Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21.

Hepatoblastoma is a malignant embryonal liver tumor that occurs almost exclusively in infants and very young children. Previous cytogenetic studies of hepatoblastoma have investigated small series or individual cases. This report is on the cytogenetics of a large series of 111 hepatoblastoma specimens, with cytogenetic results consecutively karyotyped over a 12-year period. Abnormal karyotypes were observed in 55 cases (approximately 50% of the total). Numerical aberrations were observed in 41 cases (36% of the total), particularly trisomies of chromosomes 2, 8, and 20. Chromosome losses were less common than chromosome gains. Structural abnormalities were observed in 43 cases (39% of the total). Unbalanced translocations resulting in trisomy 1q and involving breakpoints at 1q12-21 were the most common structural abnormality, observed in 20 tumors (18% of total cases); the corresponding translocated chromosome was highly varied. The previously reported t(1;4) was observed in seven cases. Most tumors with translocations involving 1q12-21 also displayed numerical chromosome aberrations, the most common of which were chromosomal trisomies, whereas tumors with other structural rearrangements had fewer numerical abnormalities.

Preradiation chemotherapy with methotrexate, cisplatin, 5-fluorouracil, and leucovorin for pediatric nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is rare in children, accounting for <1% of all cases. Treatment most commonly includes radiotherapy but long-term side effects of such treatment can produce devastating cosmetic and functional sequelae in children. Chemotherapy may help to decrease the radiotherapy dose and limit the side effects of local therapies. However, little is known regarding the chemosensitivity of NPC tumors in pediatric patients. METHODS: Patients with American Joint Committee on Cancer (AJCC) Stage I/II disease (Stratum 01) received irradiation only. Patients with AJCC Stage III/IV disease (Stratum 02) received 4 courses of preradiation chemotherapy comprising methotrexate (120 mg/m2) on Day 1, with cisplatin (100 mg/m2) 24 hours later, 5-fluorouracil 1000 mg/m2 per day as a continuous infusion for 3 days, and leucovorin 25 mg/m2 every 6 hours for 6 doses. Irradiation was given after chemotherapy and consisted of 50.4 gray (Gy) to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy. RESULTS: One patient was enrolled in Stratum 01 and 16 evaluable patients were enrolled in Stratum 02. The median age of the patients was 13 years and 65% of the patients were black. All patients tested had evidence of Epstein-Barr virus infection. Two-thirds of the patients developed Grade 3-4 mucositis during chemotherapy. The overall response rate to induction chemotherapy was 93.7%. The overall 4-year event-free and overall survival rates (+/- the standard error) were 77%+/-12% and 75%+/-12%, respectively. CONCLUSIONS: The current study demonstrated that childhood NPC was sensitive to chemotherapy and that chemotherapy before irradiation was feasible. Future trials should investigate equivalent efficacy with a reduced radiotherapy dose.

CCND1 polymorphism and age of onset of hepatoblastoma.

Cyclin D1, encoded by the gene CCND1, is a major regulator of the cell cycle transition from G1 phase to S phase. A CCND1 polymorphism (G to A) at codon 242, the boundary of exon 4 and intron 4, affects splicing such that exon 5 is not expressed in the A allele. Since exon 5 is involved in rapid turnover, the variant cyclin D1 corresponding to the A allele may have a longer half-life. A previous study demonstrated that in families with hereditary nonpolyposis colorectal cancer, the age of onset of colorectal cancer varied according to variation at this polymorphic site. We examined this CCND1polymorphism in a series hepatoblastoma, a childhood liver cancer that shares other molecular features with colon cancer. We determined in an analysis of 84 children with hepatoblastoma that the G/A exon 4 polymorphism in CCND1 is correlated with the age of onset of hepatoblastomas. The A/A genotype is associated with an earlier age of onset compared to the G/A or G/G genotype. The median age of patients with the G/G genotype was 22 months, compared to 17 months in patients with the G/A genotype and 11 months for the A/A genotype. These findings suggest that the CCND1 A polymorphism may contribute to tumor development in children with hepatoblastoma.

Myeloperoxidase promotor polymorphism and risk of hepatoblastoma.

Myeloperoxidase (MPO) is a major enzyme found in neutrophils. Oxidation by MPO produces free radicals that demonstrate genotoxic properties. A polymorphism (G to A) within the promotor region of the MPO gene reduces transcription and expression. This polymorphism is associated with a protective effect against some cancers in adults including lung cancer. The objective of our study was to investigate the effect of this MPO polymorphism on the risk of hepatoblastoma, the most common cancer of the liver in childhood. By using PCR-SSCP, we determined the genotype at this polymorphism in 48 cases of Caucasian children with hepatoblastoma and 180 normal controls. Genotypes were confirmed by a second method using Aci I restriction enzyme restriction. We found that A allele was associated with reduced risk of hepatoblastoma of 50% (OR, 0.51; 95%CI, 0.27-0.93) and G/A or A/A genotype reduced the risk by 56% (OR, 0.44; 95%CI, 0.21-0.90). Our data suggest that A allele is a protective factor with regard to the risk of hepatoblastoma, perhaps by altering genotoxic properties of xenobiotic substances which may act as carcinogens.

Development of ZD1839 in colorectal cancer.

Colorectal cancer is one of the most frequent human malignancies. Therapeutic options are mainly limited to chemotherapy with 5-fluorouracil in various schedules or in combination with irinotecan and oxaliplatin; however, novel approaches are also in development. These new agents specifically attack molecular targets involved in tumor biology. One such target is the epidermal growth factor receptor (EGFR), which is highly expressed in many tumors and is associated with a poor prognosis. The EGFR plays a key role in cell proliferation and has been implicated in several processes that mediate cancer progression. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor that has shown extensive preclinical activity and favorable tolerability in advanced clinical trials in a variety of tumors. In colorectal cancer cells, ZD1839 has shown both in vitro and in vivo antitumor activity as monotherapy or in combination with cytotoxic agents such as paclitaxel and irinotecan. Preclinical data have also shown that ZD1839 reverses resistance to irinotecan and enhances its efficacy by improving oral bioavailability. These studies indicate that EGFR inhibition by ZD1839 may have a valuable role in the treatment of colorectal cancer, and clinical studies in patients with colorectal cancer are ongoing.

Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies.

PURPOSE: This dose-escalating study investigated the toxicity, pharmacokinetics, and efficacy of the novel direct-acting antifolate ZD9331, given as a 5-day i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Forty-five patients with refractory solid malignancies received ZD9331, which was escalated from 0.125 mg/m(2)/day. RESULTS: Dose-limiting grade 4 thrombocytopenia occurred in 3 of 6 patients treated at 8 mg/m(2)/day; other drug-related toxicities, across dose levels, included skin and gastrointestinal toxicity, lethargy, and asymptomatic, reversible, elevated transaminases. The maximum plasma concentration and area under the curve increased with dose. Clearance was dose-dependent and predominantly renal. At doses >/=2.4 mg/m(2)/day, plasma 2'-deoxyuridine levels were elevated consistently indicating inhibition of thymidylate synthase. Two patients had a partial response (breast, 1 patient; ovarian, 1 patient), and 10 patients had stable disease. CONCLUSION: The maximum tolerated dose was defined as 6 mg/m(2)/day, and the toxicity profile for this regimen was considered acceptable and manageable. Administration of ZD9331 lead to elevation of 2'-deoxyuridine levels, signifying thymidylate synthase inhibition, and evidence of antitumor activity was observed.

Phase I study of an oral formulation of ZD9331 administered daily for 28 days.

PURPOSE: To define the maximum-tolerated dose and dose-limiting toxicities (DLTs) of an oral formulation of ZD9331, a novel thymidylate synthase inhibitor that is not a substrate for folylpolyglutamate synthase. PATIENTS AND METHODS: Patients had Cancer and Leukemia Group B performance status < or = 2 and refractory solid tumors. Initially, patients received ZD9331 daily for 2 weeks, with the duration of treatment escalated to a maximum of 4 weeks, followed by a 2-week rest period. Once the maximum-tolerated duration of treatment was determined, the dose of ZD9331 was increased until DLT occurred. RESULTS: Fifty-five patients were enrolled at eight dose levels. The DLTs were thrombocytopenia and neutropenia. At 3 mg/d, two of 19 patients developed DLT; one patient had grade 3 thrombocytopenia and grade 4 neutropenia, and the other patient had grade 3 thrombocytopenia only. Anemia was common, with a median hemoglobin nadir of 75% of baseline, before recovery or transfusion. The apparent oral clearance of ZD9931 was 11.6 +/- 6.3 mL/min. Dose-limiting myelosuppression was associated with both an increased 24-hour ZD9931 concentration and blood urea nitrogen. CONCLUSION: The recommended phase II dose on this schedule is 3 mg/d for 4 weeks, followed by a 2-week rest period. ZD9331 seems to have a manageable toxicity profile, although it should be used with caution in patients with renal impairment.

A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor.

PURPOSE: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. EXPERIMENTAL DESIGN: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received > or =3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m(2)/day. RESULTS: Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting > or =7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a > or =50% reduction in CA125 levels. CONCLUSIONS: The maximum tolerated dose of this schedule was 130 mg/m(2). The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.

Fibrolamellar hepatocellular carcinoma in children and adolescents.

BACKGROUND: Children with hepatocellular carcinoma (HCC) were treated on a prospective, randomized trial and were then analyzed to determine whether children with the fibrolamellar (FL) histologic variant of HCC have a more favorable presentation, increased surgical resectability, greater response to therapy, and improved outcome compared with children who have typical HCC. METHODS: Forty-six patients were enrolled on Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group Study 8945/Children's Cancer Group Study 8881) between August 1989 and December 1992. After undergoing initial surgery or biopsy, children with Stage I HCC (n = 8 patients), Stage III HCC (n = 25 patients), and Stage IV HCC (n = 13 patients) were assigned randomly, regardless of histology, to receive treatment either with cisplatin, vincristine, and fluorouracil (n = 20 patients) or with cisplatin and continuous-infusion doxorubicin (n = 26 patients). RESULTS: Ten of 46 patients (22%) had the fibrolamellar variant of HCC (FL-HCC). For the entire cohort, the estimated 5-year event free survival (EFS) rate (+/- standard deviation) was 17% +/- 6%. There was no difference in outcome among patients who were treated with either regimen. The 5-year EFS rate for patients with FL-HCC was no different the rate for patients with typical HCC (30% +/- 15% vs. 14% +/- 6%, respectively; P = 0.18), although the median survival was longer in patients with FL-HCC. There was no difference in the number of patients with advanced-stage disease, the incidence of surgical resectability at diagnosis, or the response to treatment between patients with FL-HCC and patients with typical HCC. CONCLUSIONS: Children with FL-HCC do not have a favorable prognosis and do not respond any differently to current therapeutic regimens than patients with typical HCC. Children with initially resectable HCC have a good prognosis irrespective of histologic subtype, whereas outcomes are poor uniformly for children with advanced-stage disease. The use of novel chemotherapeutic agents and the incorporation of other treatment modalities are indicated to improve the dismal survival of pediatric patients with all histologic variants of advanced-stage HCC.

Treatment of unresectable and metastatic hepatoblastoma: a pediatric oncology group phase II study.

PURPOSE: To estimate the disease-response rate, proportion of patients whose tumors can be made resectable, event-free survival (EFS), and toxicity in children with unresectable or metastatic hepatoblastoma (HB) after sequential treatment with the following: (1) carboplatin (CARBO); (2) CARBO, vincristine, and fluorouracil (CARBO-VCR-5-FU); and (3) high-dose cisplatin and etoposide (HDDP-ETOP). PATIENTS AND METHODS: Thirty-three assessable patients with stage III (n = 22) and stage IV (n = 11) HB were treated sequentially with one course of CARBO (700 mg/m(2)), followed by three courses of CARBO (700 mg/m(2)), day 0; 5-FU (1,000 mg/m(2)/d), by continuous infusion days 0 to 2; and VCR (1.5 mg/m(2)), days 0, 7, and 14. After that therapy, patients whose tumors were resectable underwent surgery and then received two additional courses of CARBO-VCR-5-FU. Children whose tumors remained unresectable after CARBO-VCR-5-FU or who demonstrated no response or progressive disease during this therapy received two courses of HDDP (40 mg/m(2)/d), days 1 to 5; and ETOP (100 mg/m(2)/d), days 2 to 4. RESULTS: Five-year EFS estimates were 59% +/- 11% for stage III disease (n = 22) and 27% +/- 16% for stage IV disease (n = 11), respectively (P =.037). Twenty-seven (82%) of 33 patients had at least a partial response to chemotherapy; 18 (55%) of 33 responded to CARBO; 24 (80%) of 30 responded to CARBO and CARBO-VCR-5-FU; and nine (75%) of 12 responded to HDDP-ETOP. Surgical resection was achieved in 19 (58%) of 33 patients, including 15 (68%) of 22 stage III patients and four (36%) of 11 stage IV patients. Five-year EFS for patients whose tumors were completely resected was 79% +/- 10%. CONCLUSION: Patients treated sequentially with CARBO, CARBO-VCR-5-FU, and HDDP-ETOP had response rates and EFS comparable to other therapeutic regimens. This regimen is effective in treating localized, unresectable HB and potentially has less toxicity than other regimens. Novel approaches are needed for patients with metastatic disease.

Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study.

PURPOSE: To determine surgical resectability, event-free survival (EFS), and toxicity in children with hepatocellular carcinoma (HCC) randomized to treatment with either cisplatin (CDDP), vincristine, and fluorouracil (regimen A) or CDDP and continuous-infusion doxorubicin (regimen B). PATIENTS AND METHODS: Forty-six patients were enrolled onto Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group (POG) 8945/Children's Cancer Group (CCG) 8881). After initial surgery or biopsy, children with stage I (n = 8), stage III (n = 25), and stage IV (n = 13) HCC were randomly assigned to receive regimen A (n = 20) or regimen B (n = 26). RESULTS: For the entire cohort, the 5-year EFS estimate was 19% (SD = 6%). Patients with stage I, III, and IV had 5-year EFS estimates of 88% (SD = 12%), 8% (SD = 5%), and 0%, respectively. Five-year EFS estimates were 20% (SD = 9%) and 19% (SD = 8%) for patients on regimens A and B, respectively (P =.78), with a relative risk of 1.2 (95% confidence interval, 0.60 to 2.3) for regimen B when compared with regimen A. Outcome was similar for either regimen within disease stages. Events occurred before postinduction surgery I in 18 (47%) of 38 patients with stage III or IV disease, and tumor resection was possible in two (10%) of the remaining 20 children with advanced-stage disease after chemotherapy. CONCLUSION: Children with initially resectable HCC have a good prognosis and may benefit from the use of adjuvant chemotherapy. Outcome was uniformly poor for children with advanced-stage disease treated with either regimen. New therapeutic strategies are needed for the treatment of advanced-stage pediatric HCC.