Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 24, No 3 (January 20), 2006: pp. 500-506
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.03.6400
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Matthay, K. K.
Right arrow Articles by Maris, J. M.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Matthay, K. K.
Right arrow Articles by Maris, J. M.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Phase I Dose Escalation of Iodine-131–Metaiodobenzylguanidine With Myeloablative Chemotherapy and Autologous Stem-Cell Transplantation in Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study

Katherine K. Matthay, Jessica C. Tan, Judith G. Villablanca, Gregory A. Yanik, Janet Veatch, Benjamin Franc, Eilish Twomey, Biljana Horn, C. Patrick Reynolds, Susan Groshen, Robert C. Seeger, John M. Maris

From the Department of Pediatrics and Radiology, University of California, San Francisco (UCSF), School of Medicine, and UCSF Children's Hospital, San Francisco; Department of Pediatrics and Preventive Medicine, Keck School of Medicine, University of Southern California and Children's Hospital Los Angeles, Los Angeles, CA; Department of Pediatrics, University of Michigan and Mott Children's Hospital, Ann Arbor, MI; and the Department of Pediatrics, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA.

Address reprint requests to Katherine K. Matthay, MD, Department of Pediatrics, University of California, San Francisco, 505 Parnassus, M647, San Francisco, CA 94143-0106; e-mail: matthayk{at}peds.ucsf.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Purpose To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131–metaiodobenzylguanidine (131I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.

Patients and Methods Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. 131I-MIBG was administered on day –21, CEM was administered on days –7 to –4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. 131I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).

Results The MTD for patients with normal GFR (≥ 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils ≥ 500/µL of 10 days and median time for platelets ≥ 20,000/µL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 ± 0.10 and 0.58 ± 0.10, respectively.

Conclusion 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Neuroblastoma, arising in the sympathetic nervous system, is the most common extracranial childhood solid tumor. One half of patients present with metastatic disease, with a 5-year survival of only 30%, despite intensive myeloablative therapy and autologous stem-cell transplantation (ASCT).1 Patients who do not achieve partial response with induction chemotherapy or have residual bone marrow disease have an even lower survival rate of below 10%.2 New approaches are needed for such resistant tumors.

Metaiodobenzylguanidine (MIBG), a norepinephrine analog, is concentrated selectively in sympathetic nervous tissue, and when labeled with iodine-123 (123I), has become an integral component of staging and response evaluation in neuroblastoma.3,4 MIBG labeled with iodine-131 (131I) has demonstrated activity for targeted therapy of neuroblastoma, both in relapsed and newly diagnosed patients.5-12 131I-MIBG as a single agent in a phase I dose-escalation study showed a response rate of 37% in children with relapsed neuroblastoma10 and dose-limiting hematologic toxicity was circumvented with ASCT.13,14

Myeloablative chemotherapy also has demonstrated efficacy against neuroblastoma. Carboplatin, etoposide, and melphalan with ASCT is an effective regimen that resulted in 55% 3-year event-free survival (EFS) in patients without progressive disease, and 10% to 20% EFS in patients who had experienced relapse.1,15,16 A combination of targeted 131I-MIBG treatment and intensive systemic chemotherapy may lead to a higher rate of EFS for children with resistant neuroblastoma. Pilot studies of 131I-MIBG with myeloablative chemotherapy and ASCT demonstrated that the therapy was well tolerated in a small number of patients,17-19 and one pilot study suggested activity in patients with relapsed or resistant disease.20 We report here a dose-escalation study to define the maximum-tolerated dose (MTD) of 131I-MIBG with myeloablative melphalan, etoposide, and carboplatin plus ASCT in patients with refractory or relapsed neuroblastoma.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patient Population
Patients with high-risk neuroblastoma who were age 1 to 21 years at diagnosis were eligible if they had poorly responding neuroblastoma, defined as stable disease or partial response at the end of at least 12 weeks of any induction therapy; bone marrow containing greater than 100 tumor cells per 105 mononuclear cells by immunocytology after 12 weeks of induction therapy,2 or progressive disease at any time. All patients were required to have demonstrated MIBG uptake in the skeleton or soft tissue tumor. Patients were required to have hematopoietic stem cells without detectable tumor by immunocytology, or to have no tumor in bone marrow by routine morphology before peripheral-blood stem-cell (PBSC) collection. Patients had normal organ function and glomerular filtration rate (GFR) of ≥ 60 mL/min/1.73 m2. Patients who had undergone prior myeloablative therapy were excluded. The study enrolled 24 patients from April 2000 to December 2004. The protocol was carried out by the New Approaches to Neuroblastoma Therapy (NANT) consortium (www.nant.org), and was approved by the US Food and Drug Administration. Patients received MIBG infusion at University of California, San Francisco (San Francisco, CA), University of Michigan (Ann Arbor, MI), or Children's Hospital of Philadelphia (Philadelphia, PA), and then returned to their respective NANT institutions for the myeloablative chemotherapy and ASCT. The study was approved by NANT institutional review boards, and informed consent was obtained for all patients. Participating NANT investigators and institutions are listed in the Appendix.

Study Design and Toxicity Evaluation
Patients received an intravenous infusion of 131I-MIBG during 2 hours with hydration, with thyroid protection with potassium iodide and potassium perchlorate, and a Foley catheter for bladder protection. Patients remained in a radiation-protected isolation room for 4 to 7 days, until radiation emissions met institutional regulations.10 The dose of radiation to the whole body from the 131I-MIBG was calculated as described using multiple measurements from a hand-held Geiger counter or ceiling-mounted monitor.11 Two weeks after MIBG infusion, the patient received carboplatin and etoposide as a continuous 96-hour infusion on days –7 to –3. Melphalan was administered by intravenous bolus at hour 0 days –7, –6, and –5. Stem cells were infused 72 hours after completion of chemotherapy. Granulocyte colony-stimulating factor was administered 4 hours after stem-cell infusion and continued to absolute neutrophil count (ANC) more than 1,500/µL. Local radiation (2.1 Gy), was administered to the primary tumor bed and to residual metastatic sites after completion of MIBG and chemotherapy, and after response evaluation. 13-cis-Retinoic acid or other biologic therapy was permitted after the response evaluation.

This study used the standard 3 + 3 phase I trial design.21 Dose escalation, expansion, and termination of escalation were done independently in the two cohorts of patients (those with a normal GFR ≥ 100 mL/min/1.73 m2 and patients with GFR between 60 and 99 mL/min/1.73 m2). The doses of 131I-MIBG and chemotherapy combination were started below the previously established MTD of each agent (Table 1). Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0 (http://ctep.cancer.gov/reporting/ctc.html), using the Common Toxicity Criteria bone marrow transplantation–specific modifications.


View this table:
[in this window]
[in a new window]

  		Table 1. Dose Escalation Schema

 
Dose-limiting toxicity (DLT) was defined as any grade 4 nonhematologic toxicity excluding fever, anorexia, inner ear/hearing, vomiting requiring parenteral nutrition, metabolic/laboratory abnormalities unless life threatening or disabling, infection unless also associated with grade 3 symptoms in other organs related to the infection that do not resolve to baseline within 7 days of occurrence. The following grade 3 nonhematologic toxicities were also defined as DLT: renal toxicity excluding grade 3 hemorrhagic cystitis, dysuria, urinary frequency/urgency, and urinary electrolyte wasting; pancreatitis; CNS bleeding; cerebrovascular ischemia; seizures; and/or aphasia. Only the following hematologic toxicities were defined as DLT: grade 4 hemolysis, platelet transfusion refractoriness associated with life-threatening bleeding, hemorrhage or hemolysis associated with life-threatening anemia, grade 4 failure to engraft, or other life-threatening blood/bone marrow toxicity. The MTD was defined as the dose level where zero of six or one of six assessable patients experienced a DLT and two or more patients experienced DLT at the next higher dose. For the diagnosis of veno-occlusive disease (VOD), two of the following criteria had to be met within 20 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant pain of liver origin, and sudden weight gain (> 2% of baseline body weight) secondary to fluid accumulation without other explanation.22 Neutrophil recovery was defined as the first of 3 consecutive days of an ANC ≥ 500/uL, and platelet recovery was defined as the first of 3 consecutive days of a platelet count ≥ 20,000/µL without platelet transfusion support. The day of MIBG infusion was the starting point for Kaplan-Meier calculation of estimated overall survival and EFS, which was defined as time to progressive disease, second malignancy, or death.

Response Evaluation
All responses were assessed by central review of MIBG and computed tomography (CT) scans by a radiologist and nuclear medicine physician, blinded to patient identity and outcome. Response in soft tissue lesions was evaluated according to Response Evaluation Criteria in Solid Tumors Group criteria if a measurable lesion was present on CT.23 To quantify the response by MIBG scan, a score was assigned to all pretherapy and day 84 post-therapy MIBG scans; response was defined as a relative score of ≤ 0.5.24,25 Overall response for all patients was assigned according to the International Neuroblastoma Response Criteria, after evaluation of bone marrow, CT scan, MIBG scan, and urine catecholamines,4 except for using the Response Evaluation Criteria in Solid Tumors Group method for solid lesions and use of semiquantitative MIBG score rather than technetium-99m bone scan for bone metastases.25


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patients
Twenty-four patients with refractory neuroblastoma were enrolled onto this study (Table 2). Although two patients were declared ineligible on retrospective review (one received chemotherapy 18 days before study entry and another received PBSCs that were not tested for tumor cells by immunocytology), all 24 patients are included in this report. Twenty-two were assessable for toxicity and response. Eight patients were treated at level 1, six patients were treated at level 2, four patients were treated at level 3, and six patients were treated at level 1A.


View this table:
[in this window]
[in a new window]

  		Table 2. Patient Characteristics (N = 24)

 
Patients had the usual high-risk characteristics at diagnosis and all the patients had extensive prior chemotherapy treatment; 22 of 24 had at least two regimens (Table 2). Most patients also had multiple sites of disease at study entry, including 10 with morphologic bone marrow tumor, 12 with soft tissue lesions, and 21 with skeletal lesions. Twenty patients had primary refractory (n = 12) or progressive neuroblastoma (n = 8) despite multiple regimens.

Dose-Limiting Toxicity
In the normal GFR cohort, six assessable patients were treated at level 1 because one patient experienced DLTs after MIBG alone (Table 3). These events likely were due to complications related to bulky tumor load and ascites, exacerbated by fluid infusion for MIBG. Chemotherapy and stem cells were never administered. There were no DLTs in the remaining five assessable patients at this level. Two additional patients were treated at this level without DLTs, but were inassessable due to modified doses. At level 2, three patients were entered initially without DLTs. At level 3, the MTD was exceeded, with DLTs in two of four patients. Three additional patients were entered at level 2, with DLTs in two (Table 3). Thus, with two of six assessable patents having experienced DLTs at level 2, level 1 (with 12 mCi/kg 131I-MIBG) was determined to be the MTD for the normal GFR cohort.


View this table:
[in this window]
[in a new window]

  		Table 3. DLTs

 
In the low-GFR cohort, six patients accrued to level 1A and were assessable for toxicity. One patient at this level experienced a DLT of grade 4 VOD (Table 3). This patient also had two subsequent adverse events of delayed platelet engraftment and esophageal stricture. Level 1A was expanded to accrue a total of six patients on the basis of the DLT. Although none of the other five patients experienced a DLT, four patients experienced grade 3 or 4 hepatic toxicity, and two more had VOD. As a result of this apparent high incidence of VOD, the dose was not escalated to level 2A in the low-GFR cohort.

There was modest incremental change in the measured whole-body radiation dose with 131I-MIBG dose level, with a range of 1.11 to 3.07 Gy, and median of 2.08, 2.11, 2.13, and 2.95 Gy for levels 1A, 1, 2, and 3, respectively. There was no difference in the whole-body radiation received in the low-GFR cohort compared with the normal GFR cohort at level 1 to account for the increase in VOD among patients with low GFR attributable to radiation.

Hematologic and Nonhematologic Toxicity
Hematologic toxicity equal to grade 3 or 4 occurred in all patients, as expected in a myeloablative protocol. All of the assessable patients engrafted, with median time to ANC more than 500/µL of 10 days and median time to platelets more than 20,000/µL of 26 days (Table 4). The one patient with delayed platelet engraftment to 224 days had other DLTs that included grade 4 VOD.


View this table:
[in this window]
[in a new window]

  		Table 4. Time to Engraftment (days from stem-cell infusion)

 
The frequent nonhematologic grade 3 and 4 toxicities were similar to those of other myeloablative regimens (Table 5). Cardiovascular toxicities included arrhythmia, capillary leak syndrome, edema, hypotension, and hypertension. Pulmonary toxicities included acute respiratory distress syndrome, dyspnea, and hypoxia. Two patients developed grade 3 renal insufficiency. Serious infection or febrile neutropenia developed in 91% of patients. Bleeding, although a frequent toxicity, was restricted to mucous membranes and GI tract. Ninety-one percent of patients had some GI toxicity, 60% of which was related to mucositis.


View this table:
[in this window]
[in a new window]

  		Table 5. Patients With Grade 3 or 4 Nonhematologic Toxicities

 
Rare toxicities included one patient receiving dose level 1A with grade 2 hypothyroidism, and another in level 1A who had a grade 2 seizure on the first day of chemotherapy infusion without neurologic sequelae. One patient who had DLT at level 3 later developed lymphoproliferative disease at day +122 after receiving CD34-selected PBSC for ASCT.

Grade 3 to 4 hepatic toxicities, seen in 55% of patients, included hepatomegaly, hypoalbuminemia, and elevations in bilirubin, alkaline phosphatase, ALT, AST, and gamma-glutamyltransferase levels. Three of the six patients in the low-GFR cohort and three of 16 patients in the normal-GFR cohort developed VOD. Neither of the two inassessable patients with incorrect dosing at level 1 had VOD, although one had grade 3 AST and ALT elevation.

Response
Responses in the 22 assessable patients are summarized in Table 6. The overall response rate including complete and partial response was six of 22 (27%; 95% CI, 13% to 50%). It is noteworthy that four of these six patients with a response to protocol therapy had primary refractory (n = 2) or progressive disease (n = 2) despite multiple prior regimens. If only patients who were dosed correctly and had a complete set of required follow-up scans were considered, then the response rate was six of 18 (33%). One of the patients with a mixed response had complete response in bone marrow, improvement on MIBG scan (relative MIBG score of 0.73), but persistence of abnormal catecholamines. The other patient with a mixed response had complete response in bone marrow but no change in primary tumor mass or in MIBG score. Four of 10 patients with morphologic bone marrow tumor at study entry cleared the marrow at the evaluation on day 84. The MIBG scan improved in nine patients, with a median relative MIBG score of 0.5 (Table 7). Five of 12 patients with measurable disease on CT/magnetic resonance imaging showed significant decrease in mass disease.


View this table:
[in this window]
[in a new window]

  		Table 6. Responses in All Evaluated Patients

 

View this table:
[in this window]
[in a new window]

  		Table 7. MIBG Scores for Patients With Improvement on MIBG Scan

 
EFS and Overall Survival
The median follow-up of surviving patients was 36.5 months (range, 6.9 to 49.5+ months). The median EFS for all patients is 18.0 months (95% CI, 13.5 to 34.2 months); the median overall survival interval is 48.1 months (95% CI, 18.7 to 49.5+ months). The estimated probability of patients remaining alive and event free at 2 and 3 years is 0.42 ± 0.10 and 0.31 ± 0.10, respectively (Fig 1). Nine patients have died as a result of progressive disease (n = 7), toxicity while on study (n = 1), and infection 14 months after study therapy (n = 1). The estimated probability of overall survival at 3 years is 0.58 ± 0.10 (Fig 1).


Figure 1
View larger version (12K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 1. Overall survival (OS) and event-free survival (EFS) for all 24 patients entered onto study. The median OS was 48.1 months (95% CI, 18.7 to 49.5+ months); the median EFS was 18.0 months (95% CI, 13.5 to 34.2 months). MIBG, metaiodobenzylguanidine.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
This study demonstrates that the combination of 131I-MIBG with carboplatin, etoposide, and melphalan followed by ASCT is feasible and effective therapy for patients with refractory neuroblastoma. The MTD for this group of heavily pretreated patients was 12 mCi/kg of 131I-MIBG with carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. This regimen allowed the delivery of targeted radiotherapy to primary and residual metastatic neuroblastoma with little more than 2.0 Gy of measured total-body dose, which should minimize potential late effects of total-body irradiation (TBI).26 Furthermore, the doses of chemotherapy in combination with 131I-MIBG at the regimen MTD were only slightly decreased from their MTD when used without TBI: by 12% for carboplatin, 11% for etoposide, 0% for melphalan. The regimen MTDs were 50% greater for carboplatin and 87% greater for etoposide than when the same drugs were combined with TBI.1,27 The MTD for the low-GFR cohort requires additional testing because of the excessive rate of VOD. Thus, this regimen allows delivery of 30.0 Gy or more to multiple metastatic sites,11 with essentially full doses of myeloablative chemotherapy but without excessive TBI.

Although the hepatic toxicity was high, particularly in the period immediately after chemotherapy administration, the type and incidence in this study were similar to those observed in other studies of high-risk neuroblastoma patients using the same chemotherapy regimen without MIBG.22 An apparently excessive rate of VOD was seen in the patients with a low GFR, suggesting that decreased clearance of either the 131I-MIBG or of the chemotherapy agents, despite dose adjustment, added to the hepatic insult. The lack of difference in the received whole-body radiation dose at 12 mCi/kg in the low-GFR cohort compared with that in the normal-GFR cohort suggests that the major problem was related to the chemotherapy clearance when combined with the radiation from the MIBG. No late hepatic toxicity has been observed in surviving patients who were treated with MIBG, either alone or in combination with chemotherapy. Furthermore, no significant hepatic toxicity has been noted in patients receiving multiple infusions of 131I-MIBG without chemotherapy, again suggesting that the radiotherapy effect alone is not sufficient to produce VOD.28 Future studies that include patients with low GFR should use a lower 131I-MIBG dose, which is still expected to be effective from previous phase I and II studies, in addition to careful toxicity monitoring or a lower dose of chemotherapy.

Other toxicities observed in this study were similar to those reported from previous studies of similar myeloablative chemotherapy.1,27,29 The single death as a result of toxicity in 24 patients is also within the acceptable range for myeloablative regimens followed by ASCT. Hematopoietic reconstitution after ASCT was also equivalent to that reported from previous neuroblastoma clinical trials, suggesting that the addition of 131I-MIBG does not have deleterious effects on bone marrow stroma or stem cells.

The response rate of 27% was encouraging in this population of patients with de novo refractory metastatic neuroblastoma, despite two or more intensive chemotherapy induction regimens. Four of the six patients with a complete or partial response had demonstrated progression or no response to multiple previous treatments. This is comparable to the 30% response reported in studies of relapsed neuroblastoma with 131I-MIBG.9-11,30 The other encouraging result is the 28% 3-year EFS and 56% overall survival. In fact, eight of the 24 patients are surviving from 14 to 49.5 months from protocol treatment without disease progression, although most are receiving biologic therapy. This result appears to be better than the previously reported 10% EFS for patients with neuroblastoma who had poor response to induction therapy.1,31,32 Furthermore, seven of 10 patients with residual bone marrow disease by morphology at the time of entry into our study are surviving at a median of 39 months (range, 12 to 44 months). This type of patient had an extremely poor outcome in a recent Children's Cancer Group study, in which less than 10% of patients with any bone marrow tumor detectable after 12 weeks of induction chemotherapy and none of those with more than 0.1% tumor in marrow 2 to 4 weeks before ASCT survived.2 Of note, all surviving patients in the current report have received additional biologic therapy, including phase I investigational agents, and the impact of such on EFS and survival is not known.

In summary, the combination of 131I-MIBG with myeloablative doses of carboplatin, etoposide, and melphalan is feasible and effective in patients with refractory neuroblastoma and normal renal function. The regimen requires additional testing with appropriate dose modification for patients with a low GFR. Stem-cell support permits prompt engraftment after 131I-MIBG and myeloablative chemotherapy. This regimen is now being tested in a NANT phase II study for patients with poor response to induction chemotherapy.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 


View this table:
[in this window]
[in a new window]

  		Appendix. List of NANT Principal Investigators Participating in N9901

 

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


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Katherine K. Matthay, Judith G. Villablanca, Gregory A. Yanik, Janet Veatch, Biljana Horn, C. Patrick Reynolds, Susan Groshen, Robert C. Seeger, John M. Maris

Administrative support: Judith G. Villablanca, Janet Veatch, Susan Groshen, Robert C. Seeger

Provision of study materials or patients: Judith G. Villablanca, Gregory A. Yanik, Benjamin Franc, Eilish Twomey, Biljana Horn, C. Patrick Reynolds, John M. Maris

Collection and assembly of data: Katherine K. Matthay, Jessica C. Tan, Judith G. Villablanca, Janet Veatch, Eilish Twomey

Data analysis and interpretation: Katherine K. Matthay, Jessica C. Tan, Judith G. Villablanca, Benjamin Franc, Eilish Twomey, Biljana Horn, C. Patrick Reynolds, Susan Groshen, Robert C. Seeger, John M. Maris

Manuscript writing: Katherine K. Matthay, Jessica C. Tan, Judith G. Villablanca, C. Patrick Reynolds, Susan Groshen, Robert C. Seeger, John M. Maris

Final approval of manuscript: Katherine K. Matthay, Judith G. Villablanca, Gregory A. Yanik, Janet Veatch, Benjamin Franc, Eilish Twomey, Biljana Horn, C. Patrick Reynolds, Susan Groshen, Robert C. Seeger, John M. Maris

 


   ACKNOWLEDGMENTS
 
We thank the NANT Operations and Data Center including Beth Hasenauer, Mandy Benavides, Karren Baptist, and Denice Wei. We thank Patricia Brophy, RN (Children's Hospital of Philadelphia), and Shelli Anuszkiewicz, RN (University of Michigan), and the referring oncologists, the nuclear medicine and radiation safety personnel, and in-patient nurses.


   NOTES
 
Supported by the National Institutes of Health Grants No. PO1 CA81403, 2MO1 RR0127, and M01-RR00240, as well by donations from the Campini Foundation, the Conner Research Fund, the Katie Dougherty Foundation, Kasle and Tkalcevik Neuroblastoma Research Fund, Alex's Lemonade Stand, the Pediatric Cancer Research Fund, the Evan Dunbar Foundation, the Milkin Family Foundation, and the Philadelphia Foundation.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 14-16, 2005, Orlando, FL.

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
1. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid: Children's Cancer Group. N Engl J Med 341:1165-1173, 1999[Abstract/Free Full Text]

2. Seeger RC, Reynolds CP, Gallego R, et al: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: A Children's Cancer Group Study. J Clin Oncol 18:4067-4076, 2000[Abstract/Free Full Text]

3. Shulkin BL, Shapiro B, Hutchinson RJ: Iodine-131-metaiodobenzylguanidine and bone scintigraphy for the detection of neuroblastoma. J Nucl Med 33:1735-1740, 1992[Abstract/Free Full Text]

4. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466-1477, 1993[Abstract/Free Full Text]

5. Hoefnagel CA, Voute PA, de Kraker J, et al: Radionuclide diagnosis and therapy of neural crest tumors using iodine-131 metaiodobenzylguanidine. J Nucl Med 28:308-314, 1987[Abstract/Free Full Text]

6. Hutchinson RJ, Sisson JC, Miser JS, et al: Long-term results of [131I]metaiodobenzylguanidine treatment of refractory advanced neuroblastoma. J Nucl Biol Med 35:237-240, 1991[Medline]

7. Voute PA, Hoefnagel CA, de Kraker J, et al: Results of treatment with 131 I-metaiodobenzylguanidine 131 I-MIBG in patients with neuroblastoma: Future prospects of zetotherapy. Prog Clin Biol Res 366:439-445, 1991[Medline]

8. Klingebiel T, Berthold F, Treuner J, et al: Metaiodobenzylguanidine (mIBG) in treatment of 47 patients with neuroblastoma: Results of the German Neuroblastoma Trial. Med Pediatr Oncol 19:84-88, 1991[Medline]

9. Garaventa A, Bellagamba O, Lo Piccolo MS, et al: 131 I-metaiodobenzylguanidine (131 I-MIBG) therapy for residual neuroblastoma: A mono-institutional experience with 43 patients. Br J Cancer 81:1378-1384, 1999[CrossRef][Medline]

10. Matthay KK, DeSantes K, Hasegawa B, et al: Phase I dose escalation of 131 I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol 16:229-236, 1998[Abstract/Free Full Text]

11. Matthay KK, Panina C, Huberty J, et al: Correlation of tumor and whole-body dosimetry with tumor response and toxicity in refractory neuroblastoma treated with (131)I-MIBG. J Nucl Med 42:1713-1721, 2001[Abstract/Free Full Text]

12. Matthay KK, Huberty JP, Hattner RS, et al: Efficacy and safety of [131I]metaiodobenzylguanidine therapy for patients with refractory neuroblastoma. J Nucl Biol Med 35:244-247, 1991[Medline]

13. Goldberg SS, DeSantes K, Huberty JP, et al: Engraftment after myeloablative doses of 131 I-metaiodobenzylguanidine followed by autologous bone marrow transplantation for treatment of refractory neuroblastoma. Med Pediatr Oncol 30:339-346, 1998[CrossRef][Medline]

14. Dubois SG, Messina J, Maris JM, et al: Hematologic toxicity of high-dose iodine-131–metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol 22:2452-2460, 2004[Abstract/Free Full Text]

15. Ladenstein R, Lasset C, Hartmann O, et al: Impact of megatherapy on survival after relapse from stage 4 neuroblastoma in patients over 1 year of age at diagnosis: A report from the European Group for Bone Marrow Transplantation. J Clin Oncol 11:2230-2341, 1993

16. Villablanca JG, Matthay KK, Swift PS, et al: Phase I trial of carboplatin, etoposide, melphalan and local irradiation (CEM-LI) with purged autologous bone marrow transplantation for children with high risk neuroblastoma. Med Pediatr Oncol 33:170, 1999[CrossRef]

17. Klingebiel T, Bader P, Bares R, et al: Treatment of neuroblastoma stage 4 with 131 I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy: A pilot study. Eur J Cancer 34:1398-1402, 1998[CrossRef][Medline]

18. Corbett R, Pinkerton R, Tait D, et al: [131I]metaiodobenzylguanidine and high-dose chemotherapy with bone marrow rescue in advanced neuroblastoma. J Nucl Biol Med 35:228-231, 1991[Medline]

19. Gaze MN, Wheldon TE, O'Donoghue JA, et al: Multi-modality megatherapy with [131I]meta-iodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: Feasibility study of a new strategy for advanced neuroblastoma. Eur J Cancer 31A:252-256, 1995[CrossRef]

20. Yanik GA, Levine JE, Matthay KK, et al: Pilot study of iodine-131–metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. J Clin Oncol 20:2142-2149, 2002[Abstract/Free Full Text]

21. Edler L: Overview of Phase I Trials, in Crowley J (ed): Handbook of Statistics in Clinical Oncology. New York, NY, Marcel Dekker, 2001, pp 1-35

22. Horn B, Reiss U, Matthay K, et al: Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: A high incidence in patients with neuroblastoma. Bone Marrow Transplant 29:409-415, 2002[CrossRef][Medline]

23. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

24. Ady N, Zucker JM, Asselain B, et al: A new 123I-MIBG whole body scan scoring method–application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma. Eur J Cancer 31A:256-261, 1995[CrossRef]

25. Matthay KK, Edeline V, Lumbroso J, et al: Correlation of early metastatic response by 123-I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol 21:2486-2491, 2003[Abstract/Free Full Text]

26. Barrett A, Nicholls J, Gibson B: Late effects of total body irradiation. Radiother Oncol 9:131-135, 1987[CrossRef][Medline]

27. Villablanca JG, Reynolds CP, Swift PS, et al: Phase I trial of carboplatin, etoposide, melphalan and local irradiation (CEM-LI) with purged autologous marrow transplantation for children with high risk neuroblastoma. Proc Am Soc Clin Oncol 17:533a, 1998 (suppl; abstr 2045)

28. Howard JP, Maris JM, Kersun LS, et al: Tumor response and toxicity with multiple infusions of high dose 131 I-MIBG for refractory neuroblastoma. Pediatr Blood Cancer 44:232-239, 2005[CrossRef][Medline]

29. Seeger RC, Villablanca JG, Matthay KK, et al: Intensive chemoradiotherapy and autologous bone marrow transplantation for poor prognosis neuroblastoma. Prog Clin Biol Res 366:527-533, 1991[Medline]

30. Hoefnagel CA, Voute PA, De Kraker J, et al: [131I]metaiodobenzylguanidine therapy after conventional therapy for neuroblastoma. J Nucl Biol Med 35:202-206, 1991[Medline]

31. Philip T, Ladenstein R, Lasset C, et al: 1070 myeloablative megatherapy procedures followed by stem cell rescue for neuroblastoma: 17 years of European experience and conclusions—European Group for Blood and Marrow Transplant Registry Solid Tumour Working Party. Eur J Cancer 33:2130-2135, 1997[CrossRef][Medline]

32. Ladenstein R, Philip T, Lasset C, et al: Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: A report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 16:953-965, 1998[Abstract]

Submitted August 2, 2005; accepted October 17, 2005.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 JCOHome page
S. Gonias, R. Goldsby, K. K. Matthay, R. Hawkins, D. Price, J. Huberty, L. Damon, C. Linker, A. Sznewajs, S. Shiboski, et al.
Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma
J. Clin. Oncol., September 1, 2009; 27(25): 4162 - 4168.
[Abstract] [Full Text] [PDF]

Home page
 Journal of Pediatric Oncology NursingHome page
M. K. Lessig
The Role of 131I-MIBG in High-Risk Neuroblastoma Treatment
Journal of Pediatric Oncology Nursing, July 1, 2009; 26(4): 208 - 216.
[Abstract] [PDF]

Home page
 JCOHome page
K. K. Matthay, A. Quach, J. Huberty, B. L. Franc, R. A. Hawkins, H. Jackson, S. Groshen, S. Shusterman, G. Yanik, J. Veatch, et al.
Iodine-131--Metaiodobenzylguanidine Double Infusion With Autologous Stem-Cell Rescue for Neuroblastoma: A New Approaches to Neuroblastoma Therapy Phase I Study
J. Clin. Oncol., March 1, 2009; 27(7): 1020 - 1025.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
M. V. Karamouzis, P. A. Konstantinopoulos, and A. G. Papavassiliou
ErbB/HER receptor family in breast cancer--the more we search the more we learn
Ann. Onc., May 1, 2008; 19(5): 1020 - 1021.
[Full Text] [PDF]

Home page
 JCOHome page
K. K. Matthay, G. Yanik, J. Messina, A. Quach, J. Huberty, S.-C. Cheng, J. Veatch, R. Goldsby, P. Brophy, L. S. Kersun, et al.
Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma
J. Clin. Oncol., March 20, 2007; 25(9): 1054 - 1060.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Matthay, K. K.
Right arrow Articles by Maris, J. M.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Matthay, K. K.
Right arrow Articles by Maris, J. M.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online