Neoadjuvant chemotherapy before surgery of Hepatoblastoma
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《美国医学杂志》
Department of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, India
Abstract
Though surgical resection is the main stay of treatment for childhood hepatoblastoma (HB), many are unsuitable for radical surgery at diagnosis due to extensive intrahepatic and/or extra hepatic disease. We report experience in five patients of HB from a single institution (2001-2005) with preoperative Neoadjuvant chemotherapy (NACT) followed by surgery. Three patients received cisplatin, doxorubicin; and two cisplatin / vincristine /5-fluorouracil. All showed more than 50% reduction in tumor size confirmed by CT scan. Hepatic resection R0 was performed in all. There was no chemotherapy related toxicity nor post surgical morbidity or mortality. All are disease free at median follow up of 4 years. NACT produces adequate down staging of the HB with acceptable toxicity. Though cisplatin with doxorubicin produced good results, new protocol with cisplatin, vincristine and 5FU is promising without cardiotoxicity.
Keywords: Hepatoblastoma; Neoadjuvant chemotherapy; Liver surgery; Liver tumor
Formerly surgical resection is the only treatment for Hepatoblastoma (HB) the most common malignant childhood hepatic malignancy with low resection rate and survival. Preoperative Neo Adjuvant Chemotherapy (NACT) with single agent or combination increased resectability and survival as shown in SIOPEL-1 study.[1],[2] The role of chemotherapy and surgery for HB in 49 patients from Mumbai was presented at 6th World Congress of IHPBA, Washington 2004.[3] From India preoperative chemotherapy in HB was reported in a 9-month-old child.[4] In ten children preoperative chemotherapy reduced tumor size by 65.9% permitting surgical resectability and 80% survival in 5 year follow-up.[5] We report preoperative NACT in 5 children with HB from a single institution with 100% survival on a median follow up of 4 years.
Case report
HB was diagnosed on clinico-radiological grounds, alpha feto-protein (AFP) levels, fine needle aspiration cytology and/or biopsy. Particulars and procedures are given in table1. NACT was given in 4 patients with unresectable tumors Figure1 and in 1 referred with a positive residual cut.
PLADO combination - cisplatin (PLA) (80mg/m 2/ iv) and doxorubicin (DO) (30 mg/m 2/24 hours iv continuous infusion was given in 3 cases; and continuous iv infusion- cisplatin (90 mg/m 2) and iv push- vincristine (1.5mg/m 2) and 5-FU(5-Flurouracil- 600 mg/m 2) in 2 patients.
After confirming good response to chemotherapy by CT Scan Figure2 the patients were operated. Intra Operative Ultra Sound (IOUS) was used to confirm the extent of the tumor and visualize intrahepatic vasculature. Liver was split by Harmonic scalpel and/or Cavitron Ultrasonic Surgical Aspirator (CUSA). Pringles maneuver was used in 2 cases, with clamp time of 15 minutes, followed by release for 5 minutes. Prophylactic antibiotics were given. Blood and blood products were used when required.
Follow up was with clinical examination, AFP estimations, and abdominal sonography every 3 months for first 2 years and then every 6 months for next 3 years.
Results
All five were male, aged 4 to 60 months (median age at diagnosis 18 months). All presented with a palpable lump in abdomen, history of recurrent fever in two and no-weight gain in three children. None had jaundice or palpable lymphadenopathy or ascites. Anemia was present in two (6 to 11.7g/dL). Serum alkaline phosphatase levels were elevated at presentation (mean 320 mU/ml). Rest of the LFT was normal. All patients were non-reactive for Hepatitis B Surface antigen, Hepatitis C and HIV. The initial AFP levels ranged 300 to 4,25,290 i.u./ml.
In 3 children PLADO regime was given - 6 cycles in two and 4 cycles in one for down staging of tumor. All had R0 resection table1. None had cardiotoxicity, febrile neutropenia, thrombocytopenia or mucositis. Postoperatively one completed 2 more cycles of PLADO regimen, and the other 2 had no further chemotherapy.
In 2 children vincristine, 5-FU and cisplatin was given. One had an episode of mucositis but recovered with conservative management. There was no other side effect of chemotherapy. Following NACT, R0 resection was carried out table1. After surgery both completed rest of the chemotherapy (total 6 cycles).
There were no intra-operative or postoperative problems in all. Surgery took 180 to 330 min and blood loss 150 to 450 ml. Blood and blood products were given only in 2 patients intra-operatively. Post-operative stay was 7 to 10 days. AFP levels returned to normal after completion of the primary NACT or surgery. All 5 followed for 24-48 months were well and disease free.
Discussion
In HB, levels of AFP are elevated in 90% of patients.[6] Complete resection of tumor results in fall in AFP levels which is normalized within 4-6 weeks. Persistence or secondary increase in AFP levels suggests residual, metastatic or recurrent disease and is useful in follow up. Abdominal CT scan reveals the lesion and vascular involvement essential for complete surgical resection. We used CT angio for preoperative assessment of resectability and Portal Doppler to decide the portal vascular involvement and or thrombosis. Tissue diagnosis (FNAC/biopsy) is recommended to all patients for accurate diagnosis.[1],[6]
SIOPEL-1 used preoperative chemotherapy PLADO 4 courses and 2 more if necessary before surgery using a staging system, PRETEXT (PRE Treatment EXTent of disease), to predict resectability and outcome.[1] SIOPEL-2 study reported favorable results after cisplatin monotherapy and surgery with tumors less than three hepatic sectors without extra hepatic disease; but less satisfactory results in HB involving all four sectors of liver with extrahepatic disease with cisplatin alternating with carboplatin and doxorubicin.[7]
In our series 3 patients received PLADO and 2 patients cisplatin/vincristine/5-Flurouracil before surgery for down staging tumor. Resections (R0 resection) could be successfully carried out in all 5 with no life-threatening toxicities or post surgical morbidity and mortality. All patients are disease free on follow up for 48 months. The newer protocol with cisplatin, vincristine and 5FU is promising without cardiotoxicity, improving resectability.
References
1. Perilongo G, Shafford E, Plaschkes J SIOPEL trials using preoperative chemotherapy in hepatoblastoma. Lancet Oncol. 2000; 1 : 94-100.
2. Pritchard J, Brown J, Shafford E 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 : 3819-3828.
3. Mullerpatan PM, Neve RS, Shah RC, Banavali SD, Jagannath P. The role of chemotherapy and surgery for hepatoblastoma in 49 patients . HPB 2004; 6 (suppl. p6)
4. Choudhury SR, Singh D. Advanced hepatoblastoma: successful liver resection following preoperative chemotherapy. Trop Gastroenterol 2004; 25 : 32-33.
5. Bajpai M, Pal K, Agarwala S, Seth T, Gupta AK. Midterm results with hepatectomy after preoperative chemotherapy in hepatoblastoma. Pediatr Surg Int 2005; 21 : 364-368.
6. Schnater JM, Kohler SE, Lamers WH, von Schweinitz D, Aronson DC. Where do we stand with hepatoblastoma A review. Cancer 2003; 98 : 668-678.
7. Perilongo G, Shafford E, Maibach R et al. Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology-SIOPEL 2. Eur J Cancer 2004; 40 : 411-421.(Udupa KV, Navadgi SM, Mul)
Abstract
Though surgical resection is the main stay of treatment for childhood hepatoblastoma (HB), many are unsuitable for radical surgery at diagnosis due to extensive intrahepatic and/or extra hepatic disease. We report experience in five patients of HB from a single institution (2001-2005) with preoperative Neoadjuvant chemotherapy (NACT) followed by surgery. Three patients received cisplatin, doxorubicin; and two cisplatin / vincristine /5-fluorouracil. All showed more than 50% reduction in tumor size confirmed by CT scan. Hepatic resection R0 was performed in all. There was no chemotherapy related toxicity nor post surgical morbidity or mortality. All are disease free at median follow up of 4 years. NACT produces adequate down staging of the HB with acceptable toxicity. Though cisplatin with doxorubicin produced good results, new protocol with cisplatin, vincristine and 5FU is promising without cardiotoxicity.
Keywords: Hepatoblastoma; Neoadjuvant chemotherapy; Liver surgery; Liver tumor
Formerly surgical resection is the only treatment for Hepatoblastoma (HB) the most common malignant childhood hepatic malignancy with low resection rate and survival. Preoperative Neo Adjuvant Chemotherapy (NACT) with single agent or combination increased resectability and survival as shown in SIOPEL-1 study.[1],[2] The role of chemotherapy and surgery for HB in 49 patients from Mumbai was presented at 6th World Congress of IHPBA, Washington 2004.[3] From India preoperative chemotherapy in HB was reported in a 9-month-old child.[4] In ten children preoperative chemotherapy reduced tumor size by 65.9% permitting surgical resectability and 80% survival in 5 year follow-up.[5] We report preoperative NACT in 5 children with HB from a single institution with 100% survival on a median follow up of 4 years.
Case report
HB was diagnosed on clinico-radiological grounds, alpha feto-protein (AFP) levels, fine needle aspiration cytology and/or biopsy. Particulars and procedures are given in table1. NACT was given in 4 patients with unresectable tumors Figure1 and in 1 referred with a positive residual cut.
PLADO combination - cisplatin (PLA) (80mg/m 2/ iv) and doxorubicin (DO) (30 mg/m 2/24 hours iv continuous infusion was given in 3 cases; and continuous iv infusion- cisplatin (90 mg/m 2) and iv push- vincristine (1.5mg/m 2) and 5-FU(5-Flurouracil- 600 mg/m 2) in 2 patients.
After confirming good response to chemotherapy by CT Scan Figure2 the patients were operated. Intra Operative Ultra Sound (IOUS) was used to confirm the extent of the tumor and visualize intrahepatic vasculature. Liver was split by Harmonic scalpel and/or Cavitron Ultrasonic Surgical Aspirator (CUSA). Pringles maneuver was used in 2 cases, with clamp time of 15 minutes, followed by release for 5 minutes. Prophylactic antibiotics were given. Blood and blood products were used when required.
Follow up was with clinical examination, AFP estimations, and abdominal sonography every 3 months for first 2 years and then every 6 months for next 3 years.
Results
All five were male, aged 4 to 60 months (median age at diagnosis 18 months). All presented with a palpable lump in abdomen, history of recurrent fever in two and no-weight gain in three children. None had jaundice or palpable lymphadenopathy or ascites. Anemia was present in two (6 to 11.7g/dL). Serum alkaline phosphatase levels were elevated at presentation (mean 320 mU/ml). Rest of the LFT was normal. All patients were non-reactive for Hepatitis B Surface antigen, Hepatitis C and HIV. The initial AFP levels ranged 300 to 4,25,290 i.u./ml.
In 3 children PLADO regime was given - 6 cycles in two and 4 cycles in one for down staging of tumor. All had R0 resection table1. None had cardiotoxicity, febrile neutropenia, thrombocytopenia or mucositis. Postoperatively one completed 2 more cycles of PLADO regimen, and the other 2 had no further chemotherapy.
In 2 children vincristine, 5-FU and cisplatin was given. One had an episode of mucositis but recovered with conservative management. There was no other side effect of chemotherapy. Following NACT, R0 resection was carried out table1. After surgery both completed rest of the chemotherapy (total 6 cycles).
There were no intra-operative or postoperative problems in all. Surgery took 180 to 330 min and blood loss 150 to 450 ml. Blood and blood products were given only in 2 patients intra-operatively. Post-operative stay was 7 to 10 days. AFP levels returned to normal after completion of the primary NACT or surgery. All 5 followed for 24-48 months were well and disease free.
Discussion
In HB, levels of AFP are elevated in 90% of patients.[6] Complete resection of tumor results in fall in AFP levels which is normalized within 4-6 weeks. Persistence or secondary increase in AFP levels suggests residual, metastatic or recurrent disease and is useful in follow up. Abdominal CT scan reveals the lesion and vascular involvement essential for complete surgical resection. We used CT angio for preoperative assessment of resectability and Portal Doppler to decide the portal vascular involvement and or thrombosis. Tissue diagnosis (FNAC/biopsy) is recommended to all patients for accurate diagnosis.[1],[6]
SIOPEL-1 used preoperative chemotherapy PLADO 4 courses and 2 more if necessary before surgery using a staging system, PRETEXT (PRE Treatment EXTent of disease), to predict resectability and outcome.[1] SIOPEL-2 study reported favorable results after cisplatin monotherapy and surgery with tumors less than three hepatic sectors without extra hepatic disease; but less satisfactory results in HB involving all four sectors of liver with extrahepatic disease with cisplatin alternating with carboplatin and doxorubicin.[7]
In our series 3 patients received PLADO and 2 patients cisplatin/vincristine/5-Flurouracil before surgery for down staging tumor. Resections (R0 resection) could be successfully carried out in all 5 with no life-threatening toxicities or post surgical morbidity and mortality. All patients are disease free on follow up for 48 months. The newer protocol with cisplatin, vincristine and 5FU is promising without cardiotoxicity, improving resectability.
References
1. Perilongo G, Shafford E, Plaschkes J SIOPEL trials using preoperative chemotherapy in hepatoblastoma. Lancet Oncol. 2000; 1 : 94-100.
2. Pritchard J, Brown J, Shafford E 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 : 3819-3828.
3. Mullerpatan PM, Neve RS, Shah RC, Banavali SD, Jagannath P. The role of chemotherapy and surgery for hepatoblastoma in 49 patients . HPB 2004; 6 (suppl. p6)
4. Choudhury SR, Singh D. Advanced hepatoblastoma: successful liver resection following preoperative chemotherapy. Trop Gastroenterol 2004; 25 : 32-33.
5. Bajpai M, Pal K, Agarwala S, Seth T, Gupta AK. Midterm results with hepatectomy after preoperative chemotherapy in hepatoblastoma. Pediatr Surg Int 2005; 21 : 364-368.
6. Schnater JM, Kohler SE, Lamers WH, von Schweinitz D, Aronson DC. Where do we stand with hepatoblastoma A review. Cancer 2003; 98 : 668-678.
7. Perilongo G, Shafford E, Maibach R et al. Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology-SIOPEL 2. Eur J Cancer 2004; 40 : 411-421.(Udupa KV, Navadgi SM, Mul)