Penelope Brock

Cisplatin, Doxorubicin, and Delayed Surgery for Childhood Hepatoblastoma: A Successful Approach—Results of the First Prospective Study of the International Society of Pediatric Oncology

PURPOSEnHepatoblastoma (HB) is a rare malignant liver tumor which occurs almost exclusively in childhood. In the 1970s, survival was approximately 20% to 30%. Since the introduction of cisplatin (PLA) and doxorubicin (DO) into the chemotherapy regimens used to treat these patients, the survival rate has improved dramatically. In most recent studies, primary surgery preceded chemotherapy. In this study by the liver group of the International Society of Pediatric Oncology the aim was to improve survival and reduce operative morbidity and mortality by using preoperative chemotherapy.nnnPATIENTS AND METHODSnAfter biopsy and assessment of pretreatment extent of disease all patients were treated with continuous 24-hour intravenous infusion of PLA 80 mg/m(2) followed by DO 60 mg/m(2) over 48 hours (PLADO). After four courses of this chemotherapy, patients were reassessed. Where possible, the primary tumor was resected and treatment completed with two more courses of chemotherapy.nnnRESULTSnOne hundred fifty-four patients were registered in the study, and 138 received preoperative chemotherapy. One hundred thirteen (82%) showed a partial response with tumor shrinkage and serial decrease of serum alpha-fetoprotein levels. One hundred fifteen patients had delayed surgery, and 106 (including six with liver transplants) had complete resection of primary tumor. Five-year event-free survival was 66%, and overall survival was 75%.nnnCONCLUSIONnThis study demonstrates that international collaboration on a large scale is feasible. The toxicity of chemotherapy and morbidity of surgery were acceptable and the overall survival gratifyingly high. We now regard PLADO chemotherapy and delayed surgery to be the best available treatment for children with HB. Other treatment programs should be measured against this standard.

Successful Treatment of Childhood High-Risk Hepatoblastoma With Dose-Intensive Multiagent Chemotherapy and Surgery: Final Results of the SIOPEL-3HR Study

PURPOSEnThe primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma.nnnPATIENTS AND METHODSnHigh risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection.nnnRESULTSnOf the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis.nnnCONCLUSIONnThe applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

Cisplatin versus Cisplatin plus Doxorubicin for Standard-Risk Hepatoblastoma

BACKGROUNDnPreoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter).nnnMETHODSnChildren with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection).nnnRESULTSnBetween June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%).nnnCONCLUSIONSnAs compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)

Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale

PURPOSEnThe platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important.nnnPATIENTS AND METHODSnThis review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection.nnnRESULTSnPlatinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss.nnnCONCLUSIONnCollaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal.

Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: The SIOPEL group experience

AIM OF THE STUDYnTo investigate the characteristics of patients with hepatoblastoma and low serum alpha-fetoprotein (AFP) at diagnosis.nnnPATIENTS AND METHODSnInclusion of all 21 patients accrued onto SIOPEL trials, whose serum AFP was <100ng/ml at diagnosis. Slides of all 15 patients with available histological material were centrally reviewed.nnnRESULTSnMedian age: 10 months. Disease extension at diagnosis: PRETEXT group: II (3 patients), III (10 patients) and IV (8 patients). Extra-hepatic extension: 8 patients. Multifocal tumour: 8 patients. Histology at review: wholly epithelial subtype: 11/15 patients including nine with a small-cell undifferentiated histology.nnnOUTCOMEnonly 9 patients achieved a partial response and 16 died. Median survival: 4.4 months. Two-year overall survival: 24% (confidence interval 10-45%).nnnCONCLUSIONnThis study clearly identifies patients with hepatoblastoma and low serum AFP at diagnosis as a high-risk subgroup with extensive disease at diagnosis, poor response to chemotherapy and a poor outcome.

Partial reversibility of cisplatin nephrotoxicity in children

To evaluate the long-term renal toxicity of cisplatin, 40 children who had been without treatment at least 18 months (range 18 months to 7 years) were observed. In all the children, glomerular filtration rate (GFR) was estimated from the plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid, both at the end of treatment and at a median follow-up of 2 years 6 months after treatment was stopped (range 18 months to 7 years). In 21 children, serum magnesium level was also measured at follow-up. Median age at diagnosis was 15 months (range 13 days to 13 years 8 months), and median cumulative doses of cisplatin was 500 mg/m2 (range 120 to 1860 mg/m2). In 22 of 24 children with an end-of-treatment GFR of less than 80 ml/min per 1.73 m2, the median improvement in GFR at follow-up was 22 ml/min per 1.73 m2 (range 2 to 56 ml/min per 1.73 m2). Hypomagnesemia was found in 6 of 21 children and was independent of GFR. No significant correlation was found between improvement in renal function and total cisplatin dose, age, gender, tumor type, or associated nephrotoxic medication. We conclude that most children have some recovery from cisplatin glomerular toxicity, especially if damage is not severe, but that hypomagnesemia may persist.

Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study

Summary Background The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma. Methods SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1–A3: cisplatin 80 mg/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m2 per day in 24 h on days 1–3 and 22–24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m2 per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389. Findings We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91–100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67–88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65–87) and 3-year overall survival was 83% (73–93). 60 (97%) patients had grade 3–4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients). Interpretation The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding Cancer Research UK and Cancer Research Switzerland/Oncosuisse.

Prognostic stratification for children with hepatoblastoma: The SIOPEL experience

PURPOSEnTo identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient.nnnPATIENTS AND METHODSnBetween 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS).nnnRESULTSnIn 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP ≥ 1.2 × 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 × 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%.nnnCONCLUSIONnPrognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Randomized trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: The European HR-NBL1/SIOPEN study

PURPOSEnTo reduce the incidence of febrile neutropenia during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction. In the High-Risk Neuroblastoma-1 (HR-NBL1) trial, the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) randomly assigned patients to primary prophylactic (PP) versus symptom-triggered granulocyte colony-stimulating factor (GCSF; filgrastim).nnnPATIENTS AND METHODSnFrom May 2002 to November 2005, 239 patients in 16 countries were randomly assigned to receive or not receive PPGCSF. There were 144 boys with a median age of 3.1 years (range, 1 to 17 years) of whom 217 had International Neuroblastoma Staging System (INSS) stage 4 and 22 had stage 2 or 3 MYCN-amplified disease. The prophylactic arm received a single daily dose of 5 microg/kg GCSF, starting after each of the eight COJEC chemotherapy cycles and stopping 24 hours before the next cycle. Chemotherapy was administered every 10 days regardless of hematologic recovery, provided that infection was controlled.nnnRESULTSnThe PPGCSF arm had significantly fewer febrile neutropenic episodes (P = .002), days with fever (P = .004), hospital days (P = .017), and antibiotic days (P = .001). Reported Common Toxicity Criteria (CTC) graded toxicity was also significantly reduced: infections per cycle (P = .002), fever (P < .001), severe leucopenia (P < .001), neutropenia (P < .001), mucositis (P = .002), nausea/vomiting (P = .045), and constipation (P = .008). Severe weight loss was reduced significantly by 50% (P = .013). Protocol compliance with the rapid induction schedule was also significantly better in the PPGCSF arm shown by shorter time to completion (P = .005). PPGCSF did not adversely affect response rates or success of peripheral-blood stem-cell harvest.nnnCONCLUSIONnFollowing these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Hepatoblastoma presenting with lung metastases

The prognosis of children who are affected by hepatoblastoma (HB) that presents with lung metastases has always been considered very poor. In light of the overall improvement in the survival of HB patients since the introduction of cisplatin (CDDP) in the therapeutic armament of this tumor, the question has been raised whether patients with metastatic HB also would benefit from this drug. The purpose of the current study was to address this issue by analyzing the treatment outcome of those patients presenting with metastases who entered into the first HB study on childhood liver tumors conducted by the International Society of Paediatric Oncology (SIOPEL 1).