lesions do occur with targeted therapy, but complete necrosis is uncommon.

Whether quantitative changes in arterial perfusion equate to a less aggressive tumor biology or a therapeutic response remains unclear. Until mRECIST has been verified to correlate with overall survival in HCC, its utilization as an endpoint in targeted therapy remains questionable. In addition, a pitfall of RECIST relates to the definition of hypervascular intrahepatic foci not fulfilling the pattern of HCC. These are common in cirrhotics and portal hypertension, find more and in HCC patients, they will likely correspond to new HCC sites.44 However, until these nonspecific nodules are confirmed by growth or by development of a typical HCC pattern, they should not be registered as progression. These concepts were ultimately the basis for the mRECIST proposal.28

Although in conventional RECIST new nodules >10 mm would be classified as progression with the potential risk of wrongly registering regenerative or dysplasic nodules as new tumor sites, mRECIST indicates that such nonspecific nodules require follow-up to detect growth or development of the diagnostic imaging profile. If ultimately classified as malignant, the time of progression is that of first detection (Fig. 3). Retrospective assessments using mRECIST in studies conducted under conventional RECIST are at risk of major bias, because the absence of follow-up of those patients classified as progressing by RECIST would not have the needed follow-up to properly classify them by mRECIST. As a result, TTP would be overestimated, because some of the recurrences that would be ultimately confirmed are no longer in the analysis. Some investigators propose progression-free survival (PFS) as an optimal tool, but this is an unreliable endpoint.