Advances in the Surgical Treatment of Neuroblastoma

Introduction

The initial diagnosis of neuroblastoma requires close collaboration among the surgical oncologist, pediatric oncologist, and pathologist, especially in the assessment of MYCN amplification, histopathology, and DNA index (ploidy) . The surgeon has a vital role in neuroblastoma management. Specifically, the surgeon must acquire an adequate tumor sample for both histopathology and molecular biological studies, while being meticulous during surgical resection of the primary tumor in order to preserve the normal organs . To ensure precise categorization of stage and risk status, the surgeon must evaluate both the ipsilateral and contralateral lymph nodes and accurately describe the extent of the primary tumor resection . Additionally, the surgeon has a crucial role in performing supportive procedures, such as acquiring vascular access, and in the management of surgical and treatment-related complications like typhlitis, bowel obstructions, and others . This chapter will describe the role of surgical intervention in the management of neuroblastoma and recent advances in the field.

History

A role for surgery in neuroblastoma was first reported in the 1950s. Among these first publications were the papers by Robert E. Gross in 1953 and C. Everett Koop in 1955. Gross noted that extensive and radical surgery has a definite place under certain circumstances and can lead to permanent cure for neuroblastoma . Koop explained the positive effect of tumor debulking on outcome in his book, Neuroblastoma in Childhood: Survival After Major Surgical Insult to the Tumor .

In the 1960s, groups in Japan and Europe also described their experiences with resection of neuroblastoma . Adjuvant chemotherapy was introduced in 1965 . In 1968, C. Everett Koop made an early attempt to define risk status when he analyzed the impact of surgical interventions based on resectable, nonresectable, or metastatic tumors .

In the 1970s, there were major advances in pediatric imaging, surgery, anesthesia, blood banking, and critical care , and the pediatric oncology cooperative groups were established. With this progress, multi-institutional data became available, and surgical reports have continued to increase.

In the 1980s, retrospective studies from the Children's Cancer Study Group discussing the role of surgery in localized and disseminated neuroblastoma were published . In 1988, a prospective study was published by investigators from the Pediatric Oncology Group, which showed that certain localized neuroblastomas could be effectively treated with surgery alone, even with the involvement of regional nodes . The authors noted that overall survival was excellent even in patients who relapsed, but without a uniform staging system, comparisons between cooperative group experiences could not be drawn. Later that same year, the International Neuroblastoma Staging System (INSS) was established and was revised in 1993 . During the 1980s and early 1990s, the efficacy of primary tumor resection in patients with advanced-stage disease became controversial.

In the 2000s, the International Neuroblastoma Risk Group (INRG) classification system was developed to allow for presurgical risk assessment. In this system, nonmetastatic tumors are assessed for surgical risk factors that predict unresectability using radiographic imaging, known as Image Defined Risk Factors (IDRFs) . Since the turn of the century, the Children's Oncology Group (COG) and the Society of Pediatric Oncology Europe Neuroblastoma (SIOPEN) have conducted several prospective studies with the goal of evaluating chemotherapy protocols. As these studies did not use surgical outcomes as primary endpoints, the prospective studies have since been retrospectively reviewed to evaluate surgical outcomes .

The controversy surrounding the efficacy of primary tumor resection in patients with advanced-stage disease continued into the 2010s. In 2014, multiple studies were published showing that high-risk, stage 4 neuroblastoma patients have increased event-free survival after undergoing primary tumor resection . Surgery has an even more important role in low-risk and intermediate-risk diseases.

Staging and Risk Status

The INSS, revised in 1993, was adopted by the COG and cooperative groups in Europe and Japan . This system emphasizes the extent of the primary tumor, presence and location of positive lymph nodes, and metastasis as criteria for categorizing the patients into stages 1, 2A/2B, 3, and 4/4S. This staging system, along with tumor biology, is the basis of COG risk stratification, which divides patients into low-risk, intermediate-risk, and high-risk groups in order to guide treatment. With the advent of the INRG classification system in the early 2000s, the comparison of published surgical outcomes has become difficult because investigators must choose one system on which to base their study . In the INRG classification system, tumors are assessed for surgical risk factors that predict unresectability using IDRFs and are separated into L1 (no IDRFs), L2 (at least one IDRF), M (metastatic), or MS (the equivalent of 4S in the INSS). Based on this stage, along with histology and tumor biology, patients are grouped into very low, low, intermediate, and high-risk groups. Regardless of which system is chosen, the stage and risk status of the patient has a great impact on the surgical intervention. It is worthwhile to review the individual groupings, as they guide the surgical decision-making.

Very Low and Low Risk

The very-low-risk group exists only in the INRG risk group classification system and includes stage L1 without MYCN amplification and stage MS without MYCN amplification or 11q aberration. The low-risk group includes INSS stage 1, stage 2A/2B without MYCN amplification and greater than 50% tumor resection, and stage 4S without MYCN amplification. This group also includes INRG stage L1, stage L2 without MYCN amplification or 11q aberration, and stage M or MS without MYCN amplification or 11q aberration if the patient's age is less than 18 months.

The goal for the low-risk group is complete primary tumor resection, accurate staging by biopsy of nonadherent nodes, and adequate tissue sampling for molecular biologic studies. Patients with low-risk disease have an overall survival of >90% with almost all patients receiving surgery alone . For this reason, the standard treatment for patients with low-risk disease is surgery alone.

Intermediate Risk

The intermediate-risk group includes INSS stage 2A/2B without MYCN amplification and <50% tumor resection, stage 3 without MYCN amplification and age <18 months with any histology or age >18 months with favorable histology, and stage 4 or 4S without MYCN amplification and age <18 months. This group also includes INRG stage L2 without MYCN amplification, but with 11q aberration or poorly differentiated histology, and stage M without MYCN amplification, but with diploid tumor and age <18 months.

The surgical goals for patients with intermediate-risk disease are to establish the diagnosis, to resect as much of the primary tumor as safely possible, to accurately evaluate the stage of the disease through the sampling of nonadherent lymph nodes, and to obtain an adequate amount of tissue for diagnostic studies. Patients in this group with unresectable tumors are treated with chemotherapy per COG guidelines. In patients with locoregional disease with intermediate-risk characteristics, surgery alone has been shown to be an effective treatment when the tumor can be completely resected .

In 2009, a single institution study of 54 patients with intermediate-risk and high-risk stage 3 MYCN-nonamplified disease found that these patients can be safely treated with minimal chemotherapy . In the study, 14 patients were treated with surgery alone, while 39 patients had neoadjuvant chemotherapy that was discontinued after surgical resection. While a higher event-free survival (EFS) (97.1 ± 3% vs. 84.6 ± 10%, P = .02) was seen in patients who received neoadjuvant chemotherapy, there was no difference in 10-year overall survival (OS) between the two groups. Patients with locoregional intermediate- and high-risk disease were able to achieve a 10-year EFS of >97% while minimizing chemotherapy.

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