[Research approach in the diagnosis and treatment of neuroblastoma].
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Biomedical subjects
Publications and source records attributed to O Hartmann.
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Between February 1979 and May 1986, 165 children were treated with autologous bone marrow transplantation after high-dose chemotherapy without total-body irradiation for a hematologic malignancy or a solid tumor. Nonbacterial nonfungal interstitial pneumonitis was observed in 24 children and was the cause of death in 11 cases. Of the 24 cases of interstitial pneumonitis, 14 were considered to be idiopathic. Cytomegalovirus was the major pathogenic agent detected in the 10 other cases of interstitial pneumonitis (n = 5), followed by Herpes zoster (n = 2), Pneumocystis carinii (n = 1), tumor (n = 1), and adenovirus (n = 1). The only factor found to correlate significantly with the increased rate of interstitial pneumonitis was the use of high-dose 1-3 bis chloroethyl-1 nitrosourea (BCNU) (600 mg/m2), whereas BCNU at a dose of 300 mg/m2 did not affect this rate. These data, when compared with the literature, show a lower incidence of interstitial pneumonitis than in allogeneic transplantations, and an incidence similar to that observed in syngeneic transplantations, although there was no radiation toxicity in this series.
Between January and December 1985, 17 children with advanced neuroblastoma who were greater than 1 year old (16 stage IV, one stage III) were administered cisplatin (CPDD, 200 mg/m2) and etoposide (VP-16, 500 mg/m2) as a pilot study of toxicity and response rates for the European Neuroblastoma Study Group (ENSG). The study was designed to assess toxicity of two courses of treatment, and evaluate response rates after this short therapy. The creatinine clearance declined in seven of 15 patients. No patient experienced clinically significant hearing loss, but formal audiometric assessment of nine children revealed characteristic high tone loss in seven patients. Peripheral neuropathy was not seen. Asymptomatic hypomagnesemia (less than 0.7 microEq/L) was frequent, despite routine supplementation. Asymptomatic electrolyte imbalances occurred frequently, but were generally transient. Myelosuppression was severe, but brief. Seven patients required platelet transfusions and seven were readmitted between courses due to febrile episodes while neutropenic. There were no treatment-related deaths. According to strictly defined criteria, 12 of 17 patients showed a partial response (PR), and extensive marrow evaluation showed complete clearing of disease in six of 15 patients. This high-dose regimen, if carefully supervised, is associated with acceptable toxicity, comparable to that seen when the dose of CPDD is spread over several months. The rapidity and degree of response was encouraging and merits further evaluation.
Seventeen patients received high-dose therapy with autologous bone marrow transplantation (ABMT) when in partial response after induction therapy. There were 11 children and six adults between 3 and 57 years old. Twelve patients were determined to have high-grade lymphoma (ten Burkitt's and two lymphoblastic), and five had intermediate-grade diffuse lymphoma. Ten patients had surgically proven active disease in the abdomen, two had active disease in the bone marrow, and five persistent neurological symptoms. The time interval between diagnosis and ABMT was 2-10 months (median 4 months). Two patients died of progressive disease and two others died while in complete remission (CR) because of toxicity. Thirteen of 17 are still alive and disease free with a median observation time of 2 years. Morbidity was high with 6/17 life threatening reversible complications but overall survival is 75% at 24 months in a group of patients clearly defined as having a very bad prognosis in previous studies.
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Two hundred and thirty-six consecutive courses of high-dose chemotherapy with autologous bone marrow transplantation in children with solid tumors were reviewed in order to assess the incidence, clinical presentation and outcome of veno-occlusive disease (VOD) of the liver. Patients conditioned with total body irradiation were excluded from this study. Eleven patients (4.6%) met the diagnostic criteria for VOD. The clinical course included sudden weight gain, jaundice, hepatomegaly and ascites. Renal dysfunction and refractoriness to platelet transfusions occurred in the most severe forms. Seven patients recovered within 7-29 days of onset and four patients died, all with renal failure and fluid overload. The time of onset appeared to determine two patterns of outcome: mild forms with early onset (before day 11) and more severe forms with onset after day 17. Analysis of pretransplant factors revealed no significant association with an increased risk of VOD. However, all the patients with severe VOD had received a conditioning regimen containing cyclophosphamide which might be involved in the pathogenesis of VOD.
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Among 62 children over 1 year of age at diagnosis who were treated for stage IV neuroblastoma, 33 entered remission after conventional therapy. They received high-dose chemotherapy and in vitro purged bone marrow transplantation as consolidation therapy. Fifteen patients received one course and 18 two courses. At present, 16/33 grafted patients are alive in CR with a median follow-up of 28 months. Toxicity of this regimen was tolerable. Under this treatment, actuarial disease free survival is improved compared with that observed under conventional therapy.
Thanks to the recent progress made concerning the biology of neuroblastoma, we can now define with greater accuracy the progression and prognosis of these tumours. Several biologic profiles distinguish the neuroblastoma at stage IV-S, the prognosis of which is usually good, thus providing it with a true biological identity.
Seventy children (3.7 +/- 3.3 y) with definitely confirmed diagnosis of neuroblastoma had 115 whole body scans carried out 24 h after injection of 3.7 MBq/kg of I-123 mIBG (83 scans) or 0.7 MBq/kg of I-131 mIBG (17 scans) or 0.9 to 4.5 GBq of I-131 mIBG (15 post-therapeutic scans). The scans were interpreted as positive in the presence of any non-physiological uptake area or of any bone uptake of the tracer, even at the level of the metaphyseal complex. For the primary tumour, the sensitivity of mIBG scans was 73%. Ten false negative patients had an overlap of the tumour with the bladder or heart images (4 cases) or with positive metastatic images (6 cases: liver, spine). Three false negative patients had neuroblastomas which did not secrete catecholamines. The specificity of mIBG was 94%. In our opinion, mIBG scans have a complementary role to assess the activity of post-therapeutic remnants. For the detection of hepatic and lymph node metastases, the sensitivity was about 50% and the specificity was 100%. The standard used for the detection of bone marrow metastases was the cytological and histological examination of 10 bone marrow aspirations and one or more biopsies (CHBMS). The sensitivity of mIBG scans was 90% and the specificity 68%. However, reviewing the data from the 16 false positive scans, we found 11 definitely proven bone metastases, 3 biological relapses and 2 cases of delayed abnormal CHBMS supporting the positivity of the mIBG scans, raising the specificity to 100%. Tc-99m diphosphonate bone scans had a sensitivity of 78% and a specificity of 51%. We suggest that positive mIBG scans may save other procedures since our data do not support false positive detection of bone or bone marrow metastases. In contrast, patients with negative mIBG findings should be further explored.
Forty-one patients (pts) presenting with a neuroblastoma underwent 52 MRI to detect bone marrow metastases. Mean age was 4 years. Acquisitions were done with a 1.5 tesla unit. T1 and T2 weighted images were obtained in coronal (legs and pelvis) and sagittal (dorso-lumbar spine) sections. In 13 cases MRI was performed for initial staging, in 30 during the follow-up. 43/52 examinations were evaluable. Out of 24 anatomically proven medullary involvement (19 pts), MRI showed focal abnormal signals in 23 (18 pts): foci hypersignal in T2 weighted images and hyposignal in T1 weighted images compared to the normal bone marrow (BM) and fat tissue. The lesions were more often detected in lower limbs than dorso-lumbar vertebral body or iliac bone. Nineteen examinations were performed in 15 pts with cytologically and histologically normal BM. MRI raised suspicion of BM metastases in 5 pts (7 MRI). Out of those 5 pts, 1 (2 MRI) had BM relapse 9 months later; 1 (2 MRI) had intra cranial relapse 6 months later; 1 (1 MRI) is disease free 1 1/2 year later; the follow-up is too short for 2 remaining pts (2 MRI). MRI's specificity was 88.9% and sensitivity 84.4%.
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Effects of high activities of I 131 meta-iodobenzylguanidine (mIBG) were evaluated in nine children with advanced neuroblastoma. All patients had been previously heavily treated and had either primarily refractory disease or resistant relapse. Twenty-two doses of mIBG labeled with 1.3 to 4 GBq (35-108 mCi) of iodine 131 were administered. Three subjective effects, especially relief of pain, and two objective effects were observed. Transient blood pressure increase was observed once and did not recur after prolongation of the infusion time to 6 hours. A major side effect was bone marrow toxicity, essentially marked by thrombopenia, particularly severe in previously bone-marrow-transplanted patients.
Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.
Among 62 children over 1 year of age at diagnosis, who were treated for stage IV neuroblastoma, 33 entered complete remission (CR) or good partial remission (GPR) after conventional therapy and received high-dose chemotherapy (HDC) with in vitro purged autologous bone marrow transplantation (ABMT) as consolidation therapy. The HDC was a combination of carmustine (BCNU), teniposide (VM-26), and melphalan. Thirty-three patients received one course of this regimen, and 18 received two courses. At present, 16 of the 33 grafted patients are alive in continuous CR, with a median follow-up of 28 months. Toxicity of this regimen was tolerable, principally marked by bone marrow depression and gastrointestinal (GI) tract complications. Four complication-related deaths were observed. Relapse post-ABMT occurred most often in the bone marrow. Under this treatment, actuarial disease-free survival is improved compared with that observed under conventional therapy.
A two-step evaluation system is proposed to analyze the results of therapy for stage IV neuroblastoma in children over 1 year of age. Since most protocols consist of first-line chemotherapy followed by surgery and often high-dose chemotherapy with bone marrow rescue, "response" should assess the effect of chemotherapy alone and "remission" indicate the status after an attempt to remove the primary tumor. A scoring system is proposed for both steps. The comparability of different studies depends on the use of such common criteria to define patient groups and treatment results.
Twenty-five patients with progressive or recurrent neuroblastoma were treated with single-agent ifosfamide. In 2 of 10 relapsing patients, an objective response was observed. If ifosfamide is administered in a dose of 3000 mg/m2 for 2 days every 3 weeks, a response can be expected in 8% of the cases.