Marleta Reynolds

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

PURPOSE Previous studies demonstrated that chemotherapy with either cisplatin, vincristine, and fluorouracil (regimen A) or cisplatin and continuous infusion doxorubicin (regimen B) improved survival in children with hepatoblastoma. The current trial is a randomized comparison of these two regimens. PATIENTS AND METHODS Patients (N = 182) were enrolled onto study between August 1989 and December 1992. After initial surgery, patients with stage I-unfavorable histology (UH; n = 43), stage II (n = 7), stage III (n = 83), and stage IV (n = 40) hepatoblastoma were randomized to receive regimen A (n = 92) or regimen B (n = 81). Patients with stage I-favorable histology (FH; n = 9) were treated with four cycles of doxorubicin alone. RESULTS There were no events among patients with stage I-FH disease. Five-year event-free survival (EFS) estimates were 57% (SD = 5%) and 69% (SD = 5%) for patients on regimens A and B, respectively (P =.09) with a relative risk of 1.54 (95% confidence interval, 0.93 to 2.5) for regimen A versus B. Toxicities were more frequent on regimen B. Patients with stage I-UH, stage II, stage III, or stage IV disease had 5-year EFS estimates of 91% (SD = 4%), 100%, 64% (SD = 5%), and 25% (SD = 7%), respectively. Outcome was similar for either regimen within disease stages. At postinduction surgery I, patients with stage III or IV disease who were found to be tumor-free had no events; those who had complete resections achieved a 5-year EFS of 83% (SD = 6%); other patients with stage III or IV disease had worse outcome. CONCLUSION Treatment outcome was not significantly different between regimen A and regimen B. Excellent outcome was achieved for patients with stage I-UH and stage II hepatoblastoma and for subsets of patients with stage III disease. New treatment strategies are needed for the majority of patients with advanced-stage hepatoblastoma.

Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study.

PURPOSE To estimate the disease-free survival rate in children with grossly resected hepatoblastoma treated with cisplatin, vincristine, and fluorouracil (CDDP/VCR/FU) and to assess the disease-response rate and disease-free survival (DFS) rate in children with unresectable or metastatic tumors treated with this combination. PATIENTS AND METHODS Sixty assessable patients with hepatoblastoma received therapy with five (stage I and II) to seven (stage III and IV) courses of CDDP (90 mg/m2), day 1, and VCR (1.5 mg/m2), and FU (600 mg/m2), day 3. RESULTS Nineteen of 21 patients with stage I or II disease survive free of disease (actuarial survival, 90% at 5 years). Twenty-four of 31 patients with stage III disease achieved a complete remission (CR) after chemotherapy and surgical excision; actuarial DFS at 4 years is 67%. Only one of eight patients with stage IV disease achieved a remission and survives. CONCLUSION Relatively brief exposure to chemotherapy with CDDP/VCR/FU provided excellent disease control to patients with grossly resected tumors. In patients with initially unresectable disease, this therapy provides a response rate and DFS rate comparable to regimens that contain doxorubicin (DOX).

Fibrolamellar hepatocellular carcinoma in children and adolescents.

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.

Treatment of High-Risk Neuroblastoma With Triple-Tandem High-Dose Therapy and Stem-Cell Rescue: Results of the Chicago Pilot II Study

PURPOSE To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. PATIENTS AND METHODS From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site. RESULTS Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively. CONCLUSION The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.

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/Childrens 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.

Neurogenic Tumors of the Thorax

Neurogenic tumors of the thorax are observed in all age groups, although they are rare in the elderly. They are more likely to be malignant in the child than in the adult. Tumors of the autonomic system are common in children, whereas the nerve sheath tumors are more likely to be found in adults. The malignant lesions are almost always symptomatic and the benign lesions asymptomatic, except in the child, in whom a benign lesion may result in symptoms because of its size relative to the volume of the childs thorax. Intraspinal canal extension, although relatively infrequent, should be sought for in all paravertebral tumors, for a significant percentage of these may be initially asymptomatic. Excision of such an hourglass tumor without foreknowledge of such extension may lead to serious spinal cord complications. Surgical excision of most of these tumors is sufficient except for the malignant lesions, especially in infancy and childhood, for which the addition of postoperative irradiation and chemotherapy may be beneficial. The prognosis after the removal of benign neurogenic tumors of the thorax is excellent. In the infant or child with Stage III or IV neuroblastoma, ganglioneuroblastoma, or an Askin tumor, the prognosis is poor. In the adult with a malignant neurogenic sarcoma or a malignant paraganglioma, the prognosis likewise is grave.

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.

Intestinal bypass of the esophagus

Esophageal replacement by a segment of isoperistaltic ileum with cecum or by transverse or left colon will allow near-normal swallowing for many years. The authors reviewed the course of 59 children who had bypass of their entire esophagus and of four whose distal esophagus was resected and replaced. The follow-up period ranges from 1 to 37 years; in 36 cases, it exceeds 5 years. Thirty children had caustic strictures and 25 had either isolated esophageal atresia or atresia with fistula. Two children with esophageal injury caused by foreign body ingestion and two with congenital strictures also required complete bypass. Four patients required resection and replacement of the distal esophagus only; two had acquired strictures from gastroesophageal reflux, one had varices, and one had a teratoma involving the esophagus. A retrosternal isoperistaltic ileocolic segment is our preference for complete esophageal replacement. Forty-eight patients underwent esophageal reconstruction with this procedure. The esophagus damaged by caustic ingestion was left in place in all patients, without any subsequent problem. The authors have not used the distal esophagus for anastomosis in patients with atresia, because this segment may be abnormal; and, in any case, an isoperistaltic cologastric anastomosis does not reflux. The right or left colon or jejunum was used in the other cases. Three children lost an interposed intestinal segment from necrosis even though the bowel appeared to be well vascularized at the end of the operation. Each patient had successful reconstruction using another type of interposition. An intrathoracic leak occurred in one infant. A cervical anastomotic leak developed in 11 children, and a stricture in 13. Strictures were more common in patients who had caustic burns. Three patients required surgery for adhesive intestinal obstruction. A redundant colon transplant with ulceration, and the herniation of an ileal segment into the pleural cavity with obstruction prompted reoperation in two other patients. There were two deaths early in the series, one of which was secondary to postoperative respiratory arrest. The other death occurred in a child who had a caustic pharyngeal burn and chronic aspiration. All patients were seen in our office recently, or they or their parents were interviewed by phone. All of them are taking all of their nutrition by mouth. Forty-three of the 61 survivors have had no difficulty with swallowing. One required reoperation to enlarge the thoracic inlet. Seventeen other have mild dysphagia that does not require treatment. The patients with esophageal atresia or atresia and fistula consistently have not grown as well as those who required replacement for an acquired condition or injury.

Pediatric Falls from Heights

Injuries resulting from falls from heights still constitute a significant portion of urban trauma. At this pediatric trauma center, 70 children were admitted from 1985 to 1988 after sustaining a fall of 10 feet or greater or at least one story. The mean patient age was 5 years and 68% of the patients were boys. Seventy-eight percent of falls occurred from 2 stories or less and usually took place at or near the home. Most patients sustained a single major injury and all survived. The majority of injuries involved the head or skeleton and residual functional deficits were uncommon. The incidence of falls from heights has remained high in urban areas despite public education and building codes that require window guards and safety rails.

Intensified Platinum Therapy Is an Ineffective Strategy for Improving Outcome in Pediatric Patients With Advanced Hepatoblastoma

PURPOSE The INT-0098 Intergroup Liver Tumor Study demonstrated no statistically significant differences in event-free and overall survival between patients randomized to treatment with either cisplatin + fluorouracil + vincristine (C5V) or cisplatin + doxorubicin. Results from this and other therapeutic trials suggested that cisplatin was the most active agent against hepatoblastoma. To increase the platinum dose-intensity, a novel regimen was developed alternating carboplatin and cisplatin (CC) every 2 weeks. The P9645 study was designed to compare the risk of treatment failure for patients with stage III/IV hepatoblastoma randomized to either C5V or CC. METHODS C5V was given according to INT-0098 and CC consisted of carboplatin at 700 mg/m2 on day 0 (560 mg/m2 after two cycles) followed by cisplatin 100 mg/m2 on day 14. Granulocyte colony-stimulating factor was used after each CC cycle. All patients received four to six cycles of chemotherapy. RESULTS From the time the study was opened until the time that random assignment was halted, 56 patients received CC and 53 patients received C5V. The 1-year event-free survival was 37% for patients receiving CC and 57% for those receiving C5V (P = .017). Patients randomly assigned to CC required more blood product support. As a result of a semiannual review by the Childrens Oncology Group Data and Safety Monitoring Committee, random assignment was discontinued after 3 years of enrollment because the projected improvement in long-term outcome associated with CC was statistically excluded as a possible outcome of this trial. CONCLUSION Intensification of therapy by alternating platinum analogs increased the risk of adverse outcome in children with unresectable or metastatic hepatoblastoma.