Correspondence
Allelic Loss of Chromosome 1p in Neuroblastoma
N Engl J Med 1996; 334:1608-1609June 13, 1996
- Article
To the Editor:
Many studies have shown amplification of the N-myc oncogene to be a highly reliable predictor of death from neuroblastoma.1-3 Caron et al. (Jan. 25 issue)3 report that allelic loss of chromosome 1p is a more powerful predictor of unfavorable outcome than N-myc amplification. Other studies of chromosome 1p loss, however, have been unable to assess its independent prognostic importance because it occurs so rarely in the absence of N-myc amplification.1,2 We suggest that a reanalysis of the data of Caron et al. might yield results similar to those in other large series.1,2
Caron et al. group patients with stage III and stage IV neuroblastoma together. We suspect that if patients with stage IV disease diagnosed after the age of one year — i.e., the largest subgroup of patients with neuroblastoma — were analyzed separately, loss of chromosome 1p would have no prognostic power because the survival rate would be so low and because only three such patients in the study had loss of chromosome 1p without N-myc amplification. The outcome of patients with stage III disease who had chromosome 1p loss was dismal, but these patients all had N-myc amplification, making it impossible to discern the prognostic power of chromosome 1p loss alone in stage III disease.
Nine patients with stage I, II, or IVS disease had loss of chromosome 1p without N-myc amplification. Their specific outcome is not described, but it is important to know precisely what events occurred in this small subgroup of patients. For example, most patients in stage I or II whose disease recurs postoperatively or “progresses” to stage IVS undergo salvage therapy, whereas in those with stage IVS the disease is known to progress in some cases before spontaneously regressing.4 Hence, survival may be a more important end point for patients not in stage IV than is event-free survival — the end point used by Caron et al. Also, patients with stage I, II, or IVS disease have died of the effects of cytotoxic therapy, obviously an event unrelated to tumor biology.
We wish to raise one other issue. Treatment itself is a major oncologic prognostic factor but could not be used by Caron et al. because their patient population received very variable treatments. Prognostic power decreases when survival rates approach zero or when therapy is highly successful. We have used high-dose cyclophosphamide-based therapy5 in four infants with newly diagnosed classic stage IV neuroblastoma who had loss of chromosome 1p and chromosomal diploidy (a poor prognostic marker), but no N-myc amplification. Three are well more than three years after the end of treatment; one infant died of infection. Three years after receiving this same therapy, two older children who had no skeletal or bone marrow involvement but whose neuroblastomas were unresectable and who had loss of chromosome 1p, diploidy, and unamplified N-myc both remain well. We suggest that curative treatment is available for infants and selected older patients with advanced-stage neuroblastomas marked by the loss of chromosome 1p but not by N-myc amplification.
5 ReferencesBrian H. Kushner, M.D.
Nai-Kong V. Cheung, M.D., Ph.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 100211
Maris JM ,White PS ,Beltinger CP , et al. Significance of chromosome 1p loss of heterozygosity in neuroblastoma. Cancer Res 1995;55:4664-4669
Web of Science | Medline2
Gehring M ,Berthold F ,Edler L ,Schwab M ,Amler LC . The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma. Cancer Res 1995;55:5366-5369
Web of Science | Medline3
Caron H ,van Sluis P ,de Kraker J , et al. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 1996;334:225-230
Full Text | Web of Science | Medline4
Kushner BH ,Cheung N-KV ,LaQuaglia MP , et al. Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy. J Clin Oncol 1996;14:373-381
Web of Science | Medline5
Kushner BH ,LaQuaglia MP ,Bonilla MA , et al. Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 1994;12:2607-2613
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We used the Cox multiple-hazard regression model to show a clear additional prognostic value of the status of chromosome 1p in comparison with other clinical factors and of the superiority of this as a prognostic marker relative to the status of N-myc. We analyzed the prognostic impact of chromosome 1p status in clinically distinct subgroups of patients. Kushner and Cheung are mainly concerned with the latter analyses. Indeed, there were only a few patients with stage III or IV disease with loss of chromosome 1p without N-myc amplification. The importance of our finding lies in patients with stage I, II, or IVS disease: in this group the loss of chromosome 1p identified all patients with a recurrence within five years after diagnosis. Kushner and Cheung argue that overall survival, rather than event-free survival, which we used, might be a more important end point for patients without stage IV disease, because of the possibility of salvage therapy in patients in this group who have recurrent neuroblastoma. Among the 38 patients with stage I, II, or IVS disease, we identified 10 (26 percent) with loss of chromosome 1p, only 1 of whom also had N-myc amplification. Seven of these 10 patients had a recurrence. Six of these seven patients died of the disease, despite intensive salvage therapy. Only one patient was disease-free 35 months later. In the remaining 28 patients without loss of chromosome 1p, no events occurred within five years after diagnosis. Furthermore, no deaths from toxicity or other events were recorded in the group with stage I, II, or IVS neuroblastoma. Therefore, loss of chromosome 1p reliably identifies patients with stage I, II, or IVS disease who are at high risk of an adverse outcome, both in terms of event-free and overall survival. Since N-myc amplification is found in less than 5 percent of such patients,1-3 it cannot equal loss of chromosome 1p as a prognostic indicator.
3 ReferencesH.N. Caron, M.D., Ph.D.
P.A. Voûte, M.D., Ph.D.
Emma Kinderziekenhuis, 1100 DE Amsterdam, the NetherlandsR. Versteeg, Ph.D.
Institute of Human Genetics, 1105 AZ Amsterdam, the Netherlands1
Ambros PF ,Ambros IM ,Strehl S , et al. Regression and progression in neuroblastoma: does genetics predict tumour behaviour? Eur J Cancer 1995;31:510-515
CrossRef | Web of Science2
Maris JM ,White PS ,Beltinger CP , et al. Significance of chromosome 1p loss of heterozygosity in neuroblastoma. Cancer Res 1995;55:4664-4669
Web of Science | Medline3
Gehring M ,Berthold F ,Edler L ,Schwab M ,Amler LC . The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma. Cancer Res 1995;55:5366-5369
Web of Science | Medline
