Stuart E. Siegel

Association of Multiple Copies of the N-myc Oncogene with Rapid Progression of Neuroblastomas

Eighty-nine patients with untreated primary neuroblastomas were studied to determine the relation between the number of copies of the N-myc oncogene and survival without disease progression. Genomic amplification (3 to 300 copies) of N-myc was detected in 2 of 16 tumors in Stage II, 13 of 20 in Stage III, and 19 of 40 in Stage IV; in contrast, 8 Stage I and 5 Stage IV-S tumors all had 1 copy of the gene (P less than 0.01). Analysis of progression-free survival in all patients revealed that amplification of N-myc was associated with the worst prognosis (P less than 0.0001); the estimated progression-free survival at 18 months was 70 per cent, 30 per cent, and 5 per cent for patients whose tumors had 1, 3 to 10, or more than 10 N-myc copies, respectively. Of 16 Stage II tumors, 2 with amplification metastasized, whereas only 1 of 14 without amplification did so (P = 0.03). Stage IV tumors with amplification progressed most rapidly: nine months after diagnosis the estimated progression-free survival was 61 per cent, 47 per cent, and 0 per cent in patients whose tumors had 1, 3 to 10, or more than 10 copies, respectively (P less than 0.0001). These results suggest that genomic amplification of N-myc may have a key role in determining the aggressiveness of neuroblastomas.

Childhood non-Hodgkin's lymphoma. The results of a randomized therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2).

Members of the Childrens Cancer Study Group treated 234 eligible patients in a randomized trial designed to study the relative effectiveness of two therapy programs for the treatment of childhood and adolescent non-Hodgkins lymphoma. Two chemotherapeutic strategies were compared: a 4-drug regimen (COMP) and a 10-drug regimen (modified LSA2-L2). Failure-free survival for all patients was 60 per cent at 24 months. In patients with disseminated disease treatment success was influenced by both the histologic subtype of disease and the therapeutic regimen followed. The 10-drug program was more effective than the 4-drug program in patients with disseminated lymphoblastic disease (two-year failure-free survival rate, 76 vs. 26 per cent, respectively; P = 0.0002), whereas the 4-drug program was more effective than the 10-drug program in those with nonlymphoblastic disease (57 vs. 28 per cent, respectively, P = 0.008). The less toxic, more easily administered 4-drug regimen was as effective as the 10-drug regimen in patients with localized disease (89 vs. 84 per cent, respectively).

Burkitt's and Burkitt‐like lymphoma in children and adolescents: a review of the Children's Cancer Group Experience

Summary. Historically, the survival of children and adolescents with Burkitts and Burkitt‐like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Childrens Cancer Group trials conducted on 470 children with disseminated Burkitts and Burkitt‐like lymphoma. Of the patients studied, the median age was 8 years (0–21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) ≥ 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4‐year event‐free survival (EFS) in patients ≥ 15‐years‐old compared with < 15‐year‐old was 34 ± 7 versus 59 ± 2% (P < 0·05), the 4‐year EFS of M2/M3 compared with M1 BM was 38 ± 5 versus 63 ± 3% (P < 0·001), and the 4‐year EFS with LDH ≥ 500 IU/l compared with LDH < 500 IU/l was 49 ± 3 versus 71 ± 4% (P < 0·001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4‐year EFS 80 ± 6 versus 54 ± 2%, P < 0·001). In summary, the outcome for childhood Burkitts and Burkitt‐like lymphoma has recently improved with the use of short and intensive B‐cell non‐Hodgkins lymphoma‐directed therapy.

Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group

PURPOSE We analyzed the long-term results of a Childrens Cancer Group (CCG) randomized study comparing cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) versus LSA2L2 as treatment for childhood non-Hodgkins lymphoma. The initial results were previously reported (N Engl J Med 308:559, 1983). PATIENTS AND METHODS A total of 429 patients are reported here, 68 with localized disease and 361 with disseminated disease. The distribution of disseminated-disease patients by histologic type was 164 lymphoblastic, 60 large-cell, and 137 undifferentiated lymphomas. Median follow-up duration of surviving patients is 8 years. RESULTS Event-free survival (EFS) of patients with localized disease was 84% at 5 years. No differences were seen between the two treatment regimens. Results for patients with disseminated disease was dependent on histologic subtype: patients with lymphoblastic lymphoma did better when treated with LSA2L2 (5-year EFS of 64% v 35% for COMP); COMP produced better results for patients with undifferentiated lymphoma (5-year EFS of 50% v 29% for LSA2L2). Results for large-cell lymphoma patients were similar (5-year EFS of 52% for COMP v 43% for LSA2L2). Five percent of patients died of treatment-related complications while on therapy (primarily infections). Only four deaths without progression have been observed off-therapy (two from restrictive lung disease, one from an acute asthma attack, one from colon cancer). Patient survival rates after recurrence were poor. CONCLUSION Treatment success can be expected in 84% of pediatric patients with localized non-Hodgkins lymphoma. For patients with disseminated disease, treatment success can be expected in 64% of those with lymphoblastic and 50% of those with undifferentiated or large-cell disease. To date, late adverse events are rare.

Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial.

Between October 1985 and March 1988, Childrens Cancer Study Group institutions entered 95 patients with recurrent brain tumors into a Phase II trial of carboplatin 560 mg/m2 every 4 weeks. Complete or partial responses were observed for one of 19 evaluable children with brainstem glioma, two of 14 with ependymoma, six of 19 with medulloblastoma or central nervous system primitive neuroectodermal tumor (PNET), and none of 15 with high‐grade astrocytoma. of 33 children with medulloblastoma, ependymoma, or central nervous system PNET, five of 12 with no prior cisplatin exposure had responses, and two of 21 with prior cisplatin exposure had responses (P = 0.03). Thirty‐four percent of patients had absolute neutrophil count nadirs less than 500/μl, and 37% had platelet count nadirs less than 25,000/ μl. Sixteen percent had moderate to severe otoxicity, 10% had nausea and vomiting, and none had nephrotoxicity.

Asparaginase antibody and asparaginase activity in children with higher-risk acute lymphoblastic leukemia: Children's Cancer Group Study CCG-1961.

We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early responders (RER) were randomly assigned to standard intensity arms and continued to receive native asparaginase. The other RER patients and all slow early responders received 6 or 10 doses of PEG-asparaginase. Serum samples (n = 3,193) were assayed for determination of asparaginase Ab titers and enzymatic activity. Three hundred ninety of 1,001 patients (39%) had no elevation of Ab among multiple evaluations—that is, were Abnegative (<1.1 over negative control)—and 611 patients (61%) had an elevated Ab titer (>1.1). Among these 611 patients, 447 had no measurable asparaginase activity during therapy. Patients who were Ab-positive but had no clinical allergies continued to receive E. coli asparaginase, the activity of which declined precipitately. No detectable asparaginase activity was found in 81 of 88 Ab-positive patients shortly after asparaginase injections (94% neutralizing Ab). The Ab-positive patients with clinical allergies subsequently were given Erwinase and achieved substantial activity (0.1–0.4 IU/ml). An interim analysis of 280 patients who were followed for 30 months from induction demonstrated that the Ab-positive titers during interim maintenance-1 and in delayed intensification-1 were associated with an increased rate of events. The CCG-1961 treatment schedule was very immunogenic, plausibly due to initially administrated native asparaginase. Anti-asparaginase Ab was associated with undetectable asparaginase activity and may be correlated with adverse outcomes in HR ALL.

Quality Cancer Care for Adolescents and Young Adults: A Position Statement

PURPOSE This consensus-based position statement on behalf of the LIVESTRONG Young Adult Alliance (Alliance) offers recommendations to enhance oncologic care of adolescent and young adult (AYA) patients with cancer. BACKGROUND In 2005 to 2006, the National Cancer Institute and the Lance Armstrong Foundation jointly sponsored the Adolescent and Young Adult Oncology Progress Review Group (PRG). The PRG report included the directive to develop standards of care for AYA patients with cancer and to disseminate these guidelines to the community. To this end, the Alliance convened a meeting of experts (clinicians, researchers, and advocates) in June 2009 and derived this position statement. RESULTS Quality care for AYAs depends on four critical elements: timely detection; efficient processes for diagnosis, initiation of treatment, and promotion of adherence; access to health care professionals who possess knowledge specific to the biomedical and psychosocial needs of this population; and research that will ultimately derive objective criteria for the development of AYA oncology care guidelines. Achieving quality care for AYAs will require assistance with management of disease and treatment effects; cognizance of the unique psychosocial context for AYA growth and development; assessment of and attention to cognitive, psychiatric, and psychosocial issues; facilitated transition to treatment care; and referral to age-appropriate information and support services. CONCLUSION Dissemination of recommendations stated here will raise awareness of the need for AYA-specific care guidelines and assist providers in the delivery of care that is responsive to the distinct needs of AYAs with cancer.

Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia

PURPOSE To evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Childrens Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002. RESULTS The 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% +/- 2.4% v 77% +/- 0.6% (P = .02) and 26 +/- 2.4 v 20 +/- 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesitys hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients > or = 10 years old at diagnosis; in this subset, obesitys adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients 10 years old, obesitys adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity. CONCLUSION Obesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

Prevalence and Correlates of Fatigue in Long-Term Survivors of Childhood Leukemia

PURPOSE To estimate the prevalence of fatigue, identify the factors associated with fatigue, and to explore the relationship between fatigue and quality of life (QOL) in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS One hundred sixty-one ALL survivors diagnosed at Childrens Hospital Los Angeles (Los Angeles, CA) before age 18 years and between January 1, 1975 and December 31, 1995, participated in a structured telephone interview. Participants were aged 18 to 41 years and off treatment for an average of 14 years. Four measures of fatigue, including the Revised-Piper Fatigue Scale, were used to assess fatigue; depression was assessed using the Center for Epidemiological Studies Depression Scale. Multivariate logistic regression models were developed to identify factors associated with fatigue and depression. RESULTS Prevalence of fatigue (30%) fell within the general population normal limits. Fatigue and depression were highly correlated (Pearson r = 0.75). Fatigue was associated with marriage (OR = 0.11; 95% CI, 0.02 to 0.50), having children (OR = 5.80; 95% CI, 1.30 to 25.82), sleep disturbances (OR = 6.15; 95% CI, 2.33 to 16.22), pain (OR = 5.56; 95% CI, 2.13 to 14.48), obesity (OR = 3.80; 95% CI, 1.41 to 10.26), cognitive impairment (OR = 2.56; 95% CI, 1.02 to 6.38), and exercise-induced symptoms (OR = 2.98; 95% CI, 1.11 to 8.02). Four factors associated with fatigue were also associated with depression: sleep disturbances, pain, obesity, and cognitive impairment. Fatigue was inversely related to QOL. CONCLUSION Some survivors of childhood ALL experience fatigue many years after treatment. Fatigued survivors represent a high-risk subgroup as they report more depression and poorer QOL than non-fatigued survivors and their peers.

Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen.

During the period 1976-1981, 3241 children were enrolled on three major studies of acute lymphoblastic leukemia by participating institutions of the Childrens Cancer Study Group. Each study included a different method of central nervous system (CNS) prophylaxis: (1) standard therapy with cranial irradiation, 2400 rads, and intrathecal methotrexate at 12 mg/m2 six times during consolidation (CCG-141); (2) a modification of CCG-141 in which the intrathecal methotrexate was initiated during induction (CCG-141A); and (3) a reduced cranial irradiation dose of 1800 rads with intrathecal methotrexate given at the same frequency as a CCG-141A, with or without maintenance intrathecal methotrexate, but with a dosage regimen derived from CNS volume considerations rather than based on body surface area (CCG-160 series). Strategy 3, a change in the intrathecal methotrexate dosage, has resulted in the lowest incidence of CNS leukemia to date (p less than 0.007). The cumulative 3-yr CNS relapse rate has decreased from 8%-10% to 2%-5% in average-risk patients (p less than 0.02; life table estimate) and from 23%-27% to 6% in high-risk patients (p less than 0.0002; life table estimate), despite a reduction in the cranial irradiation dose from 2400 to 1800 rads. Maintenance intrathecal chemotherapy has had a marginal effect among patients randomized to receive this additional therapy (p = 0.06). The overall outcome has been an increase in the continuous complete remission rate (p = 0.04) but not in the estimated 3-yr continuous hematologic remission or survival rates.