Gerald S. Gilchrist

Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial.

PURPOSE The Berlin-Frankfurt-Munster (BFM) 76/79 trial of acute lymphoblastic leukemia (ALL) in children produced impressive disease-free survival (DFS) rates with a protocol that began with 8 weeks of intensive therapy, followed by 8 weeks of maintenance therapy, and then another 6 weeks of intensive treatment. The current study was conducted to determine the relative contributions of each of these periods of intense therapy on the DFS rates of ALL patients with intermediate presenting features. In addition, due to concerns regarding the toxicity of CNS irradiation, we compared cranial irradiation (CXRT) with intrathecal methotrexate (IT MTX) administered during induction and consolidation to IT MTX during all phases of the treatment program. PATIENTS AND METHODS Between May 1983 and April 1989, more than 1,600 children with ALL and intermediate presenting features, as defined by the Childrens Cancer Group (CCG), were entered into a randomized trial that tested four systemic therapy regimens and two CNS programs. RESULTS The results with a median follow-up of 57 months show that systemic regimens with a delayed intensification (Delint) phase of therapy had a 5-year event-free survival (EFS) rate of 73% compared with the control regimen EFS rate of 61% (p = .006). For children less than 10 years of age, standard three-drug induction and Delint produced a 77% 5-year EFS. IT MTX during all phases of therapy provided CNS protection comparable to the CXRT regimen in children less than 10 years of age. Children 10 years of age or older appear to have a better EFS rate with intensive induction, Delint, and CXRT. CONCLUSION Delint improves the EFS rate of children with ALL and intermediate presenting features. Maintenance IT MTX can be safely substituted for CXRT for presymptomatic CNS therapy in children with intermediate-risk characteristics less than 10 years of age.

Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.

PURPOSE This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.

Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: A report from the Childhood Cancer Survivor Study

Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML).

Outcomes of Treatment of Children and Adolescents With Recurrent Non-Hodgkin’s Lymphoma and Hodgkin’s Disease With Dexamethasone, Etoposide, Cisplatin, Cytarabine, and l-Asparaginase, Maintenance Chemotherapy, and Transplantation: Children’s Cancer Group Study CCG-5912

PURPOSE To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and L-asparaginase (DECAL) for recurrent non-Hodgkins lymphoma (NHL) and Hodgkins disease (HD). PATIENTS AND METHODS Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. RESULTS After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% +/- 9% and 23% +/- 5% in patients with HD and NHL, respectively. Five-year survival was 31% +/- 14% and 30% +/- 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P =.002; survival, P =.011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. CONCLUSION DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.

Hemostasis in cyanotic congenital heart disease

Coagulation studies were performed in 28 children with cyanotic congenital heart disease in an effort to demonstrate intravascular coagulation. Thrombocytopenia and prolonged bleeding time were most common; hypofibrinogenemia, accelerated fibrinolysis, and prolongation of the prothrombin time occurred less frequently. The number of hemostatic defects present in any patient was related to the severity of polycythemia. The pattern of hemostatic abnormalities did not indicate that decompensated intravascular coagulation was the responsible underlying mechanism. Partially compensated intravascular coagulation also did not appear to be responsible, as heparin therapy did not correct the hemostatic defects in one patient, and the half-life of I 125 fibrinogen was normal in another. The presence of preoperative hemostatic defects correlated with the severity of postoperative hemorrhage. Correction of the defects by replacement therapy was effective in the prevention and treatment of excessive bleeding when surgical complications were not present. Incontrovertible evidence of intravascular coagulation seems necessary before heparin therapy can be recommended for the treatment of hemorrhage in patients with cyanotic congenital heart disease.

Familial erythrophagocytic lymphohistiocytosis. report of two cases and clinicopathologic review

An unusual syndrome of hepatosplenomegaly and fever followed by rapid deterioration and death has been described in 38 children from 21 families Pancytopenia, liver dysfunction, and bleeding developed prior to death from hemorrhage, sepsis, or lymphocytic meningitis. This report reviews the literature and adds a set of twins to the reported cases.

Trends and Variability in Survival Among Patients With Osteosarcoma: A 7-Year Update

This report is an update of a 1978 article on osteosarcoma in Mayo Clinic patients. It includes additional follow-up on previously reported cases and incorporates new cases treated since the time of that original study. From 1963 through 1981, 336 patients with classic, previously untreated osteosarcoma received their first definitive treatment at our institution. Survival of these patients was studied in detail. The most significant result was that survival in the 1960s was much worse than that in the 1970s. The first evidence of improvement in survival was noted in 1969; subsequently, further improvement occurred but was not consistent. This finding prevailed with respect to duration of survival to death, survival to detection of metastasis, and survival from occurrence of metastasis to death. On the basis of detailed regression analysis, several variables had independent prognostic value. From these findings, a prognostic score was developed, which was based on the number of the following unfavorable characteristics: age younger than 10 years, male sex, tumor diameter more than 15 cm, cell type osteoblastic or chondroblastic, duration of symptoms 2 months or less, and involvement of the femur or humerus. Patients with five or six of these unfavorable characteristics had a very poor survival; in contrast, patients with only one or two characteristics had a good outcome. Even when these scores were fairly constant, however, the calendar period had a strong influence on survival. Likewise, when treatment was considered and adjustments by score were made, no significant differences could be found between those patients treated by amputation only and those treated by amputation supplemented with chemotherapy or radiotherapy.

A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma.

Thirty-eight patients whose primary extremity or limb girdle osteosarcomas had been completely excised (37 amputations, one limb sparing procedure) were allocated at random to two treatment groups receiving respectively regular follow-up examinations plus a high-dose methotrexate (HDMTX) regimen or regular follow-up without primary adjuvant chemotherapy. Although the vincristine, HDMTX, leucovorin regimen was generally quite tolerable when given at three-week intervals for one year and most of the chemotherapy patients followed the planned HDMTX dose escalations from 3 to 6 to 7.5 g/m2, delayed methotrexate excretion limited dosage escalations in 25%. An estimated 52% of the 38 patients were surviving five years after randomization and an estimated 42% remained continuously relapse-free after five years. No significant differences between the outcomes of the 20 treated and the 18 untreated patients were apparent; however, power to detect differences was low. Furthermore, no significant differences in postmetastasis survival were apparent between the 12 treated and 10 untreated patients who relapsed. Approximately 20% of these failing patients appear to have been salvaged for long-term survival. This pilot study of HDMTX confirms the continuing need for controlled clinical trials in determining the therapeutic value of adjuvant chemotherapy programs for patients with primary osteosarcoma.

The effect of methotrexate on the bioavailability of oral 6-mercaptopurine.

Fourteen children (aged 3 to 14 years) with average‐risk acute lymphoblastic leukemia were studied after an oral dose of 6‐mercaptopurine (6‐MP) (75 mg/m2) administered alone and, on the next day, concurrently with oral methotrexate (20 mg/m2). When 6‐MP was administered alone, both the peak plasma concentration (15 to 150 ng · ml−1) and the AUC (36 to 340 ng ml−1 · hr) were highly variable. Concurrent methotrexate resulted in a 31% increase in the AUC (P < 0.01) and a 26% increase in peak plasma levels (P < 0.05) of 6‐MP. The AUC of methotrexate correlated with the degree of increase in 6‐MP plasma concentrations. These findings are consistent with previous in vitro studies demonstrating that methotrexate is an inhibitor of xanthine oxidase, the enzyme that catabolizes 6‐MP to the inactive metabolite thiouric acid. Although the increases in 6‐MP AUC and peak plasma concentrations resulting from concurrent methotrexate administration were statistically significant, this interaction is probably not clinically significant at standard low oral doses of methotrexate in light of the wide interpatient variability in these pharmacokinetic parameters of 6‐MP.

The Pediatric Subspecialty Workforce: Public Policy and Forces for Change

Policy has not adequately addressed the unique circumstances of pediatric subspecialties, many of which are facing workforce shortages. Pediatric subspecialties, which we define to include all medical and surgical subspecialties, are discrete disciplines that differ significantly from each other and from adult medicine subspecialties. Concerns about a current shortage of pediatric subspecialists overall are driven by indicators ranging from recruitment difficulties to long wait times for appointments. The future supply of pediatric subspecialists and patient access to pediatric subspecialty care will be affected by a number of key factors or forces for change. We discuss 5 of these factors: changing physician and patient demographics; debt load and lifestyle considerations; competition among providers of subspecialty care; equitable reimbursement for subspecialty services; and policy to regulate physician supply. We also identify issues and strategies that medical and specialty societies, pediatric subspecialists, researchers, child advocates, policy makers, and others should consider in the development of subspecialty-specific workforce-policy agendas.