Local control with multimodality therapy for Stage 4 neuroblastoma

doi:10.1016/S0360-3016(99)00399-5

International Journal of Radiation OncologyBiologyPhysics

Volume 46, Issue 4, 1 March 2000, Pages 969-974

https://doi.org/10.1016/S0360-3016(99)00399-5 Get rights and content

Abstract

Purpose: To evaluate the efficacy of 21 Gy hyperfractionated radiotherapy for local control in conjunction with surgery and intensive systemic therapy for patients with Stage 4 neuroblastoma.

Methods and Materials: After achieving a partial or complete remission, 47 children, ages 1–10 years, with Stage 4 neuroblastoma were treated on four consecutive institutional protocols (N4–N7) with dose-intensive multi-agent chemotherapy, maximal surgical debulking, and hyperfractionated radiotherapy (1.5 Gy twice a day to 21 Gy). Radiotherapy fields encompassed the initial tumor volume and regional lymph nodes plus a 3-cm margin. This was followed by consolidation with either autologous bone marrow transplantation (N4 and N5) or immunotherapy (N6 and N7).

Results: Forty-five of 47 patients had a complete response to surgery and chemotherapy prior to radiotherapy. Five-year actuarial rates of local control, progression-free survival, and overall survival were 84%, 40%, and 45%, respectively. Among 26 patients who relapsed, 1 failed only at the primary site, 22 developed distant metastases exclusively, and 3 had both local and distant failures. There were no acute complications of radiotherapy.

Conclusion: Hyperfractionated radiotherapy to 21 Gy, in conjunction with dose-intensive systemic therapy and aggressive surgical resection, is well tolerated and is associated with durable local control for most patients with Stage 4 neuroblastoma.

Introduction

Each year, approximately 500 new cases of neuroblastoma are diagnosed in the United States, with nearly two-thirds presenting with Stage 4 disease (1). Until recently, the long-term cure rate of children with Stage 4 disease diagnosed after their first birthday has been less than 10% 2, 3, 4. Common metastatic sites in this age group include bone marrow, bone, and lymph nodes 5, 6. Dose-intensive chemotherapy protocols have improved response rates while myeloablative treatments, cis-retinoic acid, and monoclonal antibody–based therapies have decreased postinduction relapse rates 7, 8, 9, 10, 11, 12.

While distant metastatic disease is the major threat to these children, local tumor control remains an important concern, given the often critical locations and bulky presentations of the primary tumors. High-dose chemotherapy alone is generally not sufficient to eradicate all malignant neuroblasts within the large tumors typical for Stage 4 disease. Local failure is a common problem for Stage 4 patients, with reports ranging from 17% to 80%, even with aggressive therapy 13, 14, 15, 16. Since 1986, we have employed a consistent strategy for preventing local failure in patients with Stage 4 neuroblastoma using intensive chemotherapy and surgical resection followed by 21 Gy hyperfractionated radiotherapy 11, 17, 18, 19, 20. This report serves as an analysis of the local control for children treated with this combined modality approach.

Section snippets

Methods and materials

Between 1986 and 1996, 47 previously untreated children with Stage 4 neuroblastoma received local radiotherapy after achieving a partial or complete response to chemotherapy on successive institutional protocols (N4: 5 patients, N5: 7 patients, N6: 27 patients, N7: 8 patients), outlined in Table 1. Radiotherapy consisted of 21 Gy, delivered in 1.5 Gy fractions, twice daily (>4 hours apart), on seven consecutive weekdays. The radiation fields encompassed the prechemotherapy and presurgery

Results

Relevant clinical characteristics of the 47 patients are presented in Table 2. The majority of patients had an abdominal primary site (n = 31), and the median age was 3 years (range 1–10 years), as children less than 1 year of age were excluded from these studies for high-risk patients. Gross total resection was achieved in 44 (94%) of 47 patients, with residual malignant neuroblastoma in the pathological specimens of all but one patient. One patient had a complete response to chemotherapy,

Discussion

In this series, actuarial local-regional control was 84% at 5 years, using aggressive induction chemotherapy, relatively early surgical intervention, and consolidative radiotherapy in modest doses. The aim of radiotherapy was to prevent tumor regrowth in areas of initial “bulky” disease. Children tolerated radiotherapy well, with successful completion of radiation as scheduled in all cases, and proceeded quickly to subsequent therapy. The survivors have not developed significant

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Patients with high-risk neuroblastoma (HR-NBL) require radiation to the primary tumor site and sites of persistent metastatic disease. Proton radiation therapy (PRT) may promote organ sparing, but long-term outcomes have not been studied.
Sequential patients with HR-NBL received PRT: 2160 cGy (relative biological effectiveness) to primary tumor bed and persistent metastatic sites, with 3600 cGy (relative biological effectiveness) to gross residual disease.
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A single-institution study showed an improvement in progression-free survival from 22 to 36% in two consecutive cohorts where radiotherapy was introduced [28]. A number of studies have reported good local control in series where radiotherapy has been used as standard [29–36]. These have variably been interpreted as suggesting that radiotherapy is an essential component of treatment or may be reduced.
External beam radiotherapy is widely used in various ways in the management of neuroblastoma. Despite extensive clinical experience, the precise role of radiotherapy in neuroblastoma remains unclear. The purpose of this systematic review was to survey the published literature to identify, without bias, the evidence for the clinical effectiveness of external beam radiotherapy as part of the initial multimodality treatment of high-risk neuroblastoma. We considered four areas: treatment of the tumour bed and residual primary tumour, identification of any dose–response relationship, treatment of metastatic sites, identification of any technical advances that may be beneficial. We also aimed to define uncertainties, which may be clarified in future clinical trials.
Bibliographic databases were searched for neuroblastoma and radiotherapy. Reviewers assessed 1283 papers for inclusion by title and abstract, with consensus achieved through discussion. Data extraction on 57 included papers was carried out by one reviewer and checked by another. Studies were assessed for their level of evidence and risk of bias, and a descriptive analysis of data was carried out.
Fifteen papers provided some evidence that radiotherapy to the tumour bed and residual tumour may possibly be of value. However, there is a significant risk of bias and no evidence that all subgroups will benefit. There is some suggestion from six papers that dose may be important, but no hard evidence. It remains unclear whether irradiation of metastatic sites is helpful. Technical advances may be of value in radiotherapy of high-risk neuroblastoma.
There are data that show that radiotherapy is of some efficacy in the management of high-risk neuroblastoma, but there is no level one evidence that shows that it is being used in the best possible way. Prospective randomised trials are necessary to provide more evidence to guide development of optimal radiotherapy treatment schedules.
Novel therapeutic targets in neuroblastoma
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This chapter introduces the molecular targeted therapies and immunotherapies currently in use to treat neuroblastoma, which is the most common extracranial solid tumor in children. It presents a clinical introduction to high-risk disease including staging and risk stratification. The chapter then identifies the tumor biology and genomic alterations that drive neuroblastoma proliferation and risk. We present an overview of the currently recommended therapy for the high-risk disease, including induction chemotherapy, local control, myeloablative consolidation, and maintenance treatment for the minimal residual disease. The chapter will discuss the various targets that have been identified for the precision treatment of neuroblastoma, as well as current clinical trials of targeted therapies. Finally, new targeted therapies under preclinical investigation and future directions will be presented.
Favorable Local Control From Consolidative Radiation Therapy in High-Risk Neuroblastoma Despite Gross Residual Disease, Positive Margins, or Nodal Involvement
2017, International Journal of Radiation Oncology Biology Physics
To report the influence of radiation therapy (RT) dose and surgical pathology variables on disease control and overall survival (OS) in patients treated for high-risk neuroblastoma at a single institution.
We conducted a retrospective study of 67 high-risk neuroblastoma patients who received RT as part of definitive management from January 2003 until May 2014.
At a median follow-up of 4.5 years, 26 patients (38.8%) failed distantly; 4 of these patients also failed locally. One patient progressed locally without distant failure. Local control was 92.5%, and total disease control was 59.5%. No benefit was demonstrated for RT doses over 21.6 Gy with respect to local relapse–free survival (P=.55), disease-free survival (P=.22), or OS (P=.72). With respect to local relapse–free survival, disease-free survival, and OS, no disadvantage was seen for positive lymph nodes on surgical pathology, positive surgical margins, or gross residual disease. Of the patients with gross residual disease, 75% (6 of 8) went on to have no evidence of disease at time of last follow-up, and the 2 patients who failed did so distantly.
Patients with high-risk neuroblastoma in this series maintained excellent local control, with no benefit demonstrated for radiation doses over 21.6 Gy, and no disadvantage demonstrated for gross residual disease after surgery, positive surgical margins, or pathologic lymph node positivity. Though the limitations of a retrospective review for an uncommon disease must be kept in mind, with small numbers in some of the subgroups, it seems that dose escalation should be considered only in exceptional circumstances.
Neuroblastoma (Peripheral neuroblastic tumours)
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Peripheral neuroblastic tumours (PNTs), a family of tumours arising in the embryonal remnants of the sympathetic nervous system, account for 7–10% of all tumours in children. In two-thirds of cases, PNTs originate in the adrenal glands or the retroperitoneal ganglia. At least one third present metastases at onset, with bone and bone marrow being the most frequent metastatic sites. Disease extension, MYCN oncogene status and age are the most relevant prognostic factors, and their influence on outcome have been considered in the design of the recent treatment protocols. Consequently, the probability of cure has increased significantly in the last two decades. In children with localised operable disease, surgical resection alone is usually a sufficient treatment, with 3-year event-free survival (EFS) being greater than 85%. For locally advanced disease, primary chemotherapy followed by surgery and/or radiotherapy yields an EFS of around 75%. The greatest problem is posed by children with metastatic disease or amplified MYCN gene, who continue to do badly despite intensive treatments. Ongoing trials are exploring the efficacy of new drugs and novel immunological approaches in order to save a greater number of these patients.
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2016, International Journal of Radiation Oncology Biology Physics
To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma.
After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT.
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Clinical InvestigationsLocal control with multimodality therapy for Stage 4 neuroblastoma

Abstract

Introduction

Section snippets

Methods and materials

Results

Discussion

J Pediatr

Int J Radiat Oncol Biol Phys

Radiother Oncol

J Pediatr Surg

Radiother Oncol

Neuroblastoma

Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival

J Pediatr Hematol Oncol

Stage IV-NA favorable subset of children with metastatic neuroblastoma

Med Pediatr Oncol

Impact of myeloablative therapy with bone marrow transplantation in advanced neuroblastoma

Bone Marrow Transplant

Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age

J Clin Oncol

Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age

J Clin Oncol

Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastomaA report of two concurrent Children’s Cancer Group studies

J Clin Oncol

Myeloablative combination chemotherapy without total body irradiation for neuroblastoma

J Clin Oncol

13-cis-retinoic acid after intensive consolidation therapy for neuroblastoma improves event-free survivalA randomized Children’s Cancer Group (CCG) study

Proc Am Soc Clin Oncol

Patterns of relapse after autologous purged bone marrow transplantation for neuroblastomaA Children’s Cancer Group pilot study

J Clin Oncol

Clinical Investigations
Local control with multimodality therapy for Stage 4 neuroblastoma