Robert J. Wells

Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate

PURPOSE To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall Survival—A Report From the Children's Oncology Group

PURPOSE To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma. PATIENTS AND METHODS Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival. RESULTS In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96). CONCLUSION The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.

Addition of Muramyl Tripeptide to Chemotherapy for Patients with Newly Diagnosed Metastatic Osteosarcoma: a Report from the Children's Oncology Group

The addition of liposomal muramyl tripeptide phosphatidylethanolamine (MTP‐PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP‐PE to chemotherapy for patients with metastatic OS.

Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study.

PURPOSE The objectives of this study were to determine if the addition of etoposide, thioguanine, and dexamethasone to daunorubicin and cytarabine (five-drug regimen) during induction would improve remission induction rates and survival of children with acute myeloid leukemia (AML) when compared with the standard regimen of cytarabine and daunorubicin (7 + 3) and whether allogeneic bone marrow transplantation (BMT) or intensive chemotherapy consolidation with or without maintenance would give a superior outcome. PATIENTS AND METHODS A total of 591 assessable children with AML entered Childrens Cancer Group (CCG) trial 213 between January 1986 and February 1989. The status of patients as of September 1, 1992 forms the basis of this report. The results were compared with previous AML studies. RESULTS The projected survival rate of all patients at 5 years is 39% (event-free survival [EFS] rate, 31%), which is superior to that of the prior CCG study (P = .01). The induction rate was 79% for 7 + 3 and 76% for the five-drug regimen (not significant). Comparisons of BMT to chemotherapy favored BMT, but these differences do not always reach statistical significance (eg, 5-year disease-free survival [DFS] rate, 46% v 38% [P = .06] with donor available and 54% v 37% [P = .002] if treated according to protocol intent). No benefit for maintenance therapy was found and, in some comparisons, it was inferior to discontinuation of therapy (5-year survival rate, 46% v 68%, P < .01). CONCLUSION The 5-year EFS rate of patients with AML is 31% and has improved. The five-drug induction regimen is no better than standard induction, BMT appears superior to chemotherapy, and maintenance therapy was not beneficial.

Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: A report from the Children's Cancer Group

Objectives To describe features of patients with acute myeloid leukemia presenting with extramedullary leukemic tumors (EML). Methods Among 1,832 patients entered on Childrens Cancer Groups chemotherapy trials with acute myeloid leukemia, 199 patients had EML, defined as any leukemic collection outside the bone marrow cavity. Three patient groups were denoted: group 1 (n = 109) with EML involving skin (with or without other sites of EML), group 2 (n = 90) with EML in sites other than skin, and group 3 (n = 1,633) without EML. Results The incidence of EML was 10.9%. Group 1 patients tended to be younger, had higher white blood cell counts, were more often CNS positive, had FAB M4 or M5 subtypes, and possessed more abnormalities of chromosome 11 than group 3 patients. Group 2 patients were younger, more often had the FAB M2 subtype, and had a higher incidence of t(8;21)(q22;q22) abnormality than group 3, but had similar white blood cell counts and incidence of CNS positivity at diagnosis. For group 1 the 5-year event-free survival was 26%, significantly worse than for group 3 at 29%. Event-free survival was better for group 2 patients (5-year estimate 46%), which remained a favorable prognostic factor by multivariate analysis. The authors retrospectively determined whether 118 (59%) of the EML patients received localized radiotherapy to the site of EML: 42 did and 76 did not. There were no differences in estimated event-free survival between patients who did and did not receive radiotherapy. Conclusions Non-skin (group 2) EML appeared to be an independent favorable prognostic factor. Localized radiotherapy to the site of EML at the end of induction chemotherapy did not improve outcome.

Intensity of CNS treatment for pediatric cancer: Prediction of social outcomes in survivors†

To evaluate the association of central nervous system (CNS) treatment intensity and the social functioning of children who have completed treatment for leukemia, lymphoma, and solid tumors outside the CNS. Furthermore, we expected that these associations would be moderated by child age at diagnosis and gender.

Safety and Efficacy of Gemtuzumab Ozogamicin in Combination With Chemotherapy for Pediatric Acute Myeloid Leukemia : A Report From The Children's Oncology Group

PURPOSE While gemtuzumab ozogamicin (GTMZ) is commonly used in the treatment of acute myeloid leukemia (AML) in combination with standard chemotherapy agents, the pediatric maximum-tolerated dose (MTD) of GMTZ in combination with chemotherapy has not been determined. PATIENTS AND METHODS The Childrens Oncology Group AAML00P2 trial sought to define the MTD of GMTZ in combination with cytarabine and mitoxantrone and cytarabine and l-asparaginase chemotherapy regimens. RESULTS The MTD for GMTZ in combination with cytarabine and mitoxantrone was 3 mg/m(2) while the MTD in combination with cytarabine and l-asparaginase was 2 mg/m(2). Toxicities observed in both treatment regimens were typical of those seen in the relapsed AML setting and consisted primarily of infectious complications. The overall remission response rate (mean +/- SE) was 45% +/- 15% and the 1 year event-free survival and overall survival estimates were 38% +/- 14% and 53% +/- 15%, respectively. CONCLUSION This trial determined the pediatric MTD for GMTZ with two commonly used AML chemotherapy combinations. Based on these results, an ongoing phase III trial conducted within the Childrens Oncology Group is evaluating the effect of GMTZ when added to standard AML therapy.

Are experimental treatments for cancer in children superior to established treatments? Observational study of randomised controlled trials by the Children's Oncology Group

Abstract Objectives To assess how often new treatments for childhood cancer assessed in phase III randomised trials are superior or inferior to standard treatments and whether the pattern of successes and failures in new treatments is consistent with uncertainty being the ethical basis for enrolling patients in such trials. Design Observational study. Setting Phase III randomised controlled trials carried out under the aegis of the Childrens Oncology Group between 1955 and 1997, regardless of whether they were published. Main outcome measures Overall survival, event free survival, and treatment related mortality. Results 126 trials were included, involving 152 comparisons and 36 567 patients. The odds ratio for overall survival with experimental treatments was 0.96 (99% confidence interval 0.89 to 1.03), indicating that new treatments are as likely to be inferior as they are to be superior to standard treatments. This result was not affected by publication bias, methodological quality, treatment type, disease, or comparator. Conclusions New treatments in childhood cancer tested in randomised controlled trials are, on average, as likely to be inferior as they are to be superior to standard treatments, confirming that the uncertainty principle has been operating.

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951

PURPOSE To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. PATIENTS AND METHODS Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. RESULTS Mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10%. The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). CONCLUSION Mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.

Postremission therapy for children with acute myeloid leukemia : the children's cancer group experience in the transplant era

We reviewed consolidation therapy results and analyzed postremission outcomes for 1464 children less than 21 years old at diagnosis in five consecutive Childrens Cancer Group acute myeloid leukemia trials between 1979 and 1996. Children in remission were allocated to allogeneic bone marrow transplantation (BMT) (N=373) in first remission, if a matched family donor was available. Remaining children were assigned consolidation chemotherapy (N=688) or autologous purged BMT (N=217), or withdrew from study before assignment, or with unknown data (N=186). Overall and disease-free survival were superior for children assigned allogeneic transplants. High (>50 000/μl) diagnostic white blood cell (WBC) count was prognostic for inferior outcome, but French–American–British (FAB) subtypes were not. Inv(16) is a favorable karyotypic feature for children in first remission and t(8;21) is not. Allogeneic transplantation benefit was evident in most children, including those with high or low diagnostic WBC count, each FAB subtype, and t(8;21), but was not seen in children with inv(16). Therefore, these data suggest reserving matched related donor allogeneic transplantation for children with inv(16) for second remission, but not those with t(8;21).