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Journal of Clinical Oncology, Vol 24, No 10 (April 1), 2006: pp. 1542-1545 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.4602 Treatment Complications in Children Diagnosed With Neuroblastoma During a Screening Program
From the Hôpital Ste-Justine and Montreal Children's Hospital, Montréal; Centre Hospitalier de l'Université Laval, Ste-Foy; Centre Universitaire de Santé de l'Estrie, Sherbrooke, Québec, Canada; AFLAC Cancer Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA Address reprint requests to Stéphane Barrette, 3175 Côte Ste-Catherine, Bureau 3415, Montréal, Québec, Canada, H3T 1C5; e-mail: stephane.barrette{at}umontreal.ca
PURPOSE: The Québec Neuroblastoma Screening Program was put in place to investigate the possibility of decreasing mortality from high-risk neuroblastoma through early screening. We assess treatment complications in the patients diagnosed during this screening program. PATIENTS AND METHODS: A total of 476,603 patients born during the screening period were eligible. Parents of 425,838 children (89%) agreed to participate in the 3-week screening, and 73% agreed to participate in the 6-month screening. Forty-five patients had neuroblastoma. We reviewed the medical and research charts for all patients diagnosed by screening. Follow-up was available from 8 to 13 years after screening. RESULTS: Forty-five patients were diagnosed by screening. All patients were treated according to the Pediatric Oncology Group recommendations of the time. All patients had surgery, and 29 patients received chemotherapy. No patient died from neuroblastoma. Eleven patients suffered complications from treatment. Two patients had life-threatening complications. CONCLUSION: In view of the lack of impact of screening programs on neuroblastoma mortality, evidence that many of the tumors detected through screening can be observed without treatment and the serious complications that may arise from therapy, we do not support neuroblastoma screening programs for children.
Neuroblastoma is the most common solid tumor in young children, affecting one in 7,000 children younger than 5 years of age.1 Prognosis is strongly correlated with the stage of the tumor, age at diagnosis, and biologic markers in the tumor tissue itself. Approximately 90% of neuroblastomas secrete catecholamines, which are readily detectable in the urines of affected children. On the basis of these facts, a number of screening programs were established with the purpose of detecting neuroblastoma at a preclinical stage of the disease. The Québec Neuroblastoma Screening Program was designed to study screening for neuroblastoma first by highly sensitive, semi-quantitative, thin-layer chromatography (TLC) on urine samples. Samples with increased homovanillic acid (HVA) or vanillylmandelic acid (VMA) normalized to creatinine were then tested by highly specific quantitative gas chromatography/mass spectroscopy (GCMS) for confirmation.2,3 The first screen was done at 3 weeks of age and the second screen at 6 months. The screening period was from May 1989 until April 1994. Incidence and mortality from neuroblastoma were compared with that of two comparable cohorts in North America and also with historical controls from the Canadian province of Québec. We showed that the incidence of neuroblastoma during the screening period was doubled,4 while mortality from neuroblastoma was not reduced.5 We now report the complications of therapy in children diagnosed by screening.
A total of 476,603 infants born in the Province of Québec during the screening period were eligible. Information regarding the study was distributed to the parents at the time of a child's birth. Parents were asked to send urine-saturated, air-dried filter papers to the screening center at both study time points (ie, 3 weeks and 6 months) for TLC for detection of increased HVA or VMA. Posting of the filter papers was considered to indicate passive consent to participate. Parents of children with positive results on both TLC and GCMS were asked for a second sample for confirmation by GCMS assay. Written informed consent was obtained for assessment of possible neuroblastoma in all patients with confirmed elevation of urinary HVA-VMA. Parents of 425,838 children (89%) voluntarily agreed to participate in the 3-week screening, and 73% complied with participation in the 6-month screening. Of the 1,175 positive GCMS screening samples, 84 were positive on the confirmation test. All patients with possible neuroblastoma were referred to one of the four pediatric teaching hospitals in the Province of Québec for uniform assessment, staging, treatment, and follow-up. Patients with negative assessment, including history, physical examination, chest x-ray, abdominal ultrasound or abdominal computed tomography scan, if older than 6 months, and repeat negative urine samples for 6 months were contacted every 3 months until 5 years of age and considered false-positive if neuroblastoma did not develop over the period of observation. Of the 84 patients, 39 were false-positive and 45 had neuroblastoma. We reviewed the medical and research charts for all patients screened. Follow-up was available from 8 to 13 years after screening.
Forty-five patients were diagnosed by screening: 18 patients at 3 weeks of age and 27 patients at 6 months of age. Among the patients detected at 3 weeks, six patients were International Neuroblastoma Staging System stage 1, three were stage 2, three were stage 3, two were stage 4, and four were stage 4S. Among the patients detected at 6 months, six patients were stage 1, eight were stage 2, three were stage 3, six were stage 4, and four were stage 4S (Table 1). Biologic aspects of the neuroblastomas are published elsewhere.6 All patients were treated according to the Pediatric Oncology Group recommendations of the time.7 All patients had surgery on the primary tumor. Eight patients detected at 3 weeks and 21 patients detected at 6 months also received chemotherapy. Chemotherapy agents included anthracyclines, alkylating agents, cisplatinum, and epipodophyllotoxins. No patient died from neuroblastoma. One patient, detected at 3 weeks, and 10 patients, detected at 6 months, developed complications of treatment (Table 2).
Chemotherapy induced complications in three patients. One of them was major, T-cell acute lymphoblastic leukemia with an 11q23 rearrangement occurring 5 years after initial diagnosis. This patient is alive in remission of his neuroblastoma and his leukemia with severe bronchiolitis obliterans 8 years after an HLA-matched sibling bone marrow transplantation. The other complications are related to either the tumor or the surgical removal of the tumor. One patient developed a volvulus because of a postoperative adhesion that progressed to hypovolemic shock. This patient suffered severe anoxic encephalopathy and is in a persistent vegetative state. None of the children with a false-positive screen subsequently developed neuroblastoma.
The Québec Neuroblastoma Screening Program was put in place to investigate the possibility of decreasing mortality from high-risk neuroblastoma through early screening. Unfortunately, the incidence of neuroblastoma was almost doubled and population-based mortality was unchanged.5 Most of the neuroblastomas diagnosed by screening were of favorable biology.6 These results are consistent with those of other screening programs. A screening program in Japan for children younger than 6 months did not decrease the mortality from neuroblastoma.8 Although postponing screening until 7 months to 1 year of age led to an increase in neuroblastomas diagnosed by screening with at least one unfavorable feature in Austria, it did not translate into decreased mortality from neuroblastoma.9 Screening at 1 year of age was undertaken in Germany. Their findings, similarly, did not support the usefulness of screening for neuroblastoma at 1 year of age.10 When surgery is performed following a period of observation, neuroblastomas diagnosed by screening demonstrate maturation.11 Also, a significant proportion of the patients observed without surgery will show a decrease in the size of the neuroblastoma. No patients have shown conversion to unfavorable biology tumors or upgrading of the stage.12 Our report is the first describing complications resulting from a neuroblastoma screening program. All patients underwent surgery and two thirds of patients received cytotoxic therapy. One fourth of patients suffered complications. Two were life threatening. Though some of the complications may have resulted from the tumor itself, none were present before treatment. The difference in the complication rate between the group diagnosed at 3 weeks versus the group diagnosed at 6 months is likely multifactorial. Eight of the 18 patients in the first group received chemotherapy, as compared with 18 of 27 patients in the second group, with the chemotherapy delivered mainly through central venous access catheters. More adrenal tumors were found in the 6-month group (19 v five), probably accounting for more kidney injuries in the older patients. The possibility of more extensive surgery having been performed in the older age group is also supported by the larger volume of tissue submitted to pathology, 54 g from the 6-month group as compared with 27 g from the 3-week cohort. Our results are comparable with those reported in the literature. Nishihira et al12 report a 10% major and minor complication rate from surgery in the MS6M mass screening program, with a 1.1% mortality rate. Schilling et al10 report a 0.5% mortality from treatment complications in 149 infants diagnosed through screening. Ikeda et al13 described surgical complications in 50 infants younger than 1 year of age, half of whom had been diagnosed by screening. Ten infants suffered complications, of which one was lethal. Screening programs can also generate false-positive results, which can be associated with a considerable degree of anxiety and inconvenience on the part of the family.14 None of the children whose screen was positive but whose assessment for neuroblastoma was negative subsequently developed neuroblastoma. However, we did not study the psychological impact on the families of the false-positive patient cases. In view of the lack of impact of screening programs on neuroblastoma mortality, evidence that many of the tumors detected through screening can be observed without treatment and the serious complications that may arise from therapy, we do not support neuroblastoma screening programs for children. Furthermore, the high rate of surgical complications in infants leads us to support initial observation of localized neuroblastomas incidentally discovered in infants, as suggested by Fritsch et al.15 Finally, our results underscore the importance of thoroughly validating any screening program before accepting it as standard of care, since, not only can it be of no benefit, but it could also be detrimental for the patients screened.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
We thank the clinical research associates of the participating institutions (Doreen Lalonde, Louise Renaud, Patricia Campion, and Aline Blais).
Supported by Grant No. CA46907 from the National Institutes of Health. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ries LAG, Eisner MP, Kosary CL, et al: SEER Cancer Statistics Review, 1975-2002. Bethesda, MD, National Cancer Institute, 2002 2. Auray-Blais C, Giguere R, Lemieux B: Thin-layer chromatography of urinary homovanillic acid and vanillylmandelic acid for large-scale neuroblastoma mass screening. Med Pediatr Oncol 17:364-367, 1989[Medline] 3. Tuchman M, Lemieux B, Auray-Blais C, et al: Screening for neuroblastoma at 3 weeks of age: Methods and preliminary results from the Quebec Neuroblastoma Screening Project. Pediatrics 86:765-773, 1990 4. Woods WG, Tuchman M, Robison LL, et al: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348:1682-1687, 1996[CrossRef][Medline] 5. Woods WG, Gao RN, Shuster JJ, et al: Screening of infants and mortality due to neuroblastoma. N Engl J Med 346:1041-1046, 2002 6. Brodeur GM, Look AT, Shimada H, et al: Biological aspects of neuroblastomas identified by mass screening in Quebec. Med Pediatr Oncol 36:157-159, 2001[CrossRef][Medline] 7. Castleberry RP: Biology and treatment of neuroblastoma. Pediatr Clin North Am 44:919-937, 1997[CrossRef][Medline] 8. Suita S, Tajiri T, Akazawa K, et al: Mass screening for neuroblastoma at 6 months of age: Difficult to justify. J Pediatr Surg 33:1674-1678, 1998[CrossRef][Medline] 9. Kerbl R, Urban CE, Ambros IM, et al: Neuroblastoma mass screening in late infancy: Insights into the biology of neuroblastic tumors. J Clin Oncol 21:4228-4234, 2003 10. Schilling FH, Spix C, Berthold F, et al: Neuroblastoma screening at one year of age. N Engl J Med 346:1047-1053, 2002 11. Iwanaka T, Yamamoto K, Ogawa Y, et al: Maturation of mass-screened localized adrenal neuroblastoma. J Pediatr Surg 36:1633-1636, 2001[CrossRef][Medline] 12. Nishihira H, Toyoda Y, Tanaka Y, et al: Natural course of neuroblastoma detected by mass screening: A 5-year prospective study at a single institution. J Clin Oncol 18:3012-3017, 2000 13. Ikeda H, Suzuki N, Takahashi A, et al: Surgical treatment of neuroblastomas in infants under 12 months of age. J Pediatr Surg 33:1246-1250, 1998[CrossRef][Medline] 14. Kerbl R, Urban CE, Ladenstein R, et al: Neuroblastoma screening of infants postponed after the sixth month of age: A trial to reduce "overdiagnosis" and to detect cases with "unfavorable" biologic features. Med Pediatr Oncol 29:1-10, 1997[CrossRef][Medline] 15. Fritsch P, Kerbl R, Lackner H, et al: "Wait and see" strategy in localized neuroblastoma in infants: An option not only for cases detected by mass screening. Pediatr Blood Cancer 43:679-682, 2004[Medline] Submitted October 4, 2005; accepted January 17, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
