Neuroblastoma Treatment & Management

Because surgery is used to manage only low-stage (stages I and II) neuroblastoma, multiple-agent chemotherapy is the conventional therapy for patients in the more advanced stages of neuroblastoma. Interestingly, infants with disseminated neuroblastoma have favorable outcomes with combined chemotherapy and surgery. In contrast, children older than 1 year with high-stage neuroblastoma have very poor survival rates despite intensive multimodal therapy. Because of these findings, pioneering work in Japan during the 1980s claimed that aggressive screening of infants younger than 6 months with urinary catecholamines could detect neuroblastoma earlier and lead to better outcomes. However, follow-up population-based, controlled trials in Europe and North America did not confirm the benefit of early screening reported in the Japanese studies.

Despite these contradictory findings, symptomatic treatments are available for patients with neuroblastoma. Adrenocortical hormone (ACTH) is thought to be fairly efficacious, although some patients are resistant. Plasmapheresis and gamma globulin have been used in the treatment of selected patients with neuroblastoma; however, chemotherapeutic agents are thought to result in better neurological outcomes.

The common chemotherapeutic agents include cisplatin, doxorubicin, cyclophosphamide, and the epipodophyllotoxins (teniposide and etoposide). Drug combination protocols have used strategies that take advantage of drug synergism, mechanisms of toxicity, and differences of adverse effects. Despite these various drug combinations, the cure rate has not been significantly affected. The long-term survival in patients with metastatic neuroblastoma is poor, perhaps because of the abundance of nonproliferating tumor cells. However, chemotherapeutic agents used to manage neuroblastoma have reduced the size of the primary tumor, occasionally sterilized the bone marrow, and, rarely, transformed the neuroblastoma into benign ganglioneuroma.

Current trends in chemotherapy for the management of neuroblastoma include (1) more dose-intensive chemotherapy with secondary surgical extirpation, (2) myeloablative therapy using escalating chemotherapeutic combinations followed by autologous bone marrow infusion, and (3) biologic response modifiers that cause tumor differentiation and a reduction in tumor involvement of the bone marrow. Some of these seminal chemotherapeutic trials have demonstrated promising results. Multimodal therapeutic protocols established by the POG are the standard of care in children diagnosed with neuroblastoma.

Topotecan, a topoisomerase I inhibitor, alone or in combination with cyclophosphamide, has been shown to have activity against recurrent neuroblastoma. This information has led to a Children's Oncology Group (COG) pilot study designed to test the clinical efficacy of incorporating topotecan into an intensive induction regimen in patients with newly diagnosed, high-risk neuroblastoma.

Retinoids, natural and synthetic derivatives of vitamin A, have been shown in vitro to down-regulate N-myc mRNA expression, which arrests tumor cell proliferation. These observations have led to clinical trials designed to test the efficacy of 13-cis-retinoic acid (RA) in children with relapsed neuroblastoma. In phase I and II trials, results were disappointing in patients with a high tumor burden; however, in patients with minimal disease, randomized phase III trials involving 13-cis RA resulted in improved survival rates.

Targeted immunotherapy has been evaluated in the treatment of multimodal resistant microscopic neuroblastoma. GD2 is an excellent target for immunotherapy because this antigen is expressed at high density in most human neuroblastoma tumors. To enhance response rates, cytokines have been used in combination with anti-GD2 antibodies to increase antibody-dependent cellular cytotoxicity (ADCC). Several other immunotherapies, including cytotoxic T lymphocytes, modified dendritic cells, recombinant IC-2, granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-2 (IL-2), have shown promising results against neuroblastoma.

In patients with high-risk neuroblastoma, the addition of an anti-GD2 antibody (ch14.18), along with GM-CSF, and interleukin-2 to standard isotretinoin therapy significantly improved outcome. Improvement in both event-free survival and overall survival was significant.^[10]

Because recurrent neuroblastoma is often a radiation-sensitive systemic disease, interest has arisen in use of radioactive molecules that are selectively concentrated in neuroblastoma cells. Clinical trials are underway in Europe and North America to delineate the efficacy of radio-labeled MIBG, with and without combined myeloablative chemotherapy followed by autologous stem cell rescue. Determining the optimal doses, schedules, and timing of MIBG therapy are the goals of these clinical trials. A recent study from 2005 showed a response rate of approximately 40% in heavily pretreated patients; however, MIBG therapy does not seem to have an independent advantage. A further multimodal therapy trial (NB2004) is currently underway.

Antiangiogenesis therapy has more than a theoretical role in the treatment of neuroblastoma. In fact, preclinical studies have demonstrated that these agents inhibit neuroblastoma growth in vivo, especially in minimal residual disease states. Phase I protocols testing angiogenesis inhibitors are in progress to determine if highly vascular neuroblastoma tumors respond to these agents.

In vitro cultures demonstrate that neuroblastoma is radiosensitive, but results from clinical trials have been inconsistent and inconclusive. As a primary treatment modality, radiation therapy has a limited yet well-defined role. It can be used in regional lymph node metastases with sequential cyclophosphamide therapy, in infants with stage-4 disease who have Pepper syndrome (to control respiratory compromise), and in total-body irradiation (TBI) combined with autologous bone marrow transplantation (ABMT).

In 1988, the POG released a prospective study that revealed that 89% of patients with localized neuroblastoma who underwent surgical extirpation had only 2 years of disease-free survival. Additionally, chemotherapy appeared to offer no advantage in patients with residual disease. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are (1) to determine an accurate diagnosis, (2) to completely remove all of the primary tumor, (3) to provide accurate surgical staging, (4) to offer adjuvant therapy for delayed primary surgery, and (5) to remove residual disease with second-look surgery.

Neuroblastoma metastatic to the paraspinal region may extend through the vertebral foramina and may manifest as cord compression. This occurs in 7-15% of patients with neuroblastoma. Cord compression is a medical emergency and should be treated aggressively to reduce the risk of neurological deficit. Unfortunately, the optimal treatment has yet to be determined for cord compression secondary to metastatic neuroblastoma.

Options to relieve cord compression in these situations include surgical resection with or without laminectomy, multimodal chemotherapy, and external beam radiation therapy. In a retrospective review of the POG experience, chemotherapy and laminectomy were associated with similar rates of neurological recovery, although laminectomy was associated with more orthopedic morbidity. Given these results, a conservative, primary medical approach might be the best initial therapy, with laminectomy reserved for patients who do not respond to chemotherapy.

Opsoclonus-myoclonus syndrome (OMS) is thought to be immune-mediated because 60% of patients who develop this in association with neuroblastoma respond to adrenocorticotropic hormone or corticosteroids. Treatment of OMS has been studied more recently given the fact that long-term outcomes have been shown to result in recurrent neurological symptoms, developmental delay, and mental retardation. Improved long-term results have been demonstrated in patients with neuroblastoma who develop OMS when they are treated with multimodal chemotherapy. Petruzzi et al have reported positive results when these patients are treated with intravenous gamma globulin.

Neuroblastoma continues to be one of the most frustrating childhood tumors to manage. Although the tumor has been studied extensively and great efforts have been made to secure appropriate therapy and achieve a cure, little has altered the prognosis in affected children over the past 20 years. Additionally, some pediatric retroperitoneal tumors cannot be determined accurately before surgery. Therefore, surgeons who treat these children must be conversant with current staging systems and treatment modalities.

An adequate history and physical examination are essential to the preoperative screening in a child being evaluated for neuroblastoma. All radiographic studies (chest radiography, bone scanning, CT scanning, MRI) should be reviewed. Serum chemistries and a CBC count are essential. Additional blood studies include a VMA-to-HVA ratio, serum ferritin, and NSE. Other studies specific to the child being evaluated include obtaining bone marrow aspirate and biopsy specimens, N-myc oncogene copy number of tumor, and chromosome studies or transketolase (TRK) analysis.

A general bowel preparation and a third-generation cephalosporin are used, depending on the clinical stage of the tumor.

All children with suspected neuroblastoma should undergo anesthetic evaluation. However, unlike in pheochromocytoma (in which the anesthetic choice is crucial), neuroblastoma does not require a specific anesthetic protocol. In patients with large or complicated tumors, an ICU bed should be obtained for postoperative management.

Adequate exposure in the child with neuroblastoma is paramount. In order to achieve this goal, the surgeon must adhere to a number of principles. The patient should be in the supine position, with all pressure points padded. Excellent light sources should be available, including main operating room (OR) lights, overhanging OR lights, and individual head lights, as needed. Various surgical incisions are available, and any surgeon operating on an adrenal mass should be familiar with them prior to surgery. Finally, the surgeon should be intimately familiar with the anatomy of the adrenal gland, surrounding organs, and their respective blood supplies.

The type of incision is partially dictated by the mass and certainly is at the discretion of the operating surgeon. For most abdominal neuroblastomas, a midline transperitoneal incision provides excellent exposure to the peritoneal cavity, retroperitoneum, and, specifically, the ipsilateral suprarenal area. Other incisions for this particular surgery include an upper transverse abdominal incision or a chevron incision for tumors that involve the upper abdomen and retroperitoneum.

Knowledge of the metastatic properties unique to neuroblastoma helps to understand the protocol for safe abdominal exploration and extirpation. The viscera are reflected to the midline and secured in an intestinal bag. The abdomen and retroperitoneum are explored. Careful attention must be given to the anatomical relationships of the tumor to the surrounding structures because this dictates the possible extirpative field. To complete the protocol, regional lymph nodes are evaluated, and a biopsy specimen is obtained from the liver.

Surgical management is dictated by the staging laparotomy. If the tumor cannot be removed primarily, a wedge biopsy of the tumor may be performed for histopathology, immunohistochemistry, and genetic studies. Proper surgical techniques are used to prevent excessive bleeding and tumor spillage.

If the staging laparotomy reveals that primary resection of the tumor is tenable, attention is turned to removal of the tumor. Neuroblastoma is known to invade the tunica adventitia of large blood vessels; therefore, the surgeon should have a vascular set and take precautions to obtain distal and proximal control of the major blood vessels. A preoperative consultation with a vascular specialist should be considered for large tumors.

Access to the tumor is gained by starting in a distal subadventitial plane and dissecting proximally. In this plane, the anterior abdominal aorta, inferior and superior mesenteric arteries, and celiac arteries are identified, isolated, and preserved (as much as possible). In cases in which the renal hilum is involved with tumor, an ipsilateral nephrectomy is performed. Other attachments to the tumor are released and the tumor can be delivered to the surface.

Proper surgical principles and techniques are critical; otherwise, the risk of morbidity and mortality is high.

Postoperative treatment in a child who has undergone a major abdominal exploration and extirpation is dictated, in part, by the extent of resection, duration of surgery, and possible intraoperative complications. The most common complication associated with the removal of a neuroblastoma is related to vascular injury. Hypotension may lead to acute renal failure and an ischemic bowel, which must be addressed appropriately in an intensive care setting.

As stated above, surgery plays a major role in children with low-stage disease and a controversial role in children with advanced disease, especially as it applies to the extent of surgical resection. A multimodal approach is suggested for the management of children with advanced neuroblastoma. Multiple-agent chemotherapy has increased the 5-year survival rate to 75% in patients younger than 1 year. Radiation therapy recently has been shown to produce superior initial and long-term disease control when administered synergistically with chemotherapy. In any event, follow-up of these patients follows a clear POG protocol.

Surgical complication rates in patients with neuroblastoma range from 5-25%, depending on the stage of the tumor. More aggressive primary abdominal extirpations carry the highest complication rate. Incidental nephrectomy or splenectomy, operative hemorrhage, postoperative intussusception, and injury to major vessels or nerves are some of the more common complications associated with high-stage tumors. Infants with neuroblastoma enjoy a significant survival advantage over all other age groups. Aggressive treatment in these children is therefore warranted only when they have complications related to tumor burden (as in Pepper syndrome), coagulopathy, and renal compromise.

Intensive multimodal treatment in patients with neuroblastoma has resulted in improved survival rates. However, the late effects, which can have diverse and devastating manifestations, should be considered. Cancer survivors should be monitored closely in multidisciplinary clinics, with emphasis on long-term sequelae. Surgery and radiation therapy can result in many late orthopedic effects, such as scoliosis, osteoporosis, and hypoplasia of bony and soft tissue structures. Chemotherapeutic regimens used to treat neuroblastoma may result in long-term toxicities, including cardiopulmonary toxicities (anthracyclines), ototoxicity (cisplatin), renal failure (ifosfamide and cisplatin), infertility and impotency (alkylating agents and radiation therapy), secondary cancers, and psychological effects.

For more than 40 years, the age at diagnosis and the stage have been the dominant independent variables used as prognosticators in children with neuroblastoma. In 1984, Shimada classified neuroblastoma, relating its histopathologic features to its clinical behavior.^[11] To this end, Shimada divided neuroblastoma into favorable and unfavorable categories, depending on the degree of neuroblast differentiation, Schwannian stromal content, mitosis-karyorrhexis index, and age at diagnosis. In 1999, the Shimada classification was modified to the International Neuroblastoma Pathology Classification system.

Because of the various approaches to risk stratification, efforts have been made in the last 2 years to develop a consensus approach that will allow comparison of patients around the world. In 2005, a large group of patients from Europe, Japan, the United States, Canada, and Australia diagnosed with neuroblastoma between 1974 and 2002 was reviewed in an effort to develop an International Neuroblastoma Risk Group (INRG). Consensus was reached to consider age (dichotomies around 18 mo), stage assessed before treatment, and N-myc status in the risk-group schema. Once the final statistical analyses are available, the specific criteria will be included in the final INRG report.

The COG recently developed a process called the Neuroblastoma Risk Stratification System (NRSS), which is used for treatment stratification. Like the Shimada Index, this new system is based on clinical and biological factors that are predictive of outcome. The NRSS is different in that it is based on the INRG system and is used for treatment-stratification purposes. Patients are assigned to low-, intermediate-, or high-risk categories based on age at diagnosis, INSS stage, histopathology, N-myc amplification status, and DNA index.

However, certain biological variables that affect the prognosis of children with neuroblastoma have been identified. Specific examples include aneuploidy of tumor DNA and N-myc oncogene amplification. N-myc amplification occurs in 20% of primary neuroblastoma tumors and is associated with a subset of neuroblastomas that have high metastatic potential and, consequently, a poor prognosis. N-myc is thought to contribute to the aggressive behavior of neuroblastoma. However, the precise role of N-myc in nonamplified tumors is unknown.

Hyperdiploid tumor DNA is associated with a favorable prognosis. N-myc amplification is associated with a poor prognosis in children older than 1 year but not in children younger than 1 year. The N-myc amplification is linked to the deletion of chromosome arm 1p and a gain of the long arm of chromosome 17. In neuroblastoma, consistent areas of chromosomal loss of heterozygosity (LOH) include chromosome bands 1p36, 11q23, and 14Q23qter. In 2000, Maris et al reported from the Children's Cancer Group (CCG) that 1p deletion independently predicted a lower event-free survival but not overall survival. The clinical relevance of 14q LOH is unclear at this time.

Allelic loss of 11q is present in 35-45% of primary tumors. Notably, this aberration is rarely seen in tumors with N-myc amplification yet remains highly associated with other high-risk features.

Other variables carry varying degrees of prognostication. These include the site of the primary tumor, serum ferritin levels, NSE, and nutritional status.

Neuroblastoma continues to be one of the most frustrating childhood tumors to manage. Although the tumor has been studied extensively and great efforts have been extended to secure appropriate therapy and achieve a cure, little has altered the prognosis in affected children over the past 20 years.

In vitro cultures demonstrate that neuroblastoma is radiosensitive, but results from clinical trials have been inconsistent and inconclusive. As a primary treatment modality, radiation therapy can be used in regional lymph node metastases with sequential cyclophosphamide therapy, in infants with stage-4 disease who have Pepper syndrome (to control respiratory compromise), and in TBI combined with ABMT.

Further consensus data are needed to provide more definitive information regarding risk stratification, treatment, and prognosis in patients with neuroblastoma.