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7/27/2019 Hepatoblastoma Sept 2012
1/5
O R I G I N A L A R T I C L E
Can we predict the prognosis of resectable hepatoblastomafrom serum alpha-fetoprotein response during preoperative
chemotherapy?
Hiroaki Fukuzawa Naoto Urushihara Koji Fukumoto
Maki Mitsunaga Kentaro Watanabe Takeshi Aoba
Shinya Yamoto Hiromu Miyake Shiro Hasegawa
Published online: 4 August 2012
Springer-Verlag 2012
Abstract
Purpose The objective of this study was to clarify whe-ther the alpha-fetoprotein (AFP) reduction rate during
preoperative chemotherapy represents a prognostic factor
for hepatoblastoma.
Method We divided 14 hepatoblastoma patients who
underwent preoperative chemotherapy and curative resec-
tion into Group A (no recurrence; n = 10) and Group B
(recurrence; n = 4). We then compared AFP levels before
and after preoperative chemotherapy between groups.
Result Mean AFP level after completing the first cycle of
chemotherapy was reduced to 7.28 % (range 1.236.8 %)
in Group A and 17.05 % (range 12.020.5 %) in Group B
(p\ 0.05). Mean AFP after total preoperative chemother-
apy was reduced to 1.42 % (range 0.078.5 %) in Group A
and 7.55 % (range 3.412.4 %) in Group B (p\ 0.02).
Eight patients in whom AFP levels decreased[1 log after
the first cycle of preoperative chemotherapy survived
without recurrence.
Conclusion A large, early decrease in AFP level during
preoperative chemotherapy may offer a strong indicator of
survival. Patients in whom AFP levels do not decrease
easily during preoperative chemotherapy may have
increased risk of recurrence and should be followed very
closely.
Keywords Hepatoblastoma Prognostic factor AFP
Chemotherapy
Introduction
Hepatoblastoma is a rare disease, accounting for around
1 % of malignancies in children. Outcomes for hepato-
blastoma have been improving with the development of
more efficient chemotherapy regimens. The Japanese Study
Group for Pediatric Liver Tumor (JPLT) reported a 5-year
overall survival rate of 80.9 % [1]. Complete resection is
necessary to achieve disease-free survival. However, some
cases show recurrence even after curative resection. Prog-
nostic factors for identifying patients at increased risk of
residual disease are thus needed. Alpha-fetoprotein (AFP)
levels at diagnosis have been reported as a prognostic
factor, with initial AFP level\100 ng/ml or[1,000,000
ng/ml associated with worse outcomes [2, 3]. However, the
abilities of AFP levels at specific time points and of serial
changes in AFP levels to predict outcomes have not been
established and have been described in detail in only a few
studies [46]. Koh et al. [6] recently reported that AFP
response to preoperative chemotherapy may offer a useful
prognostic factor. They also noted that an initial favorable
AFP response, defined as a[1 log decline in serum AFP
level after the first cycle of chemotherapy was significantly
associated with survival outcome. Similarly, Van Tornout
et al. [4] reported that patients in whom AFP levels fail to
decrease by at least 2 log during preoperative chemotherapy
may show a greater risk of recurrence.
The objective of this study was thus to clarify whether
the AFP reduction rate during preoperative chemotherapy
offers a prognostic factor for hepatoblastoma in our
institution.
H. Fukuzawa (&) N. Urushihara K. Fukumoto
M. Mitsunaga K. Watanabe T. Aoba S. Yamoto
H. Miyake S. Hasegawa
Department of Pediatric Surgery, Shizuoka Childrens Hospital,
860 Urushiyama, Aoi-ku, Shizuoka 420-8660, Japan
e-mail: [email protected]
123
Pediatr Surg Int (2012) 28:887891
DOI 10.1007/s00383-012-3139-x
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Materials and methods
Materials
Between January 1991 and August 2011, 19 patients with
hepatoblastoma were treated at our institution. Of these,
five cases were excluded from this study. In two cases,
primary surgery had been performed without preoperativechemotherapy. In another two cases, metastases remained
when hepatectomy was performed. In the final case, the
dosage of preoperative chemotherapy had to be reduced
due to severe renal failure. The 14 remaining patients
underwent curative surgery after preoperative chemother-
apy according to the JPLT protocol. Liver transplantation
was not needed at curative operation in any of these cases.
We then retrospectively reviewed the medical records for
all 14 cases.
Methods
We divided the 14 patients into two groups: Group A, no
recurrence (n = 10); and Group B, recurrence (n = 4). To
investigate possible correlations between AFP responses to
preoperative chemotherapy and outcomes, we reviewed
AFP levels in each group at diagnosis after the first cycle of
chemotherapy and after all cycles of preoperative chemo-
therapy. Responses of AFP levels to preoperative chemo-
therapy were compared between groups.
Next, we divided the 14 patients according to AFP
levels showing a decrease of[1 log or B1 log after the
first cycle of chemotherapy. We also divided the 14
patients according to AFP levels showing a decrease of[2
log or B2 log after all cycles of chemotherapy. We then re-
evaluated whether changes in AFP level before curative
operation could represent a prognostic factor.
For statistical analysis, the MannWhitney U test and
Fishers test were used for group comparisons. Values of
p\ 0.05 were considered statistically significant.
We also measured the diameter of these liver tumors
bidirectionally before initiating preoperative chemotherapy
and after two courses of preoperative chemotherapy.
Reduction rates in tumor size were calculated and com-
pared between groups.
All study protocols were approved by institutional
review board at our hospital.
Treatment
Chemotherapy was performed based on the JPLT protocol.
In the JPLT-1 protocol, the JPLT91B2 regimen was used
for preoperative chemotherapy [7]. The CITA regimen was
used in the JPLT-2 protocol [1]. These regimens were
broadly similar.
The JPLT91B2 regimen consisted of combination che-
motherapy including cisplatin (CDDP) at 80 mg/m2 and
tetrahydropyranyl (THP)-adriamycin (ADR) at 30 mg/m2
for 2 days. CITA was a modification of the JPLT91B2
regimen. THR-ADR was administered as a 1-h infusion for
2 days in CITA, whereas a 48-h infusion of THP-ADR wasperformed for the JPLT91B2 regimen. The precise protocol
has been described in the JPLT [1, 7].
Although various regimens were used in individual
cases during preoperative treatment, the first cycle of
chemotherapy comprised JPLT91B2 or CITA in all cases.
Results
Clinical outcomes
Of the four patients showing recurrence after curativeresection (Group B), lesions were in the lungs in two
patients, in the liver in one patient, and in both lungs and
liver in one patient. Only one of these four patients sur-
vived, with resection of a lung metastasis. The other three
patients died despite various treatments.
Patient characteristics
Clinical characteristics of both groups are summarized in
Table 1. Group A comprised seven boys and three girls,
while Group B comprised three boys and one girl. In Group
A, nine patients had unifocal tumors and one patient had a
multifocal tumor. In Group B, three patients had unifocal
tumors and one patient had a multifocal tumor. Mean age at
the time of diagnosis was 9.9 months in Group A and
13.0 months in Group B. According to the PRETEXT
grouping system, one patient was classified as PRETEXT I,
five as PRETEXT II, one as PRETEXT III, and three as
PRETEXT IV in Group A. In Group B, two patients were
classified as PRETEXT II, and the other two as PRETEXT
III or IV. One patient in Group B displayed multiple lung
metastases at diagnosis. These metastases totally disap-
peared during preoperative chemotherapy and the patient
was able to undergo curative resection. Mean reduction
rates in lesion size were 40.2 % in Group A and 58.7 % in
Group B. No significant differences were seen between
groups. The total number of courses of preoperative che-
motherapy including JPLT91B2, CITA and others was 3.0
(range 25) in Group A and 3.5 (range 25) in Group B. No
significant difference in the number of courses of preop-
erative chemotherapy was seen between groups. All
patients achieved curative resection histologically.
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Prognostic significance of AFP
Median levels of AFP at diagnosis were 240,000 ng/ml
(range 15,900688,000 ng/ml) in Group A and 375,000 ng/ml
(range 95,100959,700 ng/ml) in Group B. No significant
difference was seen between groups (Fig. 1).
Mean AFP level after completion of the first cycle of
chemotherapy decreased to 7.28 % (range 1.236.8 %) in
Group A and 17.05 % (range 12.020.5 %) in Group B,showing a significant difference between groups
(p = 0.0237) (Fig. 2).
Mean AFP level after all courses of preoperative che-
motherapy decreased to 1.42 % (range 0.078.5 %) in
Group A and 7.55 % (range 3.412.4 %) in Group B.
Again, a significant difference was identified between
groups (p = 0.0088) (Fig. 3).
The eight patients in whom AFP levels decreased[1
log after the first cycle of preoperative chemotherapy all
survived without recurrence. Conversely, among the sixpatients in whom AFP levels decreased B1 log after the
first course of chemotherapy, four patients experienced
recurrence (Fig. 4). A significant difference was apparent
between these groups (p = 0.006).
The seven patients in whom AFP levels decreased[2
log after all courses of preoperative chemotherapy all
survived without recurrence. On the other hand, among the
seven patients in whom AFP levels decreased B2 log after
all courses of preoperative chemotherapy, four patients
Table 1 Background characteristics of study participants
Group A Group B
Sex
Male 7 3
Female 3 1
Age at diagnosis (months) 9.9 (119) 13.0 (520)
Unifocal/Multifocal 9/1 3/1
PRETEXT
I 1 0
II 5 2
III 1 1
IV 3 1
Metastasis at diagnosis 0 1 (lung)
Reduction rate of tumour
after two courses of
chemotherapy (%)
40.2 (12.4106.2) 58.7 (24.4100.2)
Total number of courses
of preoperative
chemtherapies
(JPLT91B1/CITA etc.)
3.0 (25) 3.5 (25)
Fig. 1 Serum AFP levels at diagnosis
Fig. 2 Decreases in AFP level after the first cycle of preoperative
chemotherapy
Fig. 3 Decreases in AFP level after all cycles of preoperative
chemotherapy
Pediatr Surg Int (2012) 28:887891 889
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experienced recurrence (Fig. 5). Again, a significant dif-
ference was apparent between groups (p = 0.020).
Discussion
Recently, outcomes of hepatoblastoma have improved thanks
to cisplatin-based chemotherapy and advances in surgical
treatment, including liver transplantation. Curative resection
is necessary for cure and the outcomes for patients withunresectable and/or metastatic tumor remain poor [811].
Although curative resection was achieved for all cases of
hepatoblastoma in this series, some patients developed
recurrence. Clarification of factors contributing to an
increased risk of recurrence is thus needed. Some reports have
identified various prognostic factors. The Childrens Oncol-
ogy Group has shown small-cell undifferentiated histological
subtype as a prognostic factor significantly associated with
increased risk of death [12]. Some reports have noted that
initial AFP levels\100 ng/ml or[1,000,000 ng/ml appear
to be associated with poor outcomes [2, 3, 13, 14]. Koh et al.
[6] also suggested that the initial AFP level may offer a pre-
dictor of disease-free survival, after observing a significant
difference in this outcome measure between patients with
initial AFP level above and below the median. However, the
present study was unable to identify initial AFP level as a
prognostic factor in this series. Other reports [4, 15, 16] haveindicated that no strong relationship exists between initial
AFP level at diagnosis and outcome. Whether initial AFP
level can be used as a prognostic factor thus remains unclear.
However, the abilities of AFP levels at specifictime points
and of serial changes in AFP levels to predict outcomes have
not been established and have been describedin detail in only
a few studies, suggesting that serum AFP response during
preoperative chemotherapy may represent a good indicator
of prognosis [46]. We confirmed a large early response of
AFP to treatment as a strong predictor of good outcome.
Patients in whom AFP levels decreased[1 log after the first
cycle of chemotherapy survived without recurrence. In ourstudy, patients received various types of chemotherapy
before hepatectomy, but the first cycle was almost identical
in all patients. We can therefore reliably predict better out-
comes in patients showing a decrease in AFP of[1 log just
after completing the first cycle of chemotherapy.
Even though only a small number of reports have
included data regarding outcomes and serial changes in
AFP levels before hepatectomy, each has indicated that a
large early decrease in AFP level during preoperative
chemotherapy appears to offer a strong indicator of sur-
vival. In other words, patients showing no substantial
decrease in AFP levels after the first cycle of chemotherapy
may have an increased risk of recurrence and should thus
be followed very closely.
Conflict of interest The authors declare that they have no conflict
of interest.
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