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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1504-1510 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.3349 Localized Infant Neuroblastomas Often Show Spontaneous Regression: Results of the Prospective Trials NB95-S and NB97
From the Children's Hospital, University of Cologne; Children's Hospital, Augsburg; Children's Hospital, University of Tuebingen; Children's Hospital, University of Frankfurt, Frankfurt; and the Olgahospital, Stuttgart, Germany Corresponding author: Barbara Hero, MD, Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany; e-mail: barbara.hero{at}uk-koeln.de
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.
Neuroblastoma is known to show the highest rate of spontaneous regression among malignant tumors.1 Besides the well-known spontaneous regression in stage 4S disease,2-4 the high incidence of neuroblastic remnants found during autopsies of newborns suggested for the first time that localized lesions (designed as neuroblastic rests) may undergo a similar process.5,6 In the 1990s, screening studies reported a two- to three-fold higher incidence of neuroblastoma in areas with screening programs.7-11 This so-called overdiagnosis was explained by spontaneous regression and supports the hypothesis of spontaneous regression in non–stage 4S neuroblastoma. Finally, the prognosis for infants with stage 2 and 3 neuroblastoma is known to be excellent even without or with minimal cytotoxic treatment.12-14 Some case reports of patients experiencing spontaneous regression in stages other than stage 4S have also been published.15-21 From those data, we hypothesized that localized neuroblastoma in infancy may—to an unknown extent—undergo spontaneous regression and that observation of those patients without cytotoxic treatment would be justified in the setting of a controlled, prospective trial.
The national multicenter trial NB95-S of the German Society of Pediatric Oncology and Hematology (GPOH) was activated in 1995 for infants with localized neuroblastoma. This policy was later adopted in the trial NB97 without changes.22 Both trial protocols were approved by the ethics committee of the University of Cologne (Cologne, Germany). We here report results of both trials covering a time period of nearly 10 years and analyzed the data of all infants with neuroblastoma stage 1, 2, or 3 according to the International Neuroblastoma Staging System (INSS)23 meeting the following criteria: (a) registration in the trial NB95-S or NB97, (b) diagnosis between June 1,1995, and September 30, 2004, (c) age at diagnosis was 365 days or younger, (d) written informed consent from guardian, and (e) histologically verified neuroblastoma without MYCN-amplification. Chemotherapy was scheduled only for infants demonstrating threatening symptoms (defined in the trial protocol) caused by the tumor (eg, threatening kidney, respiratory, or bowel failure, transverse myelopathy, deteriorating poor general condition). In asymptomatic cases, complete resection was recommended only if the risk of operation was considered to be low. Otherwise, the residual tumor was observed after biopsy or incomplete resection without cytotoxic treatment. Infants younger than 3 months at clinical diagnosis could be observed before obtaining histologic verification. Instructions to handle localized neuroblastoma in infancy, as described herein, were given in the trial protocol, but the local investigator decided whether to follow the observation strategy, to attempt for surgical resection, or to utilize chemotherapy in case of symptoms. For retrospective analysis, the patients were assigned into the following groups according to the therapeutic intervention (Fig 1): (a) infants with chemotherapy (n = 57)—treated either with N4 cycles (doxorubicin, vincristine, cyclophosphamide; for infants < 6 months) or with alternating cycles N5 (cisplatin, etoposide, vindesine) or N6 (vincristine, dacarbazine, ifosfamide, doxorubicin), as reported in detail elsewhere22; (b) infants with resected tumors (n = 190)—after complete resection (as reported by the surgeon and confirmed by postoperative staging investigations) or after nearly complete resection (residual primary tissue not > 1 cm in diameter in each direction demonstrated in postoperative imaging); or (c) infants with unresected tumors (n = 93)—observed without chemotherapy for at least 4 weeks; either after biopsy, after incomplete resection with residual primary tissue exceeding 1 cm in diameter in each direction, or after clinical diagnosis before the histologic verification.
Histologic diagnosis of neuroblastoma was established locally for all patients and confirmed by a reference pathologist in 326 of 340 eligible patients (96%) and in 92 of 93 patients with unresected tumors (99%). MYCN was assessed in one or more central laboratories using fluorescence in situ hybridization (FISH; H. Christiansen, Marburg), polymerase chain reaction (PCR; M. Schwab, Heidelberg) and/or Southern blot techniques (R. Spitz, Cologne). Aberrations in 1p, 3p, and 11q, and somy chromosome 1 were assessed by FISH, and CD44 and TrkA expression by immunohistochemistry, as outlined previously.24,25 During the observation period, ultrasound was scheduled at 6-week intervals and magnetic resonance imaging (MRI) at 3-month intervals for patients with primary tumors assessable by ultrasound. Alternating chest x-ray and MRI were scheduled at 6-week intervals for patients with thoracic tumors. If progression was observed, complete staging was required before any cytotoxic treatment. The observation period was defined as the end of the first year of life, or, for patients older than 6 months at diagnosis, for at least 6 months. Because regression was observed after the first year of life in the interim analysis of the trial, observation period was extended until the end of the second year of life. Regression of the primary was defined as unambiguous decrease of tumor volume observed in at least two subsequent imaging studies. Time to regression was calculated as the time from diagnosis to the time of first signs of regression seen in imaging; time to complete regression as the time to no evidence of residual tumor. Local progression was defined according International Neuroblastoma Response Criteria (INRC),23 or clinically (mainly because of symptoms) as unambiguous progression of the primary tumor in imaging studies leading to therapeutic intervention (surgery or chemotherapy). The local investigator decided on the intervention without confirmation of progression by central review. Metastatic progression was defined as occurrence of metastases compatible with stage 4S (liver, skin, or minimal bone marrow involvement)23 or as metastatic stage 4 pattern with bone marrow involvement exceeding 10% or with bone, distant lymph node or CNS metastases. Event-free-survival (EFS) was calculated as time from diagnosis to an event or to the date of last assessment in patients without events. Events were progression as defined above and death from any cause. Metastases (stage 4)–free survival was calculated as time from diagnosis to occurrence of stage 4 pattern metastases; chemotherapy-free interval was calculated as time from diagnosis to start of chemotherapy. Time-to-event distributions were displayed according to the Kaplan-Meier method and compared with the log-rank test. Categoric variables were compared with Fisher's exact test, and continuous variables with the Mann-Whitney U test.
From June 1, 1995, to September 30, 2004, a total of 358 infants with localized neuroblastoma had been registered (Fig 1). Eighteen patients did not meet the eligibility criteria (MYCN not investigated in seven; and MYCN amplified in 11 patients; 3-year EFS, 0.73 ± 0.13; 3-year overall survival [OS], 0.91 ± 0.09). Of 340 eligible patients with MYCN-not-amplified tumors, 157 had stage 1, 113 stage 2, and 70 stage 3 disease. Fifty-seven patients were treated with chemotherapy (stage 1, n = 1; stage 2, n = 15; stage 3, n = 41), which was administered to control threatening symptoms as recommended in 46 patients, and without symptoms in 11 patients. Symptoms included existing or threatening transverse myelopathy (n = 23), compression of the urinary tract (n = 9), upper airways (n = 6), or major vessels (n = 3), severely reduced general condition (n = 4), and opsoclonus-myoclonus-syndrome (n = 1). The primary tumor was resected in 190 patients. Complete resection was achieved in 177 (stage 1, n = 156; stage 2b, n = 15; stage 3, n = 6) and nearly complete resection in 13 patients (stage 2, n = 11; stage 3, n = 2).
Patients With Observation of Unresected Primary At the end of the scheduled observation time, no change in tumor size was seen in 10 of 93 patients with unresected tumors. The observation period was extended in one, chemotherapy started in another, and complete resection achieved in eight patients, either as delayed first surgery 2 to 5 months after clinical diagnosis (n = 7), or as second surgery 8 months after incomplete primary resection (n = 1). Thirty-nine of 93 patients experienced progression (28 locally, seven to stage 4S, and four to stage 4). Fifteen patients with local progression were treated with chemotherapy ± surgery, and 13 underwent complete resection as second surgery (n = 3) or as first delayed surgery after initial clinical diagnosis (n = 10). Of seven patients with progression to stage 4S, two were treated with chemotherapy. In the others, the primary tumor was either further observed or resected. Of note, in one of those patients, the primary tumor had already regressed, at the time when liver metastases occurred. Four patients progressed to stage 4 and were treated with high-risk therapy regimens. Patients with local progression or 4S progression received one to six cycles of chemotherapy (median, 4 cycles). In total, 22 of 93 infants with unresected tumors received chemotherapy because of progression (n = 21) or lacking regression (n = 1). Chemotherapy-free interval rate at 3 years was 0.70 ± 0.05. Twenty-six patients underwent secondary surgery after progression (n = 19), with unchanged primary (n = 1) or after incomplete regression (n = 6). Surgical morbidity was not different between patients with initial surgical procedures, delayed first surgery after previous clinical diagnosis, or secondary resection after observation.
Regression
Median age of patients with regression was 1.5 months (range, 0 to 12 months) at diagnosis and 6.7 months (range, 1 to 23 months) at first signs of regression. Time to first signs of regression ranged from 1 to 18 months (median, 3.3 months) and the time to complete regression from 4 to 20 months (median, 10 months; Fig 3). Fifteen patients (34%) showed first signs of regression after the first year of life. Five of them have developed complete regression, so far.
Of 27 patients with incomplete regressed tumors, 11 underwent surgery 1 to 76 months after diagnosis (five delayed first surgeries; six second surgeries), whereas 17 patients still are under further observation with residual primary tissue left (three in partial remission, 14 in very good partial remission according to INRC23). In three patients, a substantial residual primary tumor was observed beyond the second year of life after previous minimal regression. Normalization of catecholamine metabolites was seen in all three patients. [131I]Metaiodobenzylguanidine (MIBG) scintigraphy was repeated in two patients, and showed decreased uptake in one and normalization in the other. One patient is currently under observation with a residual tumor 7 years after diagnosis. In both other patients, the tumor was completely resected 30 and 76 months after diagnosis, with histologic signs of maturation (cells with cytomorphologic differentiation toward ganglion cells, higher proportion of the ganglioneuromatous component).
Comparison of Regression and Progression
In 69 (72%) of 93 patients with unresected tumors, the neuroblastoma was found incidentally (prenatal ultrasound in 12, neuroblastoma screening in two, preventive medical check-up at the pediatrician in 30, and imaging studies for other causes in 25). Incidental diagnoses characterized a similar portion of patients belonging to the groups with regressing, locally progressing, and metastatic tumors. Molecular findings were most often favorable in the tumors investigated. Only nine patients with unresected neuroblastoma showed aberrations of chromosome 1p, 3p, or 11q. Although those aberrations were seen in 3 of 4 patients with progression to stage 4, they have also been found in a few patients with regression (n = 1) or with local (n = 4) or 4S (n = 1) progression. Aberrations in chromosome 11q seemed a promising marker and were found in five patients with progression (P = .05), but only two of them progressed to stage 4 and were treated with high-risk regimens. Two experienced local progression and were treated with surgery only. One patient was treated with minimal chemotherapy because of progression to stage 4S. Somy of chromosome 1, expression of CD44 and of TrkA were not helpful in discriminating between patients with regression and progression.
EFS and OS
Progression to stage 4 was seen in 11 patients of the whole cohort (whole cohort, 11 of 340; unresected tumor, four of 93, chemotherapy, two of 57, resected tumor, five of 190) with bone metastases, defined by positive bone scan, in five patients. Metastases (stage 4)–free survival at 3 years was 0.96 ± 0.01 and was not different between the groups (unresected tumor, 0.94 ± 0.03; chemotherapy, 0.96 ± 0.03; resected tumor, 0.97 ± 0.01; P = .51; Fig 4C). After metastatic progression, all 11 patients were treated with intensive chemotherapy, three of them with megatherapy followed by autologous stem-cell rescue. So far, one patient has died; the other 10 patients are in complete remission or very good partial remission 17 to 126 months after progression. Of those 11 patients with progression to stage 4, three of eight patients showed 1p aberrations and two of nine patients had 11q aberrations. At least one of both aberrations was present in tumors of five of eight patients.
We here report the results of a prospective trial investigating the phenomenon of spontaneous regression of unresected neuroblastoma in infants. This is, to our knowledge, the first prospective trial addressing this question in an unselected cohort of infants with localized neuroblastoma without MYCN amplification, including stage 3 neuroblastoma. Our data provide strong evidence that spontaneous regression can regularly be seen in localized infant neuroblastoma, as has been well known for many years for stage 4S neuroblastoma. Tumor regression without cytotoxic therapy was seen in 47% of our patients with unresected neuroblastoma. We speculate that the percentage of regression even would have been higher if a certain degree of tumor growth had been accepted without therapeutic intervention. In 10 patients with unresected tumors, asymptomatic tumor growth was merely found in imaging studies, and regression followed the progression in all of these cases. Since the initiation of this prospective trial, several series have been published reporting on regression of infant neuroblastoma found during the Japanese screening studies27-30 or incidentally.31 These series included only patients with small tumors not exceeding 5 cm in diameter, most of them adrenal. The percentage of regressing tumors varied between 59% and 92%, and was slightly higher than the percentage reported here, whereas complete regression was only reported from four of all 44 patients with regression compared with 16 of 44 in our study. Our analysis may be somewhat hampered by the fact that the local investigators decided on the observation strategy and on the time point of intervention. Thus, the number of spontaneously regressing neuroblastomas is influenced by the clinical experience and the therapeutic attitude of the observing physician. In contrast to the aforementioned trials, however, our study included older patients, larger tumors (including INSS stage 3), and tumors considered difficult to resect. A substantial number of tumors regressed in all those subgroups (Table 1), demonstrating a common principle. Nonetheless, a selection bias spread over the 65 participating hospitals cannot be excluded. Subgroup analysis investigating clinical risk factors was not able to identify groups with a higher probability of regression or progression. Patients with MYCN amplification were, because of the bad prognosis, not eligible for this trial, but have been treated according the high-risk arm of the trial. Currently available molecular markers, other than MYCN, were not helpful in discriminating cases with regression from those with local or metastatic (4S) progression, but the numbers of patients with available molecular data was limited. We hypothesize that patients with regression and patients with local/4S progression may be part of a similar biologic entity, but were just diagnosed at a different time point and with a different extent in the course of the disease. We further hypothesize that there are no or only minor biologic differences between the majority of localized neuroblastoma in infancy and stage 4S neuroblastoma. Progression before regression, variable time course of regression, and different kinetics of tumor and metastases development are observed in stage 4S disease as well. Localized infant neuroblastoma may reflect a stage 4S disease in different phases. It is possible that metastases have already totally regressed or are so discrete that they escape staging investigations, or that the metastases have not yet emerged, as we have seen in seven cases, where metastases to liver or to bone marrow developed during follow-up. Similar to stage 4S disease, the time course of regression in localized tumors was variable with time to first signs of regression between several weeks to more than a year. Yamamoto et al28 hypothesized that regression starts at the age of 6 months or earlier. In our series, we could clearly demonstrate that regression may start at an older age. One third of the patients showed first signs of regression after their first birthday. These findings are in line with the results of the German neuroblastoma screening study showing an overdiagnosis even at the "late" screening age of 10 to 18 months.32 This overdiagnosis can be explained only by a possible spontaneous regression of those tumors, which would have gone unnoticed if they had not been found by screening. Not all regressing tumors continued to complete regression. In three patients, substantial residual tumors after some degree of regression were observed beyond the second year of life and showed clinical signs of maturation with normalization of catecholamine metabolite levels and decreasing of MIBG uptake. Differentiation was confirmed in two tumors histologically. Again, we find parallels to stage 4S disease, where differentiation has been described clinically33-35 and where genes of neuronal differentiation are, compared with stage 4, overexpressed.36 As patients with ganglioneuroblastoma or ganglioneuroma are known to be older at diagnosis than are patients with neuroblastoma, their tumors may originate from incomplete regressing, but differentiating, infant neuroblastoma diagnosed at an older age. Progression to stage 4 was seen in 11 of 340 patients from all three groups. Metastatic progression seemed to be more often detected in patients with aberrations in chromosome 1p or chromosome 11q,37,38 although those aberrations were found in a few patients with a benign course of the disease as well. On the other hand, metastatic stage 4 relapse occurred in patients with normal 1p and 11q status (three of eight patients with both markers tested). Altogether, the numbers of patients with available data was too small to draw final conclusions. We strongly believe that the patients with progression to stage 4 do not belong to the "benign infant neuroblastoma" entity. Newer techniques addressing gene expression (eg, array techniques) may hopefully be able to identify those patients in the future.39 In conclusion, this study provides strong evidence for spontaneous regression in localized neuroblastoma in infancy. Spontaneous regression leads to complete regression in a considerable number of patients and may be observed well after the first year of life. A wait-and-see strategy avoiding chemotherapy and extensive surgical procedures is justified in infants with localized neuroblastoma, unless MYCN is amplified. The current trial, NB2004, follows the lines reported here for infants and seeks to expand the observation group to selected patients older than 1 year of age.
The author(s) indicated no potential conflicts of interest.
Conception and design: Barbara Hero, Frank Berthold Provision of study materials or patients: Astrid K. Gnekow, Hans-Guenther Scheel-Walter, Dirk Schwabe, Freimut H. Schilling Collection and assembly of data: Barbara Hero, Thorsten Simon, Ruediger Spitz Data analysis and interpretation: Barbara Hero, Thorsten Simon, Ruediger Spitz, Frank Berthold Manuscript writing: Barbara Hero Final approval of manuscript: 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
In addition to the authors’ patients, patients of the following hospitals participated in this study: Children's University Hospital Aachen (R. Mertens); Children's Hospital Aarau (R. Angst); Children's Hospital Bamberg (U. Gloeckel); Children's University Hospital Basel (T. Kuehne); Children's Hospital Bayreuth (T. Rupprecht); Children's University Hospital Berlin (G. Henze); Children's Hospital Berlin-Buch (W. Doerffel); Children's Hospital Bielefeld (N. Jorch); Children's University Hospital Bonn (U. Bode); Children's Hospital Braunschweig (W. Eberl); Children's Hospital Bremen (A. Pekrun); Children's Hospital Chemnitz (I. Krause); Children's Hospital Coburg (R. Frank); Children's Hospital Datteln (T. Wiesel); Children's Hospital Dortmund (H. Olschewski); Children's University Hospital Dresden (M. Suttorp); Children's University Hospital Düsseldorf (U. Goebel); Children's Hospital Erfurt (A. Sauerbrey); Children's University Hospital Erlangen (J.D. Beck); Children's University Hospital Essen (B. Kremens); Children's University Hospital Freiburg (C. Niemeyer); Children's University Hospital Gieβen (A. Reiter); Children's University Hospital Göttingen (L. Schweigerer); Children's University Hospital Greifswald (J.F. Beck); Children's University Hospital Halle (D. Körholz); Children's Hospital Halle (G. Günther); Children's University Hospital Hamburg (R. Erttmann); Children's University Hospital Hannover (K. Welte); Children's Hospital Hannover (U. Hofmann); Children's University Hospital Heidelberg (A. Kulozik); Children's Hospital Herdecke (A. Laengler); Children's University Hospital Homburg (N. Graf); Children's University Hospital Jena (F. Zintl); Children's Hospital Karlsruhe (A. Leipold); Children's Hospital Kassel (M. Rodehueser); Children's Hospital Kassel-Park Schoenfeld (M.L. Wright); Children's University Hospital Kiel (A. Claviez); Children's Hospital Koblenz (R. Ferrari); Children's Hospital Cologne (W. Sternschulte); Children's Hospital Krefeld (S. Voelpel); Children's University Hospital Leipzig (U. Bierbach); Children's University Hospital Lübeck (P. Bucsky); Children's Hospital Ludwigshafen (B. Selle); Children's Hospital Luzern (U. Caflisch); Children's University Hospital Mainz (P. Gutjahr); Children's Hospital Mannheim (M. Duerken); Children's University Hospital Marburg (H. Christiansen); Children's University Hospital Munich LMU (A. Borkhardt); Children's University Hospital Munich TU (S. Burdach); Children's University Hospital Muenster (H. Juergens); Children's Hospital Neubrandenburg (H.-J. Feickert); Children's Hospital Neunkirchen (O. Schofer); Children's Hospital Nuernberg (W. Scheurlen); Children's Hospital Oldenburg (H. Mueller); Children's Hospital Regensburg (O. Peters); Children's University Hospital Rostock (G. Eggers); Children's Hospital Schwerin (R. Schumacher); Children's Hospital Siegen (R. Burghard); Children's Hospital St. Augustin (R. Dickerhoff); Children's Hospital St. Gallen (J. Greiner); Children's Hospital Trier (W. Rauh); Children's University Hospital Ulm (K.-M. Debatin); Children's Hospital Wuppertal (B. Dohrn); Children's University Hospital Würzburg (P.-G. Schlegel); and Children's Hospital Zürich (F. Niggli).
We thank the laboratories of Holger Christiansen and Manfred Schwab for MYCN analysis (Southern blot and polymerase chain reaction). Special thanks to Martina Breuer, Monika Schmitz, and Heike Schroeder-Berg for their excellent work in the German Neuroblastoma Trial Office.
Supported by grants from the Deutsche Krebshilfe. Presented in part at the Advances of Neuroblastoma Research Meeting, May 17-20, 2006, Los Angeles, CA. Clinical trials Nos. NCT00002803 [ClinicalTrials.gov] and NCT00017225 [ClinicalTrials.gov] . Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
