Hepatoblastoma Sept 2012

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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]

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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

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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.

References

1. Hisiki T, Matsunaga T, Sasaki F et al (2011) Outcome of he-

patoblastomas treated using the Japanese Study Group for Pedi-

atric Liver Tumor (JPLT) protocol-2: report from the JPLT.

Pediatr Surg Int 27:182. Meyers RL, Rowland JR, Krailo M et al (2009) Predictive power

of pretreatment prognostic factors in children with hepatoblas-

toma: a report from the Childrens Oncology Group. Pediatr

Blood Cancer 53:10161022

3. Fuchs J, Rydzynski J, Von Schweinitz D et al (2002) Pretreat-

ment prognostic factors and treatment results in children with

hepatoblastoma: a report from the German Cooperative Pediatric

Liver Tumor Study HB94. Cancer 95:172182

4. Van Tornout JM, Buckley JD, Quinn JJ et al (1997) Timing and

magnitude of decline in alpha-fetoprotein levels in treated chil-

dren with unresectable or metastatic hepatoblastoma are

Fig. 4 Magnitude of decreases in AFP level after the first cycle of

preoperative chemotherapy

Fig. 5 Magnitude of decreases in AFP level after all cycles of

chemotherapy

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predictors of outcome: a report from the Childrens Cancer

Group. J Clin Oncol 15:11901197

5. Lovvorn HN 3rd, Ayers D, Zhao Z et al (2010) Defining hepa-

toblastoma responsiveness to induction therapy as measured by

tumor volume and serum alpha-fetoprotein kinetics. J Pediatr

Surg 45:121128

6. Koh KN, Park M, Kim BE et al (2011) Prognostic implication of

serum alpha-fetoprotein response during treatment of hepato-

blastoma. Pediatr Blood Cancer 57:554560

7. Sasaki F, Matsunaga T, Iwafuchi M et al (2002) Outcome of

hepatoblastoma treated with the JPLT-1 (Japanese Study Group

for Pediatric Liver Tumor) Protcol-1: a report from the Japanese

Study Group for Pediatric Liver tumor. J Pediatr Surg

37:851856

8. Perilongo G, Shafford E, Maibach R et al (2004) Risk-adapted

treatment for childhood hepatoblastoma: final report of the sec-

ond study of the International Society of Paediatric Oncology-

SIOPEL 2. Eur J Cancer 40:411421

9. Katzenstein HM, London WB, Douglass EC et al (2002)

Treatment of unresectable and metastatic hepatoblastoma:

a Paediatric Oncology Group Phase II Study. J Clin Oncol 20:

34383444

10. Matsunaga T, Sasaki F, Ohira M et al (2003) Analysis of treat-

ment outcome for children with recurrent or metastatic hepato-

blastoma. Pediatr Surg Int 19:142146

11. Malogolowkin MH, Katzenstein H, Krailo MD et al (2006)

Intensified platinum therapy is an ineffective strategy for

improving outcome in pediatric patients with advanced hepato-

blastoma. J Clin Oncol 24:28792884

12. Meyers LM, Rowland JR, Krailo M et al (2009) Predictive power

of pretreatment prognostic factors in children with hepatoblas-

toma: A report from the childrens oncology group. Pediatr Blood

Cancer 53:10161022

13. von Schweinitz D, Byrd DJ, Hecker H et al (1997) Efficiency and

toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of

childhood hepatoblastoma. Study Committee of the Cooperative

Paediatric Liver Tumour Study HB89 of the German Society for

Paediatric Oncology and Haematology. Eur J Cancer 33:12431249

14. De Ioris M, Brugieres L, Zimmermann A et al (2008) Hepato-

blastoma with low serum alpha-fetoprotein level at diagnosis: the

SIOPEL group experience. Eur J Cancer 44:545550

15. Browo J, Perilongo G, Shafford E et al (2000) Pretreatment

prognostic factors for children with hepatoblastomaresult from

the International Society of Paediatric Oncology (SIOP) study

SIOPEL1. Eur J Cancer 36:14181425

16. Jung SE, Kim KH, Kim MY et al (2001) Clinical characteristics

and prognosis of patients with hepatoblastoma. World J Surg

25:126130

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