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Treatment and early outcome of 11 children with hepatoblastoma.

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Fouad A. Fouad saleep MD., Ihab samy Fayek MD.
Department of Surgical Oncology – National Cancer Institute – Cairo University - Egypt.
Kasr el-aini medical journal Volume 18, No.4, October 2012.

Published in: Health & Medicine
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Treatment and early outcome of 11 children with hepatoblastoma.

  1. 1. 1 Treatment and outcome of 11 children with hepatoblastoma Fouad A. Fouad saleep MD., Ihab samy Fayek MD. Department of Surgical Oncology – National Cancer Institute – Cairo University - Egypt Abstract: Aim : This study was designed to retrospectively review our experience National Cancer Institute,Cairo University with the multimodality management of hepatoblastomas (HB) and to assess the outcome of childhood hepatoblastoma after a combination therapy of resection and chemotherapy. Materials and Methods: eleven patients were treated for HB between 2006 and 2010. The clinical presentations, chemotherapy tolerance and response and surgical procedure undertaken were analysed. Results: Median age of the population was 15 months (6-37 months), mean age was 16.7 months; with a male-to-female ratio of 4.5:1. Nine patients were treated with neoadjuvant chemotherapy incorporating cisplatin and adriamycin. Primary surgery was done in two patients. Extent of hepatic resection in the operated patients varied. Mixed type was the predominant histopathological diagnosis. Adjuvant chemotherapy was well tolerated with no morbidity or mortality. All the nine patients who could complete multimodality treatment are alive with no evidence of disease or complications with median follow-up of 13 months (7-19 months), mean follow up was 12.2 months. Overall Survival of all 11 patients is 91%. Conclusion: Treatment of HB with multidisciplinary approach was well tolerated. Overall Survival of patients were comparable with published studies. Keywords: hepatic resections, Chemotherapy , hepatoblastoma, multimodality treatment, neoadjuvant treatment. Introduction: Hepatoblastomas (HB) are rare pediatric neoplasms, with incidence of 1.5 per million, and comprising 1% of pediatric malignancies (1). Till 1970s, surgery was the primary modality of treatment of HB. Unfortunately, up to 60% of the patients present in an unresectable stage(1,2). Later, the chemo-responsiveness of the tumor was demonstrated which led to the incorporation of adjuvant chemotherapy with cisplatinum and doxorubicin in the treatment of HB (3,4,5). International Society of Pediatric Oncology (SIOP) pioneered the concept of neoadjuvant chemotherapy in the management of HB (6,7). Surgical resection of the tumors were made easier by reducing the size and vascularity of the tumor, and the chances for obtaining negative margins of resection were more (7,8). A partial response (PR) status could be achieved in 82% of the cases in SIOPEL-1 study. Surgical resection
  2. 2. 2 after neoadjuvant chemotherapy could be done in 87% of the cases whereas historically only 30% of the cases were operable upfront. Surgical morbidity was also less if resection was performed after neoadjuvant chemotherapy. Extended surgical resections of HB have been safely performed in the pediatric age group (8). Orthotopic Liver transplant (OLT) is an effective treatment for unresectable HB with survival rates of 82% if done as a primary treatment (1). Combined modality treatment is now the standard of care in HB. Management of HB over 4 years is reviewed in this article. Materials and Methods: This study included patients diagnosed to have HB and treated between January 2006 and December 2010 at National Cancer Institute,Cairo University. Patient demographics, mode of presentation, method of diagnosis, extent of tumor at diagnosis, surgical procedures performed, complications of treatment and outcome were recorded. Based on imaging using a computerized tomography (CT) scan (fig. 1) and/or magnetic resonance imaging (MRI), all patients were assigned a PRETEXT (Pre- treatment extent of disease) stage and four groups of patients were identified as PRETEXT I-IV. Nine patients received neoadjuvant chemotherapy followed by surgical resection. The standard of care, cisplatinum and adriamycin as in the PLADO (PLA, Platinum; DO, Doxorubicin) regimen was administered to the nine patients every 21 days. PLADO chemotherapy consisted of PLA on day 1 at a dose of 80 mg/m2, administered in a continuous 24-h infusion and DO at a dose of 30 mg/m2 per day, administered as a continuous 24-h intravenous (IV) infusion on days 2 and 3. Both drugs were administered via a central venous catheter. Patients were routinely reassessed after three cycles for surgical resection. If the tumor was found to be inoperable, patient was given one more cycle of chemotherapy. The decision regarding timing of surgery was taken by the surgical oncology team. Postoperatively, two to three cycles of chemotherapy were given to a total of six cycles. The patients were followed up after treatment with serial AFP levels and imaging. Follow-up was complete for all treated patients. Resection is typically performed through a bilateral subcostal incision . Intraoperative ultrasonography has been applied to determine the exact location of the tumor relative to the vessels. Unresectability is usually determined by involvement of hilar structures or all hepatic veins, invasion of inferior vena cava (IVC) or portal vein. Centrally located tumors are, by definition, more likely unresectable. Once deemed resectable, the resection is marked out and various tools may then be used to perform the resection; electrocautery, bipolar devices such as LigaSure for hemostasis have been used (fig. 2,3,4,5).
  3. 3. 3 Results: (Tables 1 & 2) Eleven patients were diagnosed and treated for HB. All the patients had elevated AFP levels and pathological confirmation was done in all feasible cases. There were nine males and two were females in the group (M:F, 4.5:1). The median age was 15 months (range, 6-37 months). None of the patients had any cardiac anomalies. The commonest presenting feature was that of an abdominal mass (in 10 out of 11 patients). One patient was diagnosed while being evaluated for fever. None of the patients had jaundice or was seropositive for Hepatitis B or C. All the patients had palpable hepatomegaly. AFP was elevated in all the cases with a median level of 20,000 ng/ml (range, 620-1,42,000 ng/ml). CT scan was done for 6 patients and MRI for 5. PRETEXT staging distribution was as follows; PRETEXT Stage 9.1% (n = 1), Stage II 54.5% (n = 6), Stage III 36.4% (n = 4), and Stage IV 0% (n = 0). Patients who underwent straight surgery did not have preoperative biopsy. Eight of the remaining nine patients had pretreatment fine needle aspiration (FNA) or Trucut biopsy. Surgical procedures performed included right hepatectomy in five patients, extended right hepatectomy in three patients, and left hepatectomy in three.Neoadjuvant chemotherapy was given to 9 of 11 patients. The remaining two had initial surgery (Table 1). An 18-month- child with PRETEXT 2 disease who underwent upfront surgery died 8 months later from extensive lung metastases which led to pulmonary insufficiency and failure. Of the neoadjuvant group, three patients completed four cycles and another six completed three cycles of chemotherapy before surgery. All nine patients received adjuvant chemotherapy also for a total of six cycles. The two patients who had primary surgery received adjuvant chemotherapy also. The median duration of surgery was 180 min (range, 120-260 min). The median blood loss was 250 ml (100-400 ml). The median length of postoperative hospital stay was 10 days (range, 6-17 days). The only postoperative complication was intestinal obstruction in one patient which was managed conservatively. There was no postoperative mortality. Histopathology and margins The histological types encountered were as follows: embryonal and mixed embryonal/foetal subtype in four patients and mixed epithelial and mesenchymal in seven. Pathological complete remission was noted in one patient after neoadjuvant chemotherapy, others having residual tumor. Among the eleven patients eight had tumor-free margin of at least 5 mm, three had close margins (<5 mm).
  4. 4. 4 Patient No. Age AFP Preop Liver segments involved PRETEXT Staging Initial ttt. 1 11 2,000 5,6,7 2 CHEMO 2 7 35,618 2,3,4 2 CHEMO 3 16 5,692 5,6,7 2 CHEMO 4 6 620 2,3 1 Surgery 5 8 131,861 5,6,7,8,4 3 CHEMO 6 12 960 4,8 3 CHEMO 7 32 142,000 4,5,6,7,8 3 CHEMO 8 18 121,150 5,6,8 2 Surgery 9 22 20,000 4,7,8 3 CHEMO 10 37 130,605 5,6,7 2 CHEMO 11 15 730 5,6,8 2 CHEMO Table 1: Preoperative Evaluation and treatment Patient No. Extent of liver resection Operative time (min.) Blood loss (ml.) PO hosp. stay (days) FU Current Status 1 Rt. hepatectomy 210 190 10 14 CR 2 Left hepatectomy 160 150 7 9 CR 3 Rt. hepatectomy 170 250 10 7 CR 4 Left hepatectomy 120 100 6 11 CR 5 Extended RT trisegmentectomy 230 300 17 13 CR 6 Left hepatectomy 130 150 8 18 CR 7 Extended RT trisegmentectomy 260 400 14 13 CR 8 Rt. hepatectomy 210 250 7 8 dead 9 Extended RT. trisegmentectomy 260 350 11 19 CR 10 Rt. hepatectomy 160 250 10 8 CR 11 Rt. hepatectomy 180 190 11 14 CR Table 2: Operative and Postoperative details Discussion Hepatoblastomas are the most common pediatric primary liver malignancy accounting for more than 90% of the liver tumors in less than 5 years of age (1). Most of the cases are asymptomatic and present in an advanced stage. The exact etiology is unknown. The association with preterm births and genetic conditions like Beckwith- Wiedemann syndrome is well documented in the literature (9,10). Surgical resection is the cornerstone for successful management of HB. Management of HB has evolved from extensive surgical resections through the incorporation of adjuvant chemotherapy to the current standard of care of neoadjuvant chemotherapy followed by surgery. The
  5. 5. 5 survival in 1970s with surgical resection alone was a meagre 10-20% (11). However with the arrival of chemotherapeutic regimens such as PLADO, the surgical outcomes improved tremendously. Neoadjuvant chemotherapy pioneered by SIOP has reduced the surgical complications, facilitated more complete resections and improved the cure rates (7). Presently, survival is between 75% and 90% (12,13,14). Multi-institutional trials have confirmed the feasibility of this approach in limited resource settings also (15,16). An initial surgical approach may be acceptable for resectable disease, but a neoadjuvant approach may be preferable in advanced stages (13). The patients in our study had a lower median age of presentation (15 months) and male predominance compared to some of the previous reports. PRETEXT stage II predominated in our series (54.5%). All patients in our series had a mixed type of HB comprising foetal, embryonal, and epithelial elements. Chemotherapy-related long-term toxicities were absent in our study. Most importantly all the nine patients who completed multimodality treatment are long-term survivors (up to 19 months). Relapse of the disease was not observed in any of the survivors. Only one patient died from extensive lung metastases which led to pulmonary insufficiency and failure. Excellent results have been reported from tertiary care centers in HB, thus reaffirming the role of expertise in the management of this rare neoplasm. Bajpai et al. reported excellent outcome in 10 patients with HB. Three patients recurred in their study. Fetal subtype was the most common histology (16). Ang et al. analysed outcome of 30 patients with HB treated at Royal Children's Hospital Australia, from 1984 to 2004. The 5-year EFS was 75.7% (14). From a malignancy with dismal outcome, HB has come a long way through mainly because of the combined modality treatment with improved chemotherapeutic regimes and surgical techniques. HB is one cancer where the coordinated effort of multiple specialities has given a leap in the cure rates. Conclusion: Treatment of HB with multidisciplinary approach was well tolerated, safe with promising long term survivors.
  6. 6. Figure 1: CT post chemotherapy Figure 3: Exploration of the vena cava and the hilum References: 1.Mueller Bu, Terrada DL, Finegold MJ. Hepatoblastoma. 5 th ed. Principles and practice of pediatric oncology. In: Pizzo PA, Poplack DG, editors. Houston: Lippincott 6 CT post chemotherapy Figure 2: Marking of the resection Exploration of the vena cava and the hilum Figutr 4: Tumor after resection Figure 5: Cut surface of the liver gold MJ. ed. Principles and practice of pediatric oncology. In: Pizzo PA, Poplack DG, editors. Houston: Lippincott- Williams Wilkins Publishers; 2006. p. 887. Marking of the resection Tumor after resection Williams Wilkins Publishers; 2006. p. 887.
  7. 7. 7 2.Exelby PR, Filler RM, Grosfeld JL. Liver tumours in children in particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey - 1974. J Pediatr Surg 1975;10:329-37. 3.Quinn JJ, Altman AJ, Robinson T. Adriamycin and cisplatin for hepatoblastoma. Cancer 1985;56:1926-9. 4.Ortega JA, Krailo MD, Haas JH. Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: A report from the Childrens Cancer Study Group. J Clin Oncol 1991;9:2167-76. 5.Douglass EC, Reynolds M, Finegold M, Cantor AB, Glicksman A. Cisplatin, vincristine and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 1993;11:96-9. 6.von Schweinitz D, Byrd DJ, Hecker M. Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Eur J Cancer 1997;33:1243-9. 7.Pritchard J, Brown J, Shafford E, Perilongo G, Brock P, Dicks-Mireaux C, et al. Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 2000;18:3819-28. 8.Schnater JM, Aronson DC, Plaschkes J, Perilongo G, Brown J, Otte JB, et al. Surgical View of the Treatment of Patients with hepatoblastoma: : results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 2002;94:1111-20. 9.Ansell P, Mitchell CD, Roman E, Simpson J, Birch JM, Eden TO. Relationships between perinatal and maternal characteristics and hepatoblastoma: a report from the UKCCS. Eur J Cancer 2005;41:741-8. 10.Vaughan WG, Sanders DW, Grosfeld JL, Plumley DA, Rescorla FJ, Scherer LR, et al. Favorable outcome in children with Beckwith-Wiedemann syndrome and intraabdominal malignant tumors. J Pediatr Surg 1995;30:1042-4. 11.Hermann RE, Lonsdale D. Chemotherapy, radiotherapy and hepatic lobectomy for hepatoblastoma in an infant: report of a survival. Surgery1970;68:383-8. 12.Ortega JA, Douglass EC, Feusner JH, Reynolds M, Quinn JJ, Finegold MJ, et al. Randomized comparison of cisplatin/ vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 2000;18:2665-75. 13.Katzenstein HM, Krailo MD, Malogolowkin MH, Ortega JA, Liu-Mares W, Douglass EC, et al. Hepatocellular
  8. 8. 8 carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 2002;20:2789-97. 14.Ang JP, Heath JA, Khurana S, Auldist A. Treatment outcomes for hepatoblastoma: an institution's experience over two decades. Pediatr Surg Int 2007;23:103-9. 15.Udupa KV, Navadgi SM, Mullerpatan P, Chhabra D, Shah RC, Jagannath P. Neoadjuvant chemotherapy before surgery of Hepatoblatoma. Indian J Paediatr 2006;73:735-7. 16.Bajpai M, Pal K, Agarwala S, Seth T, Gupta AK. Midterm results with hepatectomy after preoperative chemotherapy in hepatoblastoma. Paediatr Surg Int 2005;21:364-8.

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