Denman Hammond

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.

The intergroup rhabdomyosarcoma study-I: a final report

The results of treatment of 686, previously untreated patients younger than 21 years with rhabdomyosarcoma or undifferentiated sarcoma, who were entered on Intergroup Rhabdomyosarcoma Study‐I (IRS‐I) were analyzed after a minimum potential follow‐up time of 7 years. Patients in Clinical Group I (localized disease, completely resected) were randomized to receive either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC + radiation. At 5 years, approximately 80% of patients given either treatment were still disease‐free and there was no significant difference between treatments in the overall percentages of patients surviving of 93% and 81%, respectively (P = 0.67). Patients in Clinical Group II (regional disease, grossly resected) were randomized to receive either vincristine and dactinomycin (VA) + radiation or VAC + radiation. At 5 years, 72% and 65% of the patients, respectively, were disease‐free and there was no evidence of a difference between treatments (P = 0.46). The overall survival percentage at 5 years was approximately 72% for both treatments. Patients in Clinical Groups III (gross residual disease after surgery) and IV (metastatic disease) were randomized to receive either “pulse” VAC + radiation or “pulse” VAC + Adriamycin (doxorubicin) + radiation. The complete remission (CR) rate was 69% in Clinical Group III and 50% in IV, with no statistically significant difference in CR rates between treatments in either group. Those who achieved a CR had a nearly 60% chance of staying in remission for 5 years in Clinical Group III compared with approximately 30% in Clinical Group IV. The overall survival percentage at 5 years was 52% in Clinical Group III compared to 20% in Clinical Group IV (P < 0.0001). The 5‐year survival percentage for the entire cohort of 686 patients was 55%. Survival after relapse was poor, being 32% at 1 year and 17% at 2 years. The risk of distant metastasis was much greater than the risk of local recurrence within each clinical group, and there was no evidence of differing types of relapses between treatments. Primary tumors of the orbit and genitourinary tract carried the best prognosis, whereas tumors of the retroperitoneum had the worst prognosis. The authors conclude that for the therapeutic regimens evaluated there was no therapeutic advantage to including radiation in the treatment of Clinical Group I disease, or cyclophosphamide given as a daily low‐dose oral regimen in the treatment of Clinical Group II disease or Adriamycin in the treatment of Clinical Groups III and IV diseases.

The intergroup rhabdomyosarcoma study. A preliminary report

Four hundred and twenty‐three children with newly diagnosed rhabdomyosarcoma have been entered to date in the Intergroup Rhabdomyosarcoma Study (IRS), which began in 1972. Patients were classified into Clinical Disease Groups (Stages) I‐IV, based on disease extent and resectability, and treatment regimens were randomly assigned according to group. Two hundred and seventy‐eight of 423 patients are evaluable for this analysis. Thus far, for Group I disease (localized/completely resected), disease control achieved by vincristine, dactinomycin, and cyclophosphamide (VAC) given in combination for 2 years has not been enhanced by the administration of postoperative radiation to the tumor bed. To date, 92% of patients in both irradiated and nonirradiated groups exhibit no evidence of disease, and 92‐96% are still alive, with the median time of follow‐up being 72 weeks. For Group II disease (microscopic residual/nodal involvement), VAC given for 2 years has not been found to be more effective than vincristine plus dactinomycin given for 1 year, both groups also having received postoperative irradiation. Thus far, over 85% of patients on either treatment have no evidence of disease and 90% are still alive. Survival and complete remission durations range from 1+ to 143+ weeks and the median duration of follow‐up is 45 weeks. Chemotherapy as initial treatment has been studied in Group III (localized sarcoma not treated initially by gross total resection) and Group IV (metastases present at diagnosis) patients. They have received either intensive “pulse” VAC or “pulse” VAC plus Adriamycin, and radiation has been administered after 6 weeks. Eighty‐one percent of patients in Group III and 81‐83% in Group IV have responded favorably, with complete regression of disease having been observed in over one‐fourth of patients even before the start of radiation and in approximately one‐half of all the patients after receiving radiation therapy. There is no indication as yet that one treatment regimen is superior to the other. Seventy‐nine percent of patients in Group III are still alive (0+ to 154+ weeks) and 69% remain in continuous response (0+ to 139+ weeks) with the median duration of follow‐up being 41‐44 weeks. Fifty percent of patients in Group IV are still alive (0+ to 127+ weeks) with a median time of follow‐up of 41‐44 weeks. Tumors arising either from genitourinary sites or the extremities have had a higher incidence of lymphatic spread than tumors in all other primary sites of origin.

The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: Results of a randomized trial A report from the Childrens Cancer Study Group

SummaryFifty-eight patients with high-grade astrocytoma were treated by members of the Childrens Cancer Study Group in a prospective randomized trial designed to study the effectiveness of chemotherapy as an adjuvant to standard surgical treatment and radiotherapy. Following surgical therapy, patients were assigned randomly to radiotherapy with or without chemotherapy consisting of chloroethyl-cyclohexyl nitrosourea, vincristine, and prednisone. Treatment with chemotherapy prolonged survival and event-free survival. Five-year event-free survival was 46% for patients in the radiotherapy and chemotherapy group, and 18% for patients in the radiotherapy-alone group. Five-year survival was similarly improved. The differences in outcome due to treatment were statistically significant after correcting for imbalances in important prognostic factors (event-free survival, p = 0.026; survival, p = 0.067). The presence of mitoses or necrosis in the tumor specimen was associated with poorer outcome. Patients whose initial surgery was limited to biopsy, and patients with basal ganglia lesions, also had significantly worse outcome. Chemotherapy administered at the time of recurrence in a small number of patients did not produce any long-term survivors. This study is to our knowledge the only randomized trial to investigate effectiveness of chemotherapy in the treatment of high-grade astrocytoma in children.

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).

Septicemia and meningitis in children splenectomized for hodgkin's disease.

Retrospective evaluation of the occurrence of septicemia and meningitis in 200 children who had staging laparotomy iwth splenectomy for Hodgkins disease revealed 20 episodes occurring in 18 children. Symptoms were usually fulminant; only 10 of these patients survived their episode. Infections occurred eight days to three years after splenectomy. Adolescents, as well as younger children, were affected; half were older than 10 years of age. Leukopenia was not a major factor in onset or survival since the average white-cell count was 12,000 in both survivors and children who died. Pneumonococcus accounted for 50 per cent, and streptococcus for 15 per cent of infections; there was one episode each of Haemophilus influenzae and meningococcus; in 25 per cent, no organism was isolated. Predominance of penicillin-sensitive organisms and high mortality suggest that penicillin prophylaxis and the protection offered by bacterial vaccines should be evaluated in children with Hodgkins disease whose staging laparotomy includes splenectomy.

Tumors of the pineal and suprasellar region: Childrens cancer study group treatment results 1960–1975. A report from childrens cancer study group

Tumors of the pineal and suprasellar region form a rare and interesting group of lesions with germinomas accounting for over 50% of all lesions in this anatomic region. The Brain Tumor Committee of Childrens Cancer Study Group (CCSG) recently surveyed all CCSG member institutions to determine treatment parameters and assess the techniques. A total of 140 patients were seen during the period from 1960 to 1975; 118 patients were evaluable, having adequate treatment records. One hundred and one patients were less than 30 years of age with a 2:1 male predominance. Thirty‐six of the 57 biopsied patients (63%) were found to have germinomas. The survival of patients in the germinoma group (72%) was comparable to that of the patients without biopsy (71%). The overall survival rate for all patients (biopsied and unbiopsied) was 65% with follow‐up times ranging from 2 to 15 years. Nine patients developed spinal cord metastases (8%), two of whom also had simultaneous primary recurrence; none of these patients had received adjunctive spinal irradiation. Cancer 43:698–701, 1979.

Human Leukocyte Interferon for the Treatment of Varicella in Children with Cancer

Human leukocyte interferon was evaluated as a treatment for varicella in a randomized double-blind, placebo-controlled study carried out in two phases. A total of 44 children being treated for cancer were enrolled within 72 hours of the appearance of the exanthem. The mean number of days of new lesion formation was 3.8 +/- 1.89 (+/- S.D.) in the interferon recipients and 5.3 +/- 2.56 in the placebo recipients (P less than 0.05). Eighty-one per cent of the interferon recipients had had no new lesions for 24 hours by Day 7, as compared with 56 per cent of the placebo recipients (P less than 0.025). In the second, higher-dose phase of the study 92 per cent of the interferon recipients had had no new lesions for 24 hours by Day 6, as compared with 45 per cent of the placebo recipients (P less than 0.025). Three of 21 placebo recipients died of progressive varicella. Two of the 23 interferon recipients died two to three weeks after the onset of varicella; viral cultures were negative in one of these patients, and the second had recurrent viremia at the end of the treatment period. Among the survivors, treatment with interferon reduced the number of patients who had life-threatening dissemination (none of 21 vs. three of 18; P = 0.053). We conclude that interferon had an antiviral effect against varicella virus in immunocompromised patients.

Prognostic factors and therapy in acute lymphoblastic leukemia of childhood: CCG‐141: A report from childrens cancer study group

From 1975 to 1978, 880 previously untreated patients with acute lymphoblastic leukemia (ALL) were entered on CCG‐141, a protocol designed to determine the importance of clinical predictors of remission‐induction, duration of complete continuous remission (CCR), and survival, and to determine the benefit of intensive therapy in patients with a poor prognosis. Patients with initial leukocyte count <20 × 109/1 received prednisone (PDN), vincristine (VCR), L‐asparaginase (LASP), cranial irradiation and intrathecal (IT) methotrexate (MTX), and were maintained on 6‐mercaptopurine (6‐MP), MTX, and monthly PDN and VCR. Patients with initial leukocyte count >20 × 109/1 were randomly assigned to this standard regimen or to a more intensive four‐drug regimen (PDN, VCR, LASP, and cyclophosphamide) and a maintenance program consisting of alternating cycles of PDN, VCR, 6‐MP, and MTX (POMP) and PDN, VCR, cytosine arabinoside, and Adriamycin (POCA). The overall rate of complete remission (CR) was 93%. Factors associated with a significantly lower rate of CR were: M3 bone marrow (BM) on day 14, CNS leukemia at diagnosis, L3, morphology, less than 40% PAS‐positive lymphoblasts, low IgG, age >10 years, and L2 morphology. The relapse rate in patients with an initial leukocyte count <20 × 109/1 was significantly lower than in patients with an initial leukocyte count >20 × 109/1. By multivariate analysis, adverse predictors of duration of CCR were leukocyte count >50 × 109/1, Hb >10 g/dl, low IgM, massive splenomegaly, age <1 yr, M3 BM on day 14 and male sex. More intensive maintenance therapy did not prolong the duration of CCR in patients with initial leukocyte count >20 × 109/1. By life table analysis, 80% of patients with good prognostic factors remain in CCR at four years. In patients with poor prognostic factors, the CCR rate at four years is 43%. This study demonstrates the utility of clinical prognostic factors in identifying subsets of patients at low and high probability of treatment failure. Intensive induction and maintenance therapy as used in this protocol did not benefit the poor prognosis group.

RAISED NEURON-SPECIFIC ENOLASE IN SERUM OF CHILDREN WITH METASTATIC NEUROBLASTOMA: A Report from the Children's Cancer Study Group

Serum levels of neuron-specific enolase (NSE) were measured by radioimmunoassay at diagnosis in 122 children with widespread metastatic neuroblastoma (clinical stage IV). 96% of these patients had NSE levels more than three standard deviations above the mean for age-matched normal children. Mean serum NSE was 207 +/- SD257 ng/ml (range 10-1240 ng/ml), whereas that in normal age-matched children was 7.5 +/- 2.1 ng/ml (range 5.4-12.9 ng/ml). Analysis of survival in relation to the level of NSE at diagnosis suggested that serum levels greater than 100 ng/ml were associated with a poor outcome. This relation was highly significant in the subgroup of infants less than 1 year old at diagnosis; all 7 with serum NSE below 100 ng/ml were alive up to 36 months after diagnosis, whereas 7 of 8 with serum NSE above 100 ng/ml died within 12 months of diagnosis. Serum NSE may be a useful disease marker and a prognostic indicator in children with metastatic neuroblastoma.