A new trial opens: prolonged use of isotretinoin

Aflac ST1001 Prolonged Isotretinoin

C10 (p. 80) “Late effects in neuroblastoma”

Dr Lisa Diller (Boston Children’s/Dana-Farber Cancer Institute) reviewed recent published data on late effects and presented new data in the Neuroblastoma Update Course on June 21st, 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden. The session was organized by Sue Cohn and Andrew Pearson and chaired by Sue Cohn and Rani George.

The Childhood Cancer Survivor Study provided long-term survivorship data for those treated for neuroblastoma between 1970 and 1986, and results on 954 5-year survivors were published in Journal of the National Cancer Institute August 2009.[1]

Of the 954 children, 832 records were abstracted, and only about 10% were stage 4 survivors, so the vast majority (~90%) of the survivor data most likely represented low and intermediate risk survivors.  Only 38% of the survivors had surgery + chemotherapy + radiation.  Of all the survivors, at least 90% had 15 years of follow-up. Of 1358 there were 84 deaths (41 recurrences)  and higher risk of death if diagnosed over the age of 5 and had multimodal therapy. The children treated for neuroblastoma were compared to a cohort of 3899 siblings to determine if there was a higher incidence of health problems. There was a higher incidence of chronic health conditions involving the neurological, sensory, endocrine, and musculoskeletal systems in children treated for neuroblastoma.

Dr Diller also mentioned evidence from soon-to-be published institutional data that advanced bone age or epiphyseal closure is more common in children treated with cis-retinoic acid than children who did not have cis-retinoic acid. There is a theoretical toxicity proposed related to cis-retinoic acid given with anti-GD2 antibody (ch14.18) because of clearance issues, but this has yet to be verified.[2]

References

1. J Natl Cancer Inst. 2009 Aug 19;101(16):1131-40. Epub 2009 Jul 31. [fulltext]

2. ANR 2010 “Neuroblastoma Update Course” ANR 2010 Abstract Programme, p 80.

The 2010 ASCO meeting is in full swing.  Attending a meeting with more than 30,000 cancer specialists from around the world is an incredible experience and provides an unparalleled opportunity to learn about cancer. The organization, logistics, and technology displayed are absolutely mind boggling. The vast exhibitor hall has spectacular booths set up by every pharmaceutical company ever heard of. There are 350 patient advocates here–and the vast majority are focused on adult cancers. On my first shuttle ride to the conference I visited with a charming adult oncologist from Slovakia, on the return trip I chatted with a lovely young French-speaking oncologist from Montreal. The whole city of Chicago appears to be populated by oncologists!

To say the meeting is overwhelming is an understatement. I decided to purchase the Virtual Meeting as well so I can review the sessions I have heard, as well as see other presentations happening simultaneously. This means that there will be ample opportunity to carefully review the material and update this site with much more meaningful information over the next few weeks.

Day 1 and Day 2 consisted of the following presentations (termed Education Sessions).

Childhood Cancer Survivorship: Lessons Learned and Future Steps
Kevin C. Oeffinger, MD
~ Current guidelines for follow up of the survivors of pediatric cancers.
Current new areas of research including issues related to genetic
susceptibility to toxicities
Smita Bhatia, MD, MPH
~ Long-term psycho-social effects following the treatment of pediatric
cancers.
Christopher Recklitis, MPH, PhD
~ Discussion of the Childhood Cancer Survivor Study (CCSS)
Gregory T. Armstrong, MD, MSCE

Current Challenges for Cellular Therapies
~ When should immunablative therapies be considered in the treatment of
pediatric cancer?
John M. Cunningham, MBBS
~ Adoptive cellular therapies utilizing gene modified lymphocytes
Laurence Cooper, MD, PhD
~ The role of NK cells in transplant and the non-transplant scenario
Wing H. Leung, MD, PhD

The Expanding Role of Antibody-based Therapy in Children,
Adolescents, and Young Adults with Cancer
~ Progress in treatment of high-risk neuroblastoma with immunotherapy
Alice L. Yu, MD, PhD
~ Update on Immunotherapy Strategies in the Treatment of Lymphomas in
children, adolescents and young adults
Mitchell S. Cairo, MD
~ The efficacy of epitope-specific IGFR1 antibodies in therapy of pediatric,
adolescent and young adult solid tumors
Douglas Yee, MD

New Treatments for Sarcoma in Children, Adolescents, and Young Adults
~ Optimal approaches for achieving local control in children, adolescents, and
young adults with sarcoma
R. Lor Randall, MD, FACS
~ Optimal strategies for controlling metastatic disease in children,
adolescents, and young adults with sarcoma
Douglas S. Hawkins, MD
~ Treatment of childhood, adolescent, and young adult sarcoma. Where do
we go from here?
Stephen X. Skapek, MD

Last session today was a terrific presentation on how pediatric oncology clinical trials serve as a model for “comparative effectiveness research.” More on this later.

Brief comments on sessions so far:

Genetic predisposition for heart damage in some children

The most important finding shared about late effects was the genetic mutations discovered that predispose a child for cardiotoxicity from low-dose anthracyclines, and this is significant for NB parents because almost all NB kids get doxorubicin as part of induction. There is consideration now of testing children in future trials for the mutations, and if one is found, reducing or eliminating anthracyclines from frontline therapy, or using a cardioprotectant. Further information will be presented on this topic on Monday morning session.[1]

Reduced-intensity allogeneic transplants and NK and T cell therapies

The discussion on reduced intensity transplant was really interesting and I look forward to looking at the data more closely. Many studies in adults have been completed for different diseases, and most show lower toxicity and better survival. Tomorrow there is a poster presentation on a study from Italy in NB kids. I will follow up with data and referenced studies. There has been so much work on NK cell therapies it is very exciting to see the possibilities emerging for NB. If you do a search for NK cell therapies on the National Institutes of Health site (www.clinicaltrials.gov) there are more that 200 open trials for various cancers. Memorial Sloan-Kettering is currently accruing for their NK cell therapy trial, but this trial was not discussed in any detail. MD Anderson also has an open Phase II study using donor NK cells for those who relapse or are refractory after stem cell transplant. Several papers have been recently published and after reviewing them I can report more fully on this topic. It was encouraging to hear the discussant Dr Leung say that he sees NK cells as an ideal treatment after frontline induction and consolidation, before antibody treatment. He believes this could be the next big jump in survival for frontline therapy.[2]

Antibody update

Dr Yu gave an excellent presentation updating on all things anti-GD2. She reviewed the history of all antibodies for NB, and said that two humanized antibodies (hu14.18-IL2 and hu14.18K332A) and a new anti-iodiotype antibody 1A7 are all considered for future trials. The 1A7 is interesting because it works like a vaccine. Instead of injecting antibodies into a child, this antibody induces the production of antibodies against GD2 continuously. After the session I asked her about the supply of ch14.18. The supply is good for two years since NCI made two more “batches” and a manufacturer has committed to produce the ch14.18. Then we discussed the trouble in the UK with access to GM-CSF for use with the ch14.18 antibody, and she said that she was going to speak to the Genzyme representative since they recently “inherited” the drug. Later I went to talk to Genzyme too. Genzyme said that there are regulatory issues with the UK (not the US) that prohibit the importing of the drug. He said to tell families interested in working with their doctor to contact Idis (www.idispharma.com) because Idis is an expert in getting access to drugs. They developed a program called Named Patient Program (see http://idispharma.com/patients.php ) to help gain access to drugs blocked by regulatory hurdles. Another question I have though, and could not be answered yet, is will SIOP rewrite the protocol to include GM-CSF? Dr Yu mentioned they are currently using IL2 (subcutaneously). Perhaps this can be further clarified for us by the families in the UK who are on the SIOP trial. Another question I have is whether the access to GM-CSF affects the other countries in Europe.

1.  J Clin Oncol 28:7s, 2010 (suppl; abstr 9512)

2.  Leung, Wing. The Role of Natural Killer Cells in Transplant and the Nontransplant Scenario. ASCO 2010 Educational Book, p 377-381