COG 2013 Blueprint for Neuroblastoma Research
“The development of molecularly targeted agents for treatment of neuroblastoma has been hampered by difficulty in agent availability, inadequate agent formulation for oral administration to young children, lack of relevant molecular target in neuroblastoma and/or lack of sufficient pre-clinical data”1 (p. 5).
There are many challenges associated with the treatment of neuroblastoma. Most notably is the heterogeneity of the disease – the different disease stages present in very diverse ways from being a tumour that can regress without any treatment, to disease that is highly resistant to chemotherapy. Research into finding the causes, genetic variations, treatments, and novel therapies for neuroblastoma continue to occur. In 2012, the Children’s Oncology Group (COG) Neuroblastoma Committee documented the important current and future research being done to further understand this perplexing disease1. The following is a summary of that article.
Some Current Understandings of Neuroblastoma
Disease Staging and Classification
The neuroblastoma community is currently moving away from the International Neuroblastoma Staging System (INSS) and is transitioning to the International Neuroblastoma Risk Group Staging System (INGRSS). This staging system is described as follows2 (p. 299-300):
L1: The tumour is localized, does not involve vital structures, and is only found in one compartment of the body, neck chest abdomen or pelvis.
L2: The tumour is locoregional (e.g., involvement on the left side of the body or on the right side of the body) and has one or more defined risk factors.
M: The disease is metastatic and spread throughout the body (except for stage MS).
MS: The disease is metastatic but child is younger than 18 months (547 days) of age. Metastases are found in the liver, skin, and/or bone marrow (should be less than 10%).
The International Neuroblastoma Response Criteria (INRC) classifies the disease into four risk groups of: very low, low, intermediate and high3. These risk groups help ensure that patients are classified into treatment risk groups as consistently as possible, in all countries. In 2012, the National Cancer Institute (NCI) sponsored an international meeting that should result in a revised INRC in the near future. These revisions should include “primary tumor dimensions using anatomic imaging, and metastatic disease assessment using 123I-MIBG imaging and quantification of bone marrow disease”1 (p. 1).
A great deal of work continues to be done in hopes of understanding the genetic characteristics, identity and even causes of neuroblastoma. Currently, there are a number of genetic features that are understood about the disease:
- PHOX2B and ALK (anaplastic lymphoma kinase) are hereditary predisposition genes.
- The first genome wide association study (GWAS) for neuroblastoma identified other common germline variants found to be predisposition genes for sporadic neuroblastoma.
- Genetic alterations of MYCN amplification, chromosomal gains, and chromosomal losses (1p, 11q, 17q and others) are all signifiers of either poor or favourable prognosis.
In 2013, the TARGET project, supported by NCI, published their work on the whole genome, exome, and transcriptome sequencing of 240 variants of high-risk neuroblastoma4. There was a definite lack of recurring genetic mutations across the samples, shedding light on the challenges associated with personalized medicine approaches. This suggests that the small number of mutations would make it extremely challenging to develop improved treatments for high-risk neuroblastoma that would benefit a significant number of patients. The ATRX loss of function mutation, as found by others5, was also confirmed in the TARGET project4.
Non-High Risk Neuroblastoma
Approximately 50% of all new cases of neuroblastoma are non-high risk. The main area of focus for this group involves reducing the amount of therapy a patient receives, without impacting the effectiveness of treatment or long-term outcomes. Non-high risk patients, with favourable biological markers, have an excellent survival rate. However, there is a great deal of work that needs to be done for children who have non-high risk disease but have unfavourable genetic markers.
- Building on ANBL0531, future work will examine the integration of tumor genetics and histology to better inform risk categories and modify therapies for low and intermediate risk neuroblastoma patients. ANBL1231 is proposed and aims to study minimizing surgical and chemotherapeutic interventions for patients with favourable tumor markers. The ultimate goal for these patients is to reduce or even remove the possibility of late effects while continuing the current excellent rate of survival1 (p. 6).
- ANBL00P2 will be built upon to examine the use of observation only for infants with INGRSS LI tumors, without any surgical biopsy or resection. The study will extend the age limit from 6 to 12 months, will increase the maximum tumor size allowed, and will also include tumors that do not originate on the adrenal gland. The study will examine many factors, including whether adding 13-cisRA for patients with localized disease that have unfavourable genomic or histological features, will help increase survival rates1 (p. 6-7).
Improvements have been made with the treatment of high-risk neuroblastoma; however, it continues to remain a significant challenge. “Future clinical trials must incorporate precision medicine approaches using recently identified biomarkers and tractable therapeutic targets to further improve the outcome”1 (p. 4).
ALK aberrations are found in about 10-12% of neuroblastoma tumours. Currently, crizotinib (Xalkori) is being tested for activity against ALK mutated disease and is showing to have an impact. Crizotinib is a tyrosine kinase inhibitor that specifically targets ALK and has been traditionally used for the treatment of some types of lung cancer.
Future Research and Directions:
- Establishing centralized ALK testing.
- Study of the effectiveness and safety involved when introducing crizotinib into frontline therapy for patients with ALK mutated disease1 (p. 4).
Ultra-High Risk Patients:
Work is currently being done to further refine the high-risk category to better identify those patients who are considered to be at even greater risk for therapy resistance, treatment failure, and/or relapse. These patients are being informally identified as “ultra-high risk”. The hope is that by identifying ultra-high risk patients early, they could be put on a treatment pathway that is somewhat different from the ‘standard’ frontline therapy to establish disease control as soon as possible.
Current and Future Research:
Research is currently being done to determine the most effective scoring system to identify ultra-high risk patients. This may be based on the number of MIBG avid sites still present at the end of induction, or the use of a semi-quantitative MIBG scoring system, and/or Curie scores. It is possible that the measurement of residual disease in the bone marrow or blood stream, or the examination of the RNA signature using gene expression profiling may also provide predictors of treatment response1.
Busulfan and Melphalan:
The SIOP-EN trial for patients receiving BuMel [busulfan (Myleran, Busulfex IV) and melphalan (Alkeran)] therapy showed an improvement in survival in comparison to patients who received the North American treatment of carboplatin, etoposide and melphalan during high-dose chemotherapy at the start of stem-cell transplant. However, for patients receiving BuMel, there was an increased risk of sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). In addition, research into the BuMel therapy has shown differences in its level of efficacy and severity of the side-effects due to differences in how the body processes busulfan.
ANBL12P1 may study the toxicity of BuMel when combined with therapies currently used in North American protocols. “Further investigation of busulfan and melphalan pharmacokinetics and their association with toxicity and neuroblastoma outcome may lead to an improved understanding on how to maximize efficacy of BuMel regimen with minimizing toxicity”1 (p. 5). Within this trial, it will also examine1 (p. 7-8):
- The ability to do rapid ALK testing.
- The ability to identify if an mRNA expression signature is present.
- The ability to using semi-quantitative MIBG scores to identify treatment response (and may subsequently be used to identify ultra-high risk patients).
Recent studies have demonstrated the safe combination of chemotherapy agents and 131I-MIBG therapy. Vincristine and irinotecan7, topotecan7,8, and carboplatin, etoposide and melphalan9 have all been combined with MIBG therapy in past studies. ANBL09P1 is currently recruiting and is examining the use of 131I-MIBG therapy during the induction phase of treatment for newly diagnosed high-risk neuroblastoma patients.
ANBL09P1 will determine whether it is possible to use 131I-MIBG therapy on a wider scale in frontline therapy. If the trial is successful, future study may focus on whether the addition of MIBG therapy into the induction phase of treatment increases the event-free survival rate for high-risk patients1 (p. 7).
Relapsed High-Risk Neuroblastoma
The introduction of ch14.18 immunotherapy, with cytokines IL-2 and GM-CSF, into front-line therapy significantly increased the survival rate for patients with high-risk neuroblastoma10. In an effort to address the side-effects of ch14.18, specifically the degree of pain experienced by the patient, a humanized version of ch14.18 with fused IL-2 was developed to create hu14.18-IL2.
The COG ANBL1021 study is examining the effectiveness of hu14.18-IL2 when used in conjunction with GM-CSF (sargramostim), and 13-cisRA (Accutane) in between courses.
Irinotecan, Temozolomide, MLN8237, Crizotinib and Temsirolimus:
The use of irinotecan (Camptosar) and temozolomide (Temodar/Temodal) together in patients for first relapse of high-risk neuroblastoma has shown an overall objective response rate of 15%. Breaking this down, patients with disease measurable by CT or MRI had a response rate of 11%, with 50% of the patients having disease that remained stable. Patients with disease measurable by MIBG or bone marrow aspirate/biopsy had a response rate of 19%, with 56% of the patients having stable disease. The combination of irinotecan and temozolomide was shown to be well tolerated, with manageable side-effects and with patients able to remain on the regimen for 10 or more cycles11. Irinotecan and temozolomide have been illustrated to be a good foundation (backbone) upon with other drugs and agents can be given to patients to test their effectiveness. This is the case with further research that is planned for MLN8237, Crizotinib, and Temsirolimus.
Taking existing drugs and translating them into medical trials for neuroblastoma patients presents a number of challenges. MLN8237 (Alisertib) binds to Aurora A kinase (AAK) to inhibit cell proliferation and is used in a variety of cancers like colon and breast. Crizotinib (Xalkori) is an ALK and ROS1 (tyrosine kinase) inhibitor that is thought to impact the growth of cancerous cells, possibly through angiogenesis and is used in a number malignancies including lung cancer. These drugs have both been translated for use with neuroblastoma patients and have shown positive responses that could lead to further investigation and study. Temsirolimus, traditionally used for the treatment of renal cell carcinoma (RCC), will be part of a new Phase 2 COG study in 2013. It will examine the use of irinotecan and temozolomide with temsirolius or ch14.18 in patients with relapsed, refractory or progressive neuroblastoma.
Continued examination of MLN8237, crizotinib and temsirolimus with irinotecan and temozolomide as the backbone chemotherapeutic agents. It will also determination if temsirolimus and/or ch14.18 requires further Phase 3 testing.
Future Children’s Oncology Group Trials for Relapsed Neuroblastoma
Future COG trials for relapsed neuroblastoma may focus on1 (p. 8):
- The inhibition of MYC. No MYCN targeted therapies have been developed to date; however there are a number of possibilities with the use of DFMO, PI3K/mTOR, and AURKA inhibition1 (p. 3).
- Combining ALK inhibitors with other drugs or agents.
- Increasing the effectiveness of existing therapies including ch14.18, hu14.18-IL2, and/or 131I-MIBG by combining them with other agents and drugs.
Neuroblastoma Canada would like to thank Dr. J. Park for reading and editing this post. We also thank her for her continued dedication to find a cure for pediatric cancer.
- Park, J.R., Bagatell, R., and Hogarty, M. (2012) Children’s Oncology Group’s 2013 Blueprint for Research: Neuroblastoma. Pediatric Blood and Cancer, 2012 December 19 (epub ahead of print). http://www.ncbi.nlm.nih.gov/pubmed/23255319
- Monclair, T., Brodeur, G.M., Ambros, P.F., Brisse, H.J., Cecchetto, G., Holmes, K., et al. (2009). The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report. Journal of Clinical Oncology, 27 (2), 298-303. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650389/
- Cohn, S.L., Pearson, D.J., London, W.B., Monclair, T., Ambros, P.F., Brodeur, G.M., et al. (2009) The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report. Journal of Clinical Oncology, 27 (2), p. 289-297. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650388/
- Pugh, T.J., Morozova, O., Attiyah, E.F., Asgharzadeh, S., Wei, J.S., et al. (2013). The Genetic Landscape of High-Risk Neuroblastoma. Nature Genetics, published online 20 January 2013. http://www.ncbi.nlm.nih.gov/pubmed/23334666
- Cheung, N.K., Zhang, J., Lu, C., et al. (2012). Association of Age at Diagnosis and Genetic Mutations in Patients with Neuroblastoma. JAMA, 307, p. 1062-1071. http://jama.jamanetwork.com/article.aspx?articleid=1105070
- DuBois, S.G., Chesler, L., Groshen, S., et al. (2012). Phase I Study of Vincristine, Irinotecan, and 131I-Metaiodobenzylguanidine for Patients with Relapsed or Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial. Clinical Cancer Research, 18, p. 2679–2686.
- Gaze, M.N., Chang, Y.C., Flux, G.D., et al. (2005). Feasibility of Dosimetry-Based High-Dose 131I-Metaiodobenzylguanidine with Topotecan as a Radiosensitizer in Children with Metastatic Neuroblastoma. Cancer Biotherapy Radiopharmaceuticals, 20, p. 195–199.
- McCluskey, A.G., Boyd, M., Ross, S.C., et al. (2005). [131I]Meta-iodobenzylguanidine and Topotecan Combination Treatment of Tumors Expressing the Noradrenaline Transporter. Clinical Cancer Research, 11, p. 7929–7937.
- Matthay, K.K., Tan, J.C., Villablanca, J.G., et al. (2006). Phase I Dose Escalation of Iodine-131-Metaiodobenzylguanidine with Myeloablative Chemotherapy and Autologous Stem-Cell Transplantation in Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study. Journal of Clinical Oncology, 24, p. 500–506.
- Yu, A.L, Gilman, A.L., Ozkaynak, M.F., London, W.B., Kreissman, S.G., Chen, H.X., Smith, M., Anderson, B., Villablanca, J.G., Matthay, K.K., Shimada, H., Grupp, S.A., Seeger, R., Reynolds, C.P., Buxton, A., Reisfeld, R.A., Gillies, S.D., Cohn, S.L., Maris, J.M., Sondel, P.M. (2010) Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma. The New England Journal of Medicine, 363 (14), pps. 1324-1334. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086629/
- Bagatell, R., London, W.B., Wagner, L.M., Voss, S.D., Stewart, C.F., Maris, J.M. Kretschmar, C., and Cohn, S.L. (2011). Phase II Study of Irinotecan and Temozolomide in Children with Relapsed or Refractory Neuroblastoma: A Children’s Oncology Group Study. Journal of Clinical Oncology, 29 (2), p. 208-213. http://www.ncbi.nlm.nih.gov/pubmed/21115869