Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate ('Orange') in children with advanced non-lymphoblastic non-Hodgkin's lymphoma: a children's cancer group report.

Despite prolonged therapy (18 months), children with advanced non-lymphoblastic, non-Hodgkin's lymphoma (NHL) treated on previous Children's Cancer Group (CCG) trials achieved less than a 60% 5-year event-free survival (EFS). In this study we piloted a shorter but more intensive protocol ('Orange') to determine the feasibility, safety, and efficacy of this alternative treatment approach. Thirty-nine children received a CHOP-based induction, etoposide/ifosfamide consolidation, DECAL (dexamethasone, etoposide, cisplatin, cytosine arabinoside (Ara-C) and L-asparaginase) intensification, and either one or two similar but less intense maintenance courses. Patients were stratified to standard-risk (5 months) vs high-risk (7 months) treatment. High risk was defined as either bone marrow disease, CNS disease, mediastinal mass > or = one-third thoracic diameter at T5 and/or LDH > or =2 times institutional upper limits of normal. All other patients were considered to be standard risk. Results were compared with the previous CCG NHL study (CCG-503). Sixteen and 23 patients were considered standard- vs. high-risk, respectively. The 5-year EFS and overall survival (OS) were 77 +/- 7% and 80 +/- 7%, respectively. The 5-year EFS and OS were significantly better in the standard- vs. high-risk subgroups (100% vs. 61 +/- 11%) (P < 0.003) and (100% vs. 65 +/- 11%) (P < 0.01), respectively. Lactate dehydrogenase (LDH) > or =2 x normal (NL) was associated with significantly poorer outcomes (LDH > or =2 x NL vs. <2 x NL) (5-year EFS: 55 +/- 12% vs. 100%) (P < 0.0004). This CCG hybrid regimen, 'Orange', of short and more intensive therapy resulted in a significant improvement in outcomes compared with the previous CCG trial of more prolonged but less intense therapy. This regimen that deletes high-dose methotrexate, if confirmed in a larger trial, could be considered as an alternative treatment approach in children without high tumor burdens (LDH <2 x NL) and Murphy stage III disease.

Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors.

PURPOSE: The ACE Inhibitor After Anthracycline (AAA) study is a randomized, double-blind, controlled clinical trial comparing enalapril with placebo to determine whether treatment can slow the progression of cardiac decline in patients who screen positive for anthracycline cardiotoxicity. METHODS: The primary outcome measure is the rate of decline, over time, in maximal cardiac index (in liters per minute per meters squared) at peak exercise; the secondary outcome measure is the rate of increase in left ventricular end systolic wall stress (in grams per centimeters squared). Patients >2 years off therapy and <4 years from diagnosis, aged 8 years and older, were eligible if they had received anthracyclines and had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: A total of 135 patients were randomized to enalapril or placebo. Baseline characteristics were similar across treatment groups. CONCLUSIONS: The AAA study will provide important information concerning the efficacy of using angiotensin-converting enzyme inhibitors to offset the effects of late anthracycline cardiotoxicity.

A Phase II clinical trial of idarubicin administered to children with relapsed brain tumors.

BACKGROUND: Idarubicin (IDR), an anthracycline that is a derivative of daunorubicin, was synthesized in an attempt to find new analogs of daunorubicin with an improved spectrum of activity and diminished acute or chronic toxicity. Because of the favorable pharmacokinetic profile of IDR (with the persistence of its active metabolite [idarubicinol], the penetration of idarubicinol into the cerebrospinal fluid, and the lipophilicity of IDR/idarubicinol compared with other anthracyclines), its more favorable therapeutic index regarding cardiotoxicity in animals, and its potential for oral administration, a Phase II trial of IDR in children with relapsed brain tumors was undertaken. METHODS: Patients received IDR at a dose of 5 mg/m2/day x 3 days by intravenous bolus, followed by granulocyte-colony stimulating factor (G-CSF) at a dose of 5 microg/kg/day, starting on Day 7 of each cycle and continuing for at least 7 days, until the absolute neutrophil count was > or =10,000/mm3. RESULTS: Three of 19 patients with high grade astrocytoma achieved a partial response, 1 of 20 patients with medulloblastoma had a complete response, and 0 of 13 patients with ependymoma and 0 of 13 patients with brainstem tumors had responses. In nine other brain tumor patients there were no responses. The most significant toxicity was myelosuppression. CONCLUSIONS: IDR, given at a dose of 5 mg/m2/day x 3 days, is not sufficiently active against relapsed medulloblastoma, ependymoma, or brain stem tumors to warrant further study of this agent in a Phase III setting. The response rate for patients with relapsed high grade astrocytoma was 15% (95% confidence interval, 3.3-40%).

Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: a report from the Children's Cancer Group.

The outcome of children with acute lymphoblastic leukemia (ALL) and bone marrow relapse has been unsatisfactory largely because of failure to prevent subsequent leukemia relapses. Ninety-six patients were enrolled and received vincristine, prednisone, L-asparaginase, and an anthracycline as reinduction therapy. Ninety-two patients were randomized to receive either daunomycin (DNR) or idarubicin (IDR). After achievement of second complete remission (CR2), maintenance chemotherapy included the same anthracycline, IDR or DNR, high-dose cytarabine, and escalating-dose methotrexate. Compared to DNR (45 mg/m2/week x 3), IDR (12.5 mg/m2/week x 3) was associated with prolonged myelosuppression and more frequent serious infections. Halfway through the study, the dose of IDR was reduced to 10 mg/m2. Overall, second remission was achieved in 71% of patients. Reinduction rate was similar for IDR and DNR. Reasons for induction failure differed; none of 15, 1 of 5, and 5 of 7 reinduction failures were due to infection for DNR, IDR (10 mg/m2), and IDR (12.5 mg/m2), respectively. Two-year event-free survival (EFS) was better among patients who received IDR (12.5 mg/m2) (27 +/- 18%) compared to DNR (10 +/- 8%, P = 0.05) and IDR (10 mg/m2) (6 +/- 12%, P = 0.02). However, after 3 years of follow-up, late events in the high-dose IDR group result in a similar EFS to the lower-dose IDR and DNR groups. In conclusion, IDR is an effective agent in childhood ALL. When used weekly at 12.5 mg/m2 during induction, the EFS outcome during the first 2 years of treatment appears better than lower-dose IDR or DNR (45 mg/m2), although this difference was not sustained at longer periods of follow-up. Increased hematopoietic toxicity seen at this dose might be reduced through the use of supportive measures, such as hematopoietins and intestinal decontamination.

Cardiac tamponade in the pediatric oncology population: treatment by percutaneous catheter drainage.

PURPOSE: The treatment of pericardial effusion resulting in cardiac tamponade has undergone an evolution in recent years, with the use of less invasive drainage methods in selected cases. To determine optimal therapy for pediatric oncology patients with pericardial effusion and tamponade, the authors reviewed their institutional experience with percutaneous catheter drainage. METHODS: Patient records and operative reports were reviewed, and nine patients were identified who met clinical and echocardiographic criteria of cardiac tamponade and were treated with percutaneous pericardial catheter drainage. RESULTS: The median age at time of diagnosis was 14 years (range, 5 months to 19 years), and the male:female ratio was 7:3. Underlying malignancies included acute myeloblastic leukemia in three, acute lymphoblastic leukemia in one, and Hodgkin's disease, B-cell lymphoma, medulloblastoma, desmoplastic small round cell tumor, and rhabdomyosarcoma in one each. EIght patients (89%) were receiving granulocyte colony-stimulating factor (GCSF) during the period when tamponade developed. All patients had a large or moderate-to-large pericardial effusion and right ventricular collapse with hemodynamic compromise on echocardiography, and two patients (22%) also had pericardial thickening. In nine patients, percutaneous catheter drainage was performed intraoperatively and under fluoroscopic or echocardiographic guidance. A median of 300 mL (range, 82 to 500 mL) of fluid was removed from the pericardial sac during the initial drainage, and cytology was positive in one (6%). Complete echocardiographic resolution was observed in eight patients (89%); a small posterior component persisted in one patient but was not significant hemodynamically. The catheters remained in place for a median of 5 days (range, 1 to 35 days) while repeat aspirations were performed. Tamponade resolved in all patients, and one died of overwhelming systemic sepsis. The survival period was 10 to 22 months, and tamponade or the drainage procedure did not contribute to death. Four patients remain alive after 4 month to 7 years of follow-up. CONCLUSION: Cardiac tamponade was effectively treated in all patients and did not recur with percutaneous catheter drainage alone. THere was no evidence of pericardial loculation or infection despite pancytopenia being prevalent with underlying illness and chemotherapy. Percutaneous catheter drainage is an effective treatment for pediatric oncology patients with pericardial tamponade. Because of its simplicity in comparison to move invasive techniques, initial treatment with percutaneous drainage should be considered in this patient population.

Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients.

The clinical course of late symptomatic anthracycline cardiomyopathy, and resultant changes of cardiac function, were described in 15 patients. They represented a subset of 300 patients who had cardiac evaluations to identify the prevalence of late cardiotoxicity more than 4 years after anthracycline therapy in these patients. The clinical course and all available cardiac evaluations including electrocardiography, continuous taped electrocardiography, echocardiography, radionuclide cardiac angiography, cardiac catheterization, and endomyocardial biopsy, of the 15 patients were reviewed. The patients had received 285-870 (median 540) mg/M2 of daunorubicin and/or doxorubicin 6-19 (median 12) years prior to the onset of late symptoms. Seven patients also had 2,100-4,000 cGy mediastinal radiotherapy. Five patients had required treatment for cardiac symptoms at the end of chemotherapy but 10 patients had no cardiac problems anteceding their late decompensation. Fractional shortening on echocardiogram at late decompensation was 8-20% (median 17%) and radionuclide left ventricular ejection fraction was 8-59% (median 38%). All were treated with digitalis and diuretics and 13/15 with afterload reduction, with at least transient improvement of symptoms. They were followed for 1-9 (median 3) years after late decompensation. One died of uncontrollable cardiac failure. Another underwent successful cardiac transplantation. Conduction abnormalities and dysrhythmias were present in 14/15 patients and 3 died suddenly. Two more had syncope, one requiring an automatic cardiac defibrillator. Endomyocardial biopsy or autopsy revealed hypertrophy and fibrosis in 10/10 patients. Our patients with early cardiac symptoms improved transiently but decompensated later and patients with no early symptoms developed cardiac symptoms more than 10 years after anthracycline therapy. Therefore, patients who have received anthracyclines should have continued cardiac evaluation.

A prospective randomized double-blind trial of bolus urokinase in the treatment of established Hickman catheter sepsis in children.

BACKGROUND: The incidence of Hickman catheter sepsis is 10% to 40%, with resultant catheter loss in one third of infections. Urokinase causes dissolution of colonized intracatheter fibrin thrombi and may improve salvage. STUDY AIMS: To evaluate the efficacy of 12-hour-interval slow-push urokinase infusion in addition to standard antibiotic therapy in the treatment of catheter sepsis in a pediatric oncology population. METHODS: A two-arm randomized double-blind trial was undertaken, with catheter salvage rate as the end point. Patients with Hickman catheter sepsis were randomized after culture data confirmed the diagnosis. The study drug was administered by a slow intravenous push and given at 12-hour intervals for a total of four doses. The catheters were aspirated after 1 hour. RESULTS AND CONCLUSIONS: The trial was stopped after 41 patients were entered into the study; 18 patients received a placebo, and 23 received the urokinase. In the placebo group, six catheters were lost; in the urokinase group, eight were lost. The rate of bacterial clearance was equivalent for both. After administration of the study drug, each group had three episodes of fever and chills; two of these resulted in hypotension (one in each group). The authors conclude that slow-push urokinase infusion during established Hickman catheter sepsis does not result in improved catheter salvage or bacterial clearance. Slow intravenous push infusions in this setting may provoke hemodynamic instability even after initiation of antibiotics.

Development of a new intensive therapy for acute lymphoblastic leukemia in children at increased risk of early relapse. The Memorial Sloan-Kettering-New York-II protocol.

BACKGROUND: Improved survival of children with acute lymphoblastic leukemia (ALL) has made it more difficult to develop new protocols to further improve results. The authors report the pilot experience with the Memorial Sloan-Kettering-New York-II (MSK-NY-II) protocol, based on the New York regimen with changes made in an attempt to improve efficacy while reducing toxicity. METHODS: Forty-four of 46 consecutive patients were randomized to one of four regimens varying only in the sequence and mode of administration of the drugs during the first 48 hours of therapy, while the kinetics of the disappearance of the leukemic cells from the bone marrow was monitored with bone marrow aspirates and biopsies on days 0, 2, 7, and 14. RESULTS: Thirty-two high-risk and 12 average-risk patients were randomized. The marrow contained less than 25% blasts in 74.4% and 92.9% by day 7 and 14, respectively. Ninety-three percent achieved remission. Regimens beginning with daunorubicin achieved a greater and more rapid reduction in leukemic cells than those starting with cyclophosphamide. Daunorubicin infusion produced a more rapid cytoreduction than daunorubicin bolus. Two of 41 patients who achieved remission relapsed, and there was one death in remission. With a median follow-up of 54+ months, the event-free survival (EFS) rate was 86% +/- 10%. Disease-free survival (DFS) rate at 48 months was 93%. The estimated 4-year EFS rate for the high-risk and average-risk patients were 83 +/- 14% and 93 +/- 10%, respectively. Four of 18 patients given daunorubicin bolus and 0 of 18 patients given daunorubicin infusion who were monitored with serial echocardiograms had significant decrease in cardiac function (P = 0.10). The major toxicity of the therapy was infections, with 35% of patients developing serious infections during induction and consolidation. Half the patients had an episode of bacteremia from the venous catheter during the 2 years of maintenance. CONCLUSIONS: Close monitoring of kinetics of cytoreduction can rapidly distinguish between similar therapies, and the surrogate end-point may reduce the need for the long follow-up periods that may still be required to demonstrate differences in EFS. Continuous infusion of daunorubicin had less cardiotoxicity with faster antileukemic activity than bolus infusion. The MSK-NY-II protocol with a 86% 4-year EFS rate and a 95% DFS rate was a promising new regimen for the treatment of average-risk and high-risk ALL.

Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group.

The anthracycline antibiotics, daunorubicin, doxorubicin, and the newer derivatives, are important components of many antineoplastic chemotherapeutic regimens. Their usefulness is limited by their cardiotoxicity. Sequential monitoring of cardiac function of patients undergoing chemotherapy allows identification of subclinical cardiotoxicity. In many patients monitoring can thus guide the modification of the chemotherapy to minimize cumulative cardiotoxicity, reducing acute and long-term clinical and subclinical sequelae. Such monitoring also aids in the comparison of cardiotoxicity produced by different drugs and different methods and schedules of drug administration. The considerable variability of monitoring regimens between institutions and in the literature has detracted from its usefulness. The Cardiology Committee of the Childrens Cancer Study Group has, therefore, reviewed the field and has formulated recommendations for standardized noninvasive monitoring of children during and immediately after chemotherapy and for the modification of the chemotherapy where indicated.

Determination of the maximum tolerated dose of idarubicin when used in a combination chemotherapy program of reinduction of childhood ALL at first marrow relapse and a preliminary assessment of toxicity compared to that of daunorubicin: a report from the Childrens Cancer Study Group.

An escalating-dose trial of idarubicin, used weekly for 3 doses in combination with vincristine, prednisone, and L-asparaginase (VPLI), to reinduce remission of childhood ALL at first bone marrow relapse was conducted by the Childrens Cancer Study Group (CCSG). The maximum tolerated dose (MTD) of idarubicin, used in the manner, was determined to be 12.5 mg/m2/dose. Twelve of 16 (75%) evaluable patients in first marrow relapse of ALL treated at a dose of 10 or 12.5 mg/m2 entered a second complete remission, compared to 41 of 69 evaluable patients (59%) treated in a comparable way with daunorubicin (30 mg/m2) (VPLD). Prolonged myelosuppression was observed in both groups, but the frequency of documented bacterial sepsis and the duration of required hospitalization were greater among patients treated with idarubicin. No additional toxicity, specifically attributable to idarubicin, was observed at these doses.

Cardiac toxicity 4 to 20 years after completing anthracycline therapy.

OBJECTIVE: --To assess the cardiac status of long-term survivors of pediatric malignancies who received chemotherapy, including anthracyclines. DESIGN AND METHOD: -Patients were evaluated by echocardiogram from 4 to 20 years (median, 7 years) after completion of anthracyclines, with prospective and retrospective analysis. PATIENTS: --The consecutive sample of 201 patients had received a total anthracycline dose of 200 to 1275 mg/m2 (median, 450 mg/m2), and 51 patients had mediastinal radiotherapy. MAIN OUTCOME MEASURES: --The overall incidence and severity of abnormal systolic cardiac function were determined for the entire cohort. Risk factors of total anthracycline dose, mediastinal radiotherapy, age during treatment, and length of follow-up were examined. RESULTS: --Twenty-three percent (47/201) of the cohort had abnormal cardiac function on noninvasive testing at long-term follow-up. Correlation between total cumulative dose, length of follow-up, and mediastinal irradiation with incidence of abnormalities was significant. Fifty-six patients were followed up for 10 years or more (median, 12 years), with a median anthracycline dose of 495 mg/m2. Thirty-eight percent (21/56) of these patients, compared with 18% (26/145) of patients evaluated after less than 10 years, had abnormal findings. Sixty-three percent of patients followed up for 10 years or more after receiving 500 mg/m2 or more of anthracyclines had abnormal findings. Nine of 201 patients had late symptoms, including cardiac failure and dysrhythmia, and three patients died suddenly. Microscopic examination of the myocardium on biopsy and autopsy revealed fibrosis. CONCLUSION: --The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols.

Delayed cardiac toxicity from anthracycline therapy.

Survivors of childhood cancer who received anthracycline treatment have a high incidence of abnormal cardiac function. Cardiac decompensation and death can appear many years after completion of chemotherapy. These survivors require periodic evaluation of cardiac function and rhythm.

Phase I trial of homoharringtonine in children with refractory leukemia.

Continuous infusion of homoharringtonine was administered to 17 children with refractory leukemia. Ten children with acute lymphoblastic leukemia received a total of 18 courses and seven children with acute nonlymphoblastic leukemia had a total of 13 courses. Doses were escalated from 1.65 to 8.5 mg/m2 for 5-10 consecutive days. Side effects included mild nausea and vomiting and transient changes in liver enzymes. Mucositis and diarrhea were more frequently seen at higher dose levels. Grade 3 hypotension and pain were seen at doses of 7 mg/m2 for 10 days. This is considered to be the maximum tolerated dose in this limited phase I trial. None of these previously heavily treated patients achieved a marrow remission.

Phase I and clinical pharmacological study of 4-demethoxydaunorubicin (idarubicin) in children with advanced cancer.

We conducted a phase I and pharmacokinetic study of i.v. idarubicin, a new anthracycline analogue, in 42 evaluable children 1-19 years old. Twenty-seven had leukemia and 15 had various solid tumors. The drug was administered in escalating doses of 10 to 40 mg/m2/course in 3 equal fractions over 3 consecutive days at 14- to 21-day intervals. Myelosuppression and mucositis were the limiting toxicities for short-term administration. Nausea, vomiting, and elevation of liver enzymes and bilirubin were the other toxicities encountered. Peak toxicity occurred 2 weeks after drug administration with median recovery by day 24. All but 4 patients with solid tumors had prior anthracyclines. Mild cardiac function changes without clinical symptoms were observed in 17 of 35 patients measured by serial cardiac evaluations. In addition, there were 4 patients with congestive heart failure. On postmortem examination, 4 patients had changes consistent with anthracycline cardiomyopathy at a prior median total anthracycline dose of 175 mg/m2. The maximum tolerated dose for patients with solid tumors was 15 mg/m2 course in 3 divided doses. Patients with leukemia tolerated 30 mg/m2/course. Six of 15 evaluable patients with acute lymphoblastic leukemia who received greater than or equal to 30 mg/m2 idarubicin achieved a remission (M1 marrow status). The plasma clearance of idarubicin fits a 3-compartment model with a harmonic mean half-life of 2.4 min, 0.6 h, and 11.3 h for alpha, beta, and gamma phases, respectively. Idarubicinol was the only metabolite detected in the plasma and it accumulated during the 3 days of therapy. Idarubicin is similar to daunorubicin in pharmacology and toxicity. While the cardiotoxic dose still must be delineated, the complete remission achieved in multiple relapsed patients with acute lymphoblastic leukemia indicate promising activity in at least that disease.