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Journal of Clinical Oncology, Vol 22, No 19 (October 1), 2004: pp. 3909-3915
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.07.144
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Scintigraphic Response by 123I-Metaiodobenzylguanidine Scan Correlates With Event-Free Survival in High-Risk Neuroblastoma

Howard M. Katzenstein, Susan L. Cohn, Richard M. Shore, Dianna M.E. Bardo, Paul R. Haut, Marie Olszewski, Jennifer Schmoldt, Dachao Liu, Alfred W. Rademaker, Morris Kletzel

From the Division of Hematology/Oncology, Department of Pediatrics, Department of Radiology, and Stem Cell and Graft Engineering Laboratory, Northwestern University and Children's Memorial Hospital, Chicago, IL; Biostatistics Core Facility, The Robert H. Lurie Comprehensive Cancer Center, and Northwestern University Feinberg School of Medicine, Chicago, IL; Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA; James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN.

Address reprint requests to Morris Kletzel, MD, Northwestern University, Children's Memorial Hospital, 2300 Children's Plaza, Box #30, Chicago, IL 60614; e-mail: mkletzel{at}northwestern.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB).

PATIENTS AND METHODS: Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated.

RESULTS: A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% ± 11% v 80% ± 18%, respectively; P = .13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% ± 10% v 83% ± 15%, respectively; P = .06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of ≥ 3 compared to those with scores of less than 3 (0% v 58% ± 11%; P = .002). There was no correlation between bone scan scores and outcome following induction therapy.

CONCLUSION: MIBG scores ≥ 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
During the last 20 years, advances in the understanding of neuroblastoma (NB) tumor biology have resulted in the identification of prognostic variables that have been used to define risk-group criteria and guide therapy.1-2 Treatment tailored according to risk-group stratification has resulted in improved outcome and diminished toxicity for children with low- and intermediate-risk disease.3-4 However, children with high-risk NB have had only a slight improvement in outcome despite treatment with aggressive multimodality therapy. Currently, less than 30% of high-risk patients are cured of their disease.5-7

The modest improvement in survival of high-risk patients is thought to result, at least in part, from intensification of therapy.8 A number of nonrandomized studies have suggested that dose-intensification with myeloablative therapy and autologous bone marrow transplant results in an improved outcome for high-risk NB patients.5,9-11 The superiority of myeloablative therapy and autologous bone marrow transplant over conventional dose chemotherapy has been definitively demonstrated in a randomized study conducted by the Children's Cancer Group.6 Recently, we and others have reported 3-year EFS rates of ~50% in pilot studies in which consolidation was further dose-intensified with two or three cycles of high-dose therapy plus peripheral blood stem cell (PBSC) support.12-13 However, a large number of children will not be cured with this intensive multimodality therapeutic approach, and alternative treatment strategies should be considered in this resistant subset of patients. Unfortunately, at the present time, it is difficult to distinguish the group of children who are likely to achieve long-term remission with intensive multimodality therapy from those who are destined to fail, as the biologic prognostic factors that have been identified in NB have limited value within the high-risk cohort of children.14-18

Early response to therapy has been shown to have prognostic significance in many types of childhood cancers.19-21 Metaiodobenzylguanidine (MIBG) uptake has also been shown to be a highly sensitive and specific method to detect NB and to evaluate the response to therapy.22,23 Several retrospective studies have indicated that a positive MIBG scan at diagnosis or before myeloablative therapy may be predictive of a poor outcome in high-risk patients.24-27

In this study, we prospectively evaluated osteomedullary uptake on diagnostic and postinduction therapy MIBG and 99mTc-diphosphonate bone scintigraphs in 29 high-risk NB patients who received uniform intensive multimodality treatment that included three cycles of high-dose chemotherapy with PBSC rescue.12 The nuclear medicine images were semi-quantitatively scored using criteria previously described,28 and the prognostic significance of the imaging scores was evaluated. Our results suggest that patients with MIBG scores of ≥ 3 following induction therapy have an increased risk of relapse and death.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patients
The clinical characteristics of the initial 26 patients enrolled on the Chicago Pilot II protocol at Children's Memorial Hospital (Chicago, IL) have been published previously.12 Three subsequent patients who were enrolled on the Chicago Pilot II study following that report are included in this analysis, including a child who relapsed with local and widely disseminated disease after initial treatment with surgery alone for stage 2B disease. Two additional stage 4 patients were transferred to our institution, after receiving the induction therapy outlined in the study, for consolidation therapy with the three cycles of high-dose chemotherapy and PBSC rescue followed by local radiation and 13-cis-retinoic acid. Because toddlers between the ages of 12 and 18 months of age with stage 4 disease have been reported to have better outcomes than older patients,29,30 we restricted the current study to the 28 high-risk patients with stage 4 disease who were older than 18 months of age at diagnosis, and the single relapsed patient described above. The Chicago Pilot II protocol was approved by the Children's Memorial Hospital institutional review board, and written informed consent was obtained for each patient before the initiation of treatment. Written informed consent for consolidation therapy was also obtained for each of the patients transferred to our institution after induction therapy.

The diagnosis of NB was based on either histologic examination of tumor tissue or by bone marrow infiltrated with tumor cells and elevated urinary catecholamine levels. MYCN copy number was analyzed at the time of diagnosis either by Southern blot analysis or fluorescence in situ hybridization at the Pediatric Oncology Group or Children's Oncology Group reference laboratories using standard techniques.14,17,31 All patients were staged according to International Neuroblastoma Staging System (INSS) criteria,32 and extent of disease was evaluated by computed tomography of the chest and abdomen, 99Tc bone scan, bilateral bone marrow aspirates and biopsies, and MIBG scan. The response to therapy was assessed according to INSS criteria after four cycles of induction chemotherapy and again following completion of the induction regimen (seven cycles of therapy), just before consolidation with high-dose therapy and PBSC rescue.

Treatment
All patients received four initial cycles of multiagent induction chemotherapy as previously described.12 Surgical resection of all gross residual disease was then performed if the tumor was considered resectable. Patients then received three cycles of high-dose cyclophosphamide, and PBSCs were collected following each cycle as detailed elsewhere.33 In some patients with tumors that were previously considered unresectable, surgery was performed after the three cycles of high-dose cyclophosphamide. Tumor response was then re-evaluated with imaging studies, measurement of urinary catecholamines, and repeat bilateral bone marrow aspirates and biopsies. Patients with adequate organ function, no evidence of active infection, and no evidence of disease progression then proceeded to consolidation therapy consisting of three cycles of high-dose therapy and PBSC rescue followed by local radiation to the site of the primary tumor. Metastatic foci were not radiated, regardless of whether or not there was persistent MIBG positivity. All patients diagnosed after September 1996 (n = 19) received 13-cis-retinoic acid beginning 80 to 100 days following the last cycle of high-dose therapy and PBSC rescue.

Hematopoietic Stem-Cell Processing
PBSCs were harvested and processed as previously described.12,33 Aliquots were removed to perform total cell count, CD34+ cell quantification, hematopoietic progenitor cell assays, and bacterial and fungal cultures.

MIBG Analysis
MIBG labeling was performed according to the method of Mock and Weiner.34 At diagnosis, the scintigrams were obtained after a slow intravenous injection of 123I-MIBG in 24 patients (minimum administered dose was 5.0 mCi; maximum administered dose was 8.5 mCi as determined by weight). Patients were pretreated with potassium iodide (Lugols solution) or a supersaturated solution of potassium iodide which was administered orally before radiopharmaceutical administration and was continued following imaging for a total of 5 days to prevent thyroid uptake of free radioactive iodine. No breakdown of the radiopharmaceutical was documented. Multiple anterior and posterior spot scintigrams of the entire body including the cranium were obtained 20 hours following radiopharmaceutical injection using a scintillation camera set to a photopeak of 159 keV with a 20% window. A minimum of 300,000 counts and a maximum of 500,000 counts were obtained for each view. 131I-MIBG was administered to three patients who had diagnostic studies performed at outside institutions. 123I-MIBG was used in all the MIBG studies performed following induction therapy.

MIBG scintigrams and 99Tc bone scans were reviewed by two radiologists (D.M.E.B. and R.M.S.) without knowledge of the interpretation of the original report. The diagnostic scintigrams were initially interpreted by one of four board-certified radiologists. A consensus was then achieved between the original interpretation and the retrospective review of the MIBG studies. Twenty-five MIBG scans and 29 bone scans performed at diagnosis were available for review. For two patients initially treated elsewhere, the diagnostic MIBG was not retrievable for review but review of the written radiographic reports did allow interpretation of whether the scans were positive or negative, and so these patients was considered assessable for radiographic response, but imaging scores could not be determined. Two patients were excluded from the MIBG analysis for the following reasons: no scan was performed at diagnosis (n = 1); and the patient had an allergic reaction to contrast before the initial scan (n = 1). Twenty-four MIBG studies and 27 bone scans were performed before the three cycles of high-dose therapy and stem-cell rescue. The five patients who did not have assessable MIBG scans before consolidation included two patients with tumors that were not MIBG-avid, one patient who had a toxic death during induction therapy, and the two patients mentioned above who were excluded at diagnosis.

MIBG and Bone Scintigram Scoring
To standardize the comparison between MIBG and bone scintigrams, the skeleton was divided into 10 zones using a method we have previously reported28: (1) calvarium; (2) base of the skull-face; (3) cervico-thoracic spine; (4) lumbo-sacral spine; (5) ribs, sternum, and scapula; (6) pelvis; (7) upper arms; (8) forearms and hands; (9) upper legs; and (10) lower legs and feet. For each of these zones, the presence of radionuclide localization was scored as follows: 0, no pathologic localization; 1, abnormal localization in one locus; 2, abnormal localization in more than one locus but less than 50% of the zone involved; 3, abnormal localization in ≥ 50% of the skeletal zone. To ensure reproducibility, intensity of localization was not taken into account in this analysis. A total MIBG or bone scintigram score was then calculated by adding the individual scores of all 10 zones (maximum score of 30). This scoring system is quite similar to that developed and used at the Institute Curie (Paris, France).25,27 Scintigraphic response was also evaluated for both MIBG and bone scans comparing avidity at any site (positive) with no abnormal localization (negative). In addition, scintigraphic response for MIBG was evaluated comparing any osteomedullary avidity (positive) versus no osteomedullary avidity (negative).

Statistical Analysis
EFS rates from the time of diagnosis of patients according to both MIBG and bone scintigram scores at diagnosis and following induction therapy were compared. MIBG scans were also analyzed according to whether or not there was any abnormal osteomedullary uptake. Similar analyses were performed for bone scintigrams. The Kaplan-Meier method was used to estimate 6-year EFS probabilities expressed as rate ± SE.35 EFS functions were compared by the log-rank test. The calculations were done in SAS (version 8.2, SAS Institute, Cary, NC). The cut-off date for the analyses was December 17, 2003.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
The clinical and biologic characteristics of the 29 patients included in this study are shown in Table 1. The median age at diagnosis was 43 months (range, 19 to 176 months). Twenty-eight of the patients had stage 4 disease at diagnosis, and tumor MYCN amplification was present in 10 cases. An additional patient who developed widely disseminated relapsed disease after an initial diagnosis of a stage 2B tumor that lacked MYCN amplification was included in the analysis. The 4-year estimated EFS rate for the entire cohort was 45% ± 9%, with a median follow-up of 72 months (range, 30 to 95 months) from diagnosis for the disease-free surviving patients.


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  		Table 1. Clinical and Biologic Characteristics of High-Risk Neuroblastoma Patients

 
Diagnostic MIBG and Bone Scintigraphy
Twenty-nine patients had diagnostic imaging studies that were available for analysis. Twenty-five (93%) of 27 patients had MIBG avid tumors, and 20 had evidence of osteomedullary disease (Table 2). We were unable to determine MIBG scores in two patients who were initially treated elsewhere because only radiographic reports were available for review. The diagnostic MIBG score was calculated for 25 of the patients in our study, and the mean score was 8 (range, 0 to 27) with a median score of 4. Discrepancies between the MIBG and bone scintigraphy results were observed in one child who had an abnormal bone scintigram but had no abnormal osteomedullary localization on MIBG scan. No patient in this series with abnormal osteomedullary MIBG localization at diagnosis had a normal initial bone scintigram. Patients with osteomedullary disease detected by MIBG imaging at diagnosis tended to do worse, with a 4-year EFS rate of 35% ± 11%, compared to 80% ± 18% for those without osteomedullary uptake (P = .13; Table 2; Fig 1A). However, no difference in outcome was seen in patients with diagnostic MIBG scores ≥ 8 versus those with scores less than 8 (6-year EFS, 42% ± 14% v 55% ± 15%, respectively; P = .43).


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  		Table 2. Outcome According to Diagnostic MIBG and Bone Scan Scintigraphy

 


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  		Fig 1. (A) Kaplan-Meier analysis of event-free survival (EFS) for patients with high-risk neuroblastoma (NB) based on positive (POS; n = 20) or negative (NEG; n = 5) osteomedullary uptake on the diagnostic metaiodobenzylguanidine (MIBG) scan (P = .13); and (B) Kaplan-Meier analysis of EFS for patients with high-risk NB based on positive (n = 23) or negative (n = 6) diagnostic bone scan (P = .06).

 
The diagnostic bone scan was positive in 23 of the 29 patients. The estimated 4-year EFS was better for patients with negative diagnostic bone scans compared to those with abnormal skeletal uptake (83% ± 15% v 34% ± 10%, respectively; P = .06; Table 2; Fig 1B). The diagnostic bone scan scores were calculated for all 29 of the patients. The mean bone scan score was 9 (range, 0 to 20) with a median score of 9 as well. No difference in outcome was observed in patients with diagnostic bone scan scores above or below the mean (40% ± 13% v 50% ± 13%, respectively; P = .54).

MIBG and Bone Scintigraphy Following Induction Therapy
MIBG scans were performed in 24 children and bone scan imaging studies were performed in 27 children following the completion of induction therapy. Five patients were not assessable at this time: two patients had tumors that were not MIBG avid; one patient did not have a diagnostic MIBG scan; one patient had an allergic reaction to the contrast; and one patient had a toxic death before completing induction therapy. A discrepancy between the MIBG and bone scintigraphy results was seen in eight children. Three patients had abnormal MIBG localization in the skeleton with a normal bone scan, while five children had abnormal bone scintigrams, but had no osteomedullary localization detected by MIBG scan.

Fifteen of the 24 patients who were evaluated by MIBG scan postinduction therapy had persistently abnormal uptake; 10 patients had uptake in the primary tumor and eight patients had persistent positive osteomedullary uptake (Table 3). The mean postinduction MIBG score was 3 (range, 0 to 22) with a median score of 0. Patients with MIBG scores ≥ 3 had a significantly worse outcome than those with scores less than 3 (4-year EFS, 0% v 58% ± 11%, respectively; P = .002; Table 3; Fig 2A). When the scoring system was not utilized, a trend associating worse outcome for patients with osteomedullary uptake by MIBG scan compared to those without uptake was seen (25% ± 15% v 56% ± 12%, respectively; P = .12; Table 3). Analysis of the entire cohort revealed an inferior EFS in patients who had any remaining MIBG avidity in either bone or tumor compared to those whose MIBG scans had completely returned to normal (27% ± 11% v 78% + 14%, respectively; P = .05; Fig 2B).


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  		Table 3. Outcome According to Post-Induction MIBG and Bone Scan Scintigraphy

 


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  		Fig 2. (A) Kaplan-Meier analysis of event-free survival (EFS) for patients with high-risk neuroblastoma (NB) with metaiodobenzylguanidine (MIBG) scores ≥ 3 (n = 5) or < 3 (n = 19) at the time of high-dose therapy and peripheral blood stem-cell (PBSC) rescue (P = .002); and (B) Kaplan-Meier analysis of EFS for patients with high-risk NB with abnormal (n = 15) or normal (n = 9) MIBG scans at the time of high-dose therapy and PBSC rescue (P = .05).

 
Twenty-seven patients had bone scans performed after the completion of induction therapy. The bone scintigrams were abnormal in 10 patients. The mean postinduction bone scan score was 1 (range, 0 to 10) with a median score of 0. The bone scan score was not predictive of outcome. The 4-year EFS was 33% ± 16% for patients with a bone scan score ≥ 2 compared to 56% ± 12% for those with a bone scan score of less than 2 (P = .48). Similarly, when the scoring system was not used, no statistically significant difference in EFS was seen in patients with abnormal bone scans compared to those with normal bone scans (30% ± 14% v 59% ± 12%, respectively; P = .32; Table 3).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
The results of this prospective analysis of 29 children with high-risk NB indicate that postinduction therapy MIBG imaging studies can be utilized to identify a subset of ultra–high-risk patients. A trend associating worse outcome with abnormal osteomedullary uptake by MIBG or bone scintigraphy at diagnosis was also observed, but the difference was not statistically significant. In an effort to quantitatively measure metastatic disease, each image was analyzed using a scoring system we have previously described.28 Although the imaging scores calculated for the diagnostic MIBG and bone scans were not prognostic, a strong association between EFS and the postinduction MIBG score was observed. Patients with MIBG scores ≥ 3 following induction therapy had significantly worse EFS than those with scores less than 3. A trend was also seen associating a worse outcome with any abnormal MIBG osteomedullary uptake on postinduction scans, but the difference was not statistically significant. In contrast, uptake on bone scans obtained following induction therapy did not correlate with EFS.

These observations are consistent with the results we previously reported in a retrospective analysis of MIBG scintigraphy in NB patients.28 In that study, we evaluated the outcome of 30 infants and older children with stage 4 NB according to initial and postinduction MIBG and bone imaging studies.28 Although the mean diagnostic MIBG score was slightly higher in the previous study (mean score of 10 v 8), a trend associating worse outcome with diagnostic MIBG scores above the mean was observed in patients older than 1 year of age. Furthermore, similar to the current study, a trend was seen associating inferior outcome with persistent osteomedullary MIBG uptake following induction therapy. In contrast, diagnostic and post-therapy bone scans were not predictive of outcome in the retrospective study.

Other retrospective studies have also indicated that MIBG scintigraphy has prognostic value in children with high-risk NB.24,36 Osteomedullary uptake before myeloablative therapy and bone marrow transplant was associated with poor outcome in a large series reported by the European Bone Marrow Transplantation Registry.37 In another study, Suc et al24 evaluated the predictive value of diagnostic MIBG scans in 86 children older than 1 year of age with metastatic NB. In an effort to systematically measure MIBG positivity, these investigators devised a scoring system in which the skeleton was divided into seven zones, and each zone was scored as either negative (0) or positive (1). Patients with scores > 4 at diagnosis had a significantly higher risk of failing to achieve a complete response to induction therapy. More recently, Matthay et al27 conducted a retrospective analysis of 75 children with high-risk NB to determine if early response to therapy measured by MIBG correlated with EFS. In their study, the MIBG scans were scored using a system that was originally developed at the Institute Curie. Similar to our scoring system, in the Curie system, the skeleton is divided into nine zones, with a tenth zone used to score extraosseous metastases. Each zone is scored from 0 to 3, depending on the extent of involvement, with absolute total scores ranging from 0 to 30. Matthay et al also calculated a relative MIBG score for each patient, which was defined as the absolute score/diagnostic score. Similar to our results, improved EFS was seen in patients with metastatic response to induction therapy, defined as a relative score of ≤ 0 or ≤ 0.24 following two or four cycles of induction therapy, respectively.

Taken together, the results of our study and other studies indicate that early response to therapy is highly prognostic in NB. Children with persistent osteomedullary uptake on MIBG scintigraphy following induction therapy represent an ultra–high-risk group of NB patients. Furthermore, measuring the osteomedullary response using our scoring system appears to provide additional information that can help distinguish the patients who have a high likelihood of long-term remission with intensive, multimodality therapy from those that are destined to fail. Alternative therapeutic strategies such as MIBG radiotherapy,38,39 biologic agents including retinoids,40-41 tyrosine kinase inhibitors,42 antiangiogenic agents,43,44 and immunotherapy,45,46 as well as novel chemotherapeutic drugs,47-49 should be considered for this subset of ultra–high-risk patients.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Supported in part by the Friends for Steven Pediatric Cancer Research Fund and the Robert H. Lurie Comprehensive Cancer Center, National Institutes of Health, National Cancer Institute Core Grant No. 5P30CA60553C.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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27. Matthay KK, Edeline V, Lumbroso J, et al: Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol 21:2486-2491, 2003[Abstract/Free Full Text]

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Submitted July 21, 2003; accepted July 16, 2004.


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