今日の臨床サポート

神経芽腫(小児科)

著者: 井田孔明 帝京大学医学部附属溝口病院小児科

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2019/07/09
参考ガイドライン:
  1. 日本小児血液がん学会:小児がん診療ガイドライン2016年版
患者向け説明資料

概要・推奨   

  1. 神経芽腫の診断および治療は、小児腫瘍の診療に習熟した小児科医、小児外科医、病理医、放射線科医の協力のもとで行われるべきである(推奨度1)。
  1. 神経芽腫の予後因子として、病期分類、発症年齢、病理分類、腫瘍細胞の生物学的特性が重要である(推奨度1)。
  1. 低リスク群に対する治療は基本的には手術のみであるが、症例に応じて化学療法と放射線療法を併用する(推奨度1)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
井田孔明 : 特に申告事項無し[2021年]
監修:五十嵐隆 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、IDRFおよび後治療について追加記載した。
  1. 小児がん診療ガイドライン2016年版(日本小児血液がん学会)に基づいて病期分類とリスク分類を修正した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 胎児期の神経堤由来の副腎あるいは交感神経節に発生する悪性腫瘍である。約65%が腹部に発生し、その半分が副腎に発生する[1]
 
神経芽腫の臨床症状

神経芽腫は副腎や交感神経節に発症する。後腹膜に発症し椎間孔から脊柱管内に進展したものは脊髄圧迫症状を認めることがある(dumb-bell type)。低リスク群の腫瘍は被膜に覆われ安全に摘出される可能性が高いが、高リスク群では周囲組織に浸潤することが多く、全摘出は不可能となる。血行性にリンパ節や骨髄に転移することが多い、病期MSでは肝臓に転移することが特徴である。

出典

img1:  Recent advances in neuroblastoma.
 
 N Engl J Med. 2010 Jun 10;362(23):2202-1・・・
 
  1. 小児悪性固形腫瘍のなかでは脳腫瘍に次いで多く、日本において年間180~200人の新規患者が発生している[1][2]
  1. 発症年齢では0歳児が最も多く、3歳児に第2のピークがある二峰性の分布を示す[1]
  1. 1歳未満の乳児では発症し自然退縮する症例がある[3][4]
  1. 神経芽腫の約70%は診断時に遠隔転移が認められる[1]
  1. 病期分類、発症年齢、病理分類、腫瘍細胞の生物学的特性(MYCN遺伝子の増幅(図<図表>、11番線染色体長腕の異常、DNA ploidy)が予後因子として重要である[1][5]
  1. 予後因子によって、低リスク(極低リスク、低リスク)群、中間リスク群、高リスク群の3群に分類され層別化治療が行われている[1][5]。(図<図表>
  1. 5年生存率は低リスク群で約90%以上、中間リスク群では約70~90%であるが、高リスク群では大量化学療法を含む集学的治療が行われるにもかかわらず50%未満と予後不良である[1][5]
 
神経芽腫のリスク別生存曲線

米国において1986年から2001年までに治療された神経芽腫患者のEFS(event free survival)を、低リスク、中間リスク、高リスク群別にKaplan-Meier法で示した。

出典

img1:  Neuroblastoma.
 
 Lancet. 2007 Jun 23;369(9579):2106-20. d・・・
問診・診察のポイント  
  1. 初発症状は原発部位と転移部位によってさまざまで、発熱、全身倦怠感、腹部膨隆、ホルネル症候群(患側の縮瞳、眼瞼下垂、発汗異常)、眼球突出、骨痛などがある[1]
  1. 乳児期の病期MSの症例では、肝腫大による腹部膨満と呼吸障害が特徴的である[1][3]
  1. 交感神経節に発生し脊柱管内に進展するダンベル型(dumb-bell type)では、下肢麻痺や膀胱直腸障害が唯一の初発症状となる場合があり、早期診断のうえで注意を要する[1]
  1. まれに眼球運動障害と小脳失調を呈するオプソクローヌス・ミオクローヌス症候群(opsoclonus-myoclonus syndrome)を認める場合がある[1][6]

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文献 

著者: H J Nickerson, K K Matthay, R C Seeger, G M Brodeur, H Shimada, C Perez, J B Atkinson, M Selch, R B Gerbing, D O Stram, J Lukens
雑誌名: J Clin Oncol. 2000 Feb;18(3):477-86.
Abstract/Text PURPOSE: Stage IV-S neuroblastoma is a metastatic disease associated with spontaneous regression and good survival, but 10% to 20% of infants die from early complications. The purpose of this study was to evaluate outcome and prognostic factors in infants with stage IV-S neuroblastoma treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy.
PATIENTS AND METHODS: Eighty eligible infants were studied for response and survival with supportive care or, for symptomatic patients, cyclophosphamide 5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days. Staging was reviewed centrally, and MYCN gene copy number, Shimada histopathologic classification, serum ferritin levels, and bone marrow immunocytology were determined.
RESULTS: Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P =.005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age CONCLUSION: This study confirms the favorable biologic features and excellent survival of infants with stage IV-S neuroblastoma with minimal therapy. Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease may benefit from earlier and more intensive treatment.

PMID 10653863  J Clin Oncol. 2000 Feb;18(3):477-86.
著者: Barbara Hero, Thorsten Simon, Ruediger Spitz, Karen Ernestus, Astrid K Gnekow, Hans-Guenther Scheel-Walter, Dirk Schwabe, Freimut H Schilling, Gabriele Benz-Bohm, Frank Berthold
雑誌名: J Clin Oncol. 2008 Mar 20;26(9):1504-10. doi: 10.1200/JCO.2007.12.3349.
Abstract/Text PURPOSE: The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment.
PATIENTS AND METHODS: For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI).
RESULTS: Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 +/- 0.01) and metastases-free survival (rate at 3 years, 0.94 +/- 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy.
CONCLUSION: Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.

PMID 18349403  J Clin Oncol. 2008 Mar 20;26(9):1504-10. doi: 10.1200/J・・・
著者: John M Maris, Michael D Hogarty, Rochelle Bagatell, Susan L Cohn
雑誌名: Lancet. 2007 Jun 23;369(9579):2106-20. doi: 10.1016/S0140-6736(07)60983-0.
Abstract/Text The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.

PMID 17586306  Lancet. 2007 Jun 23;369(9579):2106-20. doi: 10.1016/S01・・・
著者: Katherine K Matthay, Franz Blaes, Barbara Hero, Dominique Plantaz, Pedro De Alarcon, Wendy G Mitchell, Michael Pike, Vito Pistoia
雑誌名: Cancer Lett. 2005 Oct 18;228(1-2):275-82. doi: 10.1016/j.canlet.2005.01.051.
Abstract/Text Opsoclonus-myoclonus syndrome (OMS) is a rare neurologic syndrome that, in children, associates with neuroblastoma in more than half of the cases. The etiology of this condition is thought to be immune mediated, but, though immunosuppressive therapies may ameliorate the acute symptoms, no effective treatment to prevent the common neuropsychologic sequelae has been established. This paper summarizes the results obtained at the 2004 Advances in Neuroblastoma Research meeting, providing status of the art information on immune pathogenesis, clinical features, acute and chronic neurologic manifestations, current and novel therapeutic approaches. It is emphasized that, due to the rarity of OMS in general and neuroblastoma-associated OMS in particular, international collaborations are needed to better define the pathogenesis and therapy of this disease, propose common evaluation criteria and identify new treatment modalities.

PMID 15922508  Cancer Lett. 2005 Oct 18;228(1-2):275-82. doi: 10.1016/・・・
著者: Tom Monclair, Garrett M Brodeur, Peter F Ambros, Hervé J Brisse, Giovanni Cecchetto, Keith Holmes, Michio Kaneko, Wendy B London, Katherine K Matthay, Jed G Nuchtern, Dietrich von Schweinitz, Thorsten Simon, Susan L Cohn, Andrew D J Pearson, INRG Task Force
雑誌名: J Clin Oncol. 2009 Jan 10;27(2):298-303. doi: 10.1200/JCO.2008.16.6876. Epub 2008 Dec 1.
Abstract/Text PURPOSE: The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. Because the International Neuroblastoma Staging System (INSS) is a postsurgical staging system, a new clinical staging system was required for the INRG pretreatment risk classification system.
METHODS: To stage patients before any treatment, the INRG Task Force, consisting of neuroblastoma experts from Australia/New Zealand, China, Europe, Japan, and North America, developed a new INRG staging system (INRGSS) based on clinical criteria and image-defined risk factors (IDRFs). To investigate the impact of IDRFs on outcome, survival analyses were performed on 661 European patients with INSS stages 1, 2, or 3 disease for whom IDRFs were known.
RESULTS: In the INGRSS, locoregional tumors are staged L1 or L2 based on the absence or presence of one or more of 20 IDRFs, respectively. Metastatic tumors are defined as stage M, except for stage MS, in which metastases are confined to the skin, liver, and/or bone marrow in children younger than 18 months of age. Within the 661-patient cohort, IDRFs were present (ie, stage L2) in 21% of patients with stage 1, 45% of patients with stage 2, and 94% of patients with stage 3 disease. Patients with INRGSS stage L2 disease had significantly lower 5-year event-free survival than those with INRGSS stage L1 disease (78% +/- 4% v 90% +/- 3%; P = .0010).
CONCLUSION: Use of the new staging (INRGSS) and risk classification (INRG) of neuroblastoma will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world.

PMID 19047290  J Clin Oncol. 2009 Jan 10;27(2):298-303. doi: 10.1200/J・・・
著者: H Shimada, S Umehara, Y Monobe, Y Hachitanda, A Nakagawa, S Goto, R B Gerbing, D O Stram, J N Lukens, K K Matthay
雑誌名: Cancer. 2001 Nov 1;92(9):2451-61.
Abstract/Text BACKGROUND: The International Neuroblastoma Pathology Classification was established in 1999 for the prognostic evaluation of patients with neuroblastic tumors (NTs).
METHODS: Pathology slides from 746 NTs (the Children's Cancer Group [CCG]-3881 and CCG-3891 studies) were evaluated according to the International Classification. First, prognostic effects of the morphologic indicators (grade of neuroblastic differentiation: undifferentiated [U], poorly differentiated [PD] and differentiating [D]; and mitosis-karyorrhexis index [MKI]: low [L-MKI], intermediate [I-MKI], and high [H-MKI]) for tumors in the neuroblastoma (NB) category were tested. Then, prognostic significance of the International Classification for all NTs in four categories (neuroblastoma [NB]; ganglioneuroblastoma, intermixed [GNBi]; ganglioneuroma [GN]; and ganglioneuroblastoma, nodular [GNBn]) was analyzed. Finally, age distribution of the patients in the four categories as well as three subtypes (based on the grade of differentiation) in the NB category was compared.
RESULTS: There were 630 NB tumors, 30 GNBi tumors, 10 GN tumors, and 76 GNBn tumors. In the NB category, prognostic effects of the indicators (three grades of differentiation and three mitosis-karyorrhexis index [MKI] classes: low [L], intermediate [I], and high [H]) were affected significantly by the age of the patients. The age-linked evaluation of the indicators according to the International Classification successfully distinguished two prognostic subgroups: the favorable histology (FH) subgroup (PD/D and L/I-MKI tumors in patients age < 1.5 years, D and L-MKI tumors in patients ages 1.5-5.0 years; 90.4% 5-year event free survival [EFS]) and the unfavorable histology (UH) subgroup (U and/or H-MKI tumors in patients of any age, PD and/or I-MKI tumors in patients ages 1.5-5.0 years, any grade of differentiation, and any MKI class in patients age > or = 5 years; 26.9% EFS) (P < 0.0001). The International Classification also distinguished the FH group (FH subgroup with NB, GNBi, and GN tumors) and the UH group (UH subgroup with NB and GNBn tumors) for all NTs (90.8% EFS and 31.2% EFS, respectively; P < 0.0001) and provided independent prognostic information on both patient age and disease stage (P < 0.0001). Among patients with FH tumors, the median ages of patients with the PD and D subtype tumors in the NB category were 0.43 years (range, 0-1.50 years) and 1.50 years (range, 0.02-4.65 years), respectively, and the median ages of patients with GNBi and GN tumors were 3.51 years (range, 0.96-14.85 years) and 4.80 years (range, 1.94-17.05 years), respectively. In contrast, patients with UH tumors generally were older when they were diagnosed, and with median ages of 2.99 years (range, 1.30-8.84 years) for patients with U subtype tumors, 2.59 years (range, 0.0-12.57 years) for patients with PD subtype tumors, 2.16 years (range, 0.35-9.90) for patients with D subtype tumors, and 3.26 years (range, 0.57-15.90 years) for patients with GNBn tumors.
CONCLUSIONS: This study confirmed the prognostic significance of the International Classification, substantiated age-linked prognostic effects of the morphologic indicators for patients with the tumors in the NB category, and supported the concept of an age-appropriate framework of maturation for patients with the tumors in the FH group.

Copyright 2001 American Cancer Society.
PMID 11745303  Cancer. 2001 Nov 1;92(9):2451-61.
著者: Susan L Cohn, Andrew D J Pearson, Wendy B London, Tom Monclair, Peter F Ambros, Garrett M Brodeur, Andreas Faldum, Barbara Hero, Tomoko Iehara, David Machin, Veronique Mosseri, Thorsten Simon, Alberto Garaventa, Victoria Castel, Katherine K Matthay, INRG Task Force
雑誌名: J Clin Oncol. 2009 Jan 10;27(2):289-97. doi: 10.1200/JCO.2008.16.6785. Epub 2008 Dec 1.
Abstract/Text PURPOSE: Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification.
PATIENTS AND METHODS: The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors.
RESULTS: Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively.
CONCLUSION: By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

PMID 19047291  J Clin Oncol. 2009 Jan 10;27(2):289-97. doi: 10.1200/JC・・・
著者: S J Cotterill, A D Pearson, J Pritchard, A B Foot, B Roald, J A Kohler, J Imeson
雑誌名: Eur J Cancer. 2000 May;36(7):901-8.
Abstract/Text In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey'). Clinical information was collected primarily to: (a) establish an ENSG database; and (b) investigate prognostic factors in neuroblastoma. This paper summarises the results of the survey. By 1992, 1277 patients with a median age of 26 months (range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30 centres. The median follow-up of survivors is 9.7 years (range: 1-14 years). Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS) is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic factors, stage and age, are highly significant (P<0.001). In particular, patients under 1 year of age at diagnosis, whatever the disease stage, had a more favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus 76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI 44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19), P<0.001). Multivariate analysis established that the anatomical location of the primary tumour (i.e. abdominal versus other sites) and primary tumour volume also conferred a statistically significant difference. In stage 4 disease the 20% of patients without demonstrable bone marrow involvement had a more favourable prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16% (95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no significant effect on outcome after stage and age were accounted for. 5-year survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey provides secure data for future comparisons with new prognostic factors and treatment programmes.

PMID 10785596  Eur J Cancer. 2000 May;36(7):901-8.
著者: C A Perez, K K Matthay, J B Atkinson, R C Seeger, H Shimada, G M Haase, D O Stram, R B Gerbing, J N Lukens
雑誌名: J Clin Oncol. 2000 Jan;18(1):18-26.
Abstract/Text PURPOSE: To determine prospectively whether surgery alone is sufficient therapy for Evans stages I and II neuroblastoma and to define biologic and clinical features having prognostic potential for this group.
PATIENTS AND METHODS: Between June 1989 and August 1995, 374 eligible children (age range, 0 to 18 years) with newly diagnosed stage I (n = 141) and stage II (n = 233) neuroblastoma were registered onto Children's Cancer Group trial 3881. Surgical resection was the only primary therapy except in cases with spinal cord compression, where radiation therapy was allowed. Event-free survival (EFS) and overall survival (OS) were analyzed by life-table methods according to clinical and biologic features.
RESULTS: EFS and OS (mean +/- SE) for all stage I patients were 93% +/- 3.0% and 99% +/- 1.0%, respectively, compared with 81% +/- 4.0% and 98% +/- 2. 0%, respectively, for stage II patients. The significantly higher recurrence rate among stage II patients was managed successfully in 38 of 43 children with either surgery or multimodality treatment. There was one death among stage I patients and six among stage II. For stage II patients tumor MYCN gene amplication, unfavorable histopathology, an age greater than 2 years, and positive lymph nodes predicted a lower OS (P <.05).
CONCLUSION: Children with stages I and II neuroblastoma have 98% survival with surgery alone as primary therapy. Supplemental treatment was necessary in only 10% of stage I patients and 20% of stage II patients. In children with localized neuroblastoma, a subset of patients that are at higher risk for death can be defined as those with stage II disease who have tumor MYCN amplification or who are >/= 2 years of age with either unfavorable histopathology or positive lymph nodes.

PMID 10623689  J Clin Oncol. 2000 Jan;18(1):18-26.
著者: K K Matthay, C Perez, R C Seeger, G M Brodeur, H Shimada, J B Atkinson, C T Black, R Gerbing, G M Haase, D O Stram, P Swift, J N Lukens
雑誌名: J Clin Oncol. 1998 Apr;16(4):1256-64.
Abstract/Text PURPOSE: To identify a biologically favorable and unfavorable subset of patients with Evans stage III neuroblastoma and to determine whether treatment stratification would improve the event-free survival (EFS) for high-risk patients and maintain excellent EFS for the lower-risk patients.
PATIENTS AND METHODS: Risk stratification was performed by age, MYCN gene copy number, Shimada histopathologic classification, and serum ferritin level. Lower-risk patients were treated on the less intensive Children's Cancer Group (CCG)-3881, whereas high-risk patients were treated on CCG-3891, which included more intensive multimodality therapy and, in some cases, autologous bone marrow transplantation (ABMT).
RESULTS: Of 228 Evans stage III patients entered onto the study, 92% also met the definition of International Neuroblastoma Staging System (INSS) stage 3. One hundred forty-three patients met the lower-risk criteria, which included 89 patients less than 1 year of age and 54 patients 1 year of age or greater, and favorable biology, whereas 85 patients were 1 year of age or greater and biologically unfavorable. Biologically unfavorable patients 1 year of age or greater who underwent gross surgical resection had improved survival, whereas the outcome of infants or biologically favorable older patients did not change according to resection. The EFS rate at 4 years was 100% for the patients with favorable biology of any age, 90% for those less than 1 year of age but with at least one unfavorable characteristic, and 54% for Evans stage III patients 1 year of age or greater with unfavorable biology. Age, ferritin level, MYCN copy number, Shimada histopathology, primary site, and intraspinal extension were significant univariate prognostic factors for all patients, but only MYCN copy number and age were independent factors in multivariate analyses.
CONCLUSION: The excellent survival of the biologically favorable group and the historically improved EFS of the biologically unfavorable group suggest that biologic staging should be used to define the prognosis and treatment of stage III neuroblastoma.

PMID 9552023  J Clin Oncol. 1998 Apr;16(4):1256-64.
著者: A R Evans, W Brand, A de Lorimier, S McCreadie, H Sather, S Leikin, D Hammond
雑誌名: Am J Clin Oncol. 1984 Feb;7(1):3-7.
Abstract/Text Members of children's cancer study group designed Study CCG 351 to determine whether three drug chemotherapy improved the survival experience of children with localized neuroblastoma. Patients in stages I-III were treated with surgical removal of the primary tumor and those in stages II and III received radiation therapy to the tumor bed and chemotherapy. Treatment included cyclophosphamide, imidazolecarboxamide, and vincristine given in 5-day pulses each month for 12 courses. The results were compared to those from a previous study, CCG 011, for localized neuroblastoma, in which children were randomized between a treatment regimen that included cyclophosphamide and one with no chemotherapy. There were 133 evaluable patients, subdivided as follows: stages I-26, stages II-74, and stages III-33. The 3-year life-table survival rates by stage of 96, 89 and 50% were not significantly different from the patients in CCG 011 similarly staged who received either no chemotherapy or oral CPM. These data suggest that multiagent chemotherapy, as prescribed, did not improve the outlook for children with locally advanced but nonmetastatic neuroblastoma. The staging criteria employed showed a modest difference in outcome between patients in stages I and II, but a significant poorer survival for stage III as compared to either stage I or II.

PMID 6364778  Am J Clin Oncol. 1984 Feb;7(1):3-7.
著者: C S Alvarado, W B London, A T Look, G M Brodeur, D H Altmiller, P S Thorner, V V Joshi, S T Rowe, M B Nash, E I Smith, R P Castleberry, S L Cohn
雑誌名: J Pediatr Hematol Oncol. 2000 May-Jun;22(3):197-205.
Abstract/Text PURPOSE: To prospectively analyze the outcome of patients with Stage A neuroblastoma (NB) treated with surgery alone, especially with regard to the prognostic significance of age, tumor site, MYCN copy number, tumor cell ploidy, and histology.
PATIENTS AND METHODS: The clinical course of 329 patients with Stage A disease registered on the POG NB Biology Study #9047 between February, 1990 and October, 1997 were evaluated. Age, tumor site, MYCN copy number, tumor cell ploidy, and histology were analyzed for their impact on event-free survival (EFS) and survival (S).
RESULTS: The 5-year estimated EFS and S rates for the 329 patients were 91% (+/-3%) and 96% (+/-2%), respectively. The EFS rate was similar for infants younger than 12 months and children age 12 months or older, but age older than 12 months was predictive of lower S rates (P = 0.044). Patients with adrenal, abdominal non-adrenal, thoracic, and cervical tumors had similar S rates. The majority of patients had tumors with favorable biologic features, and only 3% had MYCN amplification. For infants with diploid tumors, the EFS rate was 82% (+/-16%), but effective therapy yielded an S rate of 100%. Rate of S was 80% (+/-26%) and 64% (+/-27%) for patients with unfavorable tumor histology and MYCN-amplified tumors, respectively.
CONCLUSION: The outcome for patients with Stage A NB treated with surgery alone is excellent. Although EFS and S rates were significantly worse for patients with MYCN-amplified tumors, a subset achieved long-term remission after surgery alone. For patients with Stage A and MYCN amplification, additional factors are needed to distinguish the patients who will achieve long-term remission with surgery alone from those who will develop recurrent disease.

PMID 10864050  J Pediatr Hematol Oncol. 2000 May-Jun;22(3):197-205.
著者: Jia Jean Yiin, Cheng Siu Chang, Yee Jee Jan, Yeou Chih Wang
雑誌名: J Clin Neurosci. 2003 Sep;10(5):579-83.
Abstract/Text Neuroblastoma is the most common malignant cause of spinal compression in the paediatric population. Chemotherapy is commonly considered as the first-line treatment for these patients. The role of neurosurgical decompression and radiotherapy are still controversial. Thirteen children diagnosed as having neuroblastoma with intraspinal extension were included in this report. All patients presented with neurological deficits and were treated with chemotherapy initially, after which 3 patients recovered, 4 improved and 6 were aggravated into paraplegia. Two of the 6 aggravated patients received emergent laminectomy with removal of intraspinal tumour and recovered satisfactorily. Although spread of tumour into the spinal canal indicates an advanced disease, aggressive treatments such as chemotherapy and surgical resection can often improve neurological symptoms and life quality. Neurological decompression is recommended for patients with intraspinal neuroblastoma and rapid neurological deterioration during chemotherapy.

PMID 12948463  J Clin Neurosci. 2003 Sep;10(5):579-83.
著者: David L Baker, Mary L Schmidt, Susan L Cohn, John M Maris, Wendy B London, Allen Buxton, Daniel Stram, Robert P Castleberry, Hiroyuki Shimada, Anthony Sandler, Robert C Shamberger, A Thomas Look, C Patrick Reynolds, Robert C Seeger, Katherine K Matthay, Children’s Oncology Group
雑誌名: N Engl J Med. 2010 Sep 30;363(14):1313-23. doi: 10.1056/NEJMoa1001527.
Abstract/Text BACKGROUND: The survival rate among patients with intermediate-risk neuroblastoma who receive dose-intensive chemotherapy is excellent, but the survival rate among patients who receive reduced doses of chemotherapy for shorter periods of time is not known.
METHODS: We conducted a prospective, phase 3, nonrandomized trial to determine whether a 3-year estimated overall survival of more than 90% could be maintained with reductions in the duration of therapy and drug doses, using a tumor biology-based therapy assignment. Eligible patients had newly diagnosed, intermediate-risk neuroblastoma without MYCN amplification; these patients included infants (<365 days of age) who had stage 3 or 4 disease, children (≥365 days of age) who had stage 3 tumors with favorable histopathological features, and infants who had stage 4S disease with a diploid DNA index or unfavorable histopathological features. Patients who had disease with favorable histopathological features and hyperdiploidy were assigned to four cycles of chemotherapy, and those with an incomplete response or either unfavorable feature were assigned to eight cycles.
RESULTS: Between 1997 and 2005, a total of 479 eligible patients were enrolled in this trial (270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease). A total of 323 patients had tumors with favorable biologic features, and 141 had tumors with unfavorable biologic features. Ploidy, but not histopathological features, was significantly predictive of the outcome. Severe adverse events without disease progression occurred in 10 patients (2.1%), including secondary leukemia (in 3 patients), death from infection (in 3 patients), and death at surgery (in 4 patients). The 3-year estimate (±SE) of overall survival for the entire group was 96±1%, with an overall survival rate of 98±1% among patients who had tumors with favorable biologic features and 93±2% among patients who had tumors with unfavorable biologic features.
CONCLUSIONS: A very high rate of survival among patients with intermediate-risk neuroblastoma was achieved with a biologically based treatment assignment involving a substantially reduced duration of chemotherapy and reduced doses of chemotherapeutic agents as compared with the regimens used in earlier trials. These data provide support for further reduction in chemotherapy with more refined risk stratification. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003093.)

PMID 20879880  N Engl J Med. 2010 Sep 30;363(14):1313-23. doi: 10.1056・・・
著者: D C West, R C Shamberger, R M Macklis, H P Kozakewich, A S Wayne, S G Kreissman, B R Korf, B Lavally, H E Grier
雑誌名: J Clin Oncol. 1993 Jan;11(1):84-90.
Abstract/Text PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis.
PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors.
RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS.
CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.

PMID 8418247  J Clin Oncol. 1993 Jan;11(1):84-90.
著者: L C Bowman, R P Castleberry, A Cantor, V Joshi, S L Cohn, E I Smith, A Yu, G M Brodeur, F A Hayes, A T Look
雑誌名: J Natl Cancer Inst. 1997 Mar 5;89(5):373-80.
Abstract/Text BACKGROUND: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question.
PURPOSE: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy.
METHODS: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index > 1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m2 per day orally or intravenously on days 1-7) and doxorubicin (35 mg/m2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index = 1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m2 intravenously on day 1) and teniposide (100 mg/ m2 intravenously on day 3) after an initial course of cyclophosphamide plus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease.
RESULTS: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses--85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%-98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%-70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploid group (P = .003).
CONCLUSION: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase, would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies.

PMID 9060959  J Natl Cancer Inst. 1997 Mar 5;89(5):373-80.
著者: V Minard, O Hartmann, M C Peyroulet, J Michon, C Coze, A S Defachelle, O Lejars, Y Perel, C Bergeron, P Boutard, G Leverger, J L Stephan, A Thyss, P Chastagner, G Couillault, C Devalck, P Lutz, F Mechinaud, F Millot, D Plantaz, X Rialland, H Rubie
雑誌名: Br J Cancer. 2000 Oct;83(8):973-9. doi: 10.1054/bjoc.2000.1412.
Abstract/Text To assess the relevance of MYCN amplification and bone lesions in stage 4 neuroblastoma (NB) in infants aged <1 year, 51 infants with stage 4 NB were enrolled. Three groups of patients were defined according to the type of metastases and the resectability of the primary tumour. Group I comprised 21 infants with radiologically detectable bone lesions, Group II 22 patients with an unresectable primary tumour and Group III eight patients with only metaiodobenzylguanidine (MIBG) skeletal uptake. MYCN oncogene content was assayed in 47/51 tumours and found to be amplified in 17 (37%). The 5-year event-free survival (EFS) rate of these 51 infants was 64.1% (+/- 7.1%). In a univariate analysis, bone lesions, MYCN amplification, urinary vanillylmandelic/homovanillic acid ratio and serum ferritin levels adversely influenced outcome. In the multivariate analysis, radiologically detectable bone lesions were the most powerful unfavourable prognostic indicator: the EFS rate was 27.2% for these infants compared to 90% for infants without bone lesions (P<0.0001). Our data emphasize the poor prognosis of infants affected by stage 4 NB with bone lesions, especially when associated with MYCN amplification. Given the poor results in this group whatever the treatment, new therapeutic approaches need to be investigated in the future.

PMID 10993641  Br J Cancer. 2000 Oct;83(8):973-9. doi: 10.1054/bjoc.20・・・
著者: Katherine K Matthay, C Patrick Reynolds, Robert C Seeger, Hiroyuki Shimada, E Stanton Adkins, Daphne Haas-Kogan, Robert B Gerbing, Wendy B London, Judith G Villablanca
雑誌名: J Clin Oncol. 2009 Mar 1;27(7):1007-13. doi: 10.1200/JCO.2007.13.8925. Epub 2009 Jan 26.
Abstract/Text UNLABELLED: PURPOSE We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or to receive chemotherapy, and subsequent treatment with 13-cis-retinoic acid (cis-RA). PATIENTS AND METHODS Patients received the same induction chemotherapy, with random assignment (N = 379) to consolidation with myeloablative chemotherapy, total-body irradiation, and ABMT versus three cycles of intensive chemotherapy. Patients who completed consolidation without disease progression were randomly assigned to receive no further therapy or cis-RA for 6 months. Results The event-free survival (EFS) for patients randomly assigned to ABMT was significantly higher than those randomly assigned to chemotherapy; the 5-year EFS (mean +/- SE) was 30% +/- 4% versus 19% +/- 3%, respectively (P = .04). The 5-year EFS (42% +/- 5% v 31% +/- 5%) from the time of second random assignment was higher for cis-RA than for no further therapy, though it was not significant. Overall survival (OS) was significantly higher for each random assignment by a test of the log(-log(.)) transformation of the survival estimates at 5 years (P < .01). The 5-year OS from the second random assignment of patients who underwent both random assignments and who were assigned to ABMT/cis-RA was 59% +/- 8%; for ABMT/no cis-RA, it was 41% +/- 8% [corrected]; for continuing chemotherapy/cis-RA, it was 38% +/- 7%; and for chemotherapy/no cis-RA, it was 36% +/- 7%.
CONCLUSION: Myeloablative therapy and autologous hematopoietic cell rescue result in significantly better 5-year EFS than nonmyeloablative chemo therapy; neither myeloablative therapy with [corrected] autologous hematopoietic cell rescue nor cis-RA given after consolidation therapy significantly improved OS.

PMID 19171716  J Clin Oncol. 2009 Mar 1;27(7):1007-13. doi: 10.1200/JC・・・
著者: K K Matthay, J G Villablanca, R C Seeger, D O Stram, R E Harris, N K Ramsay, P Swift, H Shimada, C T Black, G M Brodeur, R B Gerbing, C P Reynolds
雑誌名: N Engl J Med. 1999 Oct 14;341(16):1165-73. doi: 10.1056/NEJM199910143411601.
Abstract/Text BACKGROUND: Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival.
METHODS: All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months.
RESULTS: The mean (+/-SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34+/-4 percent vs. 22+/-4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46+/-6 percent vs. 29+/-5 percent, P=0.027).
CONCLUSIONS: Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.

PMID 10519894  N Engl J Med. 1999 Oct 14;341(16):1165-73. doi: 10.1056・・・
著者: R Ladenstein, U Pötschger, O Hartman, A D J Pearson, T Klingebiel, V Castel, I Yaniv, T Demirer, G Dini, EBMT Paediatric Working Party
雑誌名: Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S118-27. doi: 10.1038/bmt.2008.69.
Abstract/Text Between 1978 and 2006, the European Group for Blood and Marrow Transplantation registered 4098 high-dose therapy (HDT) procedures followed by stem cell rescue (SCR) (3974 autologous/124 allogeneic) in patients with neuroblastoma. The 5-year rates for overall (OS) and event-free survival are 37 and 32%, respectively. The median age at diagnosis is 3.9 years (0.3-62 years) with 76 patients older than 18 years. Patients above 10 years carry a 2.5-fold higher risk. Younger patients cure significantly (<0.001) better with OS rates of 40 and 30% for age groups 2-4 years and 4-10 years, respectively. Their risks are about twofold higher than that of patients below 2 years with OS rates of 60%. The better the quality of remission status before HDT/SCT the better are the observed OS rates: 43% in CR1 (1199 patients) and 42% for CR2 (140 patients), and 36% for those in very good partial or partial remission (1413 patients) and 21% for those with sensitive relapse (134 patients). Patients reported with stable disease in first remission still had an OS rate of 30%. Multivariate analysis shows significantly better OS in the age group of less than 2 years (<0.0001), as well as a better quality of remission status before HDT/SCT (P<0.0001), with the use of peripheral stem cells (P=0.014), autologous SCT (P=0.031) and busulphan/melphalan HDT (P<0.001). Busulphan/melphalan HDT/SCT in first remission achieves an OS of 48%, while it is only 35% with other regimens (P<0.001), including melphalan alone, other melphalan-containing regimens, a variety of other drugs given as a single HDT as well as the addition of TBI or sequential HDT/SCT procedures. Further progress in the field may only be expected from large-scale international randomized trials.

PMID 18545256  Bone Marrow Transplant. 2008 Jun;41 Suppl 2:S118-27. do・・・
著者: Rani E George, Shuli Li, Cheryl Medeiros-Nancarrow, Donna Neuberg, Karen Marcus, Robert C Shamberger, Michael Pulsipher, Stephan A Grupp, Lisa Diller
雑誌名: J Clin Oncol. 2006 Jun 20;24(18):2891-6. doi: 10.1200/JCO.2006.05.6986.
Abstract/Text PURPOSE: To provide an update on long-term survival of patients with high-risk neuroblastoma treated with tandem cycles of myeloablative therapy and peripheral-blood stem-cell rescue (PBSCR).
PATIENTS AND METHODS: Ninety-seven patients with high-risk neuroblastoma were treated between 1994 and 2002. Patients underwent induction therapy with five cycles of standard agents, resection of the primary tumor and local radiation, and two consecutive courses of myeloablative therapy (including total-body irradiation) with PBSCR.
RESULTS: Fifty-one patients have experienced relapse or died. Median follow-up time among the 46 patients who remain alive without progression is 5.6 years (range, 15.1 months to 9.9 years). Progression-free survival (PFS) rate at 5 years from diagnosis was 47% (95% CI, 36% to 56%), and PFS rate at 7 years was 45% (95% CI, 34% to 55%). Overall survival rate was 60% (95% CI, 48% to 69%) and 53% (95% CI, 40% to 64%) at 5 and 7 years, respectively. The 5- and 7- year PFS rates from time of first transplantation for 82 patients who completed both transplants were 54% (95% CI, 42% to 64%) and 52% (95% CI, 40% to 63%), respectively. Five patients died from treatment-related toxicity after tandem transplantation. Relapse occurred in 37 (42%) of 89 patients, mainly within 3 years of transplantation and primarily in diffuse osseous sites. No primary CNS relapse or secondary leukemia was seen. One patient developed synovial cell sarcoma 8 years after therapy.
CONCLUSION: High-dose therapy with tandem autologous stem-cell rescue is effective for treating high-risk neuroblastoma, with encouraging long-term survival. CNS relapse and secondary malignancies are rare after this therapy.

PMID 16782928  J Clin Oncol. 2006 Jun 20;24(18):2891-6. doi: 10.1200/J・・・
著者: K W Sung, M H Son, S H Lee, K H Yoo, H H Koo, J Y Kim, E J Cho, S K Lee, Y S Choi, D H Lim, J-S Kim, D W Kim
雑誌名: Bone Marrow Transplant. 2013 Jan;48(1):68-73. doi: 10.1038/bmt.2012.86. Epub 2012 May 28.
Abstract/Text From January 2004 to December 2008, 50 consecutive patients with high-risk neuroblastoma were assigned to receive tandem HDCT (high-dose chemotherapy)/auto-SCT after nine cycles of induction chemotherapy. CEC (carboplatin + etoposide + cyclophosphamide) regimen and TM (thiotepa + melphalan)-TBI regimen (or TM regimen for stage 3 patients) were the first and second HDCT regimens. Local radiotherapy, differentiation therapy with 13-cis-retinoid acid and immunotherapy with interleukin-2 were given after tandem HDCT/auto-SCT. Of the 50 patients, 49 underwent a first HDCT/auto-SCT and 47 underwent a second HDCT/auto-SCT. The tumor relapsed or progressed in 14 patients, secondary malignancy developed in one patient and one patient died from chronic lung disease. Therefore, 34 patients remained event free with a median follow-up of 54.5 months (range, 14-94 months) from diagnosis. The probabilities of 5-year OS and EFS for all 50 patients were 77.0% (95% confidence interval (CI), 63.7-90.3) and 71.4% (95% CI, 58.7-84.1), respectively. However, all patients who remained event free for >3 years after tandem HDCT/auto-SCT experienced late adverse effects. Chemotherapeutic dose-escalation strategy using tandem HDCT/auto-SCT was very encouraging for survival. However, further studies incorporating newer treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate.

PMID 22635247  Bone Marrow Transplant. 2013 Jan;48(1):68-73. doi: 10.1・・・
著者: Alice L Yu, Andrew L Gilman, M Fevzi Ozkaynak, Wendy B London, Susan G Kreissman, Helen X Chen, Malcolm Smith, Barry Anderson, Judith G Villablanca, Katherine K Matthay, Hiro Shimada, Stephan A Grupp, Robert Seeger, C Patrick Reynolds, Allen Buxton, Ralph A Reisfeld, Steven D Gillies, Susan L Cohn, John M Maris, Paul M Sondel, Children's Oncology Group
雑誌名: N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
Abstract/Text BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.
METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.
RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).
CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

PMID 20879881  N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056・・・

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