Journal of Indian Association of Pediatric Surgeons
Journal of Indian Association of Pediatric Surgeons
                                                   Official journal of the Indian Association of Pediatric Surgeons                           
Year : 2022  |  Volume : 27  |  Issue : 3  |  Page : 317--322

Comparison of cisplatin monotherapy and PLADO in the management in children with standard-risk hepatoblastoma in a resource-challenged nation


Sandeep Agarwala1, Vishesh Jain1, Anjan Dhua1, Madur Srinivas1, Prabudh Goel1, Sameer Bakhshi2, Venkateswaran K Iyer3, Rajni Yadav3, Manisha Jana4, Priyanka Naranje4, Veereshwar Bhatnagar1,  
1 Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, BRA-Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
3 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Dr. Vishesh Jain
Department of Paediatric Surgery, All India Institute of Medical Sciences, Room No. 4002, Teaching Block, New Delhi - 110 029
India

Abstract

Background : Recent SIOPEL studies have shown cisplatin monotherapy to be equally effective in management of Standard risk Hepatoblastoma (SRHB)as compared to PLADO. Aims and Objectives: To study the chemotherapy, response and outcomes in children with SRHB. Material and Methods: A retrospective study was conducted and all children with SRHB who presented to us from June 2007 to December 2017 were included. All patients with standard risk hepatoblastoma who had received at least 2 cycles of chemotherapy were included. Data regarding the demographics, PRETEXT stage, chemotherapy, response to chemotherapy and outcomes were recorded. Kaplan Meier survival analysis was performed to calculate 5 year overall survival (OS) and event free survival (EFS). Results: Thirty two children were included in the study. The disease was PRETEXT I in 5 (15.6%), II in 9 (28.1%) and 18 (56.2%). Nineteen children (59.4%) received Cisplatin monotherapy and of these 6 patients (all PREXT III) had poor response and the chemotherapy was upgraded to PLADO. The remaining 13 (40.6%) received upfront PLADO chemotherapy. Only 31 patients could be operated. Tumor recurred in 5 patients, 2 who had upfront PLADO and 3 patients had been upgraded to PLADO. The 5 year OS and EFS was 100% in the monotherapy group (n=13), 92% and 69% in the upfront PLADO group (n=13), and 62% and 22% in the upgraded to PLADO group (n=6). Patients with PRETEXT III disease in whom chemotherapy was upgraded to PLADO had significantly lower survival (p=0.036) compared to those who received upfront PLADO chemotherapy. Conclusion: Two thirds of patients with PRETEXT stage III who received cisplatin monotherapy showed poor response and were upgraded to PLADO chemotherapy. These patients had a significantly poorer outcome compared to the rest of the cohort. PRETEXT stage III standard-risk hepatoblastoma may benefit from PLADO chemotherapy instead of cisplatin monotherapy.



How to cite this article:
Agarwala S, Jain V, Dhua A, Srinivas M, Goel P, Bakhshi S, Iyer VK, Yadav R, Jana M, Naranje P, Bhatnagar V. Comparison of cisplatin monotherapy and PLADO in the management in children with standard-risk hepatoblastoma in a resource-challenged nation.J Indian Assoc Pediatr Surg 2022;27:317-322


How to cite this URL:
Agarwala S, Jain V, Dhua A, Srinivas M, Goel P, Bakhshi S, Iyer VK, Yadav R, Jana M, Naranje P, Bhatnagar V. Comparison of cisplatin monotherapy and PLADO in the management in children with standard-risk hepatoblastoma in a resource-challenged nation. J Indian Assoc Pediatr Surg [serial online] 2022 [cited 2022 Jun 25 ];27:317-322
Available from: https://www.jiaps.com/text.asp?2022/27/3/317/345129


Full Text



 Introduction



Hepatoblastoma is the most common malignant liver tumor with an incidence of 1.5 cases per million children.[1] Hepatoblastoma accounts for 1% of all pediatric malignancies and is the fourth most common intra-abdominal neoplasm after neuroblastoma, Wilms' tumor, and rhabdomyosarcoma.[2] After institution of chemotherapy, the survival of this tumor increased markedly from 30% to 60%–70% by the end of the last century.[3],[4] With improved survival, the need arose to tailor the chemotherapy to patients to achieve better survival with minimal side effects. Hence, a need was felt to identify prognostic factors based on which chemotherapy can be tailored.

SIOPEL-1, was the first prospective international clinical trial on childhood hepatoblastoma and conducted by the Childhood Liver Tumor Strategy Group of the International Society of Pediatric Oncology (SIOPEL).[5] The SIOPEL group further conducted two trials (SIOPEL-2 [pilot] and SIOPEL-3) to treat patients according to risk stratification.[6],[7] Under the SIOPEL-3 trial, patients with standard risk (SR) were randomized to receive less toxic cisplatin monotherapy or cisplatin and doxorubicin (PLADO) combination chemotherapy.[7] The study noted similar rates of complete resection and survival among children with SR hepatoblastoma. However, the efficacy of cisplatin monotherapy has not been demonstrated in a resource-challenged nation where patients often present late with larger tumors. Many of these tumors may be as SR often based on suboptimal cross-sectional imaging. Hence, we conducted this study to retrospectively evaluate the management and outcomes of SR hepatoblastoma managed by us in the resource-challenged settings.

 Materials and Methods



A retrospective study was conducted, and all patients of hepatoblastoma, who had been treated by us from June 2007 to December 2017, were evaluated. All patients with SR hepatoblastoma who had received at least two courses of chemotherapy were included. The study was approved by the Institute Ethics Committee (IEC-104/6.3.2020).

The diagnosis of hepatoblastoma was confirmed by FNAC in earlier part of the study and in atypical cases. Patients of age 6 months to 3 years with suggestive imaging and raised AFP were presumed to have hepatoblastoma and underwent no prechemotherapy biopsy and cytology.[8] Risk stratification into SR and high risk (HR) had been performed according to the SIOPEL-2 study, i.e. PRETEXT I, II, and III without metastases, extrahepatic disease, and portal or hepatic venous involvement.[6] Cisplatin monotherapy and PLADO regimen (cisplatin and doxorubicin) was administered in accordance with the national consensus, which had been adopted from the SIOPEL protocol.[9] A total of six courses were administered, of which four courses were neoadjuvant and the remaining two courses were administered after surgery. The response to chemotherapy was assessed with clinical examination, alpha-fetoprotein (αFP) values, and radiological assessment, which included a contrast-enhanced CT (CECT) scan of the abdomen and chest after every two courses. Surgery was performed after four courses of chemotherapy. Patients showing poor response after two courses of monotherapy were upgraded to receive PLADO subsequently.

Data regarding the demographics, PRETEXT stage, chemotherapy, response to chemotherapy, and outcomes were recorded.

Demographic variables were described using median and range. Qualitative variables were analyzed using the Chi-square test. Kaplan–Meier survival analysis was performed for obtaining the 5-year overall survival (OS) and event-free survival (EFS). Events were defined as disease progression, recurrence, or death. Statistical significance was considered P < 0.05. Statistical analysis was performed using the IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.

 Results



General profile

During the study period, 62 children with hepatoblastoma were enrolled in our oncology clinic. Of these, 30 children (48.4%) were classified as HR and the remaining 32 (51.6%) belonged to the SR group. The later cohort formed our study group. The median age at presentation for the SR patients was 12 months (range: 4–72 months). The male-to-female ratio was 3:1. All patients received neoadjuvant chemotherapy. Before starting chemotherapy, the diagnosis of hepatoblastoma was confirmed on fine-needle aspiration cytology in seven patients. αFP was raised in all children with a median value of 2,61,895 ng/ml (range: 1999–14,49,190 ng/ml). Tumor extension was defined according to PRETEXT system [Table 1].{Table 1}

Chemotherapy

Preoperative chemotherapy was administered to all patients [Figure 1]. Upfront PLADO was administered to 13 (40.6%) children. In four patients, PLADO was administered upfront as the child had received two courses of PLADO elsewhere before being referred to us. In the remaining nine patients, neoadjuvant therapy was started at our institute. The decision to start PLADO upfront had been made due to the presence of a large mass with ambiguous involvement of the portal vein, hepatic veins, or inferior vena cava (IVC). The distribution of the PRETEXT stage among the two groups is shown in [Table 1].{Figure 1}

Of the 19 (59.4%) patients who received cisplatin monotherapy, chemotherapy was upgraded to PLADO in 6 (31.5%) patients [Figure 1]. The reason for upgrading of chemotherapy was poor response after two courses of monotherapy. All six patients had PRETEXT III tumors and had shown poor radiological response or progression with increase in αFP levels in three patients and modest decrease (approximately 30% decrease) in three patients. The tumor histopathology in these six patients revealed mixed (epithelial and mesenchymal) hepatoblastoma. None of the patients with PRETEXT I or II needed upgrading of chemotherapy. The need to upgrade the chemotherapy in PRETEXT III tumors compared to PRETEXT I/II tumors was statistically significant (66% vs. 0; P = 0.003).

Surgery

Anatomic hepatic resection was performed in 31 children. The biopsy was suggestive of hepatoblastoma in thirty children as one child had a completely necrotic tumor. The biopsy was reported as mixed epithelial and mesenchymal in 17 (15 – nonteratoid and 2 – teratoid) and epithelial in the remaining 12 patients (pure fetal in 1 and mixed epithelial in 11). One child abandoned treatment during neoadjuvant chemotherapy and died before surgical intervention. The surgical margins were free in thirty children. The patient with the microscopic positive margin had the tumor that was adherent at the junction of the hepatic vein and IVC. This patient died in the immediate postoperative period.

Follow-up and outcome

The median duration of follow-up of the cohort was 37 months (range: 4–131 months). At the last follow-up, 29 children (90.6%) were alive, of which 28 were disease free while one had progressive local disease. Three children (9.4%) died due to discontinuation of treatment during neoadjuvant chemotherapy (1), postoperative complication (1), and recurrence with progressive disease (1). There were no recurrences in the monotherapy group who did not need any upgraded chemotherapy. There were five recurrences in the patients who received PLADO, either upfront (n = 2) or after upgrade from cisplatin monotherapy (n = 3). Both patients with recurrence, who had received upfront PLADO chemotherapy, were salvaged with irinotecan-based chemotherapy and repeat resection of the recurrent tumor. Both these patients were in disease remission at last follow-up. Of the three recurrences in the patient who had been upgraded to PLADO chemotherapy, only one patient achieved remission with salvage chemotherapy and surgery. One child died and the remaining one had progressive disease. This difference in recurrence rate among patients who had upfront PLADO chemotherapy and those who were upgraded to PLADO chemotherapy was not statistically significant (15% vs. 50%; P = 0.26). All patients who received PLADO had an echocardiography (ECHO) immediately preoperatively and all had normal ejection fraction with no myocardial dyskinesia. Additionally, seven of these patients, who had received PLADO chemotherapy, had an ECHO performed during the later follow-up period. All of these had normal ejection fraction with no myocardial dyskinesia.

Five-year overall survival and event-free survival

The 5-year OS and EFS of the cohort were 89% (95% confidence interval [CI]: 71–96) and 80% (95 CI: 56–90). The 5-year OS and EFS of the three groups are shown in [Figure 2]. The difference in OS between these three groups was not statistically significant (P = 0.078), but the difference in EFS was significant (P = 0.001). The recurrence in the group who did not require upgrading of chemotherapy was 7.6% (2/26) and those who needed the upgrading of chemotherapy was 50% (3/6), which was statistically significant (P = 0.03).{Figure 2}

On comparing the survival outcome in children with PRETEXT III disease who had received upfront PLADO with children who were upgraded to PLADO [Figure 3], it was observed that the 5-year EFS was significantly lower in the latter group (70% vs. 22%; P = 0.036). However, the difference between the 5-year OS was not statistically significant (100% vs. 62%; P = 0.07).{Figure 3}

The 5-year OS for PRETEXT I, II, and III SRHB were 83%, 100%, and 86%, respectively. The 5-year EFS for PRETEXT I, II, and III disease were 83%, 100%, and 54%, respectively.

 Discussion



Hepatoblastoma is an extremely rare tumor in children. The exact incidence of this condition in India is difficult to determine due to the absence of population-based registry of hepatoblastoma. The National Centre for Disease Informatics and Research compiled the hospital-based cancer registry data from eight major hospitals under the National Cancer Registry Programme for 2012–2014. During these 3 years, only 43 patients with hepatoblastoma were seen in these 8 centers and comprised only 0.8%−4.2% of the childhood cancers presenting to the respective institute.[10] Due to these small numbers, there is a lack of data regarding outcomes of chemotherapy in patients with hepatoblastoma from our country.

PLADO chemotherapy has proven efficacy for treating hepatoblastoma and is the most used chemotherapy for treating hepatoblastoma in India.[11] The SIOPEL-3 study concluded that in children with SR hepatoblastoma, cisplatin monotherapy achieved similar resection rates and survival compared to PLADO chemotherapy.[7] Before these recommendations are implemented in management of children in our practice, a deeper insight is needed in the SIOPEL-3 study. The study only mentions the resection rates in the groups, and the resection in the study was achieved by either hepatectomy or liver transplantation. Simultaneously, the liver transplantation rates have increased from 12% to 21% in the SIOPEL-2 and SIOPEL-3 studies, respectively.[12] Therefore, the use of cisplatin monotherapy in the resource-challenged setting like ours can only be justified if the rates of hepatectomy are at par with those achieved with PLADO chemotherapy. The SIOPEL-3 study, however, did not provide data regarding the need for liver transplantation among both the groups. There are no studies on the use of cisplatin monotherapy from India. Few recent studies with the inclusion of patients as late as 2015 or 2016 report the use of PLADO chemotherapy irrespective of risk stratification in all patients.[13],[14]

In the index study, only 32/62 (51%) patients had SR disease. This is in contrast with SIOPEL studies where children with SR disease constitute 70% of the patients.[12] Like our findings, other large studies from India report SR disease in only 40%–50% of the patients.[14],[15] In this study, despite SR disease, 40% (13/32) of children received PLADO chemotherapy. Many patients presented to us with a CECT done elsewhere, which was not optimal in quality and extent. These CECTs often do not have a triple-phase image acquisition. Extremely poor imaging studies were repeated, however, in few cases, the decision was based on suboptimal imaging. Another reason for upfront PLADO chemotherapy in SRHB, could be the initial hesitation and gradual acceptance of cisplatin monotherapy. The acceptance of cisplatin monotherapy has increased with time in our study, with none of the SR diseases receiving PLADO chemotherapy in the later period of the study.

Of the 19 patients who were started on cisplatin monotherapy, chemotherapy was upgraded, to PLADO, in 6 (31.5%) due to the poor response. This contrasts with the SIOPEL-3 study in which 10% of the patients showed poor response in the cisplatin monotherapy group compared to 5% in the PLADO group.[7] The remaining patients showed a partial response, whose definition was unclear in the publication. In our study, upfront PLADO demonstrated a good response in contrast to a recent study which reported that 4/14 patients (28%) of children with SR disease showed progressive disease on PLADO chemotherapy.[14]

The worst outcome in our study was in patients who were started on monotherapy and who, due to a poor response, had been upgraded to PLADO chemotherapy. Disease-free survival was achieved in only 3 patients (50%) in this subset of patients compared to 92.3% and 100% in patients who received upfront PLADO and cisplatin monotherapy alone, respectively. There is a marked difference in the 5-year OS and EFS of this subgroup (62% vs. 22%). This highlights a major limitation in our setting where parents often abandon treatment after recurrence and do not report for follow-up. We also noted that two-thirds of the children with PRETEXT III tumors on cisplatin monotherapy had to be upgraded to PLADO chemotherapy, whereas none of the patients with PRETEXT I or II disease needed upgrading of chemotherapy. This difference was statistically significant, and therefore in a resource-challenged setting, the use of PLADO upfront in SR PRETEXT III tumors may be better option. Another observation in this study is that SR HB patients who do not respond to cisplatin monotherapy, do not respond favorably to PLADO too. These patients may benefit from the use of alternate drugs like irinotecan or a more intensive chemotherapy.

The 5-year OS and EFS of the cohort (n = 32) were 89% and 80%, respectively, which is comparable to the 3-year OS and EFS of 95% and 83% reported in SIOPE – 3.[7] The outcome of PRETEXT I disease was noted to be inferior to PRETEXT II as one patient with PRETEXT I disease abandoned treatment after two courses and died. Ismail et al.[16] also reported a 76% survival in 38 SR patients treated over a period of 20 years compared to 90.6% survival noted in our series. The survival rates reported from India vary from 33% to 100% from various reported series.[17] In our study, the 5-year EFS in children who were upgraded to PLADO was only 22% that was much lower than 69% in the upfront PLADO group. The reason for this difference can be the development of tumor resistance to cisplatin that makes the subsequent administration of PLADO chemotherapy less effective. Another interesting finding was that the 5-year EFS was 100% in the monotherapy group who did not need the upgrading of chemotherapy and was much higher than the upfront PLADO group. The reason can be the selection bias as the larger tumors with doubtful involvement of portal vein or hepatic vein were included in the upfront PLADO group. Hence, the need for a proper triple-phase CECT scan with suitable sections is crucial in treatment planning and proper risk grouping (PRETEXT and VPEFR).

 Conclusion



SR hepatoblastoma has a good outcome with 5-year OS of 89%. Two-thirds of the patients with PRETEXT III tumors who received cisplatin monotherapy showed poor response and were upgraded to PLADO chemotherapy. These patients had a significantly (P = 0.036) poorer outcome compared to the rest of the cohort. This subgroup of patients may benefit from second-line chemotherapy regimen other than PLADO. In a resource-challenged setting, PRETEXT stage III SR hepatoblastoma may benefit from PLADO chemotherapy instead of cisplatin monotherapy. However, due to limited numbers of such cases presenting at a single center, a multicenter study is needed to confirm these findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Mann JR, Kasthuri N, Raafat F, Pincott JR, Parkes SE, Muir KR, et al. Malignant hepatic tumours in children: Incidence, clinical features and aetiology. Paediatr Perinat Epidemiol 1990;4:276-89.
2Clatworthy HW Jr., Schiller M, Grosfeld JL. Primary liver tumors in infancy and childhood. 41 cases variously treated. Arch Surg 1974;109:143-7.
3Douglass EC, Green AA, Wrenn E, Champion J, Shipp M, Pratt CB. Effective cisplatin (DDP) based chemotherapy in the treatment of hepatoblastoma. Med Pediatr Oncol 1985;13:187-90.
4Ortega JA, Krailo MD, Haas JE, King DR, Ablin AR, Quinn JJ, et al. 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.
5Brown J, Perilongo G, Shafford E, Keeling J, Pritchard J, Brock P, et al. Pretreatment prognostic factors for children with hepatoblastoma- results from the International Society of Paediatric Oncology (SIOP) Study SIOPEL 1. Eur J Cancer 2000;36:1418-25.
6Perilongo G, Shafford E, Maibach R, Aronson D, Brugières L, Brock P, 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;40:411-21.
7Perilongo G, Maibach R, Shafford E, Brugieres L, Brock P, Morland B, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 2009;361:1662-70.
8Fuchs J, Rydzynski J, Hecker H, Mildenberger H, Bürger D, Harms D, et al. The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma – A report from the German Cooperative Liver Tumour Studies HB 89 and HB 94. Eur J Pediatr Surg 2002;12:255-61.
9Agarwala S, Gupta A, Bansal D, Vora T, Prasad M, Arora B, et al. Management of hepatoblastoma: ICMR consensus document. Indian J Pediatr 2017;84:456-64.
10Hospital Based Cancer Registry – ncdirindia.org. Available from: https://www.ncdirindia.org/NCRP/ALL_NCRP_REPORTS/HBCR_REPORT_2012_2014/ALL_CONTENT/PDF_Printed_Version/TVM__HBCR_2012_2014.pdf. [Last accessed on 2020 Nov 04].
11Arora RS. Outcomes of hepatoblastoma in the Indian context. Indian Pediatr 2012;49:307-9.
12Aronson DC, Czauderna P, Maibach R, Perilongo G, Morland B. The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. J Indian Assoc Pediatr Surg 2014;19:201-7.
13Shanmugam N, Scott JX, Kumar V, Vij M, Ramachandran P, Narasimhan G, et al. Multidisciplinary management of hepatoblastoma in children: Experience from a developing country. Pediatr Blood Cancer 2017;64. DOI: 10.1002/pbc.26249.
14Sunil BJ, Palaniappan R, Venkitaraman B, Ranganathan R. Surgical resection for hepatoblastoma-updated survival outcomes. J Gastrointest Cancer 2018;49:493-6.
15Qureshi SS, Bhagat M, Kembhavi S, Vora T, Ramadwar M, Talole S. PRETEXT II-III multifocal hepatoblastoma: Significance of resection of satellite lesions irrespective of their disappearance after chemotherapy. Pediatr Surg Int 2015;31:573-9.
16Ismail H, Broniszczak D, Kaliciński P, Dembowska-Bagińska B, Perek D, Teisseyre J, et al. Changing treatment and outcome of children with hepatoblastoma: Analysis of a single center experience over the last 20 years. J Pediatr Surg 2012;47:1331-9.
17Herzog CE, Andrassy RJ, Eftekhari F. Childhood cancers: Hepatoblastoma. Oncologist 2000;5:445-53.