Neuroblastoma Treatment & Management: Approach Considerations, Medical Therapy, Surgical Therapy (original) (raw)

Treatment

Approach Considerations

Spontaneous regression of neuroblastoma occurs commonly in infants with asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasonography. Observation, without surgical intervention or tissue diagnosis, may be a safe option in these patients. [2]

In 1988, the Pediatric Oncology Group (POG) released a prospective study showing that patients with localized neuroblastoma who were treated with surgical extirpation had a 2-year disease-free survival rate of 89%. [29] Additionally, chemotherapy appeared to offer no advantage when residual disease was present in these patients. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are as follows:

  1. Determine an accurate diagnosis
  2. Completely remove all of the primary tumor
  3. Provide accurate surgical staging
  4. Offer adjuvant therapy for delayed primary surgery
  5. Remove residual disease with second-look surgery

As stated above, surgery plays a major role in children with low-stage disease. It has 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 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.

Adult-onset neuroblastoma is rare, and there is no established therapy for it. Anti-disialoganglioside (anti-GD2) immunotherapy may be beneficial in these patients. [30]

For relapsed high-risk neuroblastoma, studies have reported response to a variety of chemotherapy regimens. However, the most effective therapeutic strategy for these patients has not been determined. [31]

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Medical Therapy

Because surgery is used to manage only low-stage (stages I and II) neuroblastoma, multiple-agent chemotherapy is the conventional therapy for patients with 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. [32]

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 cases are resistant. Plasmapheresis and gamma globulin have been used in the treatment of selected patients with neuroblastoma, but chemotherapeutic agents are thought to result in better neurological outcomes.

Commonly used 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.

A randomized, multi-arm, open-label, phase 3 trial in children with high-risk neuroblastoma who had an adequate response to induction treatment found that busulfan plus melphalan improved event-free survival and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. The 3-year event-free survival was 50% (95% confidence index [CI] 45-56%) with busulfan plus melphalan versus 38% (95% CI, 32-43%; P=0.0005) with carboplatin, etoposide, and melphalan. The researchers concluded that busulfan and melphalan should be considered standard high-dose chemotherapy. [33]

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 with neuroblastoma.

Topotecan, a topoisomerase I inhibitor, alone or in combination with cyclophosphamide, has been shown to have activity against recurrent neuroblastoma. A Thai study reported a favorable treatment response with minimal toxicity in 107 patients with high-risk neuroblastoma who received six cycles of the following induction regimen [34] :

However, a European open-label, multicenter, prospective randomized controlled trial in 422 patients with high-risk neuroblastoma reported disappointing results with the addition of two courses of topotecan, cyclophosphamide, and etoposide to six courses of standard induction chemotherapy. Patients receiving the additional courses did not have significantly improved event-free or overall survival, and they experienced a higher number of toxic adverse effects. [35]

Retinoids (natural and synthetic derivatives of vitamin A) have been shown in vitro to down-regulate MYCN mRNA expression, which arrests tumor cell proliferation. These observations have led to clinical trials designed to test the efficacy of 13-cis-retinoic acid 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. [36]

Anti-disialoganglioside monoclonal antibodies

In 2015, the US Food and Drug Administration (FDA) approved dinutuximab (Unituxin), which is a monoclonal antibody against disialoganglioside (anti-GD2), for use in the treatment of pediatric patients with high-risk neuroblastoma. It was approved for use as part of a multimodality regimen in patients who have achieved at least a partial response to prior first-line multiagent treatment. Dinutuximab is indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid. Improvement in both event-free survival and overall survival has been shown to be significant. [37]

Naxitamab (Danyelza), a humanized anti-GD2 monoclonal antibody, was granted accelerated approval by the FDA for use in combination with GM-CSF for relapsed or refractory high-risk neuroblastoma in bone or bone marrow demonstrating a partial response, minor response, or stable disease with prior therapy, in adults and in pediatric patients age 1 year or older.

Approval of naxitamab was based on two single-arm open-label studies, Study 201 and Study 12-230. In Study 201, the overall response rate (ORR) 45% (95% CI: 24%, 68%) and duration of response (DOR) ≥6 months was 30%. In Study 12-230, the ORR was 34% (95% CI: 20%, 51%) with 23% of patients having a DOR ≥6 months. For both trials, responses were observed in bone, bone marrow, or both. [38]

Eflornithine

Oral eflornithine (Iwilfin) was approved by the FDA in December 2023 to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. [39]

Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate-limiting enzyme in biosynthesis of polyamines and a transcriptional target of MYCN.

Inhibiting polyamine synthesis restores balance of the LIN28/Let-7 metabolic pathway, which is involved in regulation of cancer stem cells and glycolytic metabolism, by decreasing expression of the oncogenic drivers MYCN and LIN28B in _MYCN_-amplified neuroblastoma.

Approval was supported for postimmunotherapy maintenance of high-risk neuroblastoma from patients who received eflornithine following standard up-front or refractory/relapse treatment. Eflornithine after completion of immunotherapy was associated with improved event-free survival (P = 0.008) and overall survival (P = 0.007) compared with historical controls who received other therapies. [40]

Other therapies

Because 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 have been conducted in Europe and North America to delineate the efficacy of iodine-131–radiolabeled meta-iodobenzylguanidine (131I-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. Initially studied in relapsed or refractory neuroblastoma, 131I-MIBG has subsequently drawn interest for use as first-line therapy, alone or in combination with chemotherapeutic drugs. [41, 42]

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 whether 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. [43] Indications include the following:

Other immunotherapies that have shown promising results against neuroblastoma include the following:

Opsoclonus-myoclonus syndrome in neuroblastoma

Opsoclonus-myoclonus syndrome (OMS) is thought to be immune-mediated, because 60% of patients who develop this in association with neuroblastoma respond to ACTH or corticosteroids. However, the need for more comprehensive treatment of OMS was demonstrated by long-term outcomes in those patients, which included recurrent neurologic symptoms, developmental delay, and intellectual disability. [44]

Improved long-term results have been demonstrated in patients with neuroblastoma who develop OMS when they are treated with multimodal chemotherapy. A prospective randomized trial in 53 children with opsoclonus-myoclonus ataxia syndrome associated with neuroblastoma found that the addition of intravenous immune globulin (IVIG) to prednisone and risk-adapted chemotherapy significantly improves the response rate. [45]

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Surgical Therapy

In 1988, the Pediatric Oncology Group (POG) released a prospective study showing that patients with localized neuroblastoma who were treated by surgical extirpation had a 2-year disease-free survival rate of 89%. [29] 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 as follows:

  1. Determine an accurate diagnosis
  2. Completely remove all of the primary tumor
  3. Provide accurate surgical staging
  4. Offer adjuvant therapy for delayed primary surgery
  5. 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 for cord compression secondary to metastatic neuroblastoma has yet to be determined.

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 neurologic 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.

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.

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Preoperative Details

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 measurement of vanillylmandelic acid–to–homovanillic acid (VMA-to-HVA) ratio, serum ferritin, and neuron-specific enolase (NSE). Other studies specific to the child being evaluated include obtaining bone marrow aspirate and biopsy specimens, MCYN oncogene copy number of tumor, and chromosome studies or transketolase (TRK) analysis.

A general bowel preparation and a antimicrobial prophylaxis with 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.

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Intraoperative Details

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.

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Postoperative Details

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 kidney injury and an ischemic bowel, which must be addressed appropriately in an intensive care setting.

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Complications

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), chronic kidney disease (ifosfamide and cisplatin), infertility and erectile dysfunction (alkylating agents and radiation therapy), secondary cancers, and psychological effects.

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Author

Byron D Joyner, MD, MPA Vice Dean for Graduate Medical Education and Designated Institutional Official Professor, Department of Urology, University of Washington School of Medicine; Pediatric Urologist, Seattle Children's Hospital

Byron D Joyner, MD, MPA is a member of the following medical societies: American Academy of Pediatrics, Society of University Urologists, Washington State Medical Association, Society of Urology Chairpersons and Program Directors, American College of Surgeons, American Urological Association, The Society of Federal Health Professionals (AMSUS), Massachusetts Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Brian H Kopell, MD Associate Professor, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai; Director, Center for Neuromodulation, Co-Director, The Bonnie and Tom Strauss Movement Disorders Center, Department of Neurosurgery, Mount Sinai Health System

Brian H Kopell, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, American Society for Stereotactic and Functional Neurosurgery, Congress of Neurological Surgeons, International Parkinson and Movement Disorder Society, North American Neuromodulation Society

Disclosure: Received income in an amount equal to or greater than $250 from: Medtronic; Abbott Neuromodulation; Turing Medical.

Acknowledgements

Natalya Lopushnyan Yale University School of Medicine

Disclosure: Nothing to disclose.