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© 2001 American Society for Clinical Oncology Treatment and Outcome of 83 Children With Intraspinal Neuroblastoma: The Pediatric Oncology Group ExperienceFrom the Department of Pediatrics, Northwestern University and Children’s Memorial Hospital, Chicago, IL; Department of Statistics, University of Florida; and Pediatric Oncology Group Statistical Office, Gainesville, FL. Address reprint requests to Howard M. Katzenstein, MD, Division of Hematology/Oncology, Box 30, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614; email: hmk476{at}northwestern.edu
PURPOSE: To investigate whether the rate of neurologic recovery or the incidence of long-term sequelae differed for children with neuroblastoma (NB) initially treated with chemotherapy versus surgical decompression with laminectomy, we reviewed the Pediatric Oncology Group (POG) experience. PATIENTS AND METHODS: A retrospective review of children diagnosed with intraspinal NB registered on POG NB Biology Protocol 9047 was performed. Survival, neurologic outcome, and orthopedic sequelae were evaluated according to age of the patient at diagnosis, stage of disease, duration and severity of neurologic symptoms, and therapeutic intervention. RESULTS: Between May 1990 and January 1998, 83 children with intraspinal NB were entered onto the study. Five-year survival for this cohort of patients was 71% ± 9%. Forty-three (52%) of the patients had neurologic symptoms at diagnosis. After treatment, six of 15 severely affected patients, who presented with paralysis, completely recovered neurologic function. Two of five patients with moderate deficits, consisting of paresis and bowel/bladder dysfunction, completely recovered neurologic function. Seventeen of 22 assessable children, who had mild symptoms comprised of paresis alone, fully recovered. Seven of 24 assessable patients who had undergone laminectomy developed scoliosis, whereas spinal deformities were only detected in one of 49 assessable patients managed without laminectomy (P = .001). CONCLUSION: The frequency of complete neurologic recovery in children with intraspinal NB inversely correlated with the severity of the presenting neurologic deficits. The rate of neurologic recovery was similar for patients treated with chemotherapy compared to those managed with laminectomy. Fewer orthopedic sequelae were observed in the children managed with chemotherapy than were seen in children managed with laminectomy.
NEUROBLASTOMA (NB) IS the most common extracranial tumor of childhood.1 Approximately 7% to 15% of patients present with paraspinal tumors that extend through vertebral foramina either with or without associated spinal cord compression.2-5 Symptomatic patients may experience paralysis, bowel and bladder dysfunction, pain, weakness, loss of sensation, and gait disturbances.3 Prompt resolution of spinal cord compression may prevent the development of permanent neurologic impairment in these children. Current therapeutic strategies to relieve spinal cord compression include surgical resection either with or without laminectomy, chemotherapy, and radiation therapy.3,6-9 The optimal treatment approach for cord decompression, however, remains unknown. Furthermore, each of these treatment modalities has inherent short- and long-term associated morbidities. Thus, the initial management of children with intraspinal NB is often dependent on the bias of the institutional oncologist and surgeon. To determine whether the rate of neurologic recovery and the incidence of long-term sequelae differed in patients treated with or without surgical decompression and laminectomy, we retrospectively reviewed the Pediatric Oncology Group (POG) experience.
Patients A review of the clinical presentation, therapy, and outcome of all patients with intraspinal NB tumors registered on the POG Biology Protocol 9047 between May 1990 and January 1998 was performed. Individual institutional review boards approved the POG studies, and informed consent was obtained for all patients registered onto the studies. The diagnosis of NB was based either on histologic examination of tumor specimens or on bone marrow infiltrated with NB tumor cells and elevated urinary catecholamine metabolite levels. POG protocol 9047 opened before the development of the revised International Neuroblastoma Staging System (INSS)10; therefore, all patients were staged according to POG criteria.11 For comparative purposes, POG stages A, B, and D are analogous to INSS stages 1, 2a, and 4; POG stage C tumors may be classified as INSS 2b or 3; and POG stage D(S) is similar to INSS 4s. Primary institutions were initially contacted via questionnaire to confirm the diagnosis of an intraspinal NB tumor, stage, and the patient’s age at diagnosis. Additional data were collected on the duration and nature of neurologic symptoms at presentation, the therapeutic intervention used to alleviate spinal cord or nerve root compression and to treat the tumor, the neurologic outcome, the orthopedic sequelae, and the status of disease. Review of both radiographic and surgical reports and clinical summaries was performed when this information was available. Of the 100 patients with intraspinal tumors, seven patients were determined not to have a dumbbell NB and were excluded from analysis. Ten additional patients were excluded because data from the primary institutions were not retrievable for review. Responses were obtained for 83 patients, with missing data collected via telephone contact with the primary treating institution. Clinical, therapeutic, and biologic data from these 83 patients were analyzed to investigate whether treatment correlated with the level of neurologic recovery or the incidence of long-term orthopedic sequelae.
Neurologic and Orthopedic Evaluation
DNA Flow Cytometry and MYCN Analysis
Treatment Infants younger than 1 year of age at diagnosis and older children with stage B disease were eligible for enrollment onto either the POG intermediate-risk NB protocol 8743 or to the successor protocol 9243 as detailed elsewhere.17 Patients with hyperdiploid tumors received treatment with cyclophosphamide in combination with doxorubicin, and patients with diploid tumors were treated with either cisplatin/teniposide or carboplatin/etoposide alternating with etoposide/ifosfamide. Eight infants were treated either on POG protocol 8743 or 9243. Thirty-five additional patients were treated off study with similar chemotherapeutic regimens. Twenty-three children more than 1 year of age with either regional or disseminated disease were typically treated more intensively with multidrug combination therapy including cisplatin, etoposide, cyclophosphamide, vincristine, and doxorubicin.18 Some of these high-risk patients were further consolidated with myeloablative therapy and autologous bone marrow transplantation.19 Information on dexamethasone administration was not accessible for review.
Statistical Methods
Clinical, Therapeutic, and Biologic Characteristics The clinical features of the 83 assessable patients with intraspinal NB and the biologic characteristics of their tumors are listed in Table 1. The age at diagnosis ranged from birth to 13 years and 2 months (median, 10 months). Eight patients (10%) had completely resected tumors without evidence of nonattached node involvement (stage A); 25 patients (30%) had localized disease that was not completely resected (stage B); 28 patients (34%) had regional disease with lymph node metastasis (stage C); 21 patients (25%) had widely disseminated disease (stage D); and one patient (1%) had stage D(S) disease. The primary intraspinal component was located in the thoracic region in 55 (66%) of the 83 patients. Nineteen of the 83 patients have not survived; 12 patients died from tumor progression, three patients died from hemorrhagic complications, and one patient died from infectious complications. One patient died during a delayed tumor resection intraoperatively, another patient died during anesthesia induction for a dental procedure, and one additional patient died from an unrelated cause. The estimated survival rate ± SE of the entire group at 5 years was 71% ± 9% ( Fig 1).
The initial treatment administered to the group of patients is listed in Table 2. Sixty-six (80%) of the patients received up-front chemotherapy. A total of eight patients (10%) received initial radiotherapy. Twenty-seven patients (33%) underwent primary laminectomy, 31 patients (37%) underwent upfront surgical resection without laminectomy, and 25 patients (30%) did not undergo an initial surgical resection.
A total of 43 patients (52%) had neurologic manifestations at presentation that were attributable to their tumor. Neurologic outcome was assessable for 42 of these patients, with one patient not assessable due to an early death. Fifteen of these patients demonstrated severe symptoms, five had symptoms classified as moderate, and 23 had symptoms considered to be mild. Symptoms had been present from 1 to 180 days (median, 10 days). The percentage of patients who completely recovered neurologic function was similar for each therapy or combination of therapies, as listed in Table 3. Treatment modality was also not significantly predictive of neurologic outcome when tested in a multivariate logistic regression model. In addition, none of the characteristics listed in Table 1 (age, stage, site, MYCN, ploidy) were significantly associated with neurologic outcome. Severity of neurologic symptoms at presentation was the only factor found to be significantly associated with neurologic outcome (P = .044), as listed in Table 4. Patients with mild neurologic symptoms were five times more likely to have a complete neurologic recovery than were patients with moderate or severe neurologic symptoms (P = .017).
Neurologic Outcome of Children According to Severity of Symptoms Severe neurologic symptoms. The outcome of the 15 patients with severe neurologic symptoms at diagnosis is listed in Table 5. Six of the 15 children who presented with paralysis completely recovered neurologic function; of these six patients, four recovered after treatment with chemotherapy, including three patients who also received radiotherapy, and two recovered after surgical decompression with laminectomy. Five patients had partial resolution of their symptoms. One of these patients, who had neurologic deficits at the time of birth, was treated with chemotherapy, and the other four children underwent surgical decompression and laminectomy. All four patients who remained paralyzed were initially treated with laminectomy in combination with chemotherapy. The length of time between the development of symptoms and the initiation of therapy in this cohort of severely affected patients was inversely correlated with neurologic recovery. All three patients who had therapy initiated within 1 week of developing neurologic symptoms had significant functional improvement. In contrast, five of the 12 patients who had symptoms for more than 1 week before therapy was initiated had limited response to therapy, and four remained paralyzed.
Moderate neurologic symptoms. The outcome of the five patients with moderate neurologic symptoms at diagnosis is listed in Table 6. Two patients experienced a complete neurologic recovery, one after treatment with chemotherapy without laminectomy and one after surgical decompression with laminectomy. An additional child had partial resolution of symptoms following treatment with chemotherapy. Two patients continued to have bowel and/or bladder dysfunction, despite treatment with laminectomy in combination with chemotherapy. The relationship between the length of symptomatology and the neurologic outcome for moderately affected patients was less clear. Four of the five patients had symptoms for more than 1 week before initiation of treatment, and two of these patients improved after treatment. One additional patient, who was symptomatic for 6 days before the initiation of treatment with chemotherapy, experienced significant neurologic improvement.
Mild neurologic symptoms. The outcome of the 23 patients with mild neurologic symptoms at diagnosis is listed in Table 7. One patient was not assessable due to an early death. Seventeen of the 22 assessable patients had complete recovery of neurologic function. Eight patients recovered after treatment with chemotherapy without laminectomy, and eight patients recovered after laminectomy. One additional patient experienced a complete recovery after treatment with surgical resection alone. Five patients had partial neurologic improvement. One patient developed Horner’s syndrome after a delayed surgical resection. A second patient, who had experienced leg weakness for 6 months, subsequently was noted to have bowel and bladder dysfunction. The length of time between the development of symptoms and the initiation of therapy did not seem to correlate with neurologic recovery in mildly affected patients, as neurologic recovery was observed in patients who had symptoms for as long as 6 months.
Absence of neurologic symptoms. Forty patients did not have neurologic symptoms related to cord compression at presentation. Four of these patients underwent laminectomy. A total of five patients acquired neurologic symptoms after treatment, three developed Horner’s syndrome, one developed paraesthesias, and one child developed paralysis after a delayed surgical resection.
Orthopedic Sequelae of Children With Intraspinal Neuroblastoma
This report highlights the POG experience of 83 children with intraspinal NB managed with or without surgical decompression and laminectomy. The cohort included patients with all stages of disease, and the overall 5-year survival rate was 71% ± 9%. Forty-three (52%) of the patients had cord compression with neurologic deficits. After treatment, 37 (88%) of 42 assessable symptomatic patients experienced some improvement in neurologic function, and 25 patients (60%) completely recovered. Complete neurologic recovery was seen in 13 (68%) of 19 symptomatic children treated with chemotherapy with or without radiotherapy, including four children who presented with paralysis. For those children treated with surgical decompression with laminectomy as part of their initial management, complete neurologic recovery occurred in 11 (50%) of the 22 assessable patients. However, this difference in neurologic recovery rates might be partially explained by the fact that a slightly greater number of patients with mild symptoms did not undergo initial laminectomy. The impact of laminectomy alone was difficult to determine as only five assessable symptomatic patients were treated solely with laminectomy. All other patients who underwent laminectomy received adjuvant chemotherapy either with or without radiation therapy before it was possible to assess the full extent of neurologic recovery resulting from surgical decompression. The incidence of complete neurologic recovery was inversely associated with the severity of symptoms at diagnosis. Only six (40%) of 15 patients with severe symptoms, and two (40%) of five patients with moderate symptoms completely recovered neurologic function. In contrast, complete recovery was seen in 17 (77%) of the 22 assessable children who had mild neurologic symptoms at the time of diagnosis. Previous studies have demonstrated that permanent neurologic dysfunction can be anticipated in as many as 63% of patients with symptomatic intraspinal NB.3,4,21,22 Similar to our results, others have shown that the rate of neurologic recovery is related to the severity of neurologic symptoms at the time of diagnosis,2,23 as well as the duration of neurologic symptoms.2,3,9,24 In addition, a review of published series suggests that the majority of children with intraspinal NB present with prolonged symptomatology more than 1 week in duration.2,3,22-24 Our data suggest that both the severity and duration of neurologic symptoms need to be considered when making therapeutic decisions for children with symptomatic spinal cord compression from intraspinal neuroblastoma. Patients with paralysis for more than 1 week were more likely to experience severe permanent neurologic dysfunction. In contrast, several mildly affected patients in our series had reversible neurologic deficits and demonstrated complete neurologic recovery, irrespective of treatment, even after prolonged symptoms. Importantly, in our series there was often a significant delay between diagnosis and the initiation of therapy which ultimately might affect the outcome of severely affected patients. All 10 patients who had less than 1 week of symptoms before beginning therapy had significant improvement in neurologic function. This emphasizes the importance of the rapid institution of therapy in children with spinal cord compression secondary to intraspinal neuroblastoma. Seven (29%) of the 24 assessable patients who underwent laminectomy in our series developed scoliosis, whereas spinal deformities were diagnosed in only one (2%) of 49 assessable patients who did not undergo laminectomy (P = .001). It is possible that these figures ultimately underrepresent the true incidence of scoliosis in this population and that with additional years of follow-up more patients may develop scoliosis as these children continue to grow and mature. Earlier reports identified spinal deformities in as many as 76% of patients with NB treated with radiation and/or laminectomy.5,6,9,25 Both of these treatment modalities may independently contribute to the development of scoliosis. A recent study by Hoover et al2 demonstrated a 67% incidence of scoliosis in patients who underwent laminectomy compared with a 36% incidence in patients who did not. Almost 20 years ago, Hayes et al7,24 first reported that primary chemotherapy was effective treatment for NB patients with cord compression. Other smaller series have demonstrated similar results.3,26 More recently, a prospective study of patients with intraspinal NB from the French Society of Pediatric Oncology also demonstrated that treatment with up-front chemotherapy resulted in excellent rates of neurologic recovery.23 The reported series largely consist of patients with mild to moderate deficits, and include few patients with paralysis. Our study confirms that chemotherapy is an effective treatment for NB patients with mild and moderate neurologic symptoms related to cord compression. Furthermore, our results indicate that medical management can reverse even severe neurologic deficits, as four patients who presented with paralysis completely recovered neurologic function without undergoing laminectomy. Chemotherapy may be associated with significant sequelae, and five patients in this series died from causes related to intensive chemotherapy administration. However, the moderate-dose chemotherapy used to treat infants with NB and children with intermediate-risk disease is generally well tolerated.17 The response to the medical management of cord compression seen in our series supports the primary medical approach for the initial treatment of children with intraspinal NB recommended in the current low- and intermediate-risk Intergroup Children’s Cancer Study Group and POG clinical protocols. Our additional recommendations for management of these patients would include the following: (1) initial detailed combined evaluation of all children with suspected intraspinal NB by pediatric oncology and neurosurgical services, (2) appropriate surgical approach to obtain sufficient tissue for necessary biologic studies to guide risk-based treatment, and (3) rapid initiation of primary chemotherapy following the initial diagnostic procedure. Laminectomy should be reserved for patients who demonstrate progressive neurologic deterioration after the initiation of chemotherapy. In addition, our data suggest that patients without any neurologic symptoms can be managed initially without laminectomy. The current prospective cooperative group studies will determine the efficacy of medical management for children with neurologic deficits from cord compression. Long-term follow-up from these studies will provide further information regarding the incidence of late effects resulting from this therapeutic approach.
Supported in part by Pediatric Oncology Group grant no. CA29139, the Friends For Steven Neuroblastoma Research Fund, and the Neuroblastoma Children’s Cancer Society. We are extremely grateful for the hard work and diligence of the clinical research associates of our member institutions, in particular Christina Rigby, for data collection and responses to our inquiries.
1. Young JL Jr, Miller RW: Incidence of malignant tumors in U.S. children. J Pediatr 86: 254-258, 1975[Medline] 2. Hoover M, Bowman LC, Crawford SE, et al: Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol 32: 353-359, 1999[Medline] 3. Plantaz D, Hartmann O, Kalifa C, et al: Localized dumbbell neuroblastoma: A study of 25 cases treated between 1982 and 1987 using the same protocol. Med Pediatr Oncol 21: 249-253, 1993[Medline] 4. Traggis DG, Filler RM, Druckman H, et al: Prognosis for children with neuroblastoma presenting with paralysis. J Pediatr Surg 12: 419-425, 1977[Medline]
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King D, Goodman J, Hawk T, et al: Dumbbell neuroblastomas in children. Arch Surg 110: 888-891, 1975 6. Raffel C: Spinal cord compression by epidural tumors in childhood. Neurosurg Clin North Am 3: 925-930, 1992[Medline] 7. Hayes FA, Thompson EI, Hvizdala E, et al: Chemotherapy as an alternative to laminectomy and radiation in the management of epidural tumor. J Pediatr 104: 221-224, 1984[Medline] 8. Ch’ien LT, Kalwinsky DK, Peterson G, et al: Metastatic epidural tumors in children. Med Pediatr Oncol 10: 455-462, 1982[Medline] 9. Gutierrez FA, Oi S, McLone DG: Intraspinal tumors in children: Clinical review, surgical results and follow-up in 51 cases. Concepts Pediatr Neurosurg 4: 291-405, 1983
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Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11: 1466-1477, 1993
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Nitschke R, Smith EI, Shochat S, et al: Localized neuroblastoma treated by surgery: A Pediatric Oncology Group study. J Clin Oncol 6: 1271-1279, 1988 12. Look AT, Hayes FA, Shuster JJ, et al: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 9: 581-591, 1991[Abstract] 13. Look AT, Hayes FA, Nitschke R, et al: Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 311: 231-235, 1984[Abstract]
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Brodeur GM, Seeger RC, Schwab M, et al: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224: 1121-1124, 1984 15. Seeger RC, Brodeur GM, Sather H, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313: 1111-1116, 1985[Abstract] 16. Shapiro DN, Valentine MB, Rowe ST, et al: Detection of N-myc gene amplification by fluorescence in situ hybridization: Diagnostic utility for neuroblastoma. Am J Pathol 142: 1339-1346, 1993[Abstract]
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Bowman LC, Castleberry RP, Cantor A, et al: Genetic staging of unresectable or metastatic neuroblastoma in infants: A Pediatric Oncology Group study. J Natl Cancer Inst 89: 373-380, 1997 18. Strother D, van Hoff J, Rao PV, et al: Event-free survival of children with biologically favourable neuroblastoma based on the degree of initial tumour resection: Results from the Pediatric Oncology Group. Eur J Cancer 33: 2121-2125, 1997
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Pole JG, Casper J, Elfenbein G, et al: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 9: 152-158, 1991 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 21. Punt J, Pritchard J, Pincott JR, et al: Neuroblastoma: A review of 21 cases presenting with spinal cord compression. Cancer 45: 3095-3101, 1980[Medline] 22. Holgersen LO, Santulli TV, Schullinger JN, et al: Neuroblastoma with intraspinal (dumbbell) extension. J Pediatr Surg 18: 406-411, 1983[Medline] 23. Plantaz D, Rubie H, Michon J, et al: The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease. Cancer 78: 311-319, 1996[Medline] 24. Hayes FA, Green AA, O’Connor DM: Chemotherapeutic management of epidural neuroblastoma. Med Pediatr Oncol 17: 6-8, 1989[Medline]
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Mayfield JK, Riseborough EJ, Jaffe N, et al: Spinal deformity in children treated for neuroblastoma. J Bone Joint Surg Am 63: 183-193, 1981 26. Sanderson IR, Pritchard J, Marsh HT: Chemotherapy as the initial treatment of spinal cord compression due to disseminated neuroblastoma. J Neurosurg 70: 688-690, 1989[Medline] Submitted May 31, 2000; accepted October 5, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20° and less than 40°, or 
