Indolent cancer and pattern of progression: Two missing parameters in trial design for hepatology

Abstract

The indolent and aggressive behaviors of HCC might have a role in clinical trial (CT) results; however, the indolent HCC is less analyzed compared to others cancer. Indolent profile could be characterized as follows: (1) patients with low risk of progression itself due to the HCC molecular profile and/or due to the interaction between cancer cell their microenvironment; (2) patients who achieve objective response or present spontaneous regression; and (3) patients who develop radiological progression with no consequence on either the liver function or general status, and without trigger a change in the tumor stage. Patients with "indolent HCC" generally never develop cancer-related symptoms neither die for HCC-related causes. Thus, we hypothesize that the imbalance in the proportion of "indolent" versus "aggressive HCC" between arms or the underestimation/overestimation of HCC behavior at baseline in single-arm CT could be associated with CT failure or under-overestimation of trial results. The "indolent progression" may also explain the discrepancy between radiological progression-based end points and survival. Moreover, we discuss the related causes that explain the indolent profile of HCC and propose (1) refining the progression-related end point by the pattern of progression to minimize the limitations of the current end points; (2) considering alternative statistical tools for survival analysis such as milestone survival, or restricted mean survival time to capture the value of indolent HCC. According to these considerations, we propose incorporating novel end points into the single arm of phase I/II CT as exploratory analysis or as a secondary end point in phase III CT.

FIGURE 1

How tumor biology can explain the heterogeneity of the HCC behavior observed in clinical practice? We figured the key molecular mechanisms that could explain the heterogeneity observed in clinical practice in patients with HCC and described the biological plasticity occurring under cancer treatment. Abbreviations: Ampl, amplification; AFP, alpha-fetoprotein; EMT, epithelial-mesenchymal transition; mut, mutation; TKI, tyrosine kinase inhibitor.

FIGURE 2

Length-time bias representation according to the HCC behavior. Red balls represent the more aggressive HCC which are identify by the current screening programs but with symptoms or in advanced stages. The yellow and green balls the HCC with lower aggressivity and those which is feasible identify through the current screening programs.

FIGURE 3

Outcome of patients with HCC across the years according to their radiological response. The red area represents those patients who develop new extrahepatic lesions (NEH) or extrahepatic growth (EHG): this progression could be symptomatic progression with NEH and early HCC-related death or asymptomatic and with preserved liver function and the patients can be candidates to receive second-line treatment. The outcome of these patients could be symptomatic progression and HC-related death, or they could be candidates who follow lines of treatment and die due to other causes. The yellow area represents those patients who develop subsequent new intrahepatic lesions (NIH) or intrahepatic growth (IHG), the rate of patients who received second and further line of treatment is superior than those patients included in the red area. The green area represents those patients who achieve complete (CR), partial response (PR), or stable disease (SD) as well as those who develop isolated or nonconsecutive NIH or IHG. In this group of patients, the outcome is defined by causes different to HCC progression or liver disease decompensation.

FIGURE 4

End points or analysis to identify indolent HCC. The inclusion rate of the CT impacts indirectly in the follow-up time of the CT. As lower inclusion rate, longer median follow-up of the CT. The median time of follow-up at the same time impact on the change of identify ‘indolent HCC’. As longer follow-up time, more change of identifying indolent HCC. The primary end point will be defined according to the aim of the CT. it could be defined for identifying response survival. “Time to failure of treatment strategy” evaluates the whole patient because consider the outcome according to the cause of treatment discontinuation (progression or toxicity). Abbreviations: DCR, disease control rate; ORR, overall response rate; OS, overall survival; TTP, time to progression.