DISCUSSION
The outcome of patients with HB changed dramatically after the
establishment of Qtx protocols associated with liver resection,
pioneered by the SIOPEL11 and COG12 study groups. The
10-y expected overall survival with primary LT was 85%, and 40% in
patients who underwent LT as a “rescue
therapy”13 in the
SIOPEL-1 study. After the initial studies, and others that followed, the
absolute indication for LT, and the basis for considering a tumor
unresectable after neoadjuvant Qtx, is POST-TEXT IV or POST-TEXT III
with major vascular tumor involvement14,
15. Five-year patient survival in the
present report is similar to event-free survival, since recurrence meant
fatality in almost all patients.
Determining the risk factors associated with patient survival is
paramount to an improved selection of patients for LT, but efforts to
identify such prognostic factors in the setting of a rare tumor have
been hampered by extensive fragmentation resulting in relatively small
patient cohorts 16. In
the report of the Children’s Hepatic tumors International Collaboration
(CHIC), advanced PRETEXT group, macrovascular venous or portal
involvement, contiguous extrahepatic disease, primary tumor
multifocality and tumor rupture at enrollment, higher age
(>8 years), low AFP (<100 ng/ml), and metastatic
disease were associated with the worst outcome; however, patients in all
stages of HB were included.
Studies in children with HB undergoing LT, despite the limited number of
patients enrolled in each cohort, seem to point to the same direction.
Umeda et al. 6, in a
retrospective analysis of 24 children with unresectable HB submitted to
LT, showed that the response to Qtx at LT, evaluated by the decline
(>95%) in serum AFP levels, could predict post-LT relapse
for patients receiving both primary and rescue LT. Browne et al.17, in a cohort with 14
patients, demonstrated that a drop of 99% in peak AFP
levels
was associated with 100% survival following LT. Other authors also have
correlated the trends in AFP levels18 or pretransplant AFP
values with outcome 2,
19. In our study, a drop ≥70% in AFP
levels was associated with improved survival at 5-years (81.3% versus
40%). It showed that it is still safe to indicate LT for patients with
a more modest, but still significant drop in AFP levels post-Qtx. The
ROC curve analysis (Figure 3) presented an AUC of 0.8, demonstrating a
good performance/correlation between the studied variable and event-free
(event-No group) outcome.
Salvage or rescue LT has been associated with tumor recurrence and worse
patient survival since the SIOPEL-1 report13. Many other studies
replicated those results7,
17,
20-22, and the present study
corroborates worst patient survival with rescue transplantation, where
all primary tumors were assumed to be resected during the first
operation. Time between diagnosis and LT > 12 months
was also associated with decreased patient survival (Figure 2b, 77%
<12 mo. vs. 40% >12 mo., P=0.01). Indeed,
lengthier Qtx regimens are often required in high-risk subgroups, and
are characterized by marked chemoresistance and poor outcome23,
24.
The Cox-Regression analysis and the respective hazard ratios of the
three variables (AFP reduction < 70%, time from diagnosis to
treatment ≥ 12 months, and rescue LT) associated with increased risk of
tumor recurrence/death in this series are shown in Figure 4. Placed
together, the observed event-free survival was 84.6% (no factors),
66.7% (1 risk factor), and 32.3% (≥ 2 risk factors). Most importantly,
these are pre-operative risk factors that may be able to help
families and physicians during the decision-making process, especially
in the context of live donation. The advantage of timely LT must be
weighted at all times against the risks of the surgical procedure in the
living donor and the chances of cure of the children with unresectable
HB. In our own experience, Candido et al.25 reported a rate of
post-operative complication of 4.8% (29/601) in left liver segment
donors used in pediatric LDLT with no patient mortality; however, the
estimated rate of donor death “definitely” related to donor surgery
has been reported to be 0.15%26.
Vascular invasion has been associated with increased risk of recurrence27-29, and the explant
analysis with presence of vascular invasion in the present study was
also associated with recurrence/death [patient survival with no
vascular invasion (82.4%) vs. microvascular invasion (50%) vs.
macrovascular invasion (20%) (p=0.04)]. Most probably, if vascular
invasion is detected in the pre-transplant staging (POSTTEXT), it might
be useful to include this variable so as to compose a risk
stratification to be used with the ones described in this publication;
however, the present retrospective analysis did not allow such
inclusion/comparison.
The present report shows the experience of a transplant center. The
majority of the patients were referred to us from different oncology
groups in the country, after the pretransplant chemotherapy regimens had
already been defined. Despite the limitation in sample size, one should
keep in mind that the study was designed to determine the risk factors
for recurrence in a rare disease scenario, over a relatively long period
of time. Also, chemotherapy regimens have changed over the study period,
even the one used in the PLADO group. The authors recognize these
shortcomings but they are inherent of the retrospective nature of this
series.
In conclusion, LDLT for HB is a treatment option for unresectable HB,
with no distant metastasis and adequate response to Qtx. The following
pre-transplant factors - AFP reduction < 70%, time from
diagnosis to LT > 12 months and rescue LT - were
associated with higher recurrence/death risk and should be critically
evaluated and discussed with the patient’s family and the
multidisciplinary team in order to move forward with the LDLT in a
timely fashion in order to avoid drug toxicity and chemoresistance.
However, due to the limited number of patients enrolled in this study, a
larger number of patients is required to corroborate these findings.