Pediatr Surg Int (2012) 28:887–891 DOI 10.

1007/s00383-012-3139-x

ORIGINAL ARTICLE

Can we predict the prognosis of resectable hepatoblastoma from 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 Ó Springer-Verlag 2012

Abstract Purpose The objective of this study was to clarify whether 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 resection 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 1.2–36.8 %) in Group A and 17.05 % (range 12.0–20.5 %) in Group B (p \ 0.05). Mean AFP after total preoperative chemotherapy was reduced to 1.42 % (range 0.07–8.5 %) in Group A and 7.55 % (range 3.4–12.4 %) 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 Á Prognostic factor Á AFP Á Chemotherapy

Introduction Hepatoblastoma is a rare disease, accounting for around 1 % of malignancies in children. Outcomes for hepatoblastoma 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. Prognostic 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 00 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 [4–6]. 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 (&) Á N. Urushihara Á K. Fukumoto Á M. Mitsunaga Á K. Watanabe Á T. Aoba Á S. Yamoto Á H. Miyake Á S. Hasegawa Department of Pediatric Surgery, Shizuoka Children’s Hospital, 860 Urushiyama, Aoi-ku, Shizuoka 420-8660, Japan e-mail: fukuzawa1203@yahoo.co.jp

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The JPLT91B2 regimen consisted of combination chemotherapy including cisplatin (CDDP) at 80 mg/m2 and tetrahydropyranyl (THP)-adriamycin (ADR) at 30 mg/m2 for 2 days. Liver transplantation was not needed at curative operation in any of these cases. Although various regimens were used in individual cases during preoperative treatment. lesions were in the lungs in two patients. Responses of AFP levels to preoperative chemotherapy were compared between groups. For statistical analysis. According to the PRETEXT grouping system. the first cycle of chemotherapy comprised JPLT91B2 or CITA in all cases. Only one of these four patients survived. We then reevaluated whether changes in AFP level before curative operation could represent a prognostic factor. while Group B comprised three boys and one girl. To investigate possible correlations between AFP responses to preoperative chemotherapy and outcomes.9 months in Group A and 13. In the final case. 19 patients with hepatoblastoma were treated at our institution.888 Pediatr Surg Int (2012) 28:887–891 Materials and methods Materials Between January 1991 and August 2011. Of these. All patients achieved curative resection histologically. These regimens were broadly similar. two patients were classified as PRETEXT II. In another two cases. We also measured the diameter of these liver tumors bidirectionally before initiating preoperative chemotherapy and after two courses of preoperative chemotherapy.05 were considered statistically significant. One patient in Group B displayed multiple lung metastases at diagnosis. THR-ADR was administered as a 1-h infusion for 2 days in CITA. 123 . These metastases totally disappeared during preoperative chemotherapy and the patient was able to undergo curative resection. Mean reduction rates in lesion size were 40.0 (range 2–5) in Group A and 3. The total number of courses of preoperative chemotherapy including JPLT91B2.5 (range 2–5) in Group B. five cases were excluded from this study. and the other two as PRETEXT III or IV. Results Clinical outcomes Methods We divided the 14 patients into two groups: Group A. The precise protocol has been described in the JPLT [1. one as PRETEXT III. Patient characteristics Clinical characteristics of both groups are summarized in Table 1. The 14 remaining patients underwent curative surgery after preoperative chemotherapy according to the JPLT protocol. In two cases. Values of p \ 0. All study protocols were approved by institutional review board at our hospital. recurrence (n = 4). Mean age at the time of diagnosis was 9. in the liver in one patient. We then retrospectively reviewed the medical records for all 14 cases. CITA and others was 3. three patients had unifocal tumors and one patient had a multifocal tumor.7 % in Group B. No significant difference in the number of courses of preoperative chemotherapy was seen between groups. and in both lungs and liver in one patient. Treatment Chemotherapy was performed based on the JPLT protocol. the dosage of preoperative chemotherapy had to be reduced due to severe renal failure. we reviewed AFP levels in each group at diagnosis after the first cycle of chemotherapy and after all cycles of preoperative chemotherapy. whereas a 48-h infusion of THP-ADR was performed for the JPLT91B2 regimen. the JPLT91B2 regimen was used for preoperative chemotherapy [7]. No significant differences were seen between groups. metastases remained when hepatectomy was performed. In Group B. five as PRETEXT II. 7]. The CITA regimen was Of the four patients showing recurrence after curative resection (Group B). primary surgery had been performed without preoperative chemotherapy. In Group A. CITA was a modification of the JPLT91B2 regimen. Next. The other three patients died despite various treatments. Reduction rates in tumor size were calculated and compared between groups. no recurrence (n = 10). one patient was classified as PRETEXT I. Group A comprised seven boys and three girls.0 months in Group B. In Group B. We also divided the 14 patients according to AFP levels showing a decrease of [2 log or B2 log after all cycles of chemotherapy. nine patients had unifocal tumors and one patient had a multifocal tumor. In the JPLT-1 protocol. and three as PRETEXT IV in Group A. and Group B. with resection of a lung metastasis.2 % in Group A and 58. the Mann–Whitney U test and Fisher’s test were used for group comparisons. used in the JPLT-2 protocol [1]. we divided the 14 patients according to AFP levels showing a decrease of [1 log or B1 log after the first cycle of chemotherapy.

Pediatr Surg Int (2012) 28:887–891 Table 1 Background characteristics of study participants Group A Sex Male Female Age at diagnosis (months) Unifocal/Multifocal PRETEXT I II III IV Metastasis at diagnosis Reduction rate of tumour after two courses of chemotherapy (%) Total number of courses of preoperative chemtherapies (JPLT91B1/CITA etc.900–688. among the six patients in whom AFP levels decreased B1 log after the first course of chemotherapy. Mean AFP level after all courses of preoperative chemotherapy decreased to 1. A significant difference was apparent between these groups (p = 0.05 % (range 12.5 (2–5) Prognostic significance of AFP Median levels of AFP at diagnosis were 240.) 1 5 1 3 0 40.4 %) in Group B. 2 Decreases in AFP level after the first cycle of preoperative chemotherapy 3. On the other hand. 3 Decreases in AFP level after all cycles of preoperative chemotherapy Fig. 4). Conversely. four patients experienced recurrence (Fig.0 (5–20) 3/1 Group B 889 Fig.100–959. The eight patients in whom AFP levels decreased [1 log after the first cycle of preoperative chemotherapy all survived without recurrence.2) 0 2 1 1 1 (lung) 58. 1 Serum AFP levels at diagnosis Again.0237) (Fig.2–36.0088) (Fig.8 %) in Group A and 17.000 ng/ml (range 95.55 % (range 3. among the seven patients in whom AFP levels decreased B2 log after all courses of preoperative chemotherapy.0 (2–5) 3. Mean AFP level after completion of the first cycle of chemotherapy decreased to 7.07–8.000 ng/ml (range 15. Fig. 1).5 %) in Group A and 7.4–100.700 ng/ml) in Group B. The seven patients in whom AFP levels decreased [2 log after all courses of preoperative chemotherapy all survived without recurrence.9 (1–19) 9/1 3 1 13.42 % (range 0. showing a significant difference between groups (p = 0.2) 7 3 9.2 (12.4–106.0–20. No significant difference was seen between groups (Fig. four patients 123 . a significant difference was identified between groups (p = 0.4–12.006). 3).5 %) in Group B.7 (24.000 ng/ml) in Group A and 375. 2).28 % (range 1.

020). Some reports have identified various prognostic factors. 4 Magnitude of decreases in AFP level after the first cycle of preoperative chemotherapy Fig. some patients developed recurrence. However.000 ng/ml appear to be associated with poor outcomes [2. Other reports [4. Conflict of interest of interest. patients received various types of chemotherapy before hepatectomy. Cancer 95:172–182 4. Again.000. 5 Magnitude of decreases in AFP level after all cycles of chemotherapy experienced recurrence (Fig. including liver transplantation. Hisiki T. [6] also suggested that the initial AFP level may offer a predictor of disease-free survival. but the first cycle was almost identical in all patients. 16] have indicated that no strong relationship exists between initial AFP level at diagnosis and outcome. Clarification of factors contributing to an increased risk of recurrence is thus needed. Even though only a small number of reports have included data regarding outcomes and serial changes in AFP levels before hepatectomy. In other words. Rowland JR. outcomes of hepatoblastoma have improved thanks to cisplatin-based chemotherapy and advances in surgical treatment. Matsunaga T. after observing a significant difference in this outcome measure between patients with initial AFP level above and below the median. In our study. The Children’s Oncology Group has shown small-cell undifferentiated histological subtype as a prognostic factor significantly associated with increased risk of death [12]. 3. Sasaki F et al (2011) Outcome of hepatoblastomas treated using the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT. Curative resection is necessary for cure and the outcomes for patients with unresectable and/or metastatic tumor remain poor [8–11]. Buckley JD. 15. Van Tornout JM. suggesting that serum AFP response during preoperative chemotherapy may represent a good indicator of prognosis [4–6]. Pediatr Surg Int 27:1–8 2. Pediatr Blood Cancer 53:1016–1022 3. each has indicated that a large early decrease in AFP level during preoperative chemotherapy appears to offer a strong indicator of survival. Quinn JJ et al (1997) Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are 123 . Whether initial AFP level can be used as a prognostic factor thus remains unclear. 14]. a significant difference was apparent between groups (p = 0. Although curative resection was achieved for all cases of hepatoblastoma in this series. We can therefore reliably predict better outcomes in patients showing a decrease in AFP of [1 log just after completing the first cycle of chemotherapy. The authors declare that they have no conflict Discussion References Recently. Patients in whom AFP levels decreased [1 log after the first cycle of chemotherapy survived without recurrence. Rydzynski J. the present study was unable to identify initial AFP level as a prognostic factor in this series. initial AFP levels 00 ng/ml or [1. Von Schweinitz D et al (2002) Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB94. 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. Meyers RL. 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. Koh et al. 5). However.890 Pediatr Surg Int (2012) 28:887–891 Fig. 13. Fuchs J. Some reports have noted that 1. We confirmed a large early response of AFP to treatment as a strong predictor of good outcome. Krailo M et al (2009) Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children’s Oncology Group.

Zimmermann A et al (2008) Hepatoblastoma with low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience.Pediatr Surg Int (2012) 28:887–891 predictors of outcome: a report from the Children’s Cancer Group. De Ioris M. 9. Hecker H et al (1997) Efficiency and toxicity of ifosfamide. Eur J Cancer 40:411–421 Katzenstein HM. Park M. 10. 7. Jung SE. Byrd DJ. Pediatr Surg Int 19:142–146 891 11. J Clin Oncol 20: 3438–3444 Matsunaga T. Meyers LM. Kim KH. J Pediatr Surg 37:851–856 Perilongo G. Kim BE et al (2011) Prognostic implication of serum alpha-fetoprotein response during treatment of hepatoblastoma. von Schweinitz D. J Clin Oncol 24:2879–2884 12. Ohira M et al (2003) Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma. 8. Shafford E et al (2000) Pretreatment prognostic factors for children with hepatoblastoma—result from the International Society of Paediatric Oncology (SIOP) study SIOPEL1. Katzenstein H. Sasaki F. J Clin Oncol 15:1190–1197 Lovvorn HN 3rd. Kim MY et al (2001) Clinical characteristics and prognosis of patients with hepatoblastoma. Malogolowkin MH. Pediatr Blood Cancer 57:554–560 Sasaki F. Krailo M et al (2009) Predictive power of pretreatment prognostic factors in children with hepatoblastoma: A report from the children’s oncology group. Maibach R et al (2004) Risk-adapted treatment for childhood hepatoblastoma: final report of the second study of the International Society of Paediatric OncologySIOPEL 2. Eur J Cancer 44:545–550 15. Matsunaga T. World J Surg 25:126–130 5. Brugieres L. Rowland JR. 6. Pediatr Blood Cancer 53:1016–1022 13. 123 . Study Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric Oncology and Haematology. Shafford E. Zhao Z et al (2010) Defining hepatoblastoma responsiveness to induction therapy as measured by tumor volume and serum alpha-fetoprotein kinetics. Perilongo G. Ayers D. Douglass EC et al (2002) Treatment of unresectable and metastatic hepatoblastoma: a Paediatric Oncology Group Phase II Study. 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. Eur J Cancer 33:1243–1249 14. cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Krailo MD et al (2006) Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. Browo J. J Pediatr Surg 45:121–128 Koh KN. London WB. Eur J Cancer 36:1418–1425 16.