Response to multimodal treatment in advanced neuroblastomas. Factors associated with complete remission induction, and factors associated with prolonged survival.

The influence of patient and treatment variables upon the probabilities of response to chemotherapy in advanced neuroblastomas was investigated in 71 children with stages III-IV disease treated in Denmark between 1965-1980. The therapeutic regimens consisted of various combinations of chemotherapeutic agents with or without surgical excision of the primary tumour and irradiation. Complete response (CR) was achieved by 75% of patients in stage III, and another 17% showed partial response. In stage IV 60% responded, 19% with CR. Relationships between patient and treatment variables and the probability of being alive in CR 22 weeks after initiation of the treatment were examined by logistic regression analysis. The probability of CR was not related to age at diagnosis, the addition of an anthracycline to the chemotherapeutic regimens, or to irradiation. Factors related to the maintenance of CR could not be statistically examined due to the small number of complete responders at 22 weeks. Only age below 2 years seems, however, to have positive impact on the response duration. The influence of patient characteristics was further suggested by the result of secondary treatment attempts. 42% of the patients selected for secondary treatment responded, and 17% achieved CR. 1/25 (4%) had survived disease-free for more than 8 years. Factors related to the duration of survival were subsequently examined in the 71 children using Cox's regression analysis. Only children below 2 years of age at diagnosis had survived for more than 8 years. Resection of the tumour at diagnosis, irradiation and the addition of an anthracycline appear not to influence the length of survival in this patient population.

Signs, symptoms, metastatic spread and metabolic behavior of neuroblastomas treated in Denmark during the period 1943-1980.

The clinical manifestations of 253 neuroblastoma cases in childhood, treated in Denmark from 1943 to 1980, were reviewed. Most striking was the vagueness of symptoms in the majority of patients, only a few of whom exhibited the symptoms strongly suggestive of a neuroblastoma (i.e. the Horner syndrome, the watery diarrhoea syndrome, the dancing eye syndrome). The vagueness of the symptoms might have led to fatal procrastination of the diagnosis. The diagnostic delay has, however, no independent prognostic significance for survival in our patients (p = 0.09). The maximal tumour spread was recorded for all 253 patients, and the distribution of metastases was in accordance with the "soil-seed" hypothesis. The tumour spreads with equal frequency by local growth, by lymphatic vessels to distant lymph nodes, and by blood to bone. Only in widely disseminated tumours are metastases to the lungs, the meninges, the brain, and the reproductive organs seen to occur. Eighty-five percent of the patients, for whom data were available, excreted VMA above the normal value for their age, and 43% excreted Norepinephrine + Epinephrine (N + E) above normal levels. The excretion of both VMA and N + E was significantly correlated to stage, and thus to prognosis. Neither the level of VMA excretion nor the level of N + E had any bearing on the survival when age and stage were adjusted for. Serial VMA and N + E determinations show that patients with normal values for these parameters had significantly better prognosis than patients with elevated values during the first, second, third and fourth trimesters after the initiation of treatment. Increasing values in the individual patient were associated with a poor prognosis. We found no correlation between the initial leucocyte count and survival when age and stage were adjusted for.

Prognostic factors in neuroblastomas treated in Denmark from 1943 to 1980. A statistical estimate of prognosis based on 253 cases.

Multivariate analysis on an unselected patient population consisting of all 253 children treated for neuroblastoma in Denmark during 1943 to 1980 shows that stage, age, and treatment given are independent prognostic variables. Calendar year of diagnosis, sex of the patient, and site of primary tumor were not significant prognostic factors. Further analysis shows that multimodal treatment with surgery, irradiation, and chemotherapy, especially in patients older than 1 year of age with Stage II disease, has influenced the survival significantly. The fact that age at diagnosis and the administration of chemotherapy have independent prognostic significance can be explained by the theory that all neuroblastomas are virtually congenital; therefore, the difference in age at diagnosis largely reflects the difference in growth rates of the tumor. Thus, according to this theory, age may be a measure of the probability of micrometastases in addition to the clinical extent or stage of the disease, as it represents the duration of the disease. Additional chemotherapy may thus have eradicated these micrometastases in the older children, since the age influence on Stage II disease disappeared when multimodal treatment was given in this study. The implications for treatment policy are discussed in view of this theory.

Prognostic value of different staging systems in neuroblastomas and completeness of tumour excision.

Two hundred and fifty three patients were retrospectively assigned to eight different staging systems proposed for neuroblastomas, and the prognostic value of each staging system was evaluated individually. The ability of each system to predict prognosis was compared with the others and the system proposed by Evans et al found to be the best predictor, even better than the recently proposed Tumour-Nodes-Metastases staging system. This is probably due to the fact that factors other than the resectability of the tumour play a major role in the survival of these children. Age was found to have independent prognostic significance whatever staging system was used.

Neuroblastomas treated at the four major child oncologic clinics in Denmark 1943-1980: an evaluation of 180 cases.

One hundred and eighty cases of neuroblastomas from the four child oncology clinics are reviewed. The overall cure rate was 24%. During the 38-year period, there was a significant increase in survival from 0% during the period of 1943-1950 to 32% during the period of 1971-1980. This improved survival rate is most likely a result of adjuvant chemotherapy. Forty percent of the patients appear chronically ill, which reflects the fact that nearly 60% have metastases when they are first seen. In localized disease (stages I-II), the prognosis was favourable (cure rate 69%), while the prognosis for disseminated disease (stage III-IV) was poor (cure rate 5%). A favourable outcome was seen in patients under 1 year (survival rate 46%), and in patients with primary tumours located in the neck or mediastinum (survival rate 48%). When related to stage, however, the survival rates for the former tumours were not significantly better in patients below 1 year or in patients with cervical or thoracic tumours. As is the case in other studies, we found that survival is significantly poorer in males.

Metachromatic leukodystrophy and pseudoarylsulfatase A deficiency in a Danish family.

A child with a diagnosis of late-infantile metachromatic leukodystrophy (MLD), and a normal father with low arylsulfatase A (ASA) activity in leucocytes and cultured fibroblasts is described. The child had a pathologically increased amount of sulfatides in the urine, whereas no sulfatides could be found in the father's urine. Sulfatide-loading of the child's cultured fibroblasts showed an accumulation of sulfatides, whereas the fibroblasts from the father had a marginally decreased sulfatide turnover. It is thus possible to discriminate between these two forms of low ASA activity in this family, and to ensure a correct diagnosis should the amniotic fluid cells show a low ASA activity in future pregnancies.