- Email: [email protected]
In response to Drs. Cheung and Kushner
Int. J. Radiation Oncology Biol. Phys., Vol. 54, No. 5, pp. 1575–1580, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter
LETTERS TO THE EDITOR RISKS OUTWEIGHED BENEFITS FROM LOCAL RADIATION FOR NON–STAGE 4 NEUROBLASTOMA
5. Woods WG, Gao RN, Shuster JJ, et al. Screening of infants and mortality due to neuroblastoma. N Engl J Med 2002;346:1041–1046. 6. Schilling FH, Spix C, Berthold F, et al. Neuroblastoma screening at one year of age. N Engl J Med 2002;346:1047–1053.
To the Editor: Paulino et al. reviewed the outcome of 53 patients ⬍1 year old undergoing local radiotherapy (RT) for neuroblastoma at the University of Iowa from 1955 to 1998. Forty-seven patients had non–Stage 4 neuroblastoma (1). Twenty-one of 53 of this retrospective review were infants ⬍1 month of age. These clinical features were typical of a very favorable group of patients with neuroblastoma. Although the results were based on a very small number of patients seen over 4 decades, several observations were notable. (1) Only 1/6 infant Stage 4 has survived (16%); this contrasts with the current experience of overall survival of ⬎75% in large cooperative group studies. (2) Thirteen children with RT were evaluable for late effects. In 6 of 13, musculoskeletal late effects were significant. (3) Despite the preponderance of infants (40%) in this cohort, survival was only 79%, and freedom from progression 81%. (4) Despite local RT, the projected local-regional control was only 88%. This retrospective analysis further highlights the lack of benefit on local control or survival, and the severe long-term toxicity when RT is used in young children with low-risk neuroblastoma. For a lethal disease such as Stage 4 neuroblastoma in the older child, RT is the lesser of two evils. But for non–Stage 4 disease, the worldwide experience has clearly questioned the necessity of cytotoxic therapy (including chemotherapy and radiotherapy) (2– 4). Two recent neuroblastoma screening studies (5, 6) confirmed the clinical suspicion that a substantial proportion of these patients might not need medical intervention. They rekindled the debate on the potential harm done rather than the lives saved from cancer screening. The negative connotation in neuroblastoma screening studies is largely derived from the unproven benefit and unnecessary toxicity of medical intervention, a relevant consideration in our management of non-Stage IV neuroblastoma. The authors appropriately concluded that locoregional RT is not recommended for infants with pathologic lymph node involvement and that further studies are needed to define which INSS4 infants need RT. But for most patients with Stage 1 and 2 neuroblastoma, irrespective of age, there is generally no role for RT (2). Among patients with Stage 3 neuroblastoma without N-MYC amplification, whether a subset needs RT remains to be proven. Because the authors did not present data to show the benefit of RT among patients, the take-home message seems obvious: RT should not be done. Indeed, the use of routine RT therapy in local-regional blastoma should only be considered in the context of investigational protocols. Even the need for surgery in infants ⬍1 month of age has been questioned, and a prospective clinical trial is an ongoing study in the Children’s Oncology Group.
IN RESPONSE TO DRS. CHEUNG AND KUSHNER To the Editor: I would like to thank Drs Cheung and Kushner for their supporting comments regarding my article, which was published recently in the Journal (1). This is certainly an honor, coming from two of the top researchers in the field of neuroblastoma. We specifically looked at lymph node positivity in infants with neuroblastoma, because in children ⬎1 year of age, a Pediatric Oncology Group trial showed an improvement in event-free survival with the addition of locoregional (RT) (2). Given the excellent outcome of children with Stage I and II disease without RT in older children, we did not examine the influence of margin positivity or presence of gross residual disease. I do not think that the conclusions would be different, since there were so few locoregional relapses. I agree that the use of RT in children ⬍1 year old remains investigational, given the lack of data showing any benefit and the deleterious effects, particularly musculoskeletal abnormalities. The reason for the lower survival and progression-free rates in our series is the time span of the study, which covered four decades. During this time, improvements in medicine have occurred, including supportive therapy and imaging studies. I am not surprised that in the current cooperative trials, we currently have a ⬎75% overall survival in infants with Stage IV neuroblastoma. The late effects of RT in children are dependent on several factors, including age, radiotherapy technique, and dose. We have shown that a great proportion of children receiving RT at ⬍6 months of age develop musculoskeletal abnormalities. This further supports our conclusion not to give RT in most infants. Drs. Cheung and Kushner’s group at Memorial Sloan-Kettering Cancer Center have shown that even with a hyperfractionated technique of delivering 21 Gy in 1.5-Gy fractions, short stature occurred in 10% of children (mostly ⬎1 year of age) followed for more than 3 years (3). Certainly these are important concerns. I would not necessarily call RT an evil, because the previous trial has demonstrated an improvement in event-free survival, and the Memorial study showed a 90% 3-year local control rate (2, 3). Like any modality, including chemotherapy, RT can be both good and bad, depending on how wisely it is employed. In the subset of infants, it is hard to justify giving RT in most patients. Future studies are needed if there is a role for RT in Stage IV and n-myc–amplified infant neuroblastoma.
NAI-KONG V. CHEUNG, M.D., PH.D. BRIAN H. KUSHNER, M.D. Department of Pediatrics Memorial Sloan-Kettering Cancer Center New York, NY
ARNOLD C. PAULINO, M.D. Department of Radiation Oncology Emory University School of Medicine Atlanta, GA
PII S0360-3016(02)03714-8 1. Paulino AC, Mayr NA, Simon JH, et al. Locoregional control in infants with neuroblastoma: Role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys 2002;52:1025–1031. 2. Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 1989;7:236 –244. 3. Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: A children’s cancer group study. J Clin Oncol 2000; 18:18 –26. 4. Cheung NKV, Kushner BH, LaQuaglia MP, et al. Survival from nonstage 4 neuroblastoma without cytotoxic therapy: An analysis of clinical and biologic markers. Eur J Cancer 1997;33:2117–2121.
PII S0360-3016(02)03716-1 1. Paulino AC, Mayr NA, Simon JH, et al. Locoregional control in infants with neuroblastoma: Role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys 2002;52:1025–1031. 2. Castleberry RP, Kun LE, Shuster JJ, et al. Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group Stage C neuroblastoma. J Clin Oncol 1991;9:789 –795. 3. Kushner BH, Wolden S, LaQuaglia MP, et al. Hyperfractionated lowdose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery. J Clin Oncol 2001;19:2821–2828. 1575
LETTERS TO THE EDITOR RISKS OUTWEIGHED BENEFITS FROM LOCAL RADIATION FOR NON–STAGE 4 NEUROBLASTOMA
5. Woods WG, Gao RN, Shuster JJ, et al. Screening of infants and mortality due to neuroblastoma. N Engl J Med 2002;346:1041–1046. 6. Schilling FH, Spix C, Berthold F, et al. Neuroblastoma screening at one year of age. N Engl J Med 2002;346:1047–1053.
To the Editor: Paulino et al. reviewed the outcome of 53 patients ⬍1 year old undergoing local radiotherapy (RT) for neuroblastoma at the University of Iowa from 1955 to 1998. Forty-seven patients had non–Stage 4 neuroblastoma (1). Twenty-one of 53 of this retrospective review were infants ⬍1 month of age. These clinical features were typical of a very favorable group of patients with neuroblastoma. Although the results were based on a very small number of patients seen over 4 decades, several observations were notable. (1) Only 1/6 infant Stage 4 has survived (16%); this contrasts with the current experience of overall survival of ⬎75% in large cooperative group studies. (2) Thirteen children with RT were evaluable for late effects. In 6 of 13, musculoskeletal late effects were significant. (3) Despite the preponderance of infants (40%) in this cohort, survival was only 79%, and freedom from progression 81%. (4) Despite local RT, the projected local-regional control was only 88%. This retrospective analysis further highlights the lack of benefit on local control or survival, and the severe long-term toxicity when RT is used in young children with low-risk neuroblastoma. For a lethal disease such as Stage 4 neuroblastoma in the older child, RT is the lesser of two evils. But for non–Stage 4 disease, the worldwide experience has clearly questioned the necessity of cytotoxic therapy (including chemotherapy and radiotherapy) (2– 4). Two recent neuroblastoma screening studies (5, 6) confirmed the clinical suspicion that a substantial proportion of these patients might not need medical intervention. They rekindled the debate on the potential harm done rather than the lives saved from cancer screening. The negative connotation in neuroblastoma screening studies is largely derived from the unproven benefit and unnecessary toxicity of medical intervention, a relevant consideration in our management of non-Stage IV neuroblastoma. The authors appropriately concluded that locoregional RT is not recommended for infants with pathologic lymph node involvement and that further studies are needed to define which INSS4 infants need RT. But for most patients with Stage 1 and 2 neuroblastoma, irrespective of age, there is generally no role for RT (2). Among patients with Stage 3 neuroblastoma without N-MYC amplification, whether a subset needs RT remains to be proven. Because the authors did not present data to show the benefit of RT among patients, the take-home message seems obvious: RT should not be done. Indeed, the use of routine RT therapy in local-regional blastoma should only be considered in the context of investigational protocols. Even the need for surgery in infants ⬍1 month of age has been questioned, and a prospective clinical trial is an ongoing study in the Children’s Oncology Group.
IN RESPONSE TO DRS. CHEUNG AND KUSHNER To the Editor: I would like to thank Drs Cheung and Kushner for their supporting comments regarding my article, which was published recently in the Journal (1). This is certainly an honor, coming from two of the top researchers in the field of neuroblastoma. We specifically looked at lymph node positivity in infants with neuroblastoma, because in children ⬎1 year of age, a Pediatric Oncology Group trial showed an improvement in event-free survival with the addition of locoregional (RT) (2). Given the excellent outcome of children with Stage I and II disease without RT in older children, we did not examine the influence of margin positivity or presence of gross residual disease. I do not think that the conclusions would be different, since there were so few locoregional relapses. I agree that the use of RT in children ⬍1 year old remains investigational, given the lack of data showing any benefit and the deleterious effects, particularly musculoskeletal abnormalities. The reason for the lower survival and progression-free rates in our series is the time span of the study, which covered four decades. During this time, improvements in medicine have occurred, including supportive therapy and imaging studies. I am not surprised that in the current cooperative trials, we currently have a ⬎75% overall survival in infants with Stage IV neuroblastoma. The late effects of RT in children are dependent on several factors, including age, radiotherapy technique, and dose. We have shown that a great proportion of children receiving RT at ⬍6 months of age develop musculoskeletal abnormalities. This further supports our conclusion not to give RT in most infants. Drs. Cheung and Kushner’s group at Memorial Sloan-Kettering Cancer Center have shown that even with a hyperfractionated technique of delivering 21 Gy in 1.5-Gy fractions, short stature occurred in 10% of children (mostly ⬎1 year of age) followed for more than 3 years (3). Certainly these are important concerns. I would not necessarily call RT an evil, because the previous trial has demonstrated an improvement in event-free survival, and the Memorial study showed a 90% 3-year local control rate (2, 3). Like any modality, including chemotherapy, RT can be both good and bad, depending on how wisely it is employed. In the subset of infants, it is hard to justify giving RT in most patients. Future studies are needed if there is a role for RT in Stage IV and n-myc–amplified infant neuroblastoma.
NAI-KONG V. CHEUNG, M.D., PH.D. BRIAN H. KUSHNER, M.D. Department of Pediatrics Memorial Sloan-Kettering Cancer Center New York, NY
ARNOLD C. PAULINO, M.D. Department of Radiation Oncology Emory University School of Medicine Atlanta, GA
PII S0360-3016(02)03714-8 1. Paulino AC, Mayr NA, Simon JH, et al. Locoregional control in infants with neuroblastoma: Role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys 2002;52:1025–1031. 2. Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 1989;7:236 –244. 3. Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: A children’s cancer group study. J Clin Oncol 2000; 18:18 –26. 4. Cheung NKV, Kushner BH, LaQuaglia MP, et al. Survival from nonstage 4 neuroblastoma without cytotoxic therapy: An analysis of clinical and biologic markers. Eur J Cancer 1997;33:2117–2121.
PII S0360-3016(02)03716-1 1. Paulino AC, Mayr NA, Simon JH, et al. Locoregional control in infants with neuroblastoma: Role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys 2002;52:1025–1031. 2. Castleberry RP, Kun LE, Shuster JJ, et al. Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group Stage C neuroblastoma. J Clin Oncol 1991;9:789 –795. 3. Kushner BH, Wolden S, LaQuaglia MP, et al. Hyperfractionated lowdose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery. J Clin Oncol 2001;19:2821–2828. 1575