Article
New Approaches to Neuroblastoma
Author(s):
Neuroblastoma (NB) is the most common pediatric, intra-abdominal, extracranial, solid tumor derived from nervous tissue. This malignant neoplasm occurs at an annual rate of 9.1 cases per 1 million American children younger than 15 years and is found more frequently in boys. The median age at diagnosis is 2 years for both sexes, with most cases being diagnosed by the age of 5 years. Metastatic disease is often found at presentation and represents about 70% of all newly diagnosed cases.
Neuroblastoma (NB) is the most common pediatric, intra-abdominal, extracranial, solid tumor derived from nervous tissue. This malignant neoplasm occurs at an annual rate of 9.1 cases per 1 million American children younger than 15 years and is found more frequently in boys. The median age at diagnosis is 2 years for both sexes, with most cases being diagnosed by the age of 5 years. Metastatic disease is often found at presentation and represents about 70% of all newly diagnosed cases.1,2
Cytogenetic abnormalities also have been found in patients with NB. The most common abnormality is the nonrandom deletion or rearrangement of the short arm of chromosome 1. Staining regions that are chromosomally heterogeneous and double-minute chromosomes exist with high frequency in NB cell lines. Amplification of the N-myc oncogene has been associated with NB tumorigenesis.2-4
The early detection of NB via screening has been considered useful in improving the outcomes of children with NB; however, a Canadian study5 and a German study6 concluded that screening for NB did not necessarily reduce the incidence of disseminated disease or mortality.
HOW IS IT TREATED?
Resection forms an important treatment focus for early-stage NB. "Surgery in the low-risk patient-that is, in stages I, IIA, and IIB-produces a high survival rate. For stage I disease, survival rates approach 95%, and in stage II, the survival rate is in the range of 85%," explained Timothy A. Driscoll, MD, head of the pediatric stem cell transplant section at Duke University Medical Center, in an interview with Applied Neurology.
"For the low-risk patient with non-N-myc-amplified favorable histology and no 1p or 11q translocations, the new Children's Oncology Group [COG] protocols suggest resection followed by observation. If patients have unfavorable histological and genetic characteristics, they will go on to receive adjuvant chemotherapy in addition to resection."
NB also has been treated with radiotherapy in conjunction with chemotherapy as a primary modality for the control of low-risk disease. Unfortunately, radiotherapy has not improved survival in children with widely disseminated disease.2
"Basically, most people are moving away from radiotherapy except for treatment of high risk, stage III disease with unfavorable histology," said Driscoll. "Patients at high risk for stage IV disease are receiving stem cell transplantation. Low-risk patients who clinically progress or develop respiratory distress and often show hepatic metastases are treated with low-dose-regimen chemotherapy."
Because radiotherapy is most effective in low-risk disease but has not improved survival in patients with disseminated disease, chemotherapy has become the modality of choice in patients with unresectable or metastatic NB.2 "As far as chemotherapy is concerned," Driscoll continued, "in the low-risk and the intermediate-risk patients, the whole thrust now in COG protocols is to reduce cytotoxic therapy in patients with stage III and stage IV disease and with favorable histology with non-amplified N-myc.
"The alternating sequence cycles of N6 and N7 protocols are what most clinicians are using. These include cisplatin/ifosfamide, carboplatinum/ifosfamide, and vincristine cytotoxins," he explained. "Everybody uses variants of these protocols, and the current COG protocol for the high-risk patients [COG A3973] basically uses the N6 backbone for induction, which consists of 6 courses of alternating chemotherapy." The protocol has resulted in complete or partial remissions in about 90% of patients studied, according to Driscoll.
Patients with widely disseminated disease require another strategy. Poor response to aggressive chemotherapy in this patient population has led clinicians to try myeloablative therapy in conjunction with transplantation of autologous bone marrow (ABMT).
Treatment with ABMT has been shown to improve event-free survival in children with high-risk NB. Adjunctive isotretinoin therapy was found to be beneficial in patients without progressive disease when used following chemotherapy or transplantation.7 High-dose therapy with tandem autologous peripheral-blood stem cell rescue has been effective, with long-term survival in patients with high-risk NB.8
"Recent studies have found that survival with transplantation therapy is better than that with chemotherapy," said Driscoll. "COG data from Nai-Kong V. Cheung, MD, PhD [Enid A. Haupt Chair in Pediatric Oncology at Memorial Sloan-Kettering Cancer Center in New York City] and his team at Sloan-Kettering have found that patients who received ABMT have a 34% disease-free survival after 3 years, and patients who received chemotherapy had a disease-free survival of only 22%," said Driscoll. "These patients got an induction of 5 or 6 courses of chemotherapy, similar to the N6/N7 protocols, and then they got a single transplantation," he explained.
"Using 2 high-dose chemotherapy inductions followed by autologous stem cell transplantation rescue, our group at Duke has been able to increase the 3-year survival rate from 34% to 61%; the 5-year survival rate comes out to 54%, and the 7-year survival rate has been pretty stable at 72%," reported Driscoll. "Other investigators have produced similar results using chemotherapy followed by ABMT, and some have reported additional survival advantages using post-transplant immunotherapy with isotretinoin, achieving a 3-year progression-free survival rate of 55%."
IMMUNOTHERAPY
Although intensive chemotherapy has resulted in major regression in high-risk patients older than 1 year, lethal relapses are common. Chemoresistance can be overcome by focusing on the patient's immune defenses. To that end, a murine immunoglobulin monoclonal antibody, 3F8, has been used as targeted immunotherapy. The 3F8 monoclonal antibody reacts with the neuron-specific ganglioside GD2 that is expressed in high concentrations in NB. To increase cytotoxicity, 3F8 has been combined with granulocyte-macrophage colony-stimulating factor.
Cheung and colleague Brian H. Kushner, MD, a pediatric oncologist at Sloan-Kettering, have demonstrated that this combination shows promise in the treatment of residual NB in bone marrow.9 Because responses were not consistent, however, further investigation was undertaken wherein it was discovered that favorable responses were predicated on the presence of the FCGRA (R/R) genotype.10
Another chimeric monoclonal antibody called CH14.18 is also under study, according to Driscoll. "It acts against GD2 and is being used in randomized studies in post-transplantation patients in the Children's Oncology Group [COG ANBL0032]. Preliminary studies have shown some efficacy with this treatment. These cell-targeted approaches to NB will probably become the future direction of successful therapies in high-risk patients," he said.
References:
REFERENCES
1.
Ebb DH, Green DM, Shamberger RC, Tarbell NJ. Solid tumors of childhood. In: DeVita VT, Hellman S, Rosenberg SA, eds.
Cancer: Principles and Practice of Oncology.
7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005: 1898-1937.
2.
Santana VM, Bowman LC. Neuroblastoma. In: Rudolph AM, Hoffman JIE, Rudolph CD, eds.
Rudolph's Pediatrics.
20th ed. Stamford, Conn: Appleton & Lange; 1996:1286-1289.
3.
Bown N, Cotterill S, Lastowska M, et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma.
N Engl J Med.
1999;340: 1954-1961.
4.
Attiyeh EF, London WB, Mossé YP, et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma.
N Engl J Med.
2005;353:2243-2253.
5.
Woods WG, Gao RN, Shuster JJ, et al. Screening of infants and mortality due to neuroblastoma.
N Engl J Med.
2002;346:1041-1046.
6.
Schilling FH, Spix C, Berthold F, et al. Neuroblastoma screening at one year of age.
N Engl J Med.
2002;346:1047-1052.
7.
Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid.
N Engl J Med.
1999;341:1165-1173.
8.
George RE, Li S, Medeiros-Nancarrow C, et al. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update.
J Clin Oncol.
2006;24:2891-2896.
9.
Kushner BH, Kramer K, Cheung NK. Phase II trial of the anti-GD2 monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma.
J Clin Oncol.
2001;19:4189-4194.
10.
Cheung NK, Sowers R, Vickers AJ, et al. FCGRA polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor.
J Clin Oncol.
2006;24:2885-2889.
