Current Pharmacotherapy for Neuroblastoma


Neuroblastoma is, at once, a common and a frequently deadly cancer seen almost exclusively in children. The prognosis for patients with neuroblastoma is best in those whose tumor burden is small enough to be completely excised surgically and when the disease is diagnosed before age 18 months. In more than half of the patients with neuroblastoma at the time of diagnosis, the primary tumor is too large to be amenable to surgery alone or has metastasized widely throughout the body. Multi-agent chemotherapy, combined with radiation therapy and stem-cell transplantation, is the mainstay of treatment for these children. Even so, only 40%–50% survive 5 years after diagnosis. Promising therapies under development include strategies for differentiation induction in neuroblastoma cells; targeted, precision-medicine approaches; and novel delivery strategies that maximize the tumor and minimize the normal cell toxicity of chemotherapy.


Antimitotic agents, Differentiation induction, Drug resistance, Myeloablation, Stem cell transplantation, Targeted therapy



The specifics of treatment of neuroblastoma depend critically on the stage and prognostic features of the tumor, the age of the patient , and, increasingly, the transcriptome of the tumor cells . Children whose neuroblastomas are single, primary tumors without spread to local nodes or contiguous structures, small enough to be completely resected surgically, need no further treatment. Some children with metastatic disease can simply be observed and will experience tumor regression or differentiation; others have a poor prognosis despite highly aggressive chemotherapeutic treatment . This chapter describes the current approach to and future prospects for treatment of neuroblastoma with chemotherapy.

General Principles

Historically, conventional chemotherapy for neuroblastoma has included vincristine, cyclophosphamide, cisplatin, doxorubicin, VP16 (etoposide) and VP26 (teniposide), and melphalan. Subsequent drug development brought other agents, including ifosfamide, carboplatin, topotecan, irinotecan, and taxol, into the armamentarium . But even combination regimens with vincristine + cyclophosphamide + doxorubicin or cisplatin + VP16 produced poor results with disseminated disease, particularly in patients over the age of 18 months .

More recent regimens use much higher, myeloablative doses of these agents, a development made possible by the perfection of indwelling catheters for repeated intravenous delivery of chemotherapeutic drugs and the advent and advancement of bone marrow and hematopoietic stem cell transplantation . In addition, targeted delivery of radiation to the tumor using 131 I-methyl-iodobenzylguanidine ( 131 I-mIBG) can be combined with myeloablative chemotherapy to effect better responses, presumably without additional systemic toxicity .

Stage-Guided Chemotherapy

Staging of neuroblastoma for determination of therapy is increasingly done by the International Neuroblastoma Risk Group Staging System (INRGSS). This staging system uses image-defined risk factors to determine how aggressive therapy should be. However, some centers still gauge therapy using the International Neuroblastoma Staging System (INSS), a system devised in the 1990s to take into account the degree to which disease has been eliminated by surgery. (See Table 12.1 for a simplified comparison of these systems.) The discussion below of childhood neuroblastoma uses the INRGSS to gauge therapy.

Table 12.1

Comparison of the International Neuroblastoma (INSS) and the International Neuroblastoma Risk Group (INRGSS) Staging Systems

I: Primary site only; limited to one side of the body; completely removed by surgery; no tumor in extrinsic lymph nodes L1: Tumor has not spread from its origin and has not grown into vital structures as determined by image-defined risk factor analysis; tumor limited to one body compartment (e.g., chest)
II-A: Primary site only; limited to one side of the body; tumor cannot be completely removed by surgery; no tumor in extrinsic lymph nodes
II-B: Primary site only; limited to one side of the body; tumor can or cannot be completely removed by surgery; tumor present in extrinsic lymph nodes only on same side of the body as primary tumor
L2: Tumor has not spread far from its origin but demonstrates at least one image-defined risk factor; it may have spread, e.g., from the inferior left chest to the superior left abdomen
III: No metastasis of tumor, but:

  • Tumor cannot be completely removed by surgery and has spread across the midline; OR

  • Primary site only, but tumor present in extrinsic lymph nodes on the other side of the body from the primary tumor; OR

  • Tumor is in the midline and growing in both directions, and cannot be completely removed by surgery

M: Tumor has metastasized and does not meet criteria for stage MS
IV: Metastatic disease that does not meet criteria for stage IV-S MS: Patient <18 months of age; distant metastases only in liver, skin, or bone marrow (with <10% tumor cells); negative bone/bone marrow on mIBG scan
IV-S: Patient < 1 year of age; primary disease stage I or II; distant metastases only in liver, skin, or bone marrow (with <10% tumor cells); negative bone/bone marrow on mIBG scan

mIBG , methyl-iodobenzylguanine.

Low-Risk Disease

Children with low-risk disease have stage L1 neuroblastoma, are <18 months of age at diagnosis, have tumors without overexpression of MYCN, and have no cytogenetic abnormalities of the long arm of chromosome 11. Chemotherapy is used in these children only if necessary for symptomatic relief or, less commonly, to debulk the tumor sufficiently to enable subsequent complete or near-complete surgical resection. The number of cycles of chemotherapy given should be limited to that needed to accomplish these effects. Spontaneous regression or differentiation of the residual tumor will occur in many of these patients, underscoring the need to limit intervention, and its potential side effects, as much as possible .

Intermediate-Risk Disease

Intermediate-risk neuroblastoma is present in 10%–15% of patients at initial diagnosis. These children have stage L1 disease with MYCN overexpression, stage L2 disease without MYCN overexpression, stage M disease at age <18 months, stage MS disease with unfavorable genomics, or, in some studies and centers, stage MS disease at age >18 months. For these children, chemotherapy is often aimed at sufficient reduction in the size of the tumor to enable its complete or near complete surgical resection. This generally requires between two and eight cycles of chemotherapy.

The current 5-year survival rate is 90% for children <18 months old with stage M disease and 70% for children >18 months old with stage L2 disease .

High-Risk Disease

Children with high-risk disease comprise 40% of neuroblastoma patients at the time of initial diagnosis. The majority of these children are >1 year of age and have disseminated disease when first diagnosed. The prognosis for children with high risk neuroblastoma, although still not optimal, has improved steadily over the past two decades ( Fig. 12.1 ; ).

Apr 6, 2019 | Posted by in NEUROLOGY | Comments Off on Current Pharmacotherapy for Neuroblastoma
Premium Wordpress Themes by UFO Themes