In this post, we examine MYCN amplification in neuroblastoma, the different ways that it can present itself, and drugs that are showing promise in the treatment of this subset of the disease.  In particular, we focus on one drug that is showing some promise in pre-clinical studies – BET bromodomain inhibitors.

MYCN
MYCN is a protein and a member of the MYC family of proto-oncogenes¹.  A proto-oncogene is a normal gene that has the potential to become cancer because of mutations or some type of increased expression (expression is how information from a gene is utilized to create another genetic product such as a protein).  “Like many other MYC proteins, MYCN is a transcription factor that controls expression of many target genes, which in turn regulate fundamental cellular processes including proliferation, cell growth, protein synthesis, metabolism, apoptosis and differentiation”² (p.257).  In normal cellular function, MYCN plays a dual role in regulating cell growth by being able to both drive cellular proliferation and sensitizing cells to apoptosis (programmed cell death)^2,3.  MYCN is able to simultaneously control how cells grow and how they die.

MYC proteins, including MYCN, play multiple roles in cancer “such as altering metabolic programs, supporting angiogenesis, promoting self-renewal and “stemness,” and driving proliferation while inhibiting differentiation”⁴ (p. 145).  Amplified MYC is one of the more common genetic mutations that occur across multiple types of cancers⁵.  The MYCN oncogene was identified about 30 years⁶ ago and is found in neuroblastoma and other cancers such as rhabdomyosarcoma, glioblastoma, medulloblastoma, small cell lung cancer, and others².

There is significant evidence that MYCN is involved in the creation of neuroblastoma tumors (also known as tumorigenesis).  This comes from work done by Weiss et al (1997) where a genetically modified mouse (or transgenic mouse) was created to overexpress MYCN in neural crest cells.  These transgenic mice developed neuroblastoma several months after they were born and their disease has many similarities to the human form of high-risk neuroblastoma^7,8.  Even though this provides great evidence that MYCN plays a role in the initial formation of neuroblastoma tumors, it is thought that MYCN does not act alone, but that there are other genetic events that also play a role in the tumorigenesis of neuroblastoma.  There are limitations with the transgenic mouse in that the disease is not commonly found in the mouse’s bone marrow, and tumour formation can be comparably slow⁹.  Recent research has found that the loss of expression of caspase-8, which occurs in about 70% of neuroblastoma patients, caused the transgenic mouse to develop neuroblastoma in the bone marrow, making this model even more valuable for testing therapies for metastatic disease¹⁰.  The transgenic mouse is the most widely used mouse model in pre-clinical research and the testing of new drugs for neuroblastoma.

MYCN Amplification

When MYCN is amplified (>10 copies per cell), a large part of the chromosome band 2p24 becomes enhanced, possibly giving some type of advantage to these cells^11,12.  MYCN amplification results in high levels of cellular proliferation and growth, decreased apoptosis (cellular death), poor differentiation of the cancer cells (cells do not change from being less specialized to more specialized cell types), and increased vascularity of the tumours⁸.  In cancerous cells, MYCN amplification has the unfortunate result of putting too much emphasis on cellular growth, and not enough weight on cellular death, often causing rapid tumor progression.  MYCN amplification is also associated with high-risk and advanced stage disease, therapy resistance, and an overall poor prognosis^3,11-14.  It is one of the clearest markers for identifying a neuroblastoma patient as high-risk, no matter what disease stage.

There is a strong correlation between MYCN amplification and 1p deletion; however, not all cases of 1p deletion have MYCN amplification.  A 17q gain is also highly correlated with MYCN amplification.  Interestingly, MYCN amplification “has never been reported without either 1p loss or 17q gain.  It is therefore apparent that in many cases of neuroblastoma, MYCN alone is not sufficient to distinguish those patients who are likely to survive from those that are destined to fail treatment”¹⁵ (p. 2641).

MYCN amplification is present in about 20% of all cases of neuroblastoma^11-13.  MYCN amplification is found in^4,12:

• ~30-40% of stage 3 and stage 4 neuroblastoma patients (INGRSS – stage M)
• ~10% of stage 4s patients (INGRSS – stage MS)
• ~5% of stage 1 and 2 patients (INGRSS – stages L1 and L2)

MYCN amplified neuroblastoma displays at least 10 or more MYCN copies.  For these patients, it does not matter how many additional copies there are over the 10 marker (i.e., a 20 –fold or even 50-fold increase), all patients have a similar (unfavourable) outcome.  Most MYCN amplified patients have either a 30-fold or 15-25 fold excess of MYCN¹⁷ (for more information on MYCN copy numbers and MYCN gain, see Appendix A below).

When MYCN amplification is identified, it is typically found in all areas of the patient’s diseases – at the primary tumor site and metastases.  This is described as being “homogeneous” amplification.  However, there are cases where MYCN amplification is “heterogeneous”.  This occurs infrequently and can be classified three different ways¹⁸.

1. Clusters of MYCN amplified cells or single MYCN amplified cells that are surrounded by non-amplified neuroblastoma cells.
2. Between the primary tumor and metastases where only one or some of the sites are MYCN amplified (for example, the bone marrow is MYCN amplified but the primary tumor is not).
3. MYCN amplification is found at relapse but not at the initial diagnosis (or possibly vise versa).

For patients with stage 4 disease, the classification of homogenous and heterogeneous MYCN amplification has a limited clinical and prognostic value as all patients receive the high-risk treatment protocol.  Also, there does not appear to be a difference in survival between patients with homogeneous MYCN amplification versus heterogeneous MYCN amplification¹⁸.  However, it is possible that with further study there could be benefits to patients with lower risk disease profiles who may have MYCN amplification that is heterogeneous in nature.

MYCN Targeted Therapeutics

A significant amount of effort and research have gone into understanding MYCN since its discovery; however, this has not resulted in the development of any standard treatments able to target this very aggressive subset of the disease⁴.  There were fears that that creation of an MYC inhibitor would be too risky and dangerous for the patient, with resulting side effects that were unmanageable and irreversible.  However, these concerns are starting to fade^8,19.  “Recent studies have underlined the potential in targeting genes directly or indirectly downstream of MYCN by tipping the balance of proliferation versus apoptosis in favour of apoptosis”³ (p. 152).

The following are some examples of MYCN inhibitors that are in various stages of development and testing.

p53, MDM2 Inhibitor, Nutlin-3

In normal cells, p53 is a tumor suppressor gene and “has a major role in protecting the cell from genomic instability and tumor development by inducing apoptosis and cell cycle arrest in response to cellular stresses and DNA damage”²⁰ (p. 1).  Generally, when some sort of stress occurs within a cell, p53 is activated and specifically binds DNA with a number of ‘downstream’ genes, like MDM2, to cause the cell to die or to induce repairs to the DNA²¹.  However, in tumor cells there must be some mechanism or mutation that allows these cells to escape the controls of p53, allowing them to grow and proliferate without boundary.  In malignant cells of (sporadic) adult cancers, p53 is commonly found to be mutated about 50% of the time^20,22.  In neuroblastoma, p53 mutations are quite rare and occur in less than 2% in the initial presentation of the disease, which may account for why patients generally respond well to initial therapy.  At relapse, p53 mutations are still rare, with it occurring in about 15% of the cases.

However, it is possible that p53 can become inactivated due to other genetic disruptions²⁰.  A recent study found that a high proportion of relapsed neuroblastoma tumors have abnormalities in the p53 pathway, with p53 becoming inactivated and unable to function normally as a tumor suppressor.  In this study, 49% (20/41) of the relapsed neuroblastoma tumor samples tested exhibited abnormalities in the p53 pathway, and 13 of these 20 cases also had p53 mutations at diagnosis.  p53 mutations that were present because of upstream defects occurred in 35% of cases (MDM2 amplification and p14 abnormalities)²¹.  Overall, it was found that abnormalities in the p53 pathway were common in relapsed neuroblastoma.  It was also hypothesized that a higher percentage of adolescents may have p53 mutations present at diagnosis²¹.

These findings have been important in attempting to identify therapies for MYCN amplified tumors that might be responsive to MDM2-p53 inhibition.  “It has been previously reported that the negative regulator of p53, MDM2, is the critical oncogene product by which MYCN-amplified neuroblastomas acquire a more aggressive behaviour, and that MYCN and MDM2 work together to inhibit apoptosis”²⁰ (p. 7).  Laboratory studies have been done examining the impact of p53-MDM2 inhibitors, with two particular small-molecule inhibitors called Nutlin-3 and MI-63²⁰.  Nutlin-3 and MI-63 compete with p53 when binding to the surface of MDM2.  “Treatment with nutlin-3 thus leads to stabilization and activation of p53 and, if downstream effectors are functionally intact, to a robust p53 response”²² (p. 984).

It was found that Nutlin-3 and MI-63 inhibited cell growth and promoted apoptosis in MYCN amplified neuroblastoma cells with wild-type p53 (normal not mutated p53) and tumors with MYCN overexpression.  MYCN amplified tumor cells were more sensitive to MDM2-p53 inhibition and apoptosis than non-amplified tumors when treated with nutlin-3 and MI-63.   This laboratory research shows promise for studying something like Nutlin-3 in a clinical setting.

BEZ235 (or NVP-BEZ235), PI3-K and mTOR inhibitor.

PI3K (phosphatidylinositol 3-kinase) is a major signalling molecule and in normal cells PI3K regulates and stabilizes MYCN and also regulates angiogenesis, the process where new blood vessels are made from existing blood vessels.  Activation of PI3K and mTOR pathways results in the promotion of cellular growth, decreased apoptosis, and resistance to chemotherapy.  NVP-BEZ235 is a PI3K inhibitor and was the first to be tested in clinical trial with solid-tumors and a subset of breast cancer patients (http://clinicaltrials.gov/ct2/show/NCT00620594).  In the pre-clinical work done by Chanthery et al (2012), they found that NVP-BEZ235 was able to decrease angiogenesis and improve survival in different neuroblastoma models (in vitro and in vivo) for MYCN amplified neuroblastoma and for disease with MYCN overexpression (but not amplification)²³ (for more information on MYCN expression without amplification, see Appendix B below).  The NVP-BEZ235 was able to restrict the blood supply to the cancer, which in turn stopped the neuroblastoma from growing and resulted in the mice surviving longer.  “Though tumor regressions were not described, there was inhibition of tumor growth in both models, attributed to both reductions in tumor-associated vascular density and neuroblast proliferation.  MYCN was markedly reduced in treated tumors, and evidence for both PI3K and mTOR inhibition was demonstrated, supporting the notion that PI3K inhibition led to depression of GSK3B with resultant Thr58 phosphorylation and destabilization of MYCN”⁴ (p. 146).

A different anti-angiogenesis inhibitor called caplostatin (a water soluble version of TNP-470) was used to treat transgenic mice with neuroblastoma tumors²⁴.  Caplostatin reduced malignant cellular proliferation, increased apoptosis, and resulted in almost complete remission of advanced disease.  In comparison to TNP-470, caplostatin does not cross the blood-brain barrier, seems better tolerated, and does not carry some of the concerning side effects like those exhibited by TNP-470²⁴.  Researchers recommended moving forward with the clinical development of caplostatin for the treatment of neuroblastoma.

Aurora kinase Inhibitors

Aurora kinases are proteins that play a critical role in cellular proliferation, cellular division, and the transfer of genetic information to its daughter cells.  In humans, there are three known Aurora kinases: Aurora A, Aurora B, and Aurora C.  When any of the Aurora kinases are inhibited, this typically results in events that cause genetic instability, and ultimately cellular death through apoptosis.  Thus, the development of Aurora kinase inhibitors has become an area of anti-cancer research, with hopes of finding another tool to add to the treatment of this disease.

In relation to neuroblastoma, a number of Aurora A kinase (AURKA) inhibitors are currently in various stages of study.  In many cancers, including neuroblastoma, Aurora A kinases are often overexpressed and are suspected to be an oncogene, providing evidence that Aurora kinase A could be a viable anti-tumor treatment¹¹.

MLN8237 (alisertib) is a small molecule Aurora A kinase inhibitor that is currently being tested with neuroblastoma.  Pre-clinical research showed that both MYCN amplified and non-amplified neuroblastoma cancer cells were responsive to MN8237, “suggesting that the MYCN (and perhaps MYC) binding function of AURKA potentially contributes to, but does not determine, cytotoxicity to MLN8237”²⁵ (p. 5).  Aurora A kinase has been shown to interact with MYCN in neuroblastoma²⁶.  MLN8237 is currently being tested in combination with irinotecan and temozolomide (http://clinicaltrials.gov/show/NCT01601535 or http://www.nant.org/Patients_and_Families/N09-03.php).

Another Aurora A kinase inhibitor, CCT137690, was recently studied and MYCN amplified neuroblastoma was shown to be most sensitive to the treatment.  In vitro testing and vivo testing using the transgenic mouse model showed that CCT137690 displayed growth inhibition of the neuroblastoma cells²⁷.

DFMO (eflornithine, α-difluoromethylornithine)

DFMO is an ODC (ornithine decarboxylase) inhibitor that “acts synergistically with PI3kinase inhibitors to increase apoptosis in neuroblastoma cells”³ (p. 153).  In vitro laboratory testing of DFMO on neuroblastoma cell lines inhibited the growth of the malignant cells.  When tested using the transgenic mouse (in vivo), “DFMO also selectively cancels the proliferative response of MYCN-amplified neuroblastoma, and dramatically impairs the onset and incidence of N-Myc-driven neuroblastoma in vivo”²⁸ (p. 7).  Further in vivo testing was done using DFMO in combination with cisplatin, vincristine, or cyclophosphamide all resulted tumor regression, with the most striking results obtained with the combination of cyclophosphamide and DFMO together²⁹.

The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) has been working on a study examining the combination of DFMO with etoposide.  “Safety Study for Refractory or Relapsed Neuroblastoma with DFMO Alone and in Combination with Etoposide”, Dr. Sholler, Van Andel Research Institute.

Cancer Prevention Pharmaceuticals (CPP) is currently working NMTRC to co-sponsor a phase I/II trial of CPP’s drug CPP-1X (single agent) in use against neuroblastoma.  “Preventative Trial of DFMO in Patients with High Risk Neuroblastoma in Remission”, Dr. Sholler, Van Andel Research Institute.

A future trial is also planned with New Approaches to Neuroblastoma Therapy (NANT) to test the combination of DFMO, Celecoxib (an NSAID: non-steroidal anti-inflammatory drug), cyclophosphamide, and topotecan.  This work is being chaired by Dr. Michael Hogarty.

Other Inhibitors

The following are some other inhibitors that are currently being tested for neuroblastoma.  Those listed below are being tested for all disease characteristics; however, some are showing to have a particular impact on MYCN amplified disease in pre-clinical and clinical studies.

1. Rapamycin, a small molecule inhibitor of mTOR³⁰.
2. miR-497, a microRNA/epigenetic regulator, that targets and inhibits the WEE1 protein (tyrosine kinase) in neuroblastoma cells and causes increased cellular death³¹.
3. Valporic acid, a HDAC inhibitor and down regulator of MYCN³.
4. Bevacizumab, an anti-angiogenesis drug, is a humanized monoclonal antibody that inhibits VEGF-A (vascular endothelial growth factor A).  It has been examined as a single agent³² and multi-agent therapy³³.
5. 13-cisRA, a down-regulator of MYCN.  “Treating MYCN amplified neuroblastoma cells with retinoic acid has been shown to cause neuroblastoma cells to undergo a G1 arrest and differentiate”³ (p. 153).

A New Epigenetic Inhibitor

In March 2013, a journal article was published releasing the results of a new epigenetic inhibitor for MYCN amplified neuroblastoma³⁴.  This inhibitor has a very simple name, JQ1; however, its function is far from simple and has created quite a stir in the neuroblastoma world.

In epigenetics, parts of the genome are turned on and off at strategic times and locations through specialized chemical reactions that are triggered by signals from inside the cell, from the cells microenvironment, and from the outside world.  The epigenome essentially sits on top of the genome, carrying out changes in gene activity, without making alterations to the genetic code.  As scientists learn more about the epigenetics of normal cells, they are also working to illuminate the intricacies of the cancer epigenome.  As this understanding grows, so does the potential of developing drugs that can interact with the cancer epigenome by changing the signals and switches that are sent to cells in order to stop and reverse malignant cellular development.

A growing field of cancer research involves the manipulation of epigenetic regulators, also known as “readers”.  These readers are proteins that can identify and bind to chromatin³⁴.  Bromodomains are epigenetic readers that can recognize and bind to specific chromatin.  One particular bromodomain family, the bromodomain and extraterminal domain (BET) family is understood to be responsible for regulating transcription, cellular growth, and epigenetic memory.  The BET bromodomain family is composed of the following proteins: BRD2, BRD3, BRD4, and BRDT^34,35.

JQ1 is a small molecule inhibitor of BET bromodomains^36,37.  In general, the following happens when JQ1 is introduced to MYCN amplified neuroblastoma cells³⁴:

• In MYCN amplification, MYC recruits and binds the BET bromodomain readers.
• In particular, BRD4 binds to the MYCN promoter and recruits additional proteins, ultimately allowing for increased MYCN transcription.  In this case, MYCN enhances cellular proliferation, stops cellular death (apoptosis), and stops cells from transforming into more specialized cells (transcription).
• JQ1 competes with BRD4 and stops it from binding to the MYCN promoter.  This stops MYCN which results in the opposite events of decreased cellular proliferation, cellular death and cellular differentiation.
• For those who are interested in the science, it “displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket”³⁴ (p. 2).

In the study by Puissant et al. (2013), 673 cell lines from tumors were first screened in the laboratory to examine their response to BET bromodomain inhibition.  From this, MYCN amplified neuroblastoma cells showed sensitivity and response to treatment with JQ1³⁴.  In fact, almost all of the MYCN amplified cell lines that were tested responded to JQ1 and when JQ1 was used to treat the MYCN amplified cells, a striking majority of them resulted in cell cycle arrest and cellular death of the malignant cells.  The results from this laboratory testing provided important evidence that JQ1 was able to (down)regulate and directly target the expression of MYCN.

In the next step of the study, the researchers conducted in vivo testing using JQ1 on three different disease models of MYCN-amplified neuroblastoma using mouse models.  The following was found from these three models³⁴:

1. In the subcutaneous xenograft model, the mice were treated daily with JQ1 and this “significantly diminished tumor volume and prolonged overall survival in these mice compared with control-treated mice, without any effect on body weight and no overt toxicities were observed”³⁴ (p. 7).
2. In the human xenograft model, the tumour cells were obtained from a patient who had relapsed and treatment-resistant neuroblastoma.  These samples were then implanted into mice and they were treated daily for 28 days with JQ1.  Again, it was found to significantly improve survival.
3. In the experimental mouse model of MYCN amplified neuroblastoma, mice with tumors were treated daily with JQ1 for 28 days.  It was found to also significantly improve survival.  The testing of tumor biopsies showed reduced cellular proliferation, an increase in apoptosis, and a regulation of MYCN expression.

JQ1’s sensitivity to MYCN amplification is important for a number of reasons.  Primarily, it identifies MYCN amplified neuroblastoma (along with other MYCN amplified diseases) as a primary candidate for the development of BET bromodomain compounds and potential pre-clinical research.  It is even possible to imagine clinical studies where having MYCN amplification is a key criteria for inclusion in the trial(s)³⁸.

Overall, there is still much more to understand about the use of BET bromodomain inhibitors for cancer therapeutics.  The area of primary and secondary side-effects need to be studied further, with attempts to understand the impact of inhibition of MYC in normal tissue, both in the short and long term³⁸.  The work by Puissant et al (2013) “is a very important step in the development of precise therapeutic approaches to an important childhood cancer and may also define novel therapeutic strategies for substantial subsets of patients with other MYCN-driven malignancies”³⁸ (p. 257).  The authors note that future research could look at the combination of ALK inhibitors with BET bromodomain inhibitors.  It could also examine the combined use of BET bromodomain inhibitors with MDM2 inhibitors.

A JQ1 derivative molecule, GSK525762, is currently in phase I/II clinical trials with GlaxoSmithKline for the treatment of NUT Midline Carcinoma (NMC) and other solid tumors as long as they are MYCN amplified (for adults and adolescents: http://www.clinicaltrials.gov/ct2/show/NCT01587703).They end on a positive note saying that “..the clinical development of bromodomain inhibitors for testing in children with relapsed or refractory neuroblastoma is already under way”³⁴ (p. 12).

Conclusions

The world of neuroblastoma genetics and epigenetics is exceptionally complicated, sophisticated, and is still in the process of being understood (and kudos to the reader if you made it though this article without falling asleep!).  Work continues to be done to try and better understand a particular subset of the disease – those patients with MYCN amplified neuroblastoma.  Typically, these patients have the poorest prognosis and survival rates, signalling a need to identify other markers and characteristics of MYCN amplified neuroblastoma that could be translated into targeted therapeutics.  This is highly important for patients who are diagnosed within any stage of the disease, not only stage M (or stage 4).  It is also possible that identifying such treatments could be beneficial for a wide range of cancers, including adult malignancies.

NB Globe would like to thank Dr. Robert Seeger for reading and editing this post.

Appendix A: MYCN Gain

In a research study conducted by Spitz et al. (2004), 38 patients were identified as having MYCN gain¹⁷.  Of the 38, 33 patients had 1 or 2 additional copies of MYCN and 5 patients had 3 additional copies of MYCN.  26/38 (68%) of the patients with MYCN gain were stage 4 and were characterized as being older at diagnosis (median age of 34 months) and had a high frequency of other genetic changes such as 1p, 3p, and 11q irregularities (losses).  For all patients with MYCN gain, they are shown to have a poorer 3-year event-free survival (EFS) but not overall survival (OS) when compared to non-amplified disease.  For stage 4 patients with MYCN gain, they had the same outcome as non-amped stage 4 patients¹⁷.  In addition, gain is not considered to be a precursor to MYCN amplification.

Tumors that have 5-10 copies of MYCN are more rare and are typically found in stage 4, but also present in small portion of localized and 4s tumors.  5-10 count of MYCN is probably sufficient to increase neuroblastoma growth.

What is understood about MYCN gain at this point does not show that it has a significant prognostic value.  It is possible that with further study, there may be a different and more significant understanding that evolves about MYCN gain.  If this is the case, these findings must be carefully applied to this patient cohort to make rationale and consistent treatment decisions³⁹.

Appendix B: MYCN Expression Without Amplification

Tumors with MYCN amplification typically express MYCN at higher levels than non-amplified tumors.  This expression occurs at both the mRNA and protein levels⁴⁰.

Non-amplified tumors can express high levels of MYCN mRNA or MYCN proteins⁴¹.  There are differing opinions on whether the overexpression of MYCN in non-amplified tumors can act as a characteristic that identifies a patient’s disease differently or conveys a certain prognostic significance^11,40,42.  Some studies have shown that non-amplified neuroblastoma tumors with an overexpression of MYCN results in a favorable prognosis^40,42,43.

Studies have shown that non-amplified neuroblastoma cells with MYCN expression can bring about cellular death of the cancer cells (apoptosis)^44,45.  Other studies have illustrated that MYCN expression in combination with chemotherapy drugs can work together to trigger apoptosis of the malignant cells^46,47.

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20. Gamble, L.D., Kees, U.R., Tweddle, D.A., and Lunec, J. (2011). MYCN Sensitizes Neuroblastoma to the MDM2-p53 Antagonists Nutlin-3 and MI-63.  Oncogene, advanced online publication 4 July 2011, pps. 1-12. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191119/pdf/ukmss-35655.pdf
21. Carr-Wilkinson, J., O’Toole, K., Wood, K.M., Challen, C.C., Baker, A.G., et al. (2010). High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma. Clinical Cancer Research, 16, pps. 1108-1118.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842933/pdf/ukmss-28588.pdf
22. Van Maerken, T., Rihani, A., Dreidax, D., De Clercq, S., Yigit, N. et al. (2011). Functional Analysis of the p53 Pathway in Neuroblastoma Cells Using the Small-Molecule MDM2 Antagonist Nutlin-3. Molecular Cancer Therapeutics, 10, pps. 983-993. http://mct.aacrjournals.org/content/10/6/983.full.pdf+html
23. Chanthery, Y.H., Gustafson, W.C., Itsara, M., Persson, A., Hackett, C.S., Grimmer, M. Charron, E., Yakovenko, S., Kim, G., Matthay, K.K., and Weiss, W.A. (2012). Paracrine Signaling Through MYCN Enhances Tumor-Vascular Interactions in Neuroblastoma. Science Translational Medicine, 4 (115), pps. 1-21. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402217/pdf/nihms391825.pdf
24. Chesler, L., Goldenberg, D.D., Seales, I.T., Satchi-Fainaro, R., Grimmer, M. et al. (2007). Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma. Cancer Research, 67 (19), pps. 9435-9442. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921769/pdf/nihms225836.pdf
25. Maris, J.M., Morton, C.L., Gorlick, R., Kolb, E.A., Lock, R., et al. (2010). Initial Testing of the Aurora Kinase A Inhibitor. Pediatric Blood and Cancer, 55 (1), pps. 26-34. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874079/pdf/nihms165147.pdf
26. Carol, H., Boehm, I., Reynolds, C.P., Kang, M.H, Maris, J.M. et al. (2011). Efficacy and Pharmacokinetic/Pharmacodynamic Evaluation of the Aurora Kinase A Inhibitor MLN8237 Against Preclinical Models of Pediatric Cancer. Cancer Chemotherapy Pharmacology, 68, pps. 1291-1304. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215888/pdf/280_2011_Article_1618.pdf
27. Faisal, A., Vaughan, L., Bavetsias, V., Sun, C., Atrash, B., Avery, S. et al. (2011). The Aurora Kinase Inhibitor CCT137690 Downregulates MYCN and Sensitizes MYCN-Amplified Neuroblastoma in Vivo. Molecular Cancer Therapeutics, 10, pps. 2115-2123. http://mct.aacrjournals.org/content/10/11/2115.full.pdf+html
28. Rounbehler, R.J., Li, W., Hall, M.A., Yang, C., Fallahi, M., and Clevland, J.L. (2009). Targeting Ornithine Decarboxylase Impairs Development of MYCN-Amplified Neuroblastoma.  Cancer Research, 69 (2), pps. 1-11. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749594/pdf/nihms79768.pdf
29. Hogarty, M.D., Norris, M.D., Davis, K., Liu, X., Evageliou, N.F., et al. (2008). ODC1 is a Critical Determinant of MYCN Oncogeneis and a Therapeutic Target in Neuroblastoma. Cancer Research, 68 (23), pps. 9735-9745.
30. Schramm, A., Koster, J., Marschall, T., Martin, M., Schwermer, M. et al. (2013). Next-Generation RNA Sequencing Reveals Differential Expression of MYCN Target Genes and Suggests the mTOR Pathway as a Promising Therapy Target in MYCN-Amplified Neuroblastoma. International Journal of Cancer, 132 (3), pps. 106-115. http://www.ncbi.nlm.nih.gov/pubmed/22907398
31. Creevey, L., Ryan, J., Harvey, H., Bray, I.M., Meehan, M., Khan, A.R., and Stallings, R.L. (2013). MicroRNA-497 Increases Apoptosis in MYCN Amplified Neuroblastoma Cells by Targeting the Key Cell Cycle Regulator WEE1.  Molecular Cancer, 12 (provisional PDF), pps. 1-22). http://www.molecular-cancer.com/content/pdf/1476-4598-12-23.pdf
32. Glade Bender, J.L., Adamson, P.C., Reid, J.M., Xu, L., Baruchel, S. et al. (2008). Phase I Trial and Pharmacokinetic Study of Bevacizumab in Patients with Refractory Solid Tumors: A Children’s Oncology Group Study.  Journal of Clinical Oncology, 26 (3), pps. 399-405.  http://www.ncbi.nlm.nih.gov/pubmed/18202416
33. Navid, F., Baker, S.D., McCarville, M.B., Stewart, C.F., Billups, C.A., Wu, J., Davidoff, A.M. et al. (2013). Phase I and Clinical Pharmacology Study of Bevacizumab, Sorafenib, and Low-Dose Cyclophosphamide in Children and Young Adults with Refractory/Recurrent Solid Tumors. Clinical Cancer Research, 19, pps. 236-246. http://www.ncbi.nlm.nih.gov/pubmed/23143218
34. Puissant, A., Frumm, S.M, Alexe, G., Bassil, C.F. et al. (2013). Targeting MYCN in neuroblastoma by BET Bromodomain Inhibition. Cancer Discovery. Online First February 21, 2013, pps. 1-16. http://cancerdiscovery.aacrjournals.org/content/3/3/308.long
35. He, S., Liu, Z., Oh, D-Y, and Thiele, C.J. (2013). MYCN and the Epigenome. Frontiers in Oncology. Volume 3, pps. 1-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555505/pdf/fonc-03-00001.pdf
36. Delmore, J.E., Issa, G.C., Lemieux, M.E., Rahl, P.B., Shi, J., Jacobs, H.M. et al. (2011). BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc. Cell, 146, pps. 904-917,
37. Alderton, G.K. (2011). Targeting MYC? You BET. Nature Reviews Cancer. 11, p. 693.
38. Schnepp, R.W. and Maris, J.M. (2013). Targeting MYCN: A Good BET for Improving Neuroblastoma Therapy? Cancer Discovery, 3, pps. 255-257. http://www.ncbi.nlm.nih.gov/pubmed/23475876
39. Maris, J.M. (2005). How Does MYCN Amplification Make Neuroblastomas Behave Aggressively? Still More Questions than Answers.  Pediatric Blood and Cancer, 45, pps. 869-871.
40. Tang, X.X., Zhao, H., Kung, B., Kim, D.Y., Hicks, S.L., Cohn, S.L., Cheung, N-K, Seeger, R.C., Evans, A.E. and Ikegaki, N. (2006). The MYCN Enigma: Significance of MYCN Expression in Neuroblastoma. Cancer Research, 66, pps. 2826-2833.  http://cancerres.aacrjournals.org/content/66/5/2826.full.pdf+html
41. Westermann, F., Muth, D., Benner, A., Bauer, T. Henrich, K.O. et al. (2008). Distinct Transcriptional MYCN/c-MYC Activities are Associated with Spontaneous Regression or Malignant Progression in Neuroblastomas. Genome Biology, 9 (10), pps. 1-14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760877/pdf/gb-2008-9-10-r150.pdf
42. Cohn, S.L., London, W.B., Huang, D., Katzenstein, H.M., Salwen, H.R., Reinhart, T., Madafiglio, J., Marshall, G.M., Norris, M.D. and Haber, M. (2000). MYCN Expression is Not Prognostic of Adverse Outcome in Advanced-Stage Neuroblastoma with Nonamplified MYCN. Journal of Clinical Oncology, 18, pps. 3604-3613. http://jco.ascopubs.org/content/18/21/3604.full.pdf+html
43. Tang, X., Evans, A., Zhao, H., Cnaan, A., Brodeur, G. and Ikegaki, N. (2001). Association Among EPHB2, TrkA and MYCN Expression in Low-Stage Neuroblastomas. Medical and Pediatric Oncology, 36, pps. 80-82.  http://www.ncbi.nlm.nih.gov/pubmed/?term=11464911
44. Fulda, S., Lutz, W., Schwab, W. and Debatin, K. (2000). MycN Sensitizes Neuroblastoma Cells for Drug-Triggered Apoptosis. Medical and Pediatric Oncology, 35, pps. 582-584.  http://www.ncbi.nlm.nih.gov/pubmed/?term=11107122
45. Fulda S., Lutz, W., Schwab, M. and Debatin, M. (1999). MycN Sensitizes Neuroblastoma Cells for Drug-Induced Apoptosis. Oncogene, 18, pps. 1479-1486. http://www.nature.com/onc/journal/v18/n7/pdf/1202435a.pdf
46. Albihn, A., Mo, H., Yang, Y. and Henriksson, M. (2007). Camptothecininduced Apoptosis is Enhanced by Myc and Involves PKCdelta Signaling. International Journal of Cancer, 121, pps. 1821-1829.  http://onlinelibrary.wiley.com/doi/10.1002/ijc.22866/pdf
47. Peirce, S.K. and Findley, H.W. (2009). High Level MYCN Expression in Non-MYCN Amplified Neuroblastoma is Induced by the Combination Treatment Nutlin-3 and Doxorubicin and Enhances Chemosensitivity. Oncology Reports, 22, pps. 1443-1449.  http://www.spandidos-publications.com/serveFile/or_22_6_1443_PDF.pdf?type=article&article_id=or_22_6_1443&item=PDF

This work will combine the two areas of immunotherapeutics and genomics to create new therapies for children with hard-to-treat cancers, such as neuroblastoma.  “To test their idea, the Dream Team, which comprises some of the best pediatric cancer researchers and clinicians in the world, have devised a three-pronged approach to focus on childhood cancers that inflict the highest burden of mortality and morbidity. They will first identify and validate cancer-specific, cell-surface molecules that could serve as potential targets for immunotherapy of high-risk pediatric cancers. Armed with this knowledge, they will then develop various immunotherapeutics that recognize and kill cancer cells expressing these molecules. Examples of potential immunotherapeutics include specific antibodies, immunotoxins and engineered immune cells called chimeric-antigen receptor T cells or CAR T cells. Finally, the Dream Team plans to conduct pivotal first-in-child immunotherapeutic trials with the most promising of these agents” (From the: Stand Up to Cancer Website).

For more information, please see the press release from Stand Up to Cancer.  A full list of the pediatric dream team members is also available on-line.

New research suggests that treating patients with non-steroidal anti-inflammatory drugs (NSAIDs) may mobilise more stem cells out of the bone marrow for peripheral blood stem cell collection – in animal studies by as much as four to six times.

CHOP Investigator Sheds Light on Effects of Sequestration on Cancer Research

Peter Adamson, MD, head of the Children’s Oncology Group, expresses his fears regarding what the sequestration will mean for future funding of paediatric clinical trials by the National Cancer Institute.

‘The Cancer Letter’ carries the full interview in Vol. 39, Issue 11, and a recording is also available to download.

Renal Carcinoma After Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

In a stark reminder that more effective and less toxic treatments are desperately required, a report in the Journal of the National Cancer Institute, investigating the risk of second malignancies among adult survivors of childhood cancer, finds increased risk of renal carcinoma. In particular the highest risk was observed amongst neuroblastoma survivors.

Previous analysis of the same patient cohort found that nearly 10% of childhood cancer survivors went on to develop a secondary malignancy at up to 30 years after initial diagnosis, with Hodgkin lymphoma and Ewing sarcoma carrying the greatest risk.

Inventing the Future: Working towards the next cancer breakthrough

This interesting article discusses T-Cell immunotherapy, an area of growing research in relation to neuroblastoma treatment. In particular neuroblastoma cells express surface antigens that are also found on certain adult cancers that are the subject of ongoing clinical studies.

Functional Characteristics of Antitumor T Cells Change With Increasing Time After Therapeutic Transfer

PHILADELPHIA — Scientists have characterized how the functionality of genetically engineered T cells administered therapeutically to patients with melanoma changed over time. The data, which are published in Cancer Discovery, a journal of the American Association for Cancer Research, highlight the need for new strategies to sustain antitumor T cell functionality to increase the effectiveness of this immunotherapeutic approach.

Early immunisation with dendritic cells after allogeneic bone marrow transplantation elicits graft vs tumour reactivity

Research study into the effect of early immunisation of neuroblastoma implanted mice with dendritic cells following allogeneic stem cell transplantation.

New Way to Mass-produce Natural Cancer-killing Cells Offers Hope for Patients

In a new study published by STEM CELLS Translational Medicine, scientists report on a way to produce natural cancer-killing cells in the lab in a quantity that could one day make them viable for treating patients.

New chemo drug gentler on fertility, tougher on cancer

Nanoparticles encapsulated inside liposomes could hold promise of more effective and less toxic delivery of drugs to treat cancer.

For further details see the following links:-

SKC Introduces New International Initiative (Solving Kids Cancer).

Pediatric cancer charities partner to fund international collaborative research (EurekAlert!).

The 2013 CNCF Parent Education Conference will be held on June 28-30, 2013 at The Westin Lombard Yorktown Center, Lombard, IL. Subsidized hotel rooms are available at a rate of $65/night + tax..

Speakers will be :-
Dr. Timothy Cripe
Dr. Rupert Handgretinger
Dr. Paul Sondel
Dr. Araz Marachelian
Dr. Sam Volchenboum
Dr. Greg Yanik
Dr. Sue Cohn
Dr. Chrystal Louis
Hillary van Glatin Phd
Memorial Sloan-Kettering speaker
Dr. Giselle Sholler or alternate
+ 3 or 4 NB survivors

For full details click on the image above or follow this link to the CNCF website.

In 2011 Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), the German research group, published results of a study showing that for a small sub-group of patients who responded to salvage chemotherapy and underwent a second autologous stem cell transplant (ASCT), the potential for long-term survival justified aggressive second line treatment (1).

Dr John Maris, Chief of Oncology at Children’s Hospital of Philadelphia (CHOP), and leader in neuroblastoma research takes a somewhat different view: “In contrast to the approach at the time of the initial diagnosis, when the focus is to provide intensive therapy within as short a time as feasible, the approach to relapse needs to focus on neuroblastoma as a chronic disease that can often be managed for years.” (2)

In the United Kingdom relapsed neuroblastoma has historically been treated with a combination of chemotherapy and radiotherapy for the purposes of palliation only. In more recent times a pathway of sorts has evolved comprising salvage chemotherapy, radiotherapy and surgery, ¹³¹I-MIBG therapy, and ch14.18 monoclonal antibody therapy with subcutaneous aldesleukin-2 (IL-2) and oral isotretinoin (13-cisRA). This paper discusses the different elements of relapse treatment in the UK, availability of early phase clinical trials, and possible future plans.

Chemotherapy

In most cases of metastatic relapse, a patient in the UK will initially be treated with one of two different chemotherapy combinations; topotecan, vincristine, and doxorubicin (TVD), or temozolomide and irinotecan (TEM/IRN). The choice between the two will sometimes be guided by the patient’s treatment history. For example, on the standard SIOPEN protocol, resistance to induction therapy is followed in the first instance by cycles of TVD, so in a subsequent relapse TEM/IRN would likely be favoured if it had not been used before. However, for a frontline responder the decision seems to be generally driven by individual and institutional experiences of the two combinations.

Topotecan, Vincristine, and Doxorubicin

The principal published clinical research for TVD was conducted by an Italian group in 2003, in a Phase II study that treated 25 children; 19 refractory and 6 recurrent (3). The overall response rate was 64%, and in the 6 patients with recurrent disease there were 3 complete remissions (CR), 1 partial remission (PR), 1 stable disease (SD) and 1 progressive disease (PD). SIOPEN instituted a further Phase II study of TVD for children failing to respond to first-line treatment (Rapid COJEC) on HR-NBL-01/ E-SIOP, but as yet no results have been reported (4).

TVD is given over a period of 7 consecutive days; topotecan as 30-minute infusion on Days 1-5, and vincristine and doxorubicin administered intravenously as a 48-hour continuous infusion starting an hour after the end of topotecan on Day 5. Children receiving TVD may require blood and/or platelet transfusions, and G-CSF is normally used between rounds in response to neutropenia. Admission to the hospital for treatment of febrile neutropenia is also not uncommon. Oral mucositis is the most frequent non-hematologic toxicity, and the potential for doxorubicin-induced cardiotoxicity means an echocardiogram (ECG) should be performed at regular intervals whilst a patient continues on this therapy.

Repeat cycles of TVD, in the absence of progressive disease or persistent side-effects, usually occur every 3 weeks, or when neutrophil and platelet counts are above 1000μ/L, and 100,000μ/L, respectively.

Temozolomide and Irinotecan

A number of papers have reported on the use of temozolomide and irinotecan for the treatment of relapse in various solid tumor types, including neuroblastoma. Both have been studied separately (5,6,7,8), as well as in combination using various dose levels and administration schedules (9,10,11,12,13). Studies such as ANBL0421 (12) suggested TEM/IRN could be used as a chemotherapeutic backbone alongside inhibitors and other novel agents. Subsequently a number of new Phase I/II trials have opened abroad that use TEM/IRN in combination with bevacizumab (14), temsirolimus or ch14.18 (15), dasatanib and rapamycin (16), and MLN8237 (17).

Amongst the research are studies from Memorial Sloan-Kettering in which 12 of 36 patients showed evidence of disease regression (10), and the Children’s Oncology Group (COG) in which 8 of 55 patients (44 relapse, 11 refractory) had objective responses (CR+PR) (12). Interestingly, in the only available documented Phase II trial of temozolomide alone reponses (CR+PR) were observed in 5 of 25 patients (14 relapse, 9 refractory, 2 non-metastatic Myc-N) (8). Such results are comparable with those from the combination studies, albeit with a caveat that only very small numbers of patients were involved.

In the UK this combination is normally administered on a 5-day out-patient regimen; oral temozolomide followed by irinotecan as a 1-hour intravenous infusion. Common toxicities are bone marrow suppression, nausea and diarrhea. Repeat cycles are every 3 or 4 weeks, subject to adequate count recovery and resolution of side-effects. Treatment with TEM/IRN is often well tolerated, and generally considered to be milder than TVD in terms of toxicity. Some children suffer very few side-effects, and are able to maintain an excellent quality of life. However, for others the nausea and diarrhea can be extremely severe and debilitating.

Imodium (loperamide) is usually prescribed for the diarrhea. COG advocates continuous administration of oral antibiotics (cefpodoxime or cefixime) as prophylaxis in patients who previously experienced severe bouts of diarrhea following TEM/IRN (12), however this is not normal procedure in the UK.

Other Options

Whilst TVD and TEM/IRN are the most widely administered chemotherapy combinations for relapse in the UK, and one of them will almost certainly be used initially, they are not the only options available.

Combination therapy using cyclophosphamide (Cyclo) and topotecan (Topo) has been the subject of a number of studies in the U.S. (18,19,20). In the COG Phase II randomised study of Cyclo/Topo vs Topo alone — the largest ever conducted in children with refractory or recurrent neuroblastoma — responses (CR+PR) were observed in 18 of 57 patients (20). Cyclo/Topo is currently used as a chemotherapy backbone for Phase II clinical trials from Memorial Sloan-Kettering Cancer Center (MSKCC) and the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) (21,22).

Cyclo/Topo is typically administered on an out-patient basis over 5 consecutive days. Each drug is given separately as a 30-minute intravenous infusion, after antiemetics. Continuous hydration is given for between 3 and 6 hours, and together with intravenous mesna (Uromitexan) is used for the prevention of hemorrhagic cystitis, a potential side-effect of cyclophosphamide. Treatment is generally well tolerated, though patients will commonly require G-CSF and blood products between cycles. Treatment repeats every 3 weeks, or after recovery of adequate bone marrow function and resolution of other side-effects.

Other chemotherapy combinations that have been studied in Phase I trials include temozolomide and topotecan (TOTEM), and vincristine, irinotecan, and temozolomide (VOIT) (23, 24). A Phase II trial of TOTEM is currently ongoing in mainland Europe (25).

A recently published retrospective study on the treatment of refractory or relapsed neuroblastoma with high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) reported disease regressions in 14 of 17 new relapse patients, and 13 of 26 refractory patients (26). HD-ICE is most commonly associated with, and administered at, MSKCC. This aggressive salvage regimen is not typically used to treat relapsed neuroblastoma in the UK.

It’s clear there is no chemotherapy combination that has been shown to be generally superior for dealing with relapses. As with all treatments, what works for some children may not work so well for others. However, a number of clinical trials currently enrolling children across a range of institutions in the U.S. favour either temozolomide and irinotecan, and to a lesser extent cyclophosphamide and topotecan as a chemotherapeutic backbone to which additional experimental drugs are added. None of these trials are currently available in the UK.

¹³¹I-MIBG Therapy

¹³¹I-MIBG (Metaiodobenzylguanidine) therapy may be an appropriate treatment option for children having MIBG avid (or MIBG positive) disease i.e. that is visible on an MIBG scan. MIBG non-avid (or MIBG negative) tumors are rare, though less so at relapse than initial diagnosis. ¹³¹I-MIBG is molecular radiotherapy that uses radiation as a drug, targeting the noradrenaline transporter molecule (NET) expressed by neuroblastoma. The principle of MIBG therapy is identical to that of an MIBG scan, the difference being that the objective is to deliver a large enough dose of internal radiation to destroy neuroblastoma cells inside the body. ¹³¹I-MIBG has been used in neuroblastoma treatment for over 20 years. Whilst not having curative potential by itself, it does have proven efficacy and should certainly be considered as part of a wider relapse treatment strategy.

In the UK ¹³¹I-MIBG therapy has formed a core part of the treatment of relapsed neuroblastoma over the last few years. After receiving chemotherapy, patients have generally gone on to receive two rounds of ¹³¹I-MIBG therapy before moving on to ch14.18 monoclonal antibody therapy.

¹³¹I-MIBG has been the subject of studies on both sides of the Atlantic (27,28). The leading UK expert in the field of radionuclide therapy in the treatment of neuroblastoma is Dr Mark Gaze of University College London Hospitals (UCLH). The largest trial of ¹³¹I-MIBG therapy was a Phase II conducted by University of California, San Franscisco (UCSF), Children’s Hospital of Philadelphia (CHOP), and University of Michigan. One hundred and sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma received two different dose levels of ¹³¹I-MIBG depending whether or not they had hematopoietic stem cells available for post-therapy bone marrow rescue. Overall response rate (CR+PR) was 36%, and was significantly higher for patients who had disease limited to either bones and bone marrow or soft-tissue, compared to those with both (29).

DuBois and Matthay’s 2008 paper in Nuclear Medicine and Biology provides an extensive review of research investigating in vitro, in vivo, and clinical applications of radiolabeled MIBG for neuroblastoma (30).

Administration of ¹³¹I-MIBG requires a patient to be isolated in a special lead-lined treatment room until such time as the radioactive iodine has been excreted from the body, and their radiation level is safe enough for them to be around other people. Normal length of inpatient stays are around a week, after which patients are discharged with restrictions on using public transport and being around other children. Whilst in isolation, contact with ‘comforters and carers’ is kept largely to a minimum, and those needing to enter the room must carry a measuring device so their own cumulative levels of radiation exposure can be monitored. Due to the specialist facilities required for administration of MIBG therapy, it is currently only available at University College Hospital (UCH), The Royal Marsden (RMH), and The Christie within the UK. Repeat administrations are usually carried out two weeks apart. Anecdotal evidence suggests late responses may occur in patients treated with ¹³¹I-MIBG, however, as most patients follow-up with additional therapies this is impossible to quantify.

¹³¹I-MIBG therapy has relatively few immediate side-effects and is usually well tolerated. There is a propensity for hypertension, particularly in patients whose blood pressure is already elevated. The primary toxicity is to the bone marrow, especially when administered with concomitant chemotherapy, and patients require a re-infusion of their own stem cells after the end of treatment. It may therefore not be the most appropriate treatment for a patient with no cryopreserved stem cells, however this isn’t an absolute rule applied in every case. Some studies have suggested that the use of individual dosimetry-based treatment planning for repeated ¹³¹I-MIBG administrations could be used to maximise the delivered dose with predictable resultant bone marrow toxicity (28,31). This would enable individualised treatment based upon factors such as bone marrow reserve, availability of stem cells, etc.

A recent SIOPEN study to evaluate the use of ¹³¹I-MIBG and topotecan in neuroblastoma (MATIN) treated 69 patients across 5 European centres, 46 refractory and 23 relapsed. Unsurprisingly, the treatment was found to be most effective in refractory patients who had not previously undergone any myeloablative therapy e.g. high-dose chemotherapy. (32)

A search of ClinicalTrials.gov lists an ongoing Phase I dose escalation trial of ¹³¹I-MIBG in combination with vorinostat (33) that is open in New Approaches to Neuroblastoma Therapy (NANT) centres across the United States, and a pilot study of ¹³¹I-MIBG given with irinotecan and vincristine (34) being run out of UCSF. Steven DuBois, MD at UCSF is principal investigator for both.

¹⁷⁷Lu-DOTATATE Therapy

An alternative form of molecular radiotherapy, that so far has only been used to treat children in the UK and Australia, is ¹⁷⁷Lu-DOTATATE (LuDO) therapy. This treatment works on precisely the same principle as ¹³¹I-MIBG, but instead of NET expression it targets somatostatin receptors that are also frequently expressed on neuroblastoma cells. In order for a patient to be a candidate for this type of treatment they must have positive uptake on a ⁶⁸Ga-DOTATATE PET/CT. This scan detects the presence of the somatostatin receptor type 2 targeted by the therapy, without which treatment will be ineffective.

A pilot study of ⁶⁸Ga-DOTATATE / ¹⁷⁷Lu-DOTATATE conducted at UCLH between 2008 and 2010 enrolled 8 children, of whom 6 had positive imaging and were eligible for treatment (35). Encouraging results led to a Phase I-II trial being planned to start in 2012 (see NB Globe report here). It’s not clear from publicly available information whether such a trial was ever formally initiated, however, patients have continued to receive LuDO therapy at UCH. According to the UK Clinical Research Network database a new trial of ¹⁷⁷Lu-DOTATATE in children with refractory or relapsed neuroblastoma is now being setup (36).

The main toxicities associated with LuDO observed during the pilot study were nausea, renal, and hematologic, although all children who were enrolled had been heavily pre-treated with multiple chemothereuptic agents and prior ¹³¹I-MIBG therapy. Early reports suggest that ¹⁷⁷Lu-DOTATATE may not result in the same degree of bone marrow suppression as ¹³¹I-MIBG, obviating the need for stem cell rescue after treatment. Normal length of inpatient stay for LuDO is 2 or 3 nights, significantly shorter than ¹³¹I-MIBG, an obvious benefit in terms of the amount of time younger children must spend in isolation.

¹⁷⁷Lu-DOTATATE is still in its infancy in terms of treatment of neuroblastoma, and does not have anything like the track record of ¹³¹I-MIBG. That said it is definitely something that should be considered if results of a ⁶⁸Ga-DOTATATE scan show good uptake. Myelosuppression compares favourably to ¹³¹I-MIBG and may allow repeat administrations without the need for regular blood or platelets, and possibly stem cell rescue. For patients whose disease is MIBG-negative, radionuclide therapy may still be a treatment option now that LuDO therapy is available.

Future research may include starting to examine the use of ¹³¹I-MIBG and ¹⁷⁷Lu-DOTATATE in some sort of combination therapy, rather than repeat administrations of one or the other. The theory of this approach being that having two distinct targets (NET and somatostatin receptors) through which to deliver doses of radiation may yield better results.

Surgery & External Beam Radiotherapy

Clearly there is little to be said in terms of these forms of treatment. Depending on the type of relapse (localised vs metastatic), location of tumor, previous treatment history, etc. it may be that surgery or external beam radiotherapy (EBRT) is the most appropriate course of action, or forms a necessary part of an overall treatment strategy.

Immunotherapy

Renewed focus on immunotherapy for neuroblastoma was fuelled by COG Phase III trial ANBL0032, that reported in 2009 that adding ch14.18 plus cytokines to existing standard frontline treatments for high-risk neuroblastoma significantly improved 2-year Event Free Survival (EFS) (66% vs 46%). (37,38) Whilst it’s clearly more difficult to achieve a successful outcome with recurrent disease, it should be remembered that to make it to a Phase III clinical trial, ch14.18 had to have already demonstrated certain activity in relapse and refractory patients in earlier studies (39,40). In a Phase II trial (POG9347) of ch14.18 and GM-CSF given to 27 patients with refractory or recurrent neuroblastoma there was 1 CR, 3 PR, and 2 SD (41,42).

There is rationale for a child who has responded to second-line chemotherapy and/or MIBG therapy, and now only has minimal residual disease, to receive immunotherapy and isotretinoin (13-cisRA) in order to try and achieve long-term remission. For children with limited disease still visible on imaging or bone marrow biopsies, immunotherapy has itself been effective in disease reduction and even in achieving remission. In cases of bulky tumors, heavy disease burden, or progression through other relapse therapies, immunotherapy is unlikely to be a good treatment option (38).

The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) states the following regarding Special Exception Access to ch14.18 for patients with relapsed neuroblastoma in the United States (43) :-

"For patients with relapsed neuroblastoma having measurable disease, ch14.18 efficacy has been limited. Therefore, therapies other than ch14.18 received through Special Exception Access should be sought. The activity of ch14.18 in patients who relapse and have never received ch14.18 and who have achieved a CR or near CR is not known. Based on the potential similarity of these patients to newly diagnosed patients with minimal disease, these patients are eligible to receive ch14.18 through the special exception process as long as they meet the following eligibility criteria as listed below.

• Patients must be diagnosed with neuroblastoma and have recurrent or refractory disease.
• Patients should have received standard therapy appropriate for their stage of disease at the time of diagnosis.
• Patients who have responded to second line therapy with PR, VGPR or CR are eligible and who do not have RECIST measurable disease are eligible.
• Patients must not have received prior anti-GD2 antibody therapy; and
• Patients must meet performance scale criteria and organ function as outlined in ANBL0032 Sections 4.8 and 4.9.

Patients with recurrent disease should strongly consider entry onto research protocols including those aimed at identifying novel therapies, more effective ways to use ch14.18 or identifying alternative immunotherapy treatments."

Relapse patients from the UK first began receiving immunotherapy (ch14.18) in 2010, along with slow responders from HR-NBL-01/ E-SIOP who were ineligible for the R2 randomisation (ch14.18 plus IL-2 vs. ch14.18 alone). Between 2010 and 2012, families needed to travel to Universitätsmedizin Greifswald in North-East Germany to receive this treatment, but more recently a European-wide long-term continuous infusion antibody study has opened, which should now be available at several UK locations (44).

The administration schedule of the antibody for patients on the long-term continuous infusion study is different from that on COG and SIOPEN frontline protocols. The aim of the trial, as with almost all such trials, is not to see if there are treatments that will help children with relapsed neuroblastoma — that is merely a by-product. Rather, it’s to see whether or not some new concept can move a step forward on the path towards becoming part of standard care for treating newly diagnosed patients. In this instance the idea in question is whether ch14.18 can be administered without the use of intravenous morphine, and yet still achieve the required levels of ch14.18 and NK cell activation in blood serum samples. If the trial achieves these aims then theoretically ch14.18 could go on to be administered in an out-patient setting.

In Greifswald, each cycle of immunotherapy (ch14.18 plus IL-2) lasted 18 days in total, including ch14.18 continuously infused over a 10 day period. This was followed by 14 days of 13-cisRA differentiation therapy. The new trial has an estimated enrolment of 60 patients, and intends to vary both antibody duration and dose level. The continuous infusion will run over 10, 14, 15, and 21 days, and three daily dose levels (7 mg/m², 10 mg/m², 15 mg/m²) will be used. As Greifswald gained more experience administering antibody, the protocol moved away from IV morphine as standard, and gabapentin (Neurontin) was routinely used instead. Paracetamol was prescribed as prophylaxis for temperatures caused by IL-2 and, during the week when ch14.18 and IL-2 were given together, metamizole (Analgin, Novalgin, etc.) was also added.

The potential side-effects of immunotherapy with ch14.18 and IL-2 are wide and varied. The most common are neuropathic pain, fever, hypotension necessitating fluid support, and capillary leak syndrome that can cause fluid to accumulate around major organs such as lungs, kidneys and heart. Patients can experience reduced O2 levels and may need to be given oxygen. The challenge of giving this treatment in an out-patient setting is not simply about the management of pain, and the use of morphine.

Whilst relapse treatment over the last couple of years has often led to immunotherapy, times have changed and children in the UK who now follow standard protocol receive ch14.18 (with or without IL-2) as part of upfront therapy. Having previously received ch14.18 and subsequently suffered a relapse, there would seem to be no logical basis for repeating it again. Which means ch14.18 becoming more the preserve of frontline, and possibly refractory, treatment. It’s unlikely that ch14.18 anti-GD2 monoclonal antibody therapy, at least in its current form, will even be available to patients who have already received it before.

Without immunotherapy, though, what follows chemotherapy/surgery/radiotherapy/radionuclide therapy to consolidate a positive response? Further courses of 13-cisRA? The same reasoning would apply; taking it again, at least as a single-agent, wouldn’t make a great deal of sense. It’s a problem that parents of children relapsing are going to continue to face.

New Drug Trials

A search of the UK Clinical Research Network (UKCRN) database reveals there are currently no research studies open in the United Kingdom relating specifically to relapsed (and/or refractory) neuroblastoma.

There are (at least) 3 pediatric Phase I clinical trials (looking at dosing and safety) across all solid tumor types, and children with neuroblastoma may be enrolled on these, subject to meeting eligibility criteria. Such trials are not primarily concerned with efficacy. Drugs are studied across a range of different tumor types, and based upon these initial results future studies may be designed to examine their effectiveness in treating children with particular types of cancer. Conversely, some drugs may show little promise and never make it beyond a Phase I trial at all.

When considering enrolling on an early phase clinical trial it is important to consider that these drugs have no proven effectiveness in treating children with neuroblastoma. In most cases they will have already been used to treat adult cancers, and are now being tested to see what effect, if any, they might have against pediatric tumors. These studies are being conducted for research purposes, and patients are often required to attend hospital for examinations, or to have blood samples taken, that are of no direct benefit to them. There are also often strict requirements on blood counts, particularly platelets and neutrophils, that can be difficult for a heavily pre-treated patient to meet. In a study assessing toxicity, good starting counts are necessary to see what effect experimental treatments have on bone marrow function.

Ridaforolimus

Ridaforolimus (Rida) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) protein. It is one of number of the same class of drugs, commonly referred to as mTOR inhibitors, that are currently being trialed in the treatment of cancer in general, and neuroblastoma in particular. Similar drugs, sirolimus (rapamycin) and temsirolimus (Torisel), developed by different pharmaceutical companies, are also currently being used in trials for relapsed/refractory neuroblastoma elsewhere.

MK-8669-056 is a Merck sponsored trial of ridaforolimus in pediatric patients with advanced solid tumors. Professor Andy Pearson of The Royal Marsden Hospital (RMH), Sutton, is the lead investigator. Patients receive ridaforolimus orally, at escalating doses starting at 22 mg/m² based on body surface area (BSA), for 5 consecutive days each week in consecutive 28-day cycles.

Details of the trial can be found by following these links to the ClinicalTrials.gov and UKCRN websites (45,46).

Dalotuzumab and Dalotuzumab/Ridaforolimus

Dalotuzumab (Dalo) is a humanised IgG1 monoclonal antibody that targets the Insulin-like Growth Factor 1 Receptor (IGF-1R) , a protein found on the surface of cells, and implicated in the promotion of tumor growth in several cancers. Dalotuzumab is an inhibitor of IGF-1 and IGF-2.

MK-8669-062 is a Merck sponsored trial of dalotuzumab and dalotuzumab/ridaforolimus in pediatric patients with advanced solid tumors. Professor Andy Pearson (RMH) is the lead investigator. The study will have three parts. In part 1, dalotuzumab will be administered alone to determine the maximum tolerated dose (MTD) in a pediatric population. In part 2, dalotuzumab and ridaforolimus will be administered in combination, using information from part 1 of this study, and from the ridaforolimus study MK-8669-056, described above. In part 3 of the study an extended cohort of patients will be enrolled at the combined dose levels determined in part 2.

Dalotuzumab is administered intravenously over 60 minutes every three weeks. Details of the trial can be found by following these links to the ClinicalTrials.gov and UKCRN websites (47,48).

AT9283

AT9283 is a multi-targeted small molecule inhibitor of Aurora Kinases (A and B). These are enzymes that are essential for cell proliferation, and over-expression or amplification of them, has been linked to the development of cancer. AT9283 is one of a number of Aurora Kinase inhibitors currently being studied in the treatment of cancer. Another, MLN8237 (Alisertib), has already been the subject of a COG Phase I/II study for relapsed and refractory neuroblastoma. A second COG trial of MLN8237 as a single agent is currently ongoing, and the NANT consortium are also enrolling patients on a Phase I/II trial of MLN8237 in combination with irinotecan and temozolomide (17).

AT9283 is the subject of a Cancer Research UK (CRUK) and Children’s Cancer and Leukaemia Group (CCLG) sponsored Phase I trial in children and adolescents with relapsed and refractory solid tumors. Lead investigator is Dr Darren Hargrave of Great Ormond Street Hospital (GOSH). Initial enrolment on this study was 20 patients, of which 14 were evaluable for response. In the very small sub-group of 3 neuroblastoma patients there was one mixed response (MR) and one stable disease (SD) lasting for four or more courses (49).

AT9283 is administered intravenously over 72 hours at the start of each 21 day cycle. Patients can receive up to 6 cycles in the absence of disease progression or unacceptable toxicity. Details of the trial can be found by following these links to the ClinicalTrials.gov and UKCRN websites (50,51).

Future Trials

BEACON: A randomized phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma. At SIOP 2012, Professor Andy Pearson presented plans for new randomised two-part trial to be run at Innovative Therapies for Children with Cancer (ITCC) and SIOPEN centres. Details of the trial record can be found here.

In the first part of the trial patients will be randomised to receive one of four experimental treatment arms; (1) temozolomide only, (2) temozolomide + bevacizumab, (3) temozolomide + irinotecan, or (4) temozolomide + irinotecan + bevacizumab. The results will determine which of these is selected as the backbone to be used for the second part of the trial.

In the second part molecular targeted drugs will be added to the common backbone, to form a personalised treatment plan dependant upon predictive biomarkers for each individual patient. Tumor biology, Dynamic Contrast Enhanced MRI (DCE-MRI), mRNA expression and other techniques will be used to select agents, and monitor responses. For example, a patient whose neuroblastoma tests positive for an ALK mutation may be treating using an ALK-inhibitor such as crizotinib (Xalkori) in addition to, say, temozolomide and irinotecan if that was the most effective ‘standard’ treatment to emerge from part one of the study.

There are a number of questions about this trial that, until more details emerge, we do not have answers to:-

• The large COG randomised trial of topotecan plus cyclophosphamide vs topotecan alone (20) took a total of five years to enrol 123 patients. It will be interesting to see what the expected accrual rate is for part one of the BEACON trial, and how many patients it’s anticipated will be needed on each of the four arms for it to produce a meaningful result.
• Bevacizumab (on two of the comparator arms) in part one of the study is a noteworthy inclusion. Whilst it is currently being studied in a number of ongoing trials in patients with relapsed (and refractory) neuroblastoma (14,21,52), it’s not immediately obvious what the rationale, or clinical evidence, is for including it as a candidate for forming part of a standard treatment backbone.
• As with so much research into neuroblastoma, and pretty much all early phase clinical trials, children who are resistant to frontline therapies i.e. refractory patients, and those who respond initially but later experience disease recurrence i.e. relapse patients, are all bundled together as a homogeneous group. In reality, of course, they aren’t and so the question arises as to what effect, if any, the distribution of patients between different trial arms might have.

Treatment Abroad

It’s impossible to discuss relapse treatments in the UK without at least saying something about the option of travelling abroad for treatment. Many families now have charitable appeals running to raise funds for this purpose should their child relapse, and some are even being established within weeks of diagnosis.

CNS Relapse

There is one specific type of neuroblastoma relapse that deserves a particular mention. It is well known that neuroblastoma cells can spread to the central nervous system (CNS), putting them beyond reach of most conventional therapeutic agents used to treat the disease. The incidence of CNS disease in children with relapsed neuroblastoma is 6-8% (53,54), of which a subset have disease that is detected only within the CNS.

Historically CNS relapses were almost always fatal, with a median survival of around 6 months. However, MSKCC have developed a treatment specifically designed to treat CNS disease using compartmental intrathecal antibody-based radioimmunotherapy (cRIT). 8H9, a mouse IgG1 antibody, is radiolabelled to deliver therapeutic doses of radiation direct to disseminated tumor cells within the CNS. It forms part of an overall plan that comprises craniospinal irradiation, chemotherapy, intrathecal radioimmunotherapy (8H9), anti-GD2 monoclonal antibody 3F8, and 13-cisRA (55). Treatment for CNS relapse can be ongoing for more than two years, depending on the individual patient. Initial results reported in 2009 speak for themselves.

“Seventeen of 21 cRIT-salvage patients are alive 7–74 months (median 33 months) since CNS relapse, with all 17 remaining free of CNS neuroblastoma. …. This is significantly improved to published results with non-cRIT based where relapsed CNS NB has a median time to death of approximately 6 months. The cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of intensive cytotoxic therapies. It has the potential to increase survival with better than expected quality of life.” (55)

8H9 treatment for CNS relapse is only available at MSKCC. It costs $350,000 USD as a basic minimum, but in most cases the all-in cost will be significantly more.

General Relapse

For general, or systemic, neuroblastoma relapse it’s patently obvious that there are many more options abroad than there are in the UK. There can be no debate about this. However, these are almost universally early phase clinical trials; some of which may already have shown promise, some of which may go on to form part of the future standard-of-care for treating neuroblastoma, and some of which may prove to have little or no effectiveness once results of the research are known. If there is one undeniable truth it’s that no therapy is suitable for all, so being able to navigate sites like ClinicalTrials.gov, NANT, NMTRC, MSKCC, and others is vital in trying to find a list of possible trials. A search on ClinicalTrials.gov returns a total of 37 studies open in the United States on which patients with relapsed neuroblastoma are eligible to enrol. Some of these are neuroblastoma specific trials, and others are open to multiple different tumor types.

When choosing a study there are many factors to take into account. What pre-clinical evidence exists for the therapy? Have there been any other trials, or pilot studies, of the same or similar therapies? If so, what were the results? Is there any relevant information that might exist about children who did or didn’t respond in earlier studies; disease and treatment history, disease status prior to enrolment? What are the eligibility criteria? What are the potential toxicities and side-effects? Where is the study available? How long might treatment last? Will it involve being away from home the entire time? How much will it cost?

There is a popular misconception regarding the cost of treatment abroad. Appeals may have a target of £300,000 or £500,000, but this isn’t a price tag attached to any particular therapy. Often, the experimental component of a study is covered by the trial funding grant. Supporting medications, adjunct chemotherapy, etc. must be paid for. Where things become quite uncertain, and costs can very quickly escalate dramatically is unplanned in-patient stays, visits to the Emergency Room, etc. Staying in a Hospitality House like Ronald MacDonald might only cost around $50 USD per night, but having to spend a night on an oncology ward can cost around several thousand dollars or more per night, depending on the hospital involved. There is simply no way to predict how events will unfold, except to say that it’s very much the exception when everything works out precisely as planned. Costs can vary between institutions, and receiving the same therapy on the same clinical trial at two different hospitals can result in two very different bills.

Whilst most of the clinical trials are being conducted in North America, there is also some very promising research taking place across Europe. Sometimes, even though it’s closer to home, this can be more difficult to discover except by word-of-mouth; RIST, and Haploidentical Stem Cell Transplantation are two such examples.

RIST

RIST is a combination therapy of chemotherapy drugs temozolomide and irinotecan together with the mTOR inhibitor rapamycin and multi-kinase inhibitor dasatanib (Sprycel). It’s currently the subject of an ongoing randomised clinical trial in which the full 4-drug combination is being compared to treatment with temozolomide and irinotecan alone (16).

In the RIST design, temozolomide and irinotecan are given at higher doses than in previous trials conducted by COG and MSKCC. Treatment begins with alternating weeks of rapamycin/Sprycel (R/S) and temozolomide/irinotecan (T/I), and involves a number of phases each decreasing in intensity,

A number of UK children have received RIST under the care of Universitätsmedizin Greifswald, starting treatment at the hospital in Germany and continuing back home in the UK.

In a study of RIST used in a compassionate setting, 20 patients (18 relapsed, 2 refractory) received a median of 16 courses of R/S and 7 courses of T/I. 18 patients (90%) showed an initial response after a median of 12 weeks with CR in 12 (60%), PR in 2 (10%), and SD in 4 (20%). The median progression-free survival (PFS) was 40% at 76 weeks, with 5 patients (25%) remaining in CR. In a cohort of predominantly relapsed patients (11 after 1st relapse, and 7 after 2nd or 3rd relapse) such results are very notable.

Haploidentical Stem Cell Transplantation

This post started with reference to the results of a German study on intensive relapse treatment involving salvage chemotherapy and second autologous stem cell transplant (ASCT). Building on the premise that children can go on to achieve long-term survival after relapse, a new strategy has formed involving intensive second-line therapy e.g. RIST, ¹³¹I-MIBG Therapy, Haploidentical Stem Cell Transplantation (halplo-HSCT), and ch14.18 anti-GD2 monoclonal antibody therapy with IL-2.

This aggressive treatment approach has already achieved some encouraging results, but only time and further research will tell whether or not it can fulfil its promise of lasting remissions. Combination therapy after relapse is given in the hope of securing a good initial response i.e. complete or partial remission. ¹³¹I-MIBG therapy is then received to further improve or consolidate the response. Even in patients already in complete remission MIBG therapy is normally used, both on the basis that MIBG imaging can underestimate the amount of disease (simply because of the lower radiation dose of ¹²³I-MIBG used in scans), and as part of pre-conditioning for the subsequent haplo-HSCT.

Haplo-HSCT involves taking stem cells from a parent and transplanting them into the patient following myeloablative chemotherapy to completely destroy the existing bone marrow system. The transplant process effectively equips the patient with a new immune system, which it’s hoped will be able to target any remaining cancer cells in a way the patient’s own immune system was unable to. The ‘graft’ of donor stem cells is engineered in such a way that ‘T’ and ‘B’ cells are depleted, but large numbers of Natural Killer (NK) cells are infused. Too many ‘T’ cells can cause graft-versus-host disease (GvHD), and too many ‘B’ cells (relative to ‘T’ cells) may result other serious complications. Optimisation of the graft composition has been the focus of much research.

After an earlier study in which relapsed neuroblastoma patients were treated with haplo-HSCT alone, the present German study is looking at the additive effect of giving ch14.18 anti-GD2 antibody therapy to patients starting at around 100 days post-transplant, with the introduction of IL-2 in later rounds. The rationale is once again to use antibodies to detect minimal residual disease (MRD) and present it as a target for the patient’s (new) immune system. An appealing aspect of this approach is that the new donor-derived immune system will not have had previous exposure to anti-GD2 antibody therapy, and so the treatment is applicable even in patients who have received ch14.18 before and then gone on to relapse.

Universitätsklinikum Tübingen, near Stuttgart in Germany, is at the very forefront of haplo-HSCT for the treatment of relapsed neuroblastoma.

Conclusion

Unlike at initial diagnosis there is no standard-of-care protocol for relapsed neuroblastoma; each patient has their own history, and their own presentation. In the United Kingdom options beyond traditional treatments of chemotherapy and radiotherapy are limited. There is hope for new developments in the area of radionuclide therapy with ¹⁷⁷Lu-DOTATATE, and continuing research into optimising delivery of ¹³¹I-MIBG. It remains to be seen what difference the upcoming BEACON trial will have, but we must wait for the more exciting aspect of that when biomarkers will be used to target specific agents at specific patients. In the meantime options abroad, in places like Germany and the United States, may continue to offer the best hope for some, and the only hope for others.

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28. Gaze MN, Chang YC, Flux GD, Mairs RJ, Saran FH, Meller ST. Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma. Cancer Biother Radiopharm. 2005 Apr;20(2):195-9. PubMed PMID: 15869455.
29. Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, Veatch J, Goldsby R, Brophy P, Kersun LS, Hawkins RA, Maris JM. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007 Mar 20;25(9):1054-60. PubMed PMID: 17369569.
30. DuBois SG, Matthay KK. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol. 2008 Aug;35 Suppl 1:S35-48. doi: 10.1016/j.nucmedbio.2008.05.002. Review. PubMed PMID: 18707633; PubMed Central PMCID: PMC2633223.
31. Buckley SE, Chittenden SJ, Saran FH, Meller ST, Flux GD. Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma. J Nucl Med. 2009 Sep;50(9):1518-24. doi: 10.2967/jnumed.109.064469. PubMed PMID: 19713562.
32. Ruth Ladenstein, Jamshed B. Bomanji, Martha Hoffmann, Ana Maria Forjaz De Lacerda, Frank H. Saran, Anne Uyttebroeck, Anton Staudenherz, Alisa Alspach, Robert J. Mairs, Glenn D. Flux, Mark Gaze. Peripheral blood stem cell transplant to support dosimetry guided higher dose molecular radiotherapy with co-administration of topotecan as a radiosensitiser for metastatic neuroblastoma. A SIOPEN study. 38th Annual Meeting of the European Group for Blood and Marrow Transplantation, Geneva, Switzerland, 01.04.2012 – 04.04.2012
33. ClinicalTrials.gov identifier: NCT01019850. N2007-03: Vorinostat and 131-I MIBG in Treating Patients With Resistant or Relapsed Neuroblastoma.
34. ClinicalTrials.gov Identifier: NCT01313936. High-Dose 131I-MIBG Therapy Combined With vincristine and Five Days of irinotecan for Resistant/Relapsed Neuroblastoma.
35. Gains JE, Bomanji JB, Fersht NL, Sullivan T, D’Souza D, Sullivan KP, Aldridge M, Waddington W, Gaze MN. 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med. 2011 Jul;52(7):1041-7. doi: 10.2967/jnumed.110.085100. Epub 2011 Jun 16. PubMed PMID: 21680680.
36. UK Clinical Research Network identifier: 13254. A Phase IIa trial of 177 Lutetium Dotatate in Children with Primary Refractory or Relapsed High-Risk Neuroblastoma.
37. ClinicalTrials.gov identifier: NCT00026312. Isotretinoin With or Without Monoclonal Antibody, Interleukin-2, and Sargramostim Following Stem Cell Transplantation in Treating Patients With Neuroblastoma.
38. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children’s Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123. PubMed PMID: 20879881; PubMed Central PMCID: PMC3086629.
39. Handgretinger R, Anderson K, Lang P, Dopfer R, Klingebiel T, Schrappe M, Reuland P, Gillies SD, Reisfeld RA, Neithammer D. A Phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer. 1995;31A(2):261-7. PubMed PMID: 7718335.
40. Yu AL, Uttenreuther-Fischer MM, Huang CS, Tsui CC, Gillies SD, Reisfeld RA, Kung FH. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol. 1998 Jun;16(6):2169-80. PubMed PMID: 9626218.
41. NCI Clinical Trials (PDQ®) Protocol ID: POG-9347. Phase II Study of MOAB Ch14.18 with GM-CSF for Recurrent Neuroblastoma.
42. Yu A.L., Batoa A., Alvarado C., Rao V.J., Castleberry R.P. Usefulness of a Chimeric anti-GD2 (ch14.18) and GM-CSF for Refractory Neuroblastoma: a POG Phase II Study. Proc. Am. Soc. of Clin. Oncol. 1997, 16, Abstract 1846.
43. NCI Cancer Therapy Evaluation Program, Pharmaceutical Management Branch. The Treatment Referral Center and Non-Research Use of Investigational Agents.
44. ClinicalTrials.gov identifier: NCT01701479. Long Term Continuous Infusion ch14.18 Plus s.c. Aldesleukin (IL-2) (LTI).
45. ClinicalTrials.gov identifier: NCT01431534. A Study of Ridaforolimus in Pediatric Patients With Advanced Solid Tumors (MK-8669-056).
46. UK Clinical Research Network identifier: 11168. NCRN339: Ridaforolimus in pediatric Patients with Advanced Solid tumors.
47. ClinicalTrials.gov identifier: NCT01431547. Study of Dalotuzumab Alone and With Ridaforolimus in Pediatric Participants With Advanced Solid Tumors (MK-8669-062 AM1).
48. UK Clinical Research Network identifier: 11169. NCRN340:Dalotuzumab and Ridaforolimus-Dalotuzumab Combination Treatment in Pediatric Patients.
49. Darren R Hargrave, Andrew DJ Pearson, Lucas Moreno, Bruce Morland, Martin Elliott, Guy Makin, et. al. A Phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumors. Poster Discussion Session, Pediatric Oncology. 2012 ASCO Annual Meeting. J Clin Oncol 30, 2012 (suppl; abstr 9542).
50. ClinicalTrials.gov identifier: NCT00985868. AT9283 in Children and Adolescents With Relapsed and Refractory Solid Tumors.
51. UK Clinical Research Network identifier: 6958. CRUK / CCLG AT9283 in pediatric Patients.
52. ClinicalTrials.gov identifier: NCT00885326. N2007-02:bevacizumab,Cyclophosphamide,& Zoledronic Acid in Patients W/ Recurrent or Refractory High-Risk Neuroblastoma.
53. Matthay KK, Brisse H, Couanet D, Couturier J, Bénard J, Mosseri V, Edeline V, Lumbroso J, Valteau-Couanet D, Michon J. Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer. 2003 Jul 1;98(1):155-65. PubMed PMID: 12833468.
54. Kramer K, Kushner B, Heller G, Cheung NK. Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer. 2001 Apr 15;91(8):1510-9. Review. PubMed PMID: 11301399.
55. Kramer K, Kushner BH, Modak S, Pandit-Taskar N, Smith-Jones P, Zanzonico P, Humm JL, Xu H, Wolden SL, Souweidane MM, Larson SM, Cheung NK. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol. 2010 May;97(3):409-18. doi: 10.1007/s11060-009-0038-7. Epub 2009 Nov 5. PubMed PMID: 19890606; PubMed Central PMCID: PMC3533371.

As much as this is encouraging, it is also valuable to understand some details of the case.  Most importantly, this report is about only one patient in the larger study that is currently ongoing at University of Louisville (Kosair Children’s) and at Dana-Farber (Boston Children’s).  The paper is a “case report” which is distinct from clinical research reports that discuss results of all patients on a study. Evidence-based medicine in clinical research is built on the results of many patients, and conclusions from single case studies should be taken as anecdotal.

Immune cells (dendritic cells) were collected from the patient, pulsed with CT (cancer testes) antigens, and grown in the laboratory to return to the patient as a vaccine injection in several doses. The dendritic cells “teach” the patient’s T cells to recognize the neuroblastoma cells with the CT antigens.  Before receiving the vaccine, the patient was treated with chemotherapy (decitabine) to increase the expression of the CT antigens on the neuroblastoma cancer cells (Krishnadas et al, 2013).  This type of immunotherapy is different from other approaches using antibodies such as ch14.18 that target GD2 which is also found on the surface of neuroblastoma tumor cells.

This case is about one patient who was diagnosed with neuroblastoma (unfavourable, not MYCN amplified) at 3 years of age with a primary tumor, bone marrow involvement, and bony metastases (found by PET scan); however, HVA/VMA and MIBG scans were negative.  The patient did not respond completely to frontline therapy (COG- ANBL0532 protocol), and at the end of treatment which included ch14.18 immunotherapy, the patient’s final tests showed disease in the bone marrow.  This disease persisted even after three cycles of irinotecan and temozolomide.

The patient had his “peripheral blood mononuclear cells collected via apheresis for the culture of dendritic cells” (Krishnadas et al. 2013, p. e338) and then began the decitabine chemotherapy.  The patient received 3 cycles of the protocol: decitabine for 5 days, followed by 2 weekly vaccines (with imiquimod given before and after the vaccination), and one week of rest.  After the third cycle the patient experienced a decline in neutrophil and platelet counts, and an elevated alkaline phosphatase level.

At the end of the 3 cycles of decitabine and the vaccine, the patient had no evidence of neuroblastoma in his bone marrow aspirates and biopsies. On the one year anniversary of the patient’s last vaccination, the patient’s bone marrow continued to remain free of neuroblastoma, including clear CT scans. The decitabine/dendritic cell vaccine therapy shows some great promise and is certainly worthy of future study.  Future research in this area will involve (Krishnadas et al, 2012, p. e340):

1. Continuing this study with a larger number of patients to determine if there is a significant response rate to this therapy.
2. Examining if patients with bulky disease would also benefit from this therapy, and not just patients with a minimal disease profile.
3. Establishing a detailed understanding on how the neuroblastoma cells are being killed.
4. Determining if there are subsequent immune responses towards any disease after the vaccine treatment is completed.

Reference

Krishnadas, D.K., Shapiro, T. And Lucas, K. (2013). Complete Remission Following Decitabine/Dendritic Cell Vaccine for Relapsed Neuroblastoma. Pediatrics, Vol 131, No 1.

For ANBL0032, patients having a good response to induction therapy, and reaching stem cell transplant (SCT) within 9 months of diagnosis, were eligible for randomisation into two trial arms. Control patients received standard treatment of 6-cycles of isotretinoin (13-cis-RA), whilst patients on the experimental arm received standard treatment plus 5 cycles of immunotherapy (ch14.18 with cytokines GM-CSF and IL2 alternating with each cycle).

As has been extensively documented and reported, including here on NB Globe, interim analysis of the data from ANBL0032 in 2009 found that adding ch14.18 plus cytokines to the existing standard treatment for high-risk neuroblastoma significantly improved 2-year Event Free Survival (EFS) (66% vs 46%). (1,2)

ANBL0032 began accruing in October 2001, and took more than 7 years to enrol the required number of patients (226) before interim analysis could be undertaken. With the difference between trial arms breaching the threshold for stopping randomisation early, the protocol was modified and all children were subsequently assigned to receive immunotherapy.

A lesser known aspect to this story is that, after much deliberation and consultation, the COG Neuroblastoma Committee decided to offer immunotherapy to all of the children who had participated in ANBL0032, been randomised to the control-arm (no immunotherapy), and remained disease free. This despite a backdrop of limited supply of the monoclonal antibody ch14.18, all children now assigned to receive it rather than the previously anticipated 50%, repeated inpatient hospitalization and intravenous drug administration over a five month period, severe pain and toxicity, and a lack of evidence of clinical benefit when given beyond 110 days after stem cell transplant.

The parents of 52 eligible children from the control-arm of ANBL0032 were offered ch14.18 after the end of randomisation in 2009. Of those, only 4 elected for their children to receive immunotherapy. Each had completed treatment within the previous 4 to 9.6 months.

The paper’s focus is on ethical decision making with regards offering an experimental treatment to control-arm patients after it has been shown to be superior; it does not examine in detail why over 90% of the parents who were offered ch14.18 declined to take it. One can only surmise the reasons; lack of evidence regarding benefit when given late after stem cell transplant, significant burden of toxicity, a return to full-time treatment for a child currently well and leading a relatively normal life, fear of relapse diminishing with time from end of treatment. It seems reasonable to think that those parents whose children had completed therapy most recently had the most difficult decisions to make. That the 4 children who did go on to receive immunotherapy had all completed front-line therapy within the previous 10 months supports this view.

References

1. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34.
2. New Standard of Care in High-Risk Neuroblastoma. Medscape Medical News, Sep 30, 2010.

13-cisRA is typically administered during the maintenance phase of treatment for high-risk neuroblastoma in conjunction with immunotherapy for a total of 6 planned cycles lasting 14 days each (with a 14 day break in between each cycle).  Isotretinoin can also be prescribed outside of an experimental protocol, and in both cases it is for the treatment of minimal residual disease.  Isotretinoin is the generic name, 13-cis-retinoic acid or 13-cisRA is the chemical name, and Amnesteem, Claravis, Roaccutane and Accutane are trade names for this medication.

A feasibility study by Veal et al (3) looked at whether it was possible to adjust the dose of 13-cisRA for each cycle to ensure that patients achieved or exceeded the desired minimum concentration of the drug in the body.  This study provides recommendations for the dosing of children who are under 12kg, suggesting that their isotretinoin doses be determined by a body surface area calculation, and not by a weight calculation.  It also recommends increasing the dosage by 25% for those patients who can not swallow the capsules orally.  Overall, it shows that the therapeutic monitoring of 13-cisRA dosing could be a valuable approach to help patients reach target concentrations when taking isotretinoin.  This is important because (3):

1. Low-dose use of 13-cisRA offers limited to no benefit for patients with neuroblastoma, suggesting that a certain therapeutic level must be achieved  to make it effective.
2. Using standardized formulas to calculate a patient’s 13-cisRA dose results in a wide variation of drug concentration levels between patients.
3. As 13-cisRA is given over a period of 6 months, it is possible that patients are not receiving the appropriate dose of the medication over that entire treatment period.

In this study, patients were initially given their 13-cisRA dose based on protocol and on the 14th day of the cycle, on the day of the last dose of isotretinoin, blood work was drawn to measure the therapeutic level of the drug (using plasma pharmacokinetics).  If required, the dosing of 13-cisRA was changed for the next cycle, and any subsequent cycles, to ensure that the patient was achieving target levels of isotretinoin in the body.

71/103 patients were recruited into the arm of the study examining dose adjustment of 13-cisRA, at a median age of 4.3 years old.  Of the 103 patients, 53 required the medication to be extracted from the capsules and administered with food, 23 were given the 13-cisRA by NG-tube and 27 were able to swallow the medication.  After the first cycle of 13-cisRA, 66% of the patients were able to achieve or exceed the minimum target therapeutic dosing level (2 μmol/L); however, 14 patients required their dose to be increased by 25% and 6 required their dose to be increased by 50%.  After the second cycle of 13-cisRA, of these 20 patients who required their 13-cisRA doses to be changed, 60% were able to reach or exceed the target level, with only 6 patients requiring a 25% dose increase (3).

One major finding of the study pertained to the dosing of 13-cisRA in children who weighed less than 12kg.  According to protocol, children who weigh less than 12kg have their 13-cisRA dose determined by their weight, and not by calculating body surface area (5.33mg/kg versus 160 mg/m²).  In this patient group, 8 out of 11 children (73%) did not achieve the target level of isotretinoin in the first cycle.  After the dose was adjusted for these patients, the resulting dose was equivalent to 109 to 167 mg/m² (2) and they were able to reach the necessary concentration of the drug (3,5).

Out of the 71 patients in the dose-adjustment arm of the study, all of the patients who took the 13-cisRA orally were able to achieve the target therapeutic levels in comparison to 54% of the patients who required the medication to be extracted and mixed with food, and to 67% of the patients who took the medication by NG-tube (3).  In looking at all of the 103 patients, the target levels were achieved by 93% of the patients who could swallow the capsules (25/27) versus 55% (42/76) who were not able to take the medication orally.  Those patients who could not swallow the capsules were typically younger in age, and it is possible that other factors such as the absorption of the drug could be at play; however, the method of administering the drug does impact how well a patient is able to reach therapeutic levels.

Overall, it was shown that adapting and increasing the dose of 13-cisRA could be done safely.  The most common toxicities experienced were infections (11%), increased ALT levels (5%), nausea/vomiting (5%), and skin reactions/toxicities (5%).

This study makes two major recommendations (3):

1. Children under 12kg should not have their 13-cisRA dose determined by weight and that all patients should have their dose determined by calculating body surface area (160mg/m²).
2. A 25% dose increase should be applied to those patients (over 12kg) who are unable to swallow the 13-cisRA capsules (i.e., when the isotretinoin is extracted from the capsule and added to food or given by tube).

A longer term recommendation is the need for a more suitable oral form of 13-cisRA for patients who are unable to swallow the capsules, a “child-friendly formulation” (4).  A request was submitted to the U.S. Food and Drug Administration (FDA) by the National Institute of Child Health and Human Development (NICHD) requesting the creation of a child-friendly version of 13-cisRA.  The FDA sent this request to industry; however, they “declined” going forward with such a formulation (4).  The NICHD and the National Cancer Institute (NCI) are submitting further information to the FDA on this matter and the NIH is exploring the development of a child-friendly form of isotretinoin.

References

1. Matthay, K.K., Villablanca, J.G., Seeger, R.C., Stram, D.O., Harris, R.E., Ramsay, N.K., et al. (1999). Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-Cis-Retinoic Acid.  Children’s Cancer Group.  New England Journal of Medicine, 341, 1165-1173. http://www.nejm.org/doi/full/10.1056/NEJM199910143411601
2. Children’s Neuroblastoma Cancer Foundation. (2011). Coping with Accutane. CNCF Parent Handbook. Retrieved from: http://www.cncfhope.org/cms_images/file_185.pdf
3. Veal, G.J., Errington, J., Rowbotham, S.E., Illingworth, N.A., Malik, G., Cole, M., Daly, A.K., Pearson, A.D.J, and Boddy, A.V. (2013). Adaptive Dosing Approaches to the Individualization of 13-Cis-Retinoic Acid (Isotretinoin) Treatment for Children with High-Risk Neuroblastoma. Clinical Cancer Research, January 15, 2013, 19 (2), 469-479. http://clincancerres.aacrjournals.org/content/19/2/469.abstract
4. Matthay, K.K. (2013). Targeted Isotretinoin in Neuroblastoma: Kinetics, Genetics and Absorption.  Clinical Cancer Research, January 15, 2013, 19 (2), 311-313.  http://clincancerres.aacrjournals.org/content/19/2/311.abstract?cited-by=yes&legid=clincanres;19/2/311
5. Butcher, J. (2013, January 17). Newcastle University Scientists’ Cancer Research Leads to Drugs Change. The Journal. Retrieved from: http://www.journallive.co.uk/north-east-news/todays-news//2013/01/17/newcastle-university-scientists-cancer-research-leads-to-drugs-change-61634-32618086/

An interesting overview paper out of the UK discussing ‘Ten Challenges in the Management of Neuroblastoma’. Click on the image above of follow this link to access the full text.

See the associated press release for further details.

The 2013 NMTRC Symposium will be held on May 6-7, 2013 at WALT DISNEY WORLD®, Florida. For full details click on the image above or follow this link to the Van Andel Institute® website.

During the Tuebingen NB Symposium much of the surgery session was spent discussing this topic; the consensus being that it’s still uncertain just how important gross total resection is in patients with Stage 4 Neuroblastoma.

A systematic review and meta-analysis of related studies, conducted out of the UK, states “There have been conflicting results published in the literature as to whether aggressive gross total resection provides any survival benefit over partial resection in stage III and IV tumours. Our results show that performing less aggressive surgery in the presence of metastatic disease does not adversely affect survival. Paediatric oncology surgeons do not need to attempt gross total resection in every case of advanced neuroblastoma. By limiting the surgical resection many of the unpleasant and adverse consequences of aggressive surgery could be prevented whilst maintaining survival.”^[1]

In direct conflict with the findings above, previous studies conducted at Memorial Sloan-Kettering have concluded that progression-free and overall survival are correlated with total resection of the primary tumor^[2].

One interesting observation made during the session in Tuebingen was on the combined role of surgery and radiotherapy. On the GPOH high-risk protocol external beam radiotherapy to the primary tumor area is only indicated where a resection is incomplete, or there is evidence of uptake in the area on a post-operative MIBG scan. In a previous study the use of radiotherapy was ultimately determined by a each individual oncologist, and non-strict adherence to guidelines enabled subsequent analysis to conclude that there was a statistically significant difference in outcomes between patients who had received radiotherapy following incomplete resection, and those who had not received radiotherapy following incomplete resection. Such a finding would suggest that complete resection, or incomplete resection plus radiotherapy, produce comparable outcomes. As both COG and SIOPEN protocols have radiotherapy as standard for all high-risk neuroblastoma patients such a hypothesis is unlikely to be tested further.

Despite these recent studies, the importance of complete removal of the primary tumor in Stage 4 Neuroblastoma patients will remain a subject of discussion and debate. And for parents it will certainly continue to weigh heavily.

This is arguably the most important meeting for neuroblastoma researchers and clinicians. Whereas meetings such as ASCO boasts upwards of 30,000 oncologists and researchers who share clinical findings on an annual basis, the entire pediatric oncology crowd only account for a tiny fraction of the attendees. By contrast, ANR welcomes 500 or more attendees who gather to discuss neuroblastoma only. This meeting occurs every two years, and the last meeting was in Stockholm, Sweden in 2010.

The big news this year is that the abstracts are published online for the first time! Previously, the abstract books were printed and only available to the attendees. This makes it impossible to do any electronic searches on 600+ abstracts.

For your reading pleasure:

http://anr2012.com/uploads/ANR2012_Programme_Web_06_13_12.pdf

NB Globe will be reporting on this meeting in the next couple weeks!

This Week in Pediatric Oncology Episode 26

In this interesting episode, host Dr Tim Cripe (Nationwide Children’s) and co-hosts Dr Lionel Chow (Cincinnati Children’s), Dr Andy Kolb (AI DuPont), and Donna Ludwinski (Solving Kids’ Cancer) quiz Dr Paul Sondel and Dr Ken DeSantes (both from University of Wisconsin – Madison) on NK cells and the implications of KIR/KIR-ligand mismatch (killer immunoglobulin-like receptor) with regard to immunotherapy treatment of neuroblastoma.

References:

Delgado DC, Hank JA, Kolesar J, Lorentzen D, et al. Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy. Cancer Res. 2010 Dec 1;70(23):9554-61. Epub 2010 Oct 8.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999644/

Venstrom JM, Zheng J, Noor N, Danis KE, et al. KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. Clin Cancer Res. 2009 Dec 1;15(23):7330-4. Epub 2009 Nov 24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788079/

Alderson KL, Sondel PM. Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol. 2011;2011:379123. Epub 2011 May 24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110303/

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This Week in Pediatric Oncology Episode 25

Host Dr Tim Cripe welcomes back co-host Dr Lionel Chow to discuss somatic mutations in pediatric brain tumors. After recapping the consensus paper on molecular subgroups in medulloblastoma discussed in TWiPO episode 22 (Brain Tumor Round Robin) Dr Chow highlights the significance of the driver mutations in histone H3.3 in pediatric glioblastoma. Results of whole exome sequencing have shown that significantly more somatic mutations are present in adult tumors compared to pediatric tumors. This difference  might suggest a reason for better success rates in pediatric tumors and possibly more escape mechanisms in adult tumors. Dr Chow also discusses a paper published by the Pediatric Cancer Genome Project (a St. Jude Children’s Research Hospital–Washington University collaboration) on somatic histone H3 alterations in diffuse intrinsic pontine glioma (DIPG). The findings are significant in showing that this mutation is present in 36% of non-brain stem gliomas and in 78% of brain stem gliomas, but in none of the other pediatric tumor types.

Papers discussed:

Taylor MD, Northcott PA, Korshunov A, et al.  Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012 Apr;123(4):465-72. Epub 2011 Dec 2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306779/

Schwartzentruber J, Korshunov A, Liu XY, Jones DT, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012 Jan 29;482(7384):226-31. doi: 10.1038/nature10833. http://www.ncbi.nlm.nih.gov/pubmed/22286061

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This Week in Pediatric Oncology Episode 24

Dr Tim Cripe welcomes Dr Andy Kolb from AI DuPont in this episode of TWiPO, and special guest Dr Andromachi Scaradavou, the Medical Director of New York Blood Center’s National Cord Blood Program.

NYBC is the world’s oldest and largest public cord blood bank, and collects, processes, tests and stores cord blood that mothers donate shortly after birth. The cord blood is for children and adults with no related donor available who need a hematopoietic stem cell transplant for life-threatening illnesses. More than 60,000 units are stored at NYBC and more than 4500 units have been provided for transplants worldwide. The variety of ethic groups represented is much higher in cord blood banking than in bone marrow donor programs. The percentage of use is climbing significantly for pediatric transplants partly because of the small dose required.

Discussants cover many aspects of this fascinating subject: background and uses of cord blood, logistics of collecting, processing, storing, and selecting units for transplants, as well as the advantages and challenges currently faced in this field. For more on NYBC see http://www.nationalcordbloodprogram.org/.

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Tubingen Town Hall

This was the fourth meeting in a series on pediatric solid tumors and the first time the focus was on neuroblastoma. It was hosted at the Children’s Hospital (Kinderklinik) in the beautiful old city of Tübingen, which is home to the top ranked German University founded in 1477. The 17 hospitals in Tübingen associated with the university treat 66,000 in-patients and 200,000 out-patients on an annual basis. This unique meeting was attended by approximately 130 scientists, clinicians, surgeons, and a few parents from more than 30 countries. The festival Fasnet happened to be underway and on Thursday the gentlemen in attendance were warned not to wear ties since on that day women carrying scissors will cut men’s ties off.

This meeting provided a good overview of the three major study groups (COG, SIOPEN, and GPOH) and comparing and contrasting the approaches they each have taken in treating neuroblastoma, particularly newly diagnosed and relapsed or refractory high risk disease. Some of this information is fairly easy to obtain in published literature, abstracts from major oncology meetings, and clinical trials listings, but learning about current trials in Europe is far more difficult than in the US. Hearing many leading European researchers present on their current work was very enlightening. The meeting was preceded by the “Master Class” and the closed SIOPEN committee spring meeting. The Master Class included an overview of the pathology, staging and risk stratification, surgical and imaging issues, chemotherapy, and immunotherapy strategies for treating neuroblastoma and follow-on sessions addressed some of these topics in more detail.  The rest of the meeting consisted of presentations on current clinical and preclinical work, challenges in validation of “personalized medicine” predictive models, and progress on the genome-wide association studies and TARGET project presented by John Maris (CHOP).

Pathology.  Ivo Leuschner (Kiel, Germany) gave two talks on pathology and showed that although a tremendous body of work has been done in characterizing the complex pathology of neuroblastic tumors and remains important for diagnosis, the pathology is not as important as the genetics for prognosis.

Imaging.  Imaging advances were discussed by Jürgen Schaefer (Tübingen, Germany) in two talks and suggested the potential use for PET/MRI, other tracers and carriers, and anti-GD2 imaging. One question raised about the latter is if neutralizing antibodies could be a problem from this form of imaging and potentially interfere with future anti-GD2 antibody treatment for children who receive this type of imaging.

Roland Bares (Tübingen, Germany) presented on the development and state of the art of I131-MIBG for imaging and radiotherapy, which was first used Tübingen in the 1980s. [1]

Chemotherapy.  Frank Berthold (Cologne, Germany) presented on the various chemotherapy induction regimens developed for high risk neuroblastoma and gave a separate talk on the results of the GPOH trial. The chemotherapy agents, combinations, timing, and number of cycles have been varied considerably over the past 30 years, and the consensus is that the response rate cannot be further improved by more dose intensification given the significant toxicities of these regimens. In early studies (NB79 – NB90) 13% of children died due to treatment related toxicity or second malignancy, and in later studies (up to NB97) this rate dropped to 6%. He showed a chart comparing the induction regimens of the three major study groups COG, SIOPEN, and GPOH. The COG is currently using two cycles of topotecan and cyclophosphamide followed by four cycles of previously used alternating combinations, and the GPOH NB2004 (finished accrual but no analysis yet)  randomized adding on topotecan and cyclophoshamide to previously used 6 cycle combination. The SIOPEN uses 8 cycles of time intensive chemotherapy given every 10 days instead of every 21 as in the COG and GPOH. In further analysis of the prior GPOH trials, they found that 22-29% of survivors had no late effects, depending on the era of treatment, and 53% had hearing loss.

Staging. Tom Monclair (Oslo, Norway) discussed the INRGSS (International Neuroblastoma Risk Group Staging System) which separates localized tumors into two groups, L1 and L2, where L1 has no image-defined risk factors. The metastatic disease stages are M and MS (where MS is the same as 4S but the age can go up to 18 months).  Dr Monclair also gave another talk on the INRG risk group stratification system.

Surgery. Michael LaQuaglia (Memorial-Sloan Kettering, NY) presented twice on surgical issues that have been debated over the years, particularly the importance of complete resection and how important surgical reports are for categorizing complete resections.  Jorg Fuchs (Tübingen, Germany) presented on minimally invasive surgical techniques and on abdominal resections, Dietrich von Schweinitz (Munich, German) talked about thoracic tumors, Jan Godzinski (Wroclaw, Poland) discussed thoracic-jugular junction surgeries, and Paul Losty (Liverpool, UK) presented meta-analysis data showing aggressive surgical resections improve survival in stage 3 tumors but not in stage 4 tumors.

Immunotherapy.  Paul Sondel (University of Wisconsin-Madison) was one of the early investigators working on the ch14.18 antibody and he presented a clear overview of the COG ch14.18 (chimeric antibody) and hu14.18-IL2 (humanized antibody with IL2 bound directly to the antibody) results along with the current and future directions.  He showed the significance of KIR/KIR-L (killer-immunoglobulin receptor-ligand) mismatch in the results of the hu14.18-IL2 COG phase II trial [2] and prior evidence of significantly better survival in post-ASCT setting.  [3]

Dr Sondel also discussed future plans for a trial using MIBG therapy, reduced intensity conditioning for haploidentical transplant followed by hu14.18-IL2 and donor NK cells.

Thorsten Simon reviewed the retrospective data on the GPOH NB 90 and NB 97 trials (2004 and 2011 publications showing questionable immediate benefit but statistical long term benefit to ch14.18 without cytokines).

Holger Lode (Griefswald, Germany) has a very active group working on immunotherapy approaches. They reported preclinical work on GD2-specific NK cells, MYCN-DNA vaccine, fenretinide and ch14.18, and current use of ch14.18 with IL2 for relapse. His group has also developed an anti-idiotype antibody called ganglidiomab for the baseline of development of DNA and protein vaccines for future trials.  A similar approach was taken by Alice Yu in a trial with 1A7 [4] and at Memorial-Sloan Kettering with a trial of A1G4. [5]

A “curative” approach for relapsed neuroblastoma?

Professor Berthold went on to describe the German “curative approach for recurrences” which has included new chemotherapy combinations such as RIST (rapamycin, irinotecan, sprycel/dasatinib and temozolomide), MIBG radiation therapy, second autologous stem cell transplant, and now MIBG therapy followed by haploidentical stem cell transplant and ch14.18 immunotherapy with IL2.

RIST

Selim Corbacioglu (Regeburg, Germany) presented preliminary results of notable response rates in a small series of patients who received compassionate use of RIST combination. RIST consists of repeated courses of rapamycin/dasatinib (R/S) for 4 days followed by 5 days of irinotecan/temozolomide (I/T). Eighteen relapsed and 2 refractory children (median age 3 years old with 11 in 1st relapse, 7 in 2nd or greater relapse) received median 16 courses of R/S and 7 I/T courses. After a median of 12 weeks, 18/20 showed clinical benefit with complete response in 12 (60%), partial response in 2/20, and stable disease in 4/20. A large German multi-instituition trial is planned to randomize patients to either irinotecan/temozolomide or RIST and will begin enrolling soon. [6]

Haploidentical stem cell transplant

Peter Lang (Tübingen, Germany) gave a presentation on preliminary results of an ongoing trial treating relapsed neuroblastoma patients with MIBG radiotherapy, haploidentical stem cell transplant, followed by 6 cycles of ch14.18 with IL2. Prior to entering the trial children have disease burden reduced by chemotherapy, surgery, and/or radiation with no disease progression. Those in complete or partial response are eligible for the trial. Professor Lang and his colleagues have treated 60 children with solid tumors with haplo SCTs, and have enrolled 25 NB patients on this trial to date, and 9 patients completed the protocol thus far. There have been no treatment related mortalities and 1 transient graft-versus-host disease. Six of nine of those who have completed the protocol are in complete remission or improved their partial remission, and 3 progressed.[7]

Kenneth DeSantes (University of Wisconsin-Madison) presented early data (4 patients, 2 with NB) on his trial treating pediatric cancers with haplo SCT followed by donor NK cell infusion.  The trial has been modified to reduce the possibility of graft-versus-host disease for subsequent patients. [8]

Another haploidentical transplant trial recently opened at Kansas City by PI Doug Myers, following with tri-virus specific T cells. [9-10]

Recently an interesting case study was reported from France (with Peter Lang as co-author) where a child who relapsed after a haplo SCT had a complete response to a combination of immuno-chemotherapy based on donor NK cells transplants, IL2 infusions and temozolomide/topotecan. [11]

Profound finale

Overall the meeting was very enlightening. As a touching conclusion to the meeting, the organizers introduced a young man (27) who was diagnosed with stage 4 MYCN-amplified disease when he was 3 years old in 1988, treated there at Tübingen.  He relapsed after frontline therapy, had an allogeneic transplant, then relapsed again, and then had a haplo SCT, and was the very first child to receive antiGD2 antibodies. Today he is a doctoral student at the same university.

Nick Bird, Dad to warrior Adam, attended and wrote an excellent piece on the meeting, please see his blog:  http://adamsappeal.blogspot.com/2012/02/tubingen-symposium.html

References:

1. Prog Clin Biol Res. 1988;271:669-78. MIBG-treatment in neuroblastoma; experiences of the Tübingen/Frankfurt group. http://www.ncbi.nlm.nih.gov/pubmed/3406023

2. Cancer Res. 2010 Dec 1;70(23):9554-61. Epub 2010 Oct 8. Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy. http://www.ncbi.nlm.nih.gov/pubmed/20935224

3. Clin Cancer Res. 2009 Dec 1;15(23):7330-4. Epub 2009 Nov 24. KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788079/

4. ASCO 2010 Education Book Pediatric Cancer: Progress in Treatment of High-risk Neuroblastoma with Immunotherapy.  http://www.asco.org/ASCOv2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2010/zds00110000408.pdf

5. Phase I trial to study the effectiveness of monoclonal antibody A1G4 plus BCG in treating patients with cancer. http://clinicaltrials.gov/ct2/show/NCT00003023

6. Study of a Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma (RIST-rNB-2011)  http://clinicaltrials.gov/ct2/show/NCT01467986

7. Phase II Feasibility Study using ch14.18/CHO antibody and IL2 after Haploidential Stem Cell Transplantation in Children with Relapsed Neuroblastoma  http://www.kinder-krebs-forschung.de/wp-content/uploads/Studienmaterial-AK_Studie-englisch1.txt

8. Haploidentical Transplant With NK Cell Infusion for Pediatric Acute Leukemia and Solid Tumors  http://clinicaltrials.gov/ct2/show/NCT00582816

9. Allogeneic Stem Cell Transplantation for Advanced Neuroblastoma Using MHC Mismatched Related Donors (STALLO) http://clinicaltrials.gov/ct2/show/NCT01462396

10. Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma (STALLONe)  http://clinicaltrials.gov/ct2/show/NCT01460901

11. Pediatr Blood Cancer. 2011 Dec 16. doi: 10.1002/pbc.24030. NK Cell immunotherapy for high-risk neuroblastoma relapse after haploidentical HSCT.  http://www.ncbi.nlm.nih.gov/pubmed/22180305

Following this is an exciting meeting on neuroblastoma is taking place in Tubingen, Germany Feb 16-18, and thanks to our supportive friends, The Neuroblastoma Children’s Cancer Alliance UK, reports on this meeting from NB Globe are forth coming!  Anyone interested is invited to attend an informal debriefing in London on Sunday afternoon/evening February 19 in Gloucester Road/Piccadilly line tube station area (contact here for more information about the place and time).

Bios of the speakers are found at this link: http://www.neuroblastoma2012.com/Speakers.php

A preview of topics:

Wednesday, February 15 ^th , 2012

Thursday, February 16 ^th , 2012

Friday February 17 ^th , 2012

Saturday February 18 ^th , 2012

This Week in Pediatric Oncology Episode 23

In 2011 there were over 1300 new articles published on neuroblastoma in the medical literature.

Join Dr Tim Cripe and his co-host Dr  Lars Wagner in a fast-paced, in-depth, and comprehensive survey of 18 of the most important papers on neuroblastoma published in 2011. Dr Cripe and Dr Wagner explore and discuss the compelling evidence reported on a variety of topics, including epidemiology, risk stratification, clinical trials, ALK mutation and expression, new targets, and genetics.

All of the papers discussed are listed here with links to PubMed.

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This Week in Pediatric Oncology Episode 22

Join Dr Tim Cripe and his co-host Dr Lionel Chow for a fast-paced, in-depth, and comprehensive survey of 15 important recent papers on pediatric brain tumor research, addressing medulloblastoma, ependymomas, and gliomas. Dr Cripe and Dr Chow explore and discuss the compelling evidence reported on a variety of topics, including viral causes and therapeutic implications, biomarkers, genomics, proteomics, targets, classification, risk stratification, treatment side-effects, proton-beam radiation therapy, and results of recent clinical trials.

This robust review of current research includes all of the following papers, listed by timed location in the podcast.

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This Week in Pediatric Oncology Episode 21

Dr Tim Cripe and co-hosts Dr Maureen O’Brien and Dr Raj Nagarajan interview a pediatric hematology/oncology legend, Dr. Beatrice Lampkin, who served as Division Director of Cincinnati Children’s Division of Hematology/Oncology in the 1970’s. This enlightening and inspiring discussion explores her career and her early contributions to leukemia therapy and the challenges she faced as an early leader in the field as a female. She describes her experience with polio, early paralysis from the neck down, crutches for mobility, and later, her confinement to a wheelchair. Revealing another era in communications with parents and patients in the 1960s and 1970s, she explains how parents were advised to used the term “anemia” to describe their child’s condition rather than “leukemia” to to explain why the child would require periodic blood transfusions, and to prevent shunning by friends and family. Dr Lampkin also describes her joy at following the earliest survivors of pediatric cancer she treated who are now in their 40s and 50s.

As if all that isn’t inspiring enough, she describes her busy retirement in which she continues to teach the Cincinnati Children’s Hospital fellows how to examine blood and bone marrow smears under the microscope and her work in the founding of the GLAD House (http://www.gladhouse.org/), a sanctuary to help drug-addicted youth get off the streets.

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This Week in Pediatric Oncology Episode 20

Today’s episode features an impressive lineup for a hot topic. Host Dr Tim Cripe warns: “If your blood isn’t boiling by the end, you weren’t listening.” Hear Tim and co-host Dr Lionel Chow discuss pediatric cancer research funding with guests Dr C. Patrick (Pat) Reynolds, Dr E. Anders (Andy) Kolb, and parent Joe McDonough.

Dr Pat Reynolds puts government spending on the number one disease killer of children in the US in perspective, comparing the tiny $200M spent on pediatric cancer research to the foreign aid budget of $22B (less than 1%). For example, $1.6B goes to Egypt alone. The COG budget is a mere $46M. The DOD budget is $700B. See his slides here. Dr Lionel Chow mentions an enlightening fact – private donations to St Jude exceed $600M per year, on top of the givers’ paying taxes. This is 3 times the entire NCI budget for pediatric cancer research for all institutions in the US.

Spending per Person Years Life Lost is compared for childhood cancers and adult cancers, see graph here.

Dr C Patrick Reynolds is Director, Cancer Center and Professor of Cell Biology & Biochemistry, Internal Medicine, and Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock TX. Dr E Anders Kolb is the Director of Blood and Bone Marrow Transplantation at Alfred I. duPont Hospital for Children, and Head of the Cancer Therapeutics Laboratory at Nemours Biomedical Research, Wilmington, DE. Joe McDonough is father to Andrew, and founder of The Andrew McDonough B+ (Be Positive) Foundation, raising money for families and research.

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Neuroblastoma is the most common ‘solid’ cancer diagnosed in babies and children. It accounts for around 15 percent of cancer deaths in children and around 100 children are diagnosed every year in the UK. Of these 100, approximately half will have high risk disease and the long term survival rate for these patients is less than 40 percent.

A pilot study that was given funding by the Neuroblastoma Children’s Cancer Alliance, a charity that helps children and families affected by neuroblastoma, has investigated a new radiotherapy treatment that targets a particular receptor on neuroblastoma cells. Dr Jenny Gains presented the promising results of the of this pilot study at the Neuroblastoma Children’s Cancer Alliance parents’ meeting July 23, 2011 in London.

Following the success of the pilot study, a three-year Phase II clinical trial is expected to start in the UK in early 2012. During the trial, the new radiotherapy treatment will be offered to all UK patients who meet the eligibility criteria – primarily patients who have relapsed neuroblastoma. Although it is a UK-wide trial, the treatment itself will take place at the Royal Marsden and University College Hospital (UCH) in London.

The pilot was carried out by a team of researchers, including Dr Mark Gaze, Consultant Clinical Oncologist at UCH and Great Ormond Street and Dr Jenny Gains, Clinical Research Fellow at UCH . Six children were offered the new radiotherapy treatment, of which five were found to have stable or improved disease following treatment.

Currently the targeted radiotherapy treatment offered to neuroblastoma patients is a compound called ¹³¹I-mIBG. However, this treatment has various limitations as some neuroblastoma cells do not have the receptors which this compound attaches to, so will not be killed by this treatment. Also ¹³¹I-mIBG can have serious side effects for neuroblastoma patients as it is toxic to bone marrow, which is already depleted in neuroblastoma patients.

The new treatment uses a compound called ¹⁷⁷Lutetium-DOTATATE, or LuDO for short, which attaches to a different receptor that many neuroblastoma cells have on their surface. It is hoped that LuDO will be as effective in killing neuroblastoma cells as ¹³¹I-mIBG, but have fewer and less severe side effects. It is possible that it will be offered in combination with other radiotherapy drugs in the future.

“This pilot study, offers new hope for the families of children affected by the disease,” said Dr Gaze. “If the trial proves that the new drug is safe and effective, it may become part of the standard treatment for neuroblastoma patients receiving radiotherapy treatment. It is likely to be offered with other drugs in the future – combining drugs is likely to be more effective as more cells will be killed.”

Notes:

For more information, contact Alison Moy, Chief Executive of the Neuroblastoma Alliance UK, on 020 8203 0100, 07580 964 709 or alison@nballiance.org.uk; or Ingrid Marson on 01707 328 511 or ingrid@acornpr.org.uk

The clinical trial has been approved by National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group (CTRad) and Clinical Trials Advisory Committee (CTAC), although it is still awaiting approval from the Ethics Committee, Medicines and Healthcare products Regulatory Agency and Administration of Radioactive Substances Advisory Committee (ARSAC).

The pilot was funded by the JACK appeal of the Neuroblastoma Alliance. The JACK appeal was set up by Yvonne and Richard Brown to raise money for their son Jack’s neuroblastoma treatment. Jack sadly died in May 2009.

More information on the pilot study are available in: J. E. Gains, J. B. Bomanji, N. L. Fersht, T. Sullivan, D. D’Souza, K. P. Sullivan, M. Aldridge, W. Waddington, M. N. Gaze. 177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma. Journal of Nuclear Medicine, 2011; DOI: 10.2967/jnumed.110.085100

The Neuroblastoma Alliance UK works to help children and families affected by neuroblastoma through providing financial assistance for treatment and to fund leading clinical research in recognised cancer centres.

The Neuroblastoma Children’s Cancer Alliance is a registered charity (no. 1135601), based at 3-4 Sentinel Square, Brent Street, London, NW4 2EL.

This Week in Pediatric Oncology Episode 19

Several just-published papers in the literature relate to recent podcast episodes, and host Dr Tim Cripe and co-host Dr Lionel Chow review these interesting developments.

0:55 Hedgehog Signaling: Recent papers discussing this pathway in neuroblastoma and rhabdomyosarcoma are discussed, with implications for treatment in these tumor types with itraconozole.

6:40 Cell phone and brain tumor risk: The controversy concerning criticism by the Environmental Health Trust of a study showing that cell phone use does not increase risk of brain tumors in children is explored.

Accelerated approval of cancer drugs by the FDA and implications for pediatric cancers.

15:30 Brentuximab for two types of lymphoma

21:20 Vemurafenib for melanoma

28:30 Crizotinib for non-small cell lung cancer (and potential use in neuroblastoma)

42:30 Response to email regarding personalized medicine TWiPO episode #17 and lab blog for Dr Charles Keller at OHSU

References:

Pediatr Blood Cancer. 2011 Dec 1;57(6):930-8. doi: 10.1002/pbc.23174. Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children’s Oncology Group.

Int J Oncol. 2011 Oct;39(4):899-906. doi: 10.3892/ijo.2011.1076. Pharmacological inhibition of the Hedgehog pathway preventshuman rhabdomyosarcoma cell growth.

Cancer Lett. 2011 Nov 28;310(2):222-31. Inhibition of the sonic hedgehog pathway by cyplopaminereduces the CD133+/CD15+ cell compartment and the in vitrotumorigenic capability of neuroblastoma cells.

Cell Phone Study Was Flawed, Say Some Experts by Roxanne Nelson Medscape Oncology News.

The JNCI Study by Aydin et al on Risk of Childhood Brain Cancer from Cellphone Use Reveals Serious Health Problems, Environmental Health Trust.

N Engl J Med. 2010 Nov 4;363(19):1812-21. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas.

FDA Approves Brentuximab for Two Lymphomas By: ELIZABETH MECHCATIE, Oncology Report Digital Network.

Clin Cancer Res. 2011 Oct 15;17(20):6428-36. Brentuximab Vedotin (SGN-35).

FDA Approves Vemurafenib for Advanced Melanoma. By: JANE SALODOF MACNEIL,  Oncology Report Digital Network.

N Engl J Med. 2011 Jun 30;364(26):2507-16. Improved survival with vemurafenib in melanoma with BRAFV600E mutation.

N Engl J Med. 2011 Jun 30;364(26):2547-8. Been there, not done that–melanoma in the age of molecular therapy.

Biochem J. 2011 Aug 15. Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.

N Engl J Med. 2010 Oct 28;363(18):1693-703. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

Nature. 2007 Aug 2;448(7153):561-6. Epub 2007 Jul 11. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

Science. 1994 Mar 4;263(5151):1281-4. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma.

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This Week in Pediatric Oncology Episode 18

Host Dr Tim Cripe and co-host Dr Lionel Chow welcome special guest Dr Jeff Toretsky on TWiPO to discuss his clinical and research interest in Ewing’s sarcoma. Dr Toretsky explains the challenges of developing a clinical grade drug from a small molecule for a specific target such as EWS-FLI1. The small market for a disease like Ewing’s creates formidable hurdles for researchers, yet Dr Toretsky is driven on by the question “If I don’t do this, who will?” (17:54 mins)

Dr Jeff Toretsky is Professor of Oncology and Pediatrics at Georgetown University. He graduated with BS in Biochemistry from University of Wisconsin, Madison, WI, and recieved his MD from University of Minnesota, Minneapolis, MN. He completed fellowship training at the NCI Pediatric Branch.

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They were invited to present on opposite sides of the question:

Are randomized clinical trials ethical for children with cancer? 

Presented by Mooki Salzman, mom to Toby Pannone, at the annual meeting of the American Society of Bioethics and Humanities in Minneapolis, Minnesota on October 14, 2011. Mooki debated the ethics of phase III clinical trials in pediatric cancer research with her brother Dr Yoram Unguru, Attending Physician/Faculty Member, Division of Pediatric Hematology/Oncology at Herman and Walter Samuelson Children’s Hospital at Sinai, and Associate Faculty, Johns Hopkins Berman Institute of Bioethics.  Dr. Unguru argued to defend the ethical use of phase III clinical trials in pediatric oncology clinical research. He serves as an ethics committee and IRB member and is a member of the Children’s Oncology Group, Committee on Bioethics, and the American Academy of Pediatrics section on Bioethics.

Mooki extends special thanks to her brother Dr Yoram Unguru, Donna Ludwinski, Carie Carter, Pat Lacey and most of all to John London, who started it all with his heartwrenching words and compelling argument.

Who Shall Live and Who Shall Die?

It’s a provocative question, one with Old Testament roots and an attendant seriousness. It’s a question with wide application in ethical discourse.

And although it may be uncomfortable and perhaps sensationalistic, it is a question that we cannot ignore. Certainly in the world of pediatric cancer, “who shall live and who shall die” has very real meaning. For me, since my son Toby was diagnosed with stage IV neuroblastoma, the question “who shall live and who shall die” has become a constant backdrop to daily life.

Neuroblastoma is the most common solid tumor cancer in infants. The median age at diagnosis is 2 years old. At diagnosis, more than half of neuroblastoma patients have disease that has already metastasized to other parts of the body. Children with high-risk disease undergo aggressive high-dose chemotherapy, radiation, surgery, stem cell transplant, differentiation therapy, and antibody therapy. Even after this intense treatment, only 30% survive. If a patient relapses or stops responding to therapy, neuroblastoma is usually viewed as a terminal illness with less than a 10% chance of survival. For those that do survive, the late effects are significant: hearing loss, neurocognitive problems, sterility and secondary cancers.

Since my son was diagnosed in 2007 I have watched helplessly as child after child has died an often agonizing and prolonged death. Neuroblastoma parents describe the death of their children like this: “I’m literally seeing disease erupt all over his body, extraordinarily painful bone mets, fractured bones from disease, organ failure, breathing difficulty, seizures, paralysis, blindness.“ These families face the unthinkable.

In the blink of an eye, we have said goodbye to Liam and Evan, to Lucas, Penelope, Max, Erik, Sam, Erin and so many others that I could burn through my allotted time by reading their names. I think about these children every day. I try not to question their deaths, out of fear that I won’t be able to find my way back to sanity. So instead I remember their vibrancy, their beauty, their quintessential child-ness.

But in the dark hours, I ask why did Liam die? Why does Toby live? It is a terrible question. The randomness howls. And the world spins madly on.

*****

In March 2009, the Children’s Oncology Group released a statement halting the phase 3 trial of ANBL0032, a randomized study of chimeric antibody 14.18 in high risk neuroblastoma. Preliminary results of the phase 3 trial showed a significant increase in survival among those patients who received the antibody, as compared with those who didn’t. Not only was the trial stopped prematurely, but COG also stated that ch14.18 immunotherapy should become a standard part of upfront nb treatment.

The neuroblastoma world is not used to hearing good news. As a reminder, children diagnosed with high-risk disease have a 2 in 3 chance of DYING. So a trial that shows a 20% increase in survival is almost beyond belief.

This is what Dr. John Maris, Chief of the Oncology Division at Children’s Hospital of Philadelphia said about ANBL0032:

“The last clinical trial that showed a new treatment improving outcome in neuroblastoma was published in 1999, which means the study ended in about 1996. That was the one that showed that transplant helped and that Accutane helped, so it’s been a long time.”

But elation quickly turned to unease, as it became clear that ANBL0032 was a randomized trial that started accruing patients almost 8 years earlier, in October 2001. By the time of its halting, over 200 children had been accrued, ½ randomized to receive the antibody and the other ½ not.

Toby was not part of this trial. As a patient at Memorial Sloan-Kettering he, like every child treated there for the last 20 years, received a mouse-derived antibody as part of upfront treatment.

Before I go any further, I want to point out that I am a believer in research. Research has allowed my child to receive the best available treatment and it is important to understand that most neuroblastoma families gratefully sign their children up for trials, because the prognosis otherwise is so poor. In fact, virtually all children treated for neuroblastoma, both high and low-risk, are enrolled on a clinical trial. The cancer is ruthless and research offers a chance at new agents and therapies. I cannot relay how many times parents confess that they just need to keep their children alive until the next trial opens. String together enough trials and maybe you can buy another year or two for your child.

So back to ANBL0032: I, like many others, found myself asking if it was truly necessary to do a phase 3 randomized trial when the phase 1 and 2 data demonstrated that antibody was substantially better than anything we had seen before in the treatment of high-risk neuroblastoma.

More than 30 preclinical and early phase studies on this antibody were completed before ANBL0032 even started. If children were knowingly randomized to the non-antibody arm that was thought to be inferior, the trial was unethical. And more importantly, lives, children’s lives, were sacrificed.

Listen to John London, whose daughter Penelope was randomized to the non-antibody arm:

“I have to say how unethical it is to have designed a trial where 1) the average age of diagnosis is 2; 2) the survival rate for high risk is around 30%; and 3) the survival rate for relapse is below 10% AND then take a potentially promising agent and DISALLOW 50% of these children to receive it. All in the name of “perfect science”. My daughter was one of the children who was turned away. Would it have saved her? Who knows? But I sure would have liked the chance to see. Can you imagine if one of the scientists/researchers/clinicians/protocol designers for ANBL0032 had a child with high risk NB who was denied a potentially promising agent? Randomized studies in High Risk Stage 4 NB sacrifice too many children in the name of science and it needs to change.” 

Not all trials need to be randomized. Many in the medical community say that randomization is necessary to determine the best treatment and that improved survival in pediatric cancer is due to randomized trials. I would counter that increased survival is due to researchers using strong early phase evidence in choosing new treatment to test against old treatment. They are really good at this. Furthermore, if randomization provides better outcomes, why have changes to induction, radiation therapy and use of growth factors NOT been tested in RCTs? And if RCTs supposedly provide “proof” that one treatment is better than another, why is Memorial Sloan-Kettering not doing transplants when this was supposedly proven by 3 separate RCTs? And why is COG not doing rapid induction, as recommended by the International Society of Paediatric Oncology in Europe?

Earlier this year, the New York Times published an acclaimed series of articles on clinical trials in the treatment of melanoma. Many clinicians and researchers have said that the science behind the new drugs has eclipsed the old rules, and ethics, of testing them.

Dr. Charles Sawyers, chairman of human oncology at MSK on melanoma: “With these drugs (in development) that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, “Look, our system has to change.’”

To that point, if the odds of NB are already so abysmal, why not allow a promising agent to be used for all children? A different trial design could have built on previous knowledge. Perhaps results could have been compared historically to other studies. Perhaps children could have been allowed to cross-over. Either way it is clear that children did not need to be sacrificed to show that antibody is an effective treatment.

Dr. Richard Pazdur, director of the cancer drug office at the FDA has said, “new drugs in development, especially for intractable cancers, might require individual evaluation: This is an unprecendented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion.”

The blunt truth is that we cannot control whether our child is diagnosed with cancer. WE do not determine when we live and when we die.

BUT we CAN control what treatment we provide. And where we have the opportunity to offer an increased chance at survival, we have the obligation to do so.

A society is defined by how it treats its most powerless and vulnerable members. We cannot turn a blind eye to injustice. As Abraham Joshua Heschel said, “To accept passively an unjust system is to cooperate with that system.” Yes, I say this to you as the parent of a child with cancer, but we are also fellow human beings. I urge you to search inside, locate our common humanity and give ALL our children a chance at life.

.
******

I am able to stand here today in large part thanks to the support and smarts of my brother, who is sitting right there. His care and advocacy during the past 4 years of treatment have been nothing short of incredible.

It’s not often that a brother and sister find themselves on the front lines of a cancer diagnosis, occupying opposite yet congruent sides of what some term the research/care divide. I believe that with Toby’s diagnosis, brother and sister have been able to transcend our respective boundaries. Certainly in the case of ANBL0032, I hope we are on the same side.

Toby has been the beneficiary of the dedication and care of a team of incredible doctors and nurses at multiple institutions. As a parent, I cope with one child who has cancer. Our doctors and NPs cope with the pain of hundreds of children every day. I want to thank them. They have chosen to face death, yet they engage with life. They care enough about our children to embrace hope, and through their work they affirm that people can change.

Thank you for giving me the opportunity to share my thoughts. I am grateful to be here in your company. I would also like to thank Donna Ludwinski, mother to Erik. She is the force behind my words. Her vast knowledge, pinpoint clarity and graceful support to the neuroblastoma community deserve unending recognition.

Thank you.

This Week in Pediatric Oncology Episode 17

Host Dr Tim Cripe and co-hosts Dr Lars Wagner and Dr Lionel Chow welcome guest Dr Giselle Sholler on this episode of TWiPO. Dr Sholler gives the background to her current research interest in neuroblastoma, and describes her nifurtimox trials and how she formed the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC). The physicians also discuss the specifics of the personalized medicine feasibility trial now open for neuroblastoma.

Dr. Sholler is a Pediatric Oncologist with Spectrum Health Medical Group, Helen DeVos Childrens Hospital, and directs the Pediatric Oncology Therapeutic Discovery Clinic. She is also Co-Director of the VARI/TGen Pediatric Oncology Research Program, and Associate Professor of the Neuroblastoma Translational Research Laboratory at Van Andel Research Institute. She has a faculty appointment within Michigan State University’s College of Human Medicine, and continues as adjunct faculty at University of Vermont. Dr Sholler is also a Guest Researcher in the Pediatric Oncology Branch at the NCI.

References:

J Clin Oncol. 2010 Nov 20;28(33):4877-83. Epub 2010 Oct 4. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers.

Science 16 Sept 2011: Vol. 333 no. 6049 pp. 1569-1571. Pushing the Envelope in Neuroblastoma Therapy

Mol Cancer Ther August 2011 10; 1311. A Pilot Clinical Study of Treatment Guided by Personalized Tumorgrafts in Patients with Advanced Cancer

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This Week in Pediatric Oncology Episode 16

Dr Tim Cripe and co-hosts Dr Lionel Chow and Dr Lars Wagner welcome special guest Dr Stephen Lessnick for an in-depth discussion on the progress to date in understanding the genetics of Ewing’s sarcoma. The challenges of interpreting the gene expression data as well as the ethics of collecting tumor specimens for research purposes are also explored.

Dr. Stephen Lessnick is a Professor of Pediatrics and Oncological Sciences at the University of Utah, where he also serves as an Attending Physician in Pediatric Hematology/Oncology at Primary Children’s Medical Center in Salt Lake City, UT. He received his PhD in Molecular Biology from UCLA in 1994, and his MD from UCLA in 1996, followed by a residency at Children’s Hospital in Boston, and a fellowship at the Dana-Farber Cancer Institute and Children’s Hospital.  Currently, Dr. Lessnick is the Director of the Center for Children’s Cancer Research at Huntsman Cancer Institute, a Jon and Karen Huntsman Presidential Professor in Cancer Research at the University of Utah, and is the Vice Chair for Biology of the Bone Tumor Committee in the Children’s Oncology Group.

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This Week in Pediatric Oncology Episode 15

Join host Dr Tim Cripe with his co-hosts  Drs Jim Geller, Lionel Chow, and Lars Wagner in a robust discussion with special guest Dr Kathryn Wikenheiser-Brokamp on the implications of DICER1, rare tumor registries, and difficult issues surrounding genetic counseling.

Kathryn A. Wikenheiser-Brokamp, MD, PhD, is an Associate Professor in Pathology and Pulmonary Biology at Cincinnati Children’s Hospital Medical Center. Her research is focused on pediatric and adult lung diseases, including cancer. She seeks to determine the molecular mechanisms underlying Rb/p16, p53, and Dicer1 pathway function in lung development and the pathogenesis of lung disease. Dr Wikenheiser-Brokamp holds a PhD in Developmental Biology, Developmental Biology and an MD from University of Cincinnati.

Papers discussed:

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet. 2011 Apr;48(4):273-8.

Extending the Phenotypes Associated with DICER1 Mutations. Hum Mutat. 2011 Aug 31. doi: 10.1002/humu.21600.

Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol. 2011 Aug;122(2):246-50.

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by Caryn Franca and Shirley Staples

It was summer of 2007.  A group of parents had asked Dr. Nai-Kong Cheung to meet and update them on new treatments for neuroblastoma at Memorial Sloan-Kettering Cancer Center.  Most had children with relapsed neuroblastoma; all knew the terrible odds.  Dr. Cheung, head of the neuroblastoma program at MSKCC, and a long-time proponent of antibody therapy, met with the group at Ronald McDonald House.  After the presentation, one dad posed a question.  “What,” he asked, “do you need, to give our children more treatment options?”   “Money” was the simple, yet daunting answer.

Dr. Cheung then described an important research goal—the development of a new, humanized form of the 3F8 antibody that had been used since 1986 to treat neuroblastoma at MSKCC.  Researchers believed the new version, “Hu3F8,” had the potential to be many times more effective in fighting neuroblastoma, but Dr. Cheung estimated that $2-3 million dollars would be needed to fund the development of the drug.  After the meeting, parents excitedly discussed this revelation. The consensus was that they could and would do whatever was necessary to make hu3F8 treatment a reality.  A crusade was born.

Within a matter of days, an online group had been created and parents had begun brainstorming.  The name of the new parent group came from a California dad:  the “Band of Parents.”  One group of parents began the discussions and eventually the legal steps to form a tax-exempt foundation. Seven dads began planning to bike across the United States to raise funds and awareness–a ride they called “The Loneliest Road” to reflect the daily challenges facing neuroblastoma families. Ultimately they raised over $200,000 for hu3F8. Soon there were 60 families in the “BOP,” and the energy was palpable, from garage and jewelry sales, to writing fundraising letters to friends, to telling individual stories to local newspaper reporters.

Donations began to pour in, some from as far away as the Middle East.  As December approached, a New York City mom conceived the idea of a massive bake sale of holiday cookies.  Over several weeks, parents, friends, and volunteers from the culinary world baked, packaged and shipped 96,000 cookies from a small rented kitchen, raising several hundred thousand dollars. A few months later, families in Virginia banded together to organize the “Rock’n for a Cure.”  Band of Parent funds were mounting.

The efforts that followed were too many and varied to detail, but the key phrase is “banded together” – parents of children with neuroblastoma, along with family, friends and perfect strangers, came together to raise the funds needed to create a new treatment option for children with neuroblastoma.  Great personal determination was required.  As the months passed, many Band of Parents members lost their child to neuroblastoma – including the parent who coined the name “Band of Parents,” the mother who conceived the cookie bake-off, three of the bikers on The Loneliest Road, and the first three presidents of the BOP.  However, parents pushed forward despite the grief and loss felt by all in the group.  Golf tournaments, yard sales, and concerts were organized, sometimes from hospital bedsides; holiday decorations, tee-shirts, and greeting cards were designed and sold.  Last but not least, the dedicated neuroblastoma team at MSKCC cleared the regulatory and many other hurdles to taking a new drug from the laboratory to the clinic.

In August 2011 the day finally arrived that so many had worked for and dreamed of.  A new phase 1 trial of hu3F8, a drug specifically designed for the treatment of neuroblastoma, opened at Memorial Sloan-Kettering, and the very first child received the promising new treatment. Ordinary people had accomplished an extraordinary labor of love. For all those involved, this will be remembered as a time when it was shown that, by banding together, a group of parents could give new hope in the battle against an aggressive childhood cancer.  Today, the members of the Band of Parents are still working to raise awareness and funding for research, so that someday no child will suffer from the terrible disease of neuroblastoma.

Editors note: the trial opened in August 2011 and is listed here: http://clinicaltrials.gov/ct2/show/NCT01419834

The trial allows for relapsed or refractory NB with evidence of disease, and is given without cytokines IL2 or GM-CSF.

This Week in Pediatric Oncology Episode 14

In this enlightening interview with Dr Kate Matthay, a reknown leader in the neuroblastoma research community, host Dr Tim Cripe draws out the inspiration for her early interest in medicine and why her career grew with a focus on neuroblastoma. Dr Matthay explains the history and challenges of clinical research for neuroblastoma:

10:00 challenges in planning and conducting the CCG-3891 double randomized trial questioning the need for transplant and cis-retinoic acid

15:00 discussion of the COG-A3973 trial questioning the need for purged stem cells

15:50 rationale for the COG-ANBL0532 single versus tandem transplant trial

16:13 discussion of the COG-ANBL0032 ch14.18 with cytokines trial

18:00 MIBG COG pilot trial

22:00 work with SIOP and NB protocol development for children in Morocco (N Africa)

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This Week in Pediatric Oncology Episode 13

Host Dr Tim Cripe and co-hosts Dr Lionel Chow and Dr Jim Geller discuss updates to previous TWiPO episodes reporting on recent press coverage and publications of BiTE antibodies and modified T-cell approaches, and then discuss recent studies on birth defects, birth order, and cell phone use and possible link to risk of childhood cancers.

N Engl J Med. 2011 Aug 10. Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia.

Sci Transl Med 10 August 2011:  T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia; Vol. 3, Issue 95, p. 95ra73.

07:40 Decitabine upregulation of NY-ESO-1 and MAGE family expression in NB. Cancer Immunol Immunother. 2011 May 28. MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing Bao L, Dunham K, Lucas K.

09:50 Discussion of Rosenberg paper on immunotherapy in solid tumors; Nat Rev Clin Oncol. 2011 Aug 2.  Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. Rosenberg SA

13:00 Birth anomolies in CNS pediatric tumors, Pediatrics. 2011 Aug 8

29:00 Absolute risk is small; will this lead to genome-wide association studies?

31:51 Birth order and risk of pediatric cancers, Int J Cancer. 2011 Jun 1;128(11):2709-16

42:30 Mobile phone use and incidence of pediatric CNS tumors. J Natl Cancer Inst. 2011 Aug 17;103(16):1264-76. Epub 2011 Jul 27.

46:47 Listener question about elapsed time from planning clinical trials to opening.

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This trial will enroll 6 patients at 2 dose levels for IL2 given with fixed dose of zoledronic acid. Zoledronic acid will be given IV once every 3 weeks, and daily subcutaneous IL2 given weekdays for 2 weeks.

Patients must have evidence of disease and have not received prior antibody therapy with IL2.

See NIH listing for rationale:

To further explore means of harnessing the immune system to attack NB, the investigators are studying the combination of zoledronic acid (ZOL) and interleukin-2 (IL-2). ZOL has been demonstrated to have direct anti-neuroblastoma effects in laboratory studies. ZOL also augments the production of tumor killing white blood cells called gamma-delta T cells. When used in combination with IL-2, ZOL is capable of eliciting potent anti-cancer effects in patients, in part, via the expansion of gamma-delta T cells. In this present trial the investigators aim to study the tolerability of the combination of ZOL and IL-2 in pediatric NB patients. Patients will also be monitored radiologically for tumor response to therapy. Correlative biological studies will study the ability of this drug combination to elicit the production of NB killing gamma-delta T cells in children.

Joseph Pressey, MD
Assistant Professor of Pediatrics at University of Alabama at Birmingham, and Director, Experimental Therapeutics Program

Dr. Pressey is a graduate of the University of Georgia and the Medical College of Georgia. After completing his pediatric residency at the Children’s Hospital Medical Center in Cincinnati, he trained in pediatric hematology-oncology at the Children’s Hospital of Philadelphia.  Dr. Pressey’s primary clinical interest is in the treatment of pediatric solid tumors, with a particular focus on pediatric sarcomas.  He serves as UAB’s principal investigator for the Children’s Oncology Group Phase I developmental therapeutics program and the Sarcoma Alliance for Research Through Collaboration (SARC) consortium.  Through these organizations, Dr. Pressey is interested in providing patients with access to cutting edge therapies for all types of relapsed and refractory cancers.  Dr. Pressey’s primary research interest is the biology and treatment of sarcomas. Working with others at UAB, he is studying pediatric tumors with the intent of finding more effective and tolerable therapies.  

This Week in Pediatric Oncology Episode 12

Host Dr Tim Cripe and co-host Maureen O’Brien discuss recent papers on immunotherapy and DNA sequencing studies revealing new potential targets in acute lymphoblastic leukemia (ALL).

01:45 Results on use of BiTE antibody (Bi-specific T-cell engaging) blinatumomab in adults with lymphoma and leukemia:

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The SIOPEN trial now accruing in 20 countries in Europe randomizes children to the antibody ch14.18 alone or ch14.18 with subcutaneous IL2. Part of this trial was amended after the March 2009 release of the Children’s Oncology Group early results showing 2-year event free survival of 66% with ch14.18, IL2, and GM-CSF versus 46% in children who received no antibody treatment. Both groups received cis-retinoic acid (isotretinoin). SIOPEN began accruing in the fall of 2009.

GM-CSF (Leukine or Sargramostim, a cytokine acquired by Genzyme) is not available in Europe. Ch14.18 was used without cytokines in a German trial and not reported to improve survival in a 2004 study (non-randomized) “Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients.” In a 2011 publication, the German’s reported on long-term follow-up and  concluded that ch14.18 antibody therapy “may prevent late relapses.” In an April 2010 interview with Dr John Maris discussing the results of the COG trial, Dr Maris said: “for the cancer community in general, this is the first study to show that adding in the cytokines, the chemicals to rev up the immune system, are an important piece of the picture. Now, we didn’t study whether or not antibody alone, or if you need the GMCSF or the IL2 or both. We may never know that, but what we do know is that the whole package is effective, so now our obligation is to build on that, and our future clinical trials will take this result and try to improve upon that.”

The family of a child randomized to ch14.18 alone challenged the NHS trust and the court ruled that “it would be in her best interests to receive immunotherapy treatment that includes isotretinoin, anti-GD2 and IL2.”

The press release is below:

children’s cancer charity neuroblastoma alliance uk celebrates high court order against nhs trust

3 August 2011: The Neuroblastoma Children’s Cancer Alliance UK is today celebrating a High Court order that it is in the best interests of a child with neuroblastoma to receive a combination of immunotherapy drugs, if she withdraws from a clinical trial in which she had been randomly allocated to receive a single drug.

The Neuroblastoma Alliance UK, which was until recently known as the 2Simple Trust, helps families affected by neuroblastoma, an aggressive childhood cancer of the nervous system. The charity has supported the family during the legal case and has funded treatment for the child in the USA, as – despite the order – the NHS Trust, in the South of England, said it was unable to confirm it could provide the drugs in the UK to the mother.

“We are over the moon about this judgement. While we welcome further research, the interests of today’s children must come first. This mother was not prepared to accept the status quo and fought for her child to receive the drugs in the UK. We’re delighted she won this order and her hard work in taking this matter to court is likely to help many more parents in the future,” said Alison Moy, Chief Executive of the Neuroblastoma Alliance UK.

Anne-Marie Irwin, a solicitor at Irwin Mitchell, who helped the mother bring her case to the High Court said: “It was a hard fought battle to achieve this significant legal step for our client. Even though this order is too late for many, including the family of the claimant who have been forced to move to the USA so that their daughter has the best chance of survival, it is a step in the right direction for families who want their children to receive the best available treatment in the UK.”

The four-year-old child – known as CB* – suffers from high risk neuroblastoma, an advanced form of the cancer that has a very poor prognosis. The child is in the final stage of neuroblastoma treatment, known as immunotherapy. In the UK, immunotherapy treatment is only available to children that enrol onto a randomised trial, where they are randomly allocated either one or two drugs by a computer based in Austria*².

Last year, a study published in the New England Medical Journal in America, reported that giving children three drugs*³ – including two of the drugs being tested in the UK trial – during immunotherapy resulted in a 20 percent lower relapse rate and an 11 percent higher survival rate over a two year period.

When the mother heard in June that her child had been allocated to receive only one of the two drugs available in the UK, she decided to take her NHS Trust to court.

“When I heard that a computer had randomly selected my child to receive one of the three drugs that American scientists have shown can save a child’s life, I decided to take action,” said the mother. “Given that American scientists have already proven the effects of the three drugs in a clinical trial, why do UK doctors need to continue experimenting on children? I didn’t want my little girl to be part of this experiment.”

On 23 July, High Court judge Mr Justice Ryder ordered*⁴ that if the child withdrew from the clinical trial, it would be in her best interests to receive both drugs. This interim order opens the way for other neuroblastoma sufferers, who have only been allocated one drug in the trial, to challenge the decision.

The NHS Trust resisted CB’s application and has not yet confirmed that it would provide the drugs to the mother outside the trial. On the 22 July, the family travelled to the US, where CB started immunotherapy treatment on 25 July. The Neuroblastoma Alliance has funded the child’s treatment from the charity’s reserves. The treatment is expected to cost between $300,000-$400,000 (approximately £185,000-£245,000).

The mother plans to continue her legal battle against the NHS Trust, and hopes that all three immunotherapy drugs will be made available to UK neuroblastoma patients in the future.

“We were left with no choice but to take her to the USA, and I am just extremely grateful to the Neuroblastoma Alliance UK for helping us to fund the treatment,” she said. “I only hope that this court action paves the way for other families to receive the best possible cancer drug treatment for their children without having to travel abroad.”

The order was also welcomed by many of the other families that the Neuroblastoma Alliance UK supports, including John Rogers and Allison Hyde, whose three-year-old daughter Stella received treatment for neuroblastoma in the US last year.

“Until this legal action, parents were forced to accept the treatment they were offered in the randomised trial – even if the alternative treatment might offer better prospects for their child,” said John. “This court order is putting the interests of children before research – the lives of children shouldn’t come secondary to research.”

There are a number of other families in a similar situation and it may also be in their best interests to receive both drugs.

Notes 

* The child, the mother and the Trust are anonymous in this release on order of the court, which said the child should be known as “CB”, the mother as “SB” and the Trust as “S Trust”.

*² Neuroblastoma sufferers taking part in the SIOPEN trial (a neuroblastoma immunotherapy trial taking place in the UK and Europe) are offered either anti-GD2 (an antibody) or anti-GD2 and IL2 (a cytokine).

*³ The study carried out by the Child Oncology Group (COG) in US, Canada and Australia gave one set of patients standard neuroblastoma therapy of isotretinoin, and the other set of patients a combination of three drugs: anti-GD2, IL2 and GM-CSF (another type of cytokine).

The trial found that children receiving the immunotherapy treatment (anti-GD2, IL2 and GM-CSF) had an increased event-free survival rate (66% vs. 46% for standard therapy) and an increased overall survival rate (86% vs. 75% for standard therapy) over two years.

The study was published in the New England Medical Journal in September 2010. http://www.nejm.org/doi/full/10.1056/NEJMoa0911123

*⁴ The exact court order is as follows:

“IT IS DECLARED ON AN INTERIM BASIS THAT

1.         In the event that the Claimant withdraws from the current clinical trial at the <hospital name>, it would be in her best interests to receive immunotherapy treatment that includes isotretinoin, anti-GD2 and IL2″

The hospital name has been removed, in accordance with the judge’s order that the family and Trust are to remain anonymous.

http://www.childrenscancer.org.uk/latest-news/children-s-cancer-charity-neuroblastoma-alliance-uk-celebrates-high-court-order-against-nhs-trust.php

This Week in Pediatric Oncology Episode 11

SIOP’s BuMel results discussed, implications for COG

In this eleventh episode of “This Week in Pediatric Oncology” hosts Dr Tim Cripe and Dr Lars Wagner discuss with guest Dr Brian Weiss (Cincinnati Children’s Hospital) the implications of the recent results comparing two chemotherapy combinations for transplant regimens in children with high-risk neuroblastoma in Europe. The BuMel (busulfan, melphalan) regimen resulted in better survival and lower toxicity than CEM (carboplatin, etoposide, melphalan), a regimen used for transplant in the COG for a decade.

This SIOP trial was one of the plenary presentations at ASCO in June 2011.  In this lively and informative discussion, Dr Brian Weiss explains the COG response to these results due to the difference in induction regimens. The BuMel regimen will be used in the upcoming MIBG frontline pilot that Dr Weiss is leading as principal investigator.

Dr Weiss and TWiPO hosts also discussed the recent paper Safety and efficacy of tandem (131) I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma authored by Johnson et al in Pediatr Blood Cancer. 2011 Apr 14.

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This Week in Pediatric Oncology Episode 10

Top neuroblastoma researcher discusses career, advances in research

Host Dr Tim Cripe interviews Dr Robert Seeger from CHLA (Children’s Hospital of Los Angeles) about his contributions to improvements in treating neuroblastoma as well as his vision for future advances.

Dr Seeger’s career has been remarkable in that he began with an interest in immunotherapy and neuroblastoma as an intriguing model for this approach, and has consequently been involved in every major advance in treating neuroblastoma, including the pivotal 1984 discovery of the first-ever amplification of an oncogene for any cancer – MYCN and the 1985 demonstration that MCYN could be used to predict survival. Authoring over 180 publications, Dr Seeger has made a significant contribution to every step toward developing better therapies for neuroblastoma, including induction therapy, myeloablative therapy, immunotherapy with anti-GD2 antibody and cytokines, maintenance therapy with retinoids, and most recently, work in tumor microenvironment and developing reproducible biomarkers for detecting minimal residual disease. At the beginning of Dr Seeger’s career, survival for high-risk neuroblastoma was abysmal at about 5%, and now survival is about 45%. Dr Seeger has been a leader in the NANT consortium (New Approaches to Neuroblastoma Therapy) and involved in planning the early phase clinical trials conducted by this 15-member consortium.

When questioned about current challenges in his research, Dr Seeger mentioned the increased regulatory burdens associated with developing new treatments, and also discussed the need for preclinical (mouse) models that are predictive and well-validated. Dr Seeger believes that improvements can be made in functional imaging, including developing pharmacodynamic markers to detect impact of therapy on tumor.

Dr Seeger is Professor and Division Head for Basic and Translational Research at Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles/USC School of Medicine in Los Angeles, CA. His research interests are neuroblastoma risk assessment by gene expression profiling at diagnosis; evaluating response to treatment by quantifying rare neuroblastoma cells in blood and bone marrow; immunotherapy of neuroblastoma (natural killer cells, anti-tumor antibodies, tumor associated macrophages). Dr Seeger is a reviewer for several high-impact oncology journals, and is a member of the COG NB steering committee. He earned his MD at Oregon Health Sciences University School of Medicine in Portland and completed pediatric internship and residency at the University of Minnesota Medical School in Minneapolis. Additionally, Dr Seeger obtained research fellowship training at the National Cancer Institute (NCI) and the ICRF Tumor Immunology Unit at University College London, UK.

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Looking back at the idea formulated in discussions with John Rogers and Graeme Tucker (see About) last June at the Advances in Neuroblastoma Research meeting, I see we have accomplished some of what we set out to do, and come up short in some areas.

Shortcomings and successes

It is harder to write quality, in-depth analysis of current research than I thought.  After ASCO 2010 I had over 70 pages of notes and spent countless hours viewing the virtual meeting presentations, but only managed to post on a few of the topics. Because it is so time-consuming to do literature searches of background publications for reference, the first year total of posts stands at only 61, which is only a little more than once per week. My goal was at least 3 posts per week.

Is there really that much happening in the neuroblastoma research world? You bet! PubMed shows neuroblastoma articles in the last 12 months tops 1260+ publications. That is 24 per week! That does not include interesting industry news, reports on presentations at meetings, or clinical trial openings.

Consequently we have a goal to pick up the pace for year 2. It would be wonderful to have guest writers contribute regularly. (Contact NB Globe if you or anyone you know would like to contribute an article!)

Even with infrequent posts, the response metrics shown by Google analytics has been very encouraging. In the 10.5 months Google analytics has been tracking visitors, there have been 15,740 unique visitors and 57,691 page views and over 50% arrive from search engines.  The US and Canada represent 73% of the visits and 18% are from Europe. Many of the domains of visitors are from universities and research institutions.

Hubspot has a free “website grader” that grades us poorly for the infrequent posts, and thinks the readability level is too high:

E. Readability Level: Advanced / Doctoral Degree

Really? I would love to have feedback on this — is the readability too high?

The opportunity to host the podcast by Dr Tim Cripe for Solving Kids’ Cancer is an exciting development and episode downloads now exceed 950x!

Meeting mania

Is it possible to attend too many meetings? Attended since June 2010:

• ASCO 2010 Chicago June
• ANR 2010 Stockholm June
• CNCF 2010 Chicago July
• FDA patient rep workshop DC Sept
• SIOP 2010 Boston Oct
• NANT 2011 Los Angeles Feb
• AACR 2011 Orlando April
• ASCO 2011 Chicago June

Travel was generously supported by partner foundations, my family, FDA, ASCO, and AACR. In fact, because of this site, I was able to get a press pass to AACR!

The rest of 2011 includes presentations invited to give at:

• UK NB parent meeting in London — on history of NB clinical trials and current research
• APHON (Association of Pediatric Hematology/Oncology Nurses) in Los Angeles — on parent decision making and expectations when enrolling children in phase I and phase II trials
• SIOP in Auckland —  on research news source for parents of children with neuroblastoma

An educational year

I have learned some interesting things along the way. Some information is repeated, repeatedly. I saw three presentations last year on MIBG and Curie scoring at three different meetings, and several variations on the ALK mutation, expression, and inhibition research. Repetition certainly helps me learn incrementally and cements the content in place!

I also found it was essential to explore the bigger picture of pediatric oncology with regard to drug development and regulation, clinical trial design and interpretation, overlap of research in other solid tumors informing different disease groups, bioethics, psycho-oncology, palliative care research, and so many other related topics because they have filled in the gaps of my understanding with my narrow focus on neuroblastoma. It has indeed been an intense education and I am looking forward to year 2.

Caution: good information is not enough

Ultimately, the children who suffer this dread disease are the focus and reason for this work. I believe this is a worthwhile endeavor.

But unfortunately, good information is not enough. Some parents, like me, have an insatiable desire to learn all there is to know about neuroblastoma and its treatment after their child is diagnosed. Sadly, this does not guarantee a good outcome.  A strong caution is offered here: find a medical team you trust.

Being an informed parent will enhance communication with your child’s oncologist and help you provide the best possible care for your child.  My own experience involved a difficult struggle with this issue.  Two years of no sleep after my son relapsed—staying up all hours reading and researching—I was a basket case fighting for his life and stressed to the limit. I was ultimately saved by another parent’s cautionary tale. Their doctor had gently warned them that if they never decided to trust a physician—and took full responsibility upon themselves—the consequences would be severe in blaming themselves if the outcome was not good.

This hit me like a ton of bricks.  I suddenly realized how unrealistic my endeavors and expectations were—I was not and never will be an oncologist. The conscious decision to trust our medical team was made at that moment.  I remained every bit as engaged in care and treatment decisions, of course, but I realized it was not up to me to save my son. We all did our very best. Because of this firm understanding I emphatically believe that my son had the best possible care, and therefore have no regrets.

This Week in Pediatric Oncology Episode 9

Chair of Children’s Oncology Group (COG) discusses career, drug development

Host Dr Tim Cripe of  ”This Week in Pediatric Oncology” podcast interviews Dr Peter Adamson, new COG Chair. Co-hosts for this episode are Dr Jim Geller, Dr Raj Nagarajan, and Dr Lionel Chow. This conversation includes Dr Adamson’s background and interest in pediatric oncology, and openly addresses the much-needed advances in drug development for pediatric tumors that are distinct from adult tumors. On the heels of the remarkable ch14.18 development story in neuroblastoma, Dr Adamson explains the need for a “virtual” drug company that consists of a public-private partnership to develop drugs in a similar narrow venue, which is underway.

References:

Making Better Drugs for Children with Cancer. Institute of Medicine Consensus Report. Peter C. Adamson, Susan L. Weiner, Joseph V. Simone, and Hellen Gelband, Editors. April 18, 2005

Background:

Dr Adamson was elected by principal investigators of more than 200 Children’s Oncology Group sites. COG includes more than 5,000 experts in childhood cancer at leading children’s hospitals, universities and cancer centers across North America, Australia, New Zealand and Europe.

In 1999 Dr. Adamson came to The Children’s Hospital of Philadelphia (CHOP) from the National Cancer Institute (NCI), and is the director of Clinical and Translational Research and chief of the Division of Clinical Pharmacology and Therapeutics at Children’s Hospital. He also is a professor of Pediatrics and Pharmacology at the University of Pennsylvania School of Medicine. He remains on the staff of Children’s Hospital and on the Penn faculty while serving as Children’s Oncology Group chair.

Dr. Adamson’s previous roles at COG include leading the 21-site phase 1 consortium. During the eight years that Dr. Adamson led this effort, the collaborating sites conducted more than 25 studies designed to test the safety of novel anticancer drugs.

Says Dr Adamson, “I hope to fully leverage the emerging discoveries being made at a rapid pace by transforming how research moves from the bench to the bedside in a very large collaboration.”

Dr. Adamson received his MD from Cornell University and completed his residency at CHOP in 1987. He then spent 10 years at the NCI where he finished his fellowship in Pediatric Hematology/Oncology and Biotechnology, and worked as an investigator and an attending physicians before returning to CHOP.

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An open meeting for parents to meet and discuss NB topics. Donna Ludwinski will present history of frontline NB treatment, relapse therapies, and current research in US and Europe. Other speakers TBD. See meeting poster for details: NB Parent Meeting London 23 July 2011

http://www.childrenscancer.org.uk/

http://j-a-c-k.org/

Travel supported by NCCA and J-A-C-K Foundation

This Week in Pediatric Oncology Episode 8

An oncolytic virus for a common childhood brain tumor

In this eighth episode of “This Week in Pediatric Oncology” podcast hosts Dr Tim Cripe, Dr Lars Wagner and Dr Lionel Chow discuss a recent publication by researchers at Baylor/Texas Children’s in Houston that shows remarkable results of Seneca Valley virus SVV-001 on orthotopic mouse models of medulloblastoma.

The TWiPO hosts raise many interesting points about this research and highlight the strengths as well as limitations of this work. This exciting research provides new evidence of promise for oncolytic virus therapy for childhood tumors.

For more information about oncolytic virus trials for pediatric cancers, see a recent webinar “Oncolytic Virotherapy for Pediatric Solid Tumors” presented by the principal investigators of five clinical trials in children and sponsored by Solving Kids’ Cancer.

The article discussed in this episode can be found here:

A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models. Yu L, Baxter PA, et al. Neuro Oncol. 2011 Jan;13(1):14-27. Epub 2010 Nov 12.

Another related article by the same group:

Treatment of invasive retinoblastoma in a murine model using an oncolytic picornavirus. Wadhwa L, Hurwitz MY, et al. Cancer Res. 2007 Nov 15;67(22):10653-6. [fulltext]

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Considering that neuroblastoma accounts for 7% of pediatric cancers, and pediatric cancers comprises only 1% of adult cancers (that is .07% of all cancers, and high-risk NB makes up only half that number), it is really quite remarkable when highlighted presentations at ASCO focus on neuroblastoma.  This is on the heels of the ch14.18 results which was also big news at ASCO in 2009.

The European SIOPEN trial accrued 1,577 high-risk children since 2002.  Only 43% of these children were randomized for transplant regimen. The randomization was stopped after review showed superiority of BuMel (busulfan + melphalan) over CEM (carboplatin + etoposide + melphalan) in survival. Toxicity was greater in CEM arm, although more VOD (veno-occlusive disease) was observed in BuMel arm.

Dr Julie Park presented data as discussant comparing outcomes with the COG CEM transplant regimen. Clearly BuMel is better than CEM after Rapid COJEC induction, but a question remains if this would be true for the COG induction, which is very different (21 day schedule vs 10 day schedule which presents a different toxicity profile, higher cisplatin use in SIOPEN and no carboplatin is used in COG induction).

This treatment is now standard in SIOP, and COG is incorporating BuMel in a pilot trial.

For more information, see “Can New Standard of Care in Neuroblastoma Be Used in the US?” by Medscape.

http://abstract.asco.org/AbstView_102_79897.html

Abstract:

Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS).

Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m² in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m²/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m²day or 4x200mg/m²/day*], melphalan [3x70mg/m²/day or 3x60mg/m²/day*. *reduced if GFR<100ml/min/1.73m²]). A minimum of 3x10E6 CD34/kgBW PBSC were requested. VOD prophylaxis included ursadiol, but not prophylactic defibrotide. Local control included surgery and radiotherapy of 21 Gy. A total of 598 patients were randomised (296 BuMel, 302 CEM). The median age at randomisation was 3 years (1-17.2) with a median follow up of 3 years.

Results: At the last analysis, the Peto rule of p<0.001 was met. A significant difference in EFS in favour of BuMel (3-years EFS 49% vs 33%) was observed as well as for overall survival (3-years OS 60% vs 48%, p=0.004). This difference was mainly related to the relapse and progression incidence, which was significantly (p<0.001) lower with BuMel (48% vs 60%). The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p=0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute MAT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%). Based on these results and following advice from the DMC, the randomisation was closed early.

Conclusions: BuMel was demonstrated to be superior to CEM and hence is recommended as standard treatment.

This Week in Pediatric Oncology Episode 7

Advances in Target Discovery and Drug Development in Pediatric Cancers

In this seventh episode of “This Week in Pediatric Oncology” TWiPO podcast, host Dr Tim Cripe interviews Dr E. Anders Kolb and Dr Andrew Napper from Nemours in Wilmington, Delaware.

This informative discussion covers the strategies, scope, and challenges of target discovery, drug development, and preclinical testing for pediatric cancers, a complex process that has been accelerated by high throughput screening technology that has only recently become available in academic settings.

Dr Kolb is the Director of Blood and Bone Marrow Transplantation at Alfred I. duPont Hospital for Children, and Head of the Cancer Therapeutics Laboratory at Nemours Biomedical Research. He is also a Principal Investigator in the Pediatric Preclinical Testing Program (PPTP), a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models.

Dr Andrew Napper joined the research team at the Nemours Center for Childhood Cancer Research (NCCCR) in 2009 to establish its High Throughput Screening and Drug Discovery Laboratory. Dr. Napper came to Nemours from the University of Pennsylvania, where he was the Director of High Throughput Screening for the Penn Center for Molecular Discovery, one of the original ten centers established as part of the National Institutes of Health’s Roadmap initiative to discover drugs for neglected diseases.

For more information on this program:

Lab Offer Hope for Kids with Cancer, Wilmington News Journal (8/24/09)

Academic screening goes high-throughput, Nature Methods 7, 787–792 (2010)

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June 3 – 7  I will be in Chicago with 30,000 oncologists and oncology-related professionals (and 350 patient advocates) for the American Society of Clinical Oncology (ASCO) annual meeting, easily the largest oncology meeting in the world. Over 4000 abstracts have been accepted and many different types of sessions are presented including Education, Special, Plenary, Oral Abstract, Clinical Science Symposia, Clinical Problems in Oncology, Posters Discussion, and Trials in progress posters. These sessions are described in more detail on the ASCO site:

http://chicago2011.asco.org/AbouttheMeeting/DescriptionsofSessionTypes.aspx

The sessions are grouped into Tracks, which makes planning easier for attendees. My focus will be on pediatric oncology and clinical trial design, along with close attention to promising clinical trial results in adult solid tumors which may signify promising agents in the near future for pediatric solid tumors.

Below is a short list of items of interest, and the full abstract is available by clicking on each title. I will be reporting on the meeting beginning next week.

Abstracts on neuroblastoma

• PARP-1 inhibitor MK-4827 in combination with radiation as a treatment strategy for metastatic neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• Phase I study of vincristine, irinotecan, and 131I-MIBG for patients with relapsed or refractory neuroblastoma: A New Approach toNeuroblastoma Therapy (NANT) study. | 2011 ASCO Annual Meeting Abstracts
• Toxicity of 131I-MIBG combined with high-dose chemotherapy in children with refractory neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• Can the well-credentialed neuroblastoma tumor antigen GD2 be exploited for T-cell-based immunotherapy of pediatric sarcomas? | 2011 ASCO Annual Meeting Abstracts
• A novel anti-GD2 monoclonal antibody (mAb), hu14.18K322A, in children with refractory or recurrent neuroblastoma: Early-phase evaluation. | 2011 ASCO Annual Meeting Abstracts
• Dosimetry, toxicity, and response in a phase IIa trial of no-carrier added iobenguane I-131 (nca-MIBG): A New Approach to NeuroblastomaTherapy (NANT) study. | 2011 ASCO Annual Meeting Abstracts
• Allogeneic transplantation for patients with high-risk or refractory neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• The prognostic value of semi-quantitative 123I mIBG scintigraphy at diagnosis in high-risk neuroblastoma: Validation of the SIOPEN score method. | 2011 ASCO Annual Meeting Abstracts
• Ototoxicity in children with high-risk neuroblastoma: Prevalence, risk factors, and concordance of grading scales—A report from the Children’s Oncology Group (COG). | 2011 ASCO Annual Meeting Abstracts
• Association of GSTP1 hypermethylation with reduced protein expression and its correlation with clinical stage in neuroblastoma. | 2011 ASCO Annual Meeting Abstracts
• Phase I trial of TPI 287 as a single agent and in combination with temozolomide (TMZ) in patients with refractory or recurrent neuroblastoma (NB) or medulloblastoma (MB). | 2011 ASCO Annual Meeting Abstracts
• Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial. | 2011 ASCO Annual Meeting Abstracts
• Stratification of patients with neuroblastoma for targeted ALK inhibitor therapy. | 2011 ASCO Annual Meeting Abstracts

Abstracts on pediatric solid tumors

• Cell cycle and apoptotic effects of PM00104 in pediatric cell lines and xenographs. | 2011 ASCO Annual Meeting Abstract
• Second malignant tumors in childhood cancer survivors. | 2011 ASCO Annual Meeting Abstracts
• A phase I study of ifosfamide, oxaliplatin, and etoposide (IOE) in pediatric patients with refractory solid tumors. | 2011 ASCO Annual Meeting Abstracts
• Melanoma as a subsequent neoplasm in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. | 2011 ASCO Annual Meeting Abstracts
• Characterization of novel potent and selective anaplastic lymphoma kinase (ALK) inhibitors. | 2011 ASCO Annual Meeting Abstracts
• A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: A Children’s Oncology Group study. | 2011 ASCO Annual Meeting Abstracts
• A comparison of safety and efficacy of cytotoxic versus molecularly targeted drugs in pediatric phase I solid tumor oncology trials. | 2011 ASCO Annual Meeting Abstracts
• Changes in incidence of infant cancer: Analysis of SEER data 1992-2007. | 2011 ASCO Annual Meeting Abstracts
• Randomized double-blind controlled trial (RCT) of pegfilgrastim as prophylactic therapy in pediatric patients with solid tumors during myelosuppressive chemotherapy. | 2011 ASCO Annual Meeting Abstracts
• Phase I study of pazopanib in children with relapsed or refractory solid tumors (ADVL0815): A Children’s Oncology Group Phase I Consortium Trial. | 2011 ASCO Annual Meeting Abstracts
• Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors. | 2011 ASCO Annual Meeting Abstracts
• A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies. | 2011 ASCO Annual Meeting Abstracts
• A phase I study of temsirolimus and valproic acid for refractory solid tumors in children. | 2011 ASCO Annual Meeting Abstracts
• Feasibility and pharmacokinetic study of potential ABCG2 inihibitor, gefitinib (GB), in combination with irinotecan (IRN) for adolescents and young adults (AYA). | 2011 ASCO Annual Meeting Abstracts
• Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors. | 2011 ASCO Annual Meeting Abstracts
• A phase I trial of IMC-A12 and temsirolimus in children with refractory solid tumors: A Children’s Oncology Group Study. | 2011 ASCO Annual Meeting Abstracts

This Week in Pediatric Oncology Episode 6

An icon in pediatric oncology: Dr Archie Bleyer interviewed on TWiPO

In this sixth episode of TWiPO, Dr Tim Cripe interviews Dr Archie Bleyer about his career and research interest in improving survival rates in adolescents and young adults (AYA) affected by cancer.

Dr Bleyer  is the Medical Director of , Clinical Research at St. Charles Cancer Care in Bend, Oregon and a Clinical Research Professor at Oregon Health & Sciences University in Portland. He also is a Professor of Pediatrics at The University of Texas Medical School at Houston and Senior Advisor of the Aflac/CureSearch Adolescent and Young Adult Cancer Research, and founding member of the LiveStrong Young Adult Alliance.

Dr. Bleyer chaired the Children’s Cancer Group for 10 years, then the world’s largest pediatric cancer research organization, and the Department and Division of Pediatrics at the University of Texas MD Anderson Cancer Center.  He was the American Cancer Society Professor of Clinical Oncology and in charge of the cancer curriculum in the University of Washington School of Medicine. During the past three decades, Dr. Bleyer was awarded research grants totaling more than $75 million as a principal investigator from the National Institutes of Health, the American Cancer Society, and the Leukemia Society of America. His research has been published in more than 300 peer-reviewed articles, chapters, and books.

This is an inspiring and enlightening discussion of the progress and challenges of the past 3 decades of treating children and young adults with cancer, and an optimistic view of future improvements in survival, quality of life, and reducing late effects in survivors.

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This Week in Pediatric Oncology Episode 5

Discussion of the role of hedgehog signaling and repositioning of drugs for pediatric cancers such as anti-fungal drug itraconazole

In this fifth episode, hosts Dr Tim Cripe and Dr Maureen O’Brien discuss the role of hedgehog signaling in diffuse intrinsic pontine glioma (DIPG) and the use of drugs designed for other uses — such as itraconazole, an anti-fungal drug found to suppress hedgehog signaling — as a possible treatment for medulloblastoma.

01:20 Feedback and comments on previous TWiPO episode.

02:58 Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma; (Full-text) Proc Natl Acad Sci U S A. 2011 March 15; 108(11): 4453–4458.

09:22 Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 2010 Apr 13;17(4):388-99.

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This Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) feasibility trial will accrue 14 patients.

http://clinicaltrials.gov/ct2/show/NCT01355679

Inclusion Criteria:

Read more about this trial here:

http://www.nmtrc.org/personalized-medicine/

This Week in Pediatric Oncology Episode 4

Oncolytic virus meeting, conference on DIPG, and promising targeted T-cell immunotherapy against sarcoma

In this fourth episode of TWiPO host Dr Tim Cripe and co-host Dr Jim Geller discuss updates after two recent meetings and then discuss an exciting paper just published on  ”Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1″ J Clin Oncol. 2011 Mar 1;29(7):917-24. Epub 2011 Jan 31 by Paul Robbins and colleagues at the NCI.

01:23 Conference on oncolytic viruses (see recent webinar on pediatric trials).

07:28 Conference on DIPG (Diffuse Intrinsic Pontine Glioma) at Cincinnati Children’s; discussion on biology, new tumor models, and genetic profiling.

12:50 Discussion on adoptive immunotherapy using tumor-infiltrating lymphocytes in patients with metastatic melanoma and synovial cell sarcoma.

28:28 Listener email questions and answers. Send emails to twipo@solvingkidscancer.org

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