Many therapies, robust rationale needed

For years I have (obsessively) tracked clinical trials and therapies available to children with relapsed and refractory neuroblastoma, driven by hope that curing relapsed NB is possible. Since there are many therapies for “unspecified solid tumors” as well as specifically for neuroblastoma, the resulting variety of trials is quite astounding.

I started tracking these trials for possibilities for my son, discussing with other astute parents, and watching and praying for responses in their children to new treatments. I searched for meeting abstracts for unpublished results, and scrutinized the published results of trials. Between the heterogeneity of the disease and the varied treatment paths of each child the comprehensive study of effective relapse therapies is nearly impossible.

A parent naturally wants to know what options are available when their child is fighting for survival–but far more critical is knowing which option to choose at a given point in time. Finding all the options is conceivable, but determining the best possible option is a completely different problem. The question “What is available?” is easy to answer. The question “What should we do?” is not easy to answer.

In part, this activity led to a bigger project. Several volunteers (about 30 in all) worked on a “NB Parent Handbook” during the period 2006 – 2008 for Children’s Neuroblastoma Cancer Foundation. The entire book (220 pages) can be found on the CNCF site at cncfhope.org. The project is ongoing–new chapters are being added and material is being updated. I am currently updating the relapse chapter.

My purpose in posting this update on relapse treatment is two-fold:

1 – draw attention to the Handbook project and attract more help

2 – generate some dialogue concerning the question of relapse therapy — is a “rational” approach even possible?

Approach to relapse therapy differs widely from one study group to another, and one institution to another. There are no firm rules or universal recommendations, although one study group has recently recommended a very general plan for NB relapse treatment using salvage chemotherapy and MIBG only.  Much depends on the experience of the treating oncologist, careful consideration of the child’s history and status, and trials that may be open and accruing at the local institution.

What makes this landscape so incredibly complex is that there are many options, but the options are spread far and wide. Once a parent begins to consider options at a distant facility, the close oversight of the oncologist most familiar with the child is often jeopardized, and the parents have to make choices based on limited information.

It is impossible to describe just how terrifying and overwhelming it is for a parent to walk away from a child’s trusted primary oncologist and the loyalty developed for the home hospital, into the unknown. An unintended but serious consequence is the risk of the parent assuming full responsibility for the outcome–especially when things do not go well.

“Of all the treatments available, what is best for my child at this point in time?”

Think about how difficult this is to answer. The primary oncologist has a limited set of treatments to offer, and limited experience with treatments that are not offered at the home hospital. This creates a difficulty for the parents when they look beyond the confines of the home hospital, and strive to understand the potential for treatments available elsewhere. What we need is an oncologist who is familiar with every treatment and intimately knows the patient, and can recommend the best course of action in a thoroughly objective manner. But the reality is — that is asking too much — no oncologist has the time to scrutinize 50 or 100 open trials in addition to many off-the-shelf therapies to determine the best fit for a particular child. There is no incentive to send patients away, either.

So what is the solution? Is there a solution? I don’t know. That is why I am asking for feedback.

The medical community recognizes that there is a role in this arena for patient advocates. However, the patient advocate role presents a grave quandary — the advocate may be trusted for lack of any agenda other than concern for a child’s life, but the patient advocate is not a doctor and not qualified to recommend any treatment decisions.

Your feedback, thoughts, ideas, concerns, and brainstorms are greatly appreciated. What if you had a comprehensive list of every treatment possible, right now. How would you chose the best treatment for a given situation? What would help you the most? What do you think?

An outline of the of the draft follows — see the CNCF website for the full chapter (pages 113- 123).

Dealing with Relapse — draft outline

(treatments discussed are being updated now)

Beginning Relapse Treatment.

Relapse Treatment Rationale

Your doctor will take into consideration many factors when recommending treatment for relapse:

• Age of child
• How long the child was in remission after treatment
• Where disease is located
• How much disease (tumor burden)
• Rate of tumor growth
• Prior treatment history
• Organ function
• Available stem cells
• Changing characteristics of the child’s NB, or new information
• Goals of treatment

Treatments for relapse vary in approach and intensity.

Can we know what will actually work against my child’s NB?

• High-dose chemo/radiation.
• Medium-dose chemo.
• Low-dose chemo.
• Targeted drugs (“small molecules”) and biologics.
• Immunological treatments – antibodies.
• Immunological treatments – vaccines and viruses.

Second remission treatment issues.

Special issues with late relapse.

Maximizing your child’s treatment options is an important part of the relapse decision process.

Weighing quality of life and other considerations.

Investigating doctors and clinical trials.

It is common for children to see one or more of the following treatment categories during the battle against relapse:

• Enrollment on phase I or II clinical trials. These may be specific to NB or for unspecified solid tumors. Phase III studies are rare for relapsed pediatric tumors including NB.
• Treatment “per” a clinical trial protocol although not enrolled, if not eligible and drugs are already FDA approved.
• Treatment with “off the shelf” agents that are FDA approved.
• Treatment on a “compassionate use” basis with drugs not yet FDA approved.

Phase I and Phase II distinctions.

Timing of entry.

Interpreting “response” from study reports.

Risks and benefits of treatment.

SUMMARY

The rigors of relapse treatment cannot be minimized. You may be consulting with new and different doctors, traveling far from home for your child’s treatment on various clinical trials, weighing difficult quality of life issues for your family, and at times making treatment decisions based on a leap of faith. An oncologist with experience in treating relapsed NB, and equally importantly, someone you feel comfortable with and can communicate with effectively, is the key resource in making your treatment decisions. However, the more informed you are, the more comfortable you will feel that you have made the best possible choices for your child.

There are successes in relapse situations.  Unfortunately, because the relapse population involves such variation in relapse sites, in amount of disease, types of treatments tried, multiple treatment centers, and many other variables, it is virtually impossible to report long-term survival statistics. Even so, the reports of long-term survivors in some studies, the increasing numbers and approaches of available treatments, and the anecdotal evidence — all suggest that the prospect for long survivorship after relapse is improving.  There is increasing hope for relapsed children, and having an NB team who expresses and shares your hope is also essential to this stage of the battle.

Paediatric Oncology in Developing Countries (PODC)

Opening Keynote Lecture: Cancer Survival Need Not Be Determined by Income: Lessons from Developing Countries and Focusing on Children ~ Felicia Knaul, United States

Dr Knaul’s talk was extremely eye-opening. She detailed cancer survival rates as a function of per capital income and health spending among developed, developing, and undeveloped countries. What was universally surprising was that the graphs were not at all linear or correlated as expected but rather looked like a scatter plot in each case. There was as much as a 50% spread in survival for the same middle expenditure levels, indicating that although the same resources exist to pay for cancer treatment, some countries perform much better than others. A 2008 BBC news article decried this fact in the UK, citing research on 2 million cancer patients worldwide published in The Lancet.[1]

Nevertheless, looking at the lowest expenditures in undeveloped countries, survival rates were dismal as expected. Elizabeth Van Dyne, a pediatric resident from LA wrote an excellent three part series for The Lancet Student on the PODC presentations (quote includes her original references): [2] [3] [4]

According to the World Health Organization, cancer is the leading cause of death worldwide; it kills more people than tuberculosis, malaria, or HIV/AIDS [1]. The number of annual deaths from cancer is projected to increase by 45% over the next two decades to reach 12 million by 2030 [1]. In 2005, 70% of those who died from cancer lived in middle- or low-income countries [1]. It is particularly difficult to treat cancer in these settings due to the overall lack of resources, which translates into poor diagnostic facilities and late diagnoses, poor pain control, inadequate supportive care, malnutrition, high rates of abandonment of treatment, and infection.

“No child should suffer.” “No child should die unnecessarily.” [2] The undeniable truths professed by Eden Tim on the last day of the SIOP’s 2010 Congress should guide us through strategic execution toward increased rates of cancer survival and effective palliative care. Currently however, whereas survival rates are approximately 75% in high-income countries, less than 20% of children with cancer in middle- or low-income countries typically survive [3]. Furthermore, many of the estimated 100,000 children who die without treatment also suffer without any palliative and analgesic care [3].

Nonetheless, there have been remarkable successes over the last 10 years. Endemic Burkitt lymphoma is treated in Malawi with 4 weeks of chemotherapy (cyclophosphamide and intrathecal methotrexate) that costs in total less than US$ 50, leading to a 48% cure rate [4]. The National Cancer Institute Columbia and Dana-Farber Cancer Institute/Children’s Hospital Boston have focused on having permanent social services, overnight doctor coverage and updated protocols with reduced intensity chemotherapy [6]. These measures dramatically decreased mortality rates during initial treatment [6]. In Recife, Brazil, the 5-year event-free survival rate for acute lymphoblastic leukemia has doubled from 32% to 63% [7].

After attending several presentations in the PODC track, I am left with two powerful impressions:

1.       70% of the world’s children with cancer receive either very substandard care or none at all.

2.       Impressive improvement in care and cures have resulted with training (“Twinning” programs matching hospitals in developed countries with Third World hospitals) using crude adaptations for care, and limited resources.

Nevertheless, a difficult ethical question must be addressed. Why spend limited resources on a “few” children with cancer if there are many children dying of malaria and malnutrition? The surprising answer was not so intuitive for me. Where the most rudimentary cancer care for children has been introduced, the level of basic care for children with other diseases has been dramatically improved. Local institutions are better supported by their governments, and they can attract funds from more sources when they begin to focus on the most curable cancers like Wilm’s tumor and ALL. It is a matter of great prestige for these institutions to be able to offer treatments (however basic) for children with cancer. I was surprised to learn in follow-up discussions with the Director of Outreach at St Jude’s, Dr Scott Howard, that most of the money raised to support newly established programs is raised locally.

In Malawi they measure response to chemo with a tape measure around the abdomen! But the nutritional status of all children in the region has been improved since local doctors have begun to tackle cancer. St Jude’s launched a twinning program where hospitals in US team up with a hospital in a developing country and they send nurses and pediatric oncologists back and forth for training and have weekly tumor boards via skype/teleconferences. Other countries are doing this as well – we heard about a Swedish hospital that teamed up with a hospital in Vietnam. Right now the educational resource cure4kids.org has 24,000 health professionals using it in 175 countries. They also set up a free database for registries to track diagnosis and survival called POND4kids.org. In North Africa a focus on neuroblastoma and retinoblastoma has been added to the study group. Dr Kate Matthay is a key participant in the French-African Pediatric Oncology Group, and she recently spent a year on sabbatical in France and North Africa developing protocols for neuroblastoma.

Twinning sites are shown in this slide (presentation by Dr Quintana at the UICC World Cancer Congress in Shenzhen, China, August 2010): [5]

In the 2009 report on activities of the International Outreach Program at St Jude’s tangible results in increased cure rates are detailed:

The mission of the International Outreach Program (IOP) at St. Jude Children’s Research Hospital is to improve the survival rate of children with cancer and other catastrophic diseases worldwide through the sharing of knowledge, technology and organizational skills. There are an estimated 160,000 newly diagnosed cases of childhood cancer worldwide each year, making cancer the leading cause of childhood death in developing regions of Asia, South and Central America, Africa and the Middle East. During the past 30 years, improvements in therapy have dramatically increased survival rates for children with cancer, yet more than 70 percent of the world’s children with cancer still do not have access to modern treatment. St. Jude strives to address the needs of children with cancer in countries that lack sufficient resources and to help these countries effectively manage their burden of cases. One of the key accomplishments of the IOP in 2009 was the inauguration of a new state-of-the-art children’s cancer center in Guatemala. The Unidad Nacional de Oncología Pediátrica (UNOP) in Guatemala City was opened at a cost of $4.1 million U.S. through the efforts of the local supporting foundation Ayúdame a Vivir, local government leaders, volunteers, local industry and the IOP. The new center provides 40 inpatient beds, more than doubling the previous capacity. The UNOP anticipates seeing approximately 300 new patients per year and will treat more than 100 patients each day in the outpatient clinic. Since the IOP partnership was initiated in 2000, the survival rate in Guatemala City has greatly improved from 28 percent to 75 percent. The achievement of the Guatemalan program is emblematic of the success that other IOP partner sites may achieve in the future. [6]

Since SIOP represents pediatric oncology worldwide, there was understandably widespread interest at the meeting in advances in care for 70% of the world’s children who do not reside in developed countries. A little goes a long way in these countries. One reason is that the pay for medical professionals and supportive staff is very low. For example, a social worker in India with a Master’s Degree in SW typically earns $250 per month. Treatments are very inexpensive. An allogeneic transplant costs $12,000 in Pakistan (now used primarily for thalassemia), $120,000 in Italy, and $360,000+ in the US.

To summarize, there was a sense of optimism about the efforts underway to improve care and save lives for the vast numbers of children who will benefit greatly from modest investments of time and resources from the resource-rich countries.

It reminds me of the story:

A little boy went out on a beach after a great storm. There were piles of starfish as far as the eye could see. The boy began throwing them back in the water, one by one, as fast as he could. A man standing on the dunes above saw the boy and perceived the futility of the boy’s efforts. He screamed to the boy below him on the shore: “THERE ARE TOO MANY! YOU’LL NEVER MAKE A DIFFERENCE!” and the boy yelled back as he threw another starfish in the ocean: “IT WILL … FOR THIS ONE!”

[2] Van Dyne E, Congress of the International Society of Paediatric Oncology Part 1: “No child should die of cancer!” Lancet Student, November 15, 2010 [link]

[3] Van Dyne E, Congress of the International Society of Pediatric Oncology Part 2: The Strategies and Successes of The “Incurable” Third World. Lancet Student, November 17, 2010 [link]

[4] Van Dyne E, Congress of the International Society of Paediatric Oncology Part 3: HIV-related Malignancies in Children. Lancet Student, November 18, 2010 [link]

5.  St. Jude Children’s Research Hospital International Outreach Program, presentation by Dr Quintana at the UICC World Cancer Congress, Shenzhen, China, August 19, 2010 [slides]

6. International Outreach Program Report of Activities 2009 [link]

Presentations with implications for neuroblastoma

Antiangiogentic agents

Rakesh Jain, Raghu Kalluri, and Marsha Moses talked about angiogenesis and why metastases are promoted when giving antiangiogenetic agents. The agents create hypoxia in the tumor and an interesting series of experiments they performed support the theory that hypoxia drives metastases. Candidate biomarkers have been proposed SDF1-alpha and receptor CXCR4 to help determine which patients may benefit from antiangiogenetic agents and who should not get these agents. In the second presentation they showed a model of how they induced metastases in mice – providing a better understanding of mechanism so it can be blocked. They can induce metastases with both hypoxia-dependent mechanism and hypoxia-independent mechanism.

Validation of survivin as target

Fieke Lamers (Netherlands) gave an interesting presentation on validation of survivin as therapeutic target. They have a drug YM155 by Astellas pharmaceuticals that suppresses survivin, which is highly expressed in most neuroblastomas. They had 24 NB cell lines, some were resistant to YM155 and they found that cyclosporin will sensitize NB lines that show MDR1 resistance to YM155, and then NB will undergo apoptosis in presence of YM155.

Neuroblastoma bits from November 2010

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NCI featured article on ALK inhibitor Crizotinib

While encouraging responses are being seen in lung cancer patients with ALK mutation, drug resistance is expected to be a problem.

Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

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FDA discusses Crizotinib pediatric trial design

Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) Nov 30, 2010

“If the current COG Phase I/II studies evaluating crizotinib in refractory pediatric solid tumors or ALCL shows promising activity in neuroblastoma, should crizotinib be evaluated in the post-transplant relapsed/refractory setting or should a randomized trial in a less heavily treated population be considered? If the former population (i.e., post-transplant relapsed or refractory) is a more appropriate setting, please discuss whether Progression Free Survival (PFS) is an adequate endpoint.”

Committee discussion questions

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Insight Genetics Awarded Qualifying Therapeutic Discovery Program Grant

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http://www.eurojournals.com/ejsr_40_1_15.pdf

www.eurojournals.com

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Scientific American describes the recent advances in viruses that kill cancer — now available to children this year for the first time –

Cancer Therapy Goes Viral: Progress Is Made Tackling Tumors with Viruses: Scientific American

“A new generation of oncolytic viruses are entering late-stage clinical trials, repurposing smallpox and herpesvirus to take on tough tumors.”

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Search goes on for toxins to kill neuroblastoma

“Luesch is experimenting with toxins—drawn from several species of cyanobacteria—on several types of cancer, including neuroblastoma, a childhood disease that attacks nerve cells. In July 2009, he launched a four-year, $1.2 million NCI-funded study, part of which entails… largazole testing on mice.”

Why Scientists Are Searching for Cures Underwater – Newsweek

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Childhood cancer survival in Australia

“Survival outcomes using the period method for 11903 children diagnosed with cancer between 1983 and 2006 and prevalent at any time between 1997 and 2006. The overall relative survival was 90.4% after 1 year,  79.5% after 5 years and 74.7% after 20 years.”

Population-based survival estimates for childhood cancer in Australia during the period 1997–2006

www.nature.com

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Accutane (cis-retinoic acid or isotretinoin) and depression?

A child with neuroblastoma is far more more often a preschooler than a teen. So the risk of suicide and depression is unlikely with such small children. It is a concern with the few teens and young adults with neuroblastoma on this drug, especially since the dosing is 2 to 10 times higher than what is prescribed for acne, and the lower dose is the basis for all the previous studies looking at incidence of depression and suicide. This small study gives important evidence that the drug may not contribute entirely to increased risk:

Severe Acne Linked to Suicide Risk Even Before Treatment Is Started

cme.medscape.com

In a retrospective Swedish cohort, suicide attempts were associated with severe acne even before treatment with isotretinoin was started.

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A review of a new therapy for neuroblastoma

Significant and accelerating progress is underway in the oncolytic virus arena. In the past decade numerous clinical trials using several different oncolytic viruses against adult cancers have been completed and more are underway. Many trials have shown anti-tumor activity in various adult tumors. A major milestone was reached this year with three oncolytic virus trials open to children for the first time in the US using vaccinia, Seneca Valley virus, and herpes simplex virus, and two more to open next year using reovirus and modified measles. In addition, a Newcastle disease virus trial will enroll children in Jerusalem.[1] Researchers from Spain published a recent report describing a few cases of oncolytic adenovirus given to children with neuroblastoma, with encouraging responses observed in two children.[2] One more oncolytic virus is in early development, Maraba, so at least eight oncolytic viruses are currently of interest for treating children with cancer.

This exciting field holds great promise for many reasons. After decades of exploring combination therapies that primarily utilize highly toxic treatments, 80% of all children diagnosed with a malignancy (in the most developed countries) can expect to still be alive after five years. While this denotes a significant degree of success, there are still 20% who do not survive five years. Added to this, the serious issue of late effects, late relapses, secondary malignancies, and increased morbidity continue to darken the future for childhood cancer survivors. Clearly more work is needed to find non-toxic and more effective therapies for all of these children. There is great potential for oncolytic viruses to dramatically solve these challenges – the increasing possibility of tumor-specific viruses that replicate in tumor tissue and kill tumor cells only while completely sparing normal tissue presents an extremely attractive scenario.

This report outlines the “state-of-the-art” of oncolytic virus therapy for children.

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A spotted history

An excellent review, “Oncolytic Virotherapy Reaches Adolescence” published August 2010 in Pediatric Blood & Cancer by Drs Adrienne Hammill and Timothy Cripe (Cincinnati Children’s), reads more like an intriguing historical account than a dry scientific treatise.[3] Beginning with anecdotal observations of infections followed by spontaneous remissions of various cancers documented since the mid-1800s, the authors trace the efforts of researchers to advance the understanding and use of oncolytic viruses. Numerous studies in the 1960s and 1970s were performed and remissions documented. However, some investigators planned and carried out unethical experiments, such as extracting viruses from infected patients and directly infecting other patients with body fluids, and even injecting human tumor cells into prisoners and patients without consent.[4] The resulting public outrage led to the modern era of robust regulatory oversight for all phases of clinical research. Meanwhile, interest in oncolytic virotherapy research diminished during the next few decades.

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A virus revival

Why then has there been a sudden resurgence of research in this field now? Renewed interest has soared the past decade because of dramatic progress in understanding cell processes, tumor biology and microenvironment, immunology, and the advent of recombinant DNA technology among many other advances. In the past, wild-type viruses carried the risk of uncontrolled infectious complications. Newly created attenuated viruses are harmless to normal tissue and engineered to be far more tumor-specific. Techniques have been developed and regulations defined to safely produce, purify, and administer the oncolytic viruses to patients. Many new viruses have been identified, modified, and tested on cancer cell lines and in animal models. Publications have exponentially increased, and hundreds of researchers in both academic and industry-sponsored laboratories are actively involved in cancer virotherapy research. The 2009 NCI funded research portfolio returns 532 results totaling over $200 million in a search with the keyword “oncolytic virus.”[5]

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Oncolytic virus trials for childhood tumors

These are indeed exciting times for advances in treating pediatric cancer, and rapid progress in opening these trials for children is the direct result of significant funding and support from pediatric cancer research non-profit charities such as Solving Kids’ Cancer in addition to public funding. In the Hamill review, four oncolytic virus trials for pediatric tumors are described including the background of preclinical studies and adult trials. Currently five oncolytic virus trials are open (or soon to open) for children in the US:

• Herpes simplex virus-1 (HSV1716) – intratumoral injection: CURRENTLY OPEN for enrollment for patients aged 13-30 years with solid tumors (non-CNS)
• Vaccinia (JX-594) – intratumoral injection: CURRENTLY OPEN for enrollment for patients for patients aged 2-21 years with solid tumors (non-CNS)
• Seneca Valley virus (SVV-001/NTX-010) – intravenous route: CURRENTLY OPEN for enrollment for patients for patients aged 3-21 years with solid tumors (non-CNS)
• Modified Measles virus (MV-CEA) – local injection into resected recurrent tumor bed: NOT OPEN/estimated to open first quarter 2011 for patients aged 2-21 years with recurrent medulloblastoma
• Reovirus (Reolysin) – intravenous route: NOT OPEN/estimated to open fourth quarter 2011, for patients aged 3-21 with solid tumors.

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Prior experience in adult tumors

HSV1716

The safety of intratumoral injection of HSV1716 virus has been studied in five phase I clinical trials in glioma, melanoma, and squamous cell carcinoma. No toxicities were observed, and evidence of tumor necrosis and viral replication in tumor were seen. Tumor response was seen in a glioma and melanoma patient.[3]

JX-594

The vaccinia virus is a poxvirus, and has been tested in five clinical trials using intratumoral injection from 1964 to 2001. In metastatic melanoma, 25/44 showed an objective response, with complete response in injected tumor site in 11/25  patients. In bladder cancer, 3 of 4 patients were in complete response four years later. Modifications to increase tumor specificity in vaccinia resulted in the JX-594 virus. Four trials have been launched in adults using both intratumoral and intravenous administration in several adult cancers with responses and stable disease observed. The recently completed phase II in hepatocellular carcinoma will have results released in 2011. Mild flu-like symptoms only were observed.[3]

SVV-001/NTX-010

A phase I of intravenous Seneca Valley virus (SVV-001) in 30 adults with advanced solid tumors (with neuroendocrine features) showed objective response in a carcinoid tumor and stable disease longer than 16 months in a lung cancer patient. A phase II is currently ongoing for lung cancer to determine if efficacy is improved in combination with chemotherapy.[3]

MV-CEA

The modified measles (MV-CEA) was tested in a phase I trial for ovarian carcinoma in 21 women with recurrent ovarian carcinoma by intraperitoneal injection. No dose limiting toxicity observed with fever, fatigue, and abdominal pain. A phase I Intra-tumoral MV-CEA for recurrent glioblastoma is ongoing at Mayo Clinic.[8]

Reovirus/Reolysin

Numerous studies have been completed in adults with the reovirus in various tumors with both intravenous and intratumoral injection. Indications of efficacy have been observed, with no toxicities beyond flu-like symptoms. More studies using combination therapies have been completed and are underway, including plans for a phase III with chemotherapy for head and neck cancers.[3]

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Delivering the virus to the tumor

Oncolytic viruses can be safely administered via intratumoral injection or intravenous route. The virus self-replicates in the tumor and can then spread throughout the body. Tumor kill in distant metastases has been observed, as well as vaccine-like effects with anti-tumor immune responses. The intravenous route delivers the virus systemically, but some viruses stimulate an immune response and the antibodies produced can interfere with the desired effect.  Ongoing research seeks to solve this challenge.

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Current status of pediatric trials

Investigators have provided updates on the oncolytic virus trials November 2010 for various pediatric solid tumors. The first child to receive an oncolytic virus in the US was treated with Seneca Valley (SVV-001/NTX-010) virus at the University of Minnesota in March 2010. As of November 2010 eight children (four with neuroblastoma, four with other solid tumors including carcinoid tumors) have been treated with SVV-001/NTX-010 at six different COG (Children’s Oncology Group) phase I consortium sites (MN, AL, PA, IN, TN, TX) with six children receiving the first dose level and two receiving the second dose level. Three young patients have been treated with HSV1716 (at lung, pelvic, and neck sites) at Cincinnati Children’s and the second dose level cohort will be open to enrollment December 2010 after routine safety review. The first child enrolled November 2010 in the JX-594 trial at Cincinnati Children’s with hepatocellular carcinoma. The reovirus trial has just been approved CTEP (Cancer Therapy Evaluation Program), and will be open at COG phase I consortium sites in 2011. This trial includes low-dose oral cyclophosphamide and children will be eligible to receive up to 12 cycles of the reovirus (given days 1-5 of each 28 day cycle). Plans to open the measles virus trial for recurrent medulloblastoma are also underway.

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Toxicities

Some children have had mild flu-like symptoms and some have had pain at tumor sites from tumor swell. No other serious toxicities have been observed, and virus clearance has occurred as expected. Many adult trials have established the safety of virus administration, as well as demonstrating responses and disease stabilization. A significant point to consider is the low “opportunity cost” for a child enrolling in an oncolytic virus trial—the risk of eliminating the child from further therapy options is very unlikely. Most of these trials require a month or less of observation for virus clearance, and no other toxicities are expected to affect eligibility for other trials, such as bone marrow suppression or organ toxicities. This provides a promising option for children with resistant disease because many current therapies contribute to cumulative organ toxicities.

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Future directions

New viruses have been recently identified and modified that demonstrate potent tumor specificity such as double-mutated Maraba virus in neuroblastoma.[6] These promising viruses deserve the attention of funding mechanisms and accelerated introduction to clinical trials. With encouraging results from adult trials being reported,[7] growing enthusiasm is appropriate for the use of oncolytic virus therapy in children.

More information on oncolytic virus trials in adults can be found in recent Molecular Therapy editorial [9], European Journal of Scientific Research [10], NCI Journal [11], and  companies involved in developing oncolytic viruses in a market analysis on BioMedReports.[12]. A 2009 review discusses preclinical work testing herpes simplex viruses in pediatric cell lines, including neuroblastoma.[13]

The chart below shows adult phase II and III oncolytic virus trials (click on the image below to go to the April 2010 JNCI article) [11]:

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References

1. Clinical Application of Intravenous New Castle Disease Virus – HUJ Oncolytic Virus in the Treatment of Advanced Glioblastoma Multiforme, Soft and Bone Sarcomas and Neuroblastoma Patients, Resistant to Conventional Anti- Cancer Modalities. NCT01174537
2. Discovery Medicine. Oct 2010; 53.  Oncolytic Virotherapy for Neuroblastoma.
3. Pediatric Blood Cancer. 2010 Dec 15;55(7):1253-63. Oncolytic Virotherapy Reaches Adolescence.
4. New England Journal of Medicine 2004; 351:628-630. Sins of Omission — Cancer Research without Informed Consent.
5. NCI Funded Research Portfolio 2009 (keyword: oncolytic virus)
6. Molecular Therapy. 2010 Aug;18(8):1440-9. Epub 2010 Jun 15. Identification of genetically modified Maraba virus as an oncolytic rhabdovirus.
7. Pediatr Blood Cancer. 2010 Dec 15;55(7):1253-63. Oncolytic Virotherapy Reaches Adolescence.
8. Personal communication, Dr Corey Raffel, Nationwide Children’s Hospital, Columbus, OH
9. Molecular Therapy 2010 18 (2), 233–234. doi:10.1038/mt.2009.314  Oncolytic Viruses: An Approved Product on the Horizon?
10. European Journal of Scientific Research, ISSN 1450-216X Vol.40 No.1 (2010), pp.156 -171. Oncolytic Viruses in Cancer Therapy
11. J Natl Cancer Inst. 2010 May 5;102(9):590-5. Epub 2010 Apr 26. Oncolytic viruses move forward in clinical trials.
12. BioMedReports, Nov 22, 2010. Oncolytic Viruses: Are They The Future of Cancer Therapy?
13. Molecular Therapy 2009  July; 17(7): 1125–1135. Herpes Simplex Virus Oncolytic Therapy for Pediatric Malignancies [full text]

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Trial open at Penn State Hershey Medical Center

A Phase I Trial Combining Decitabine, IFN-gamma, and Vaccine Therapy for Patients With Neuroblastoma

The phase I trial will enroll 15 children ages 2 months to 17 years who have relapsed neuroblastoma.

The stated purpose:

This treatment study for relapsed high-risk neuroblastoma involves an autologous cancer testis (CT) antigen specific dendritic cell (DC) vaccine preceded by decitabine as a demethylating chemotherapy and IFN-gamma to stimulate an immune response.

The vaccine is given in the following schedule:

The neuroblastoma oral papers (OP2) presented on Friday October 22, 2010 at SIOP in Boston covered a range of topics including prognostic factors, targets, and stem cell contamination. This report will focus on the presentation on prognostic significance of segmental alterations in neuroblastoma tumors.

Accumulation of segmental alterations determines progression in neuroblastoma (O024)

Neuroblastoma tumor biology has long been an intense subject of study because of the heterogeneous nature of this disease. Looking at macro, micro, and genetic features reveals the differences in tumors, and why some children with neuroblastoma survive without treatment and others do poorly with the most intense treatments conceived. Now that technology is accessible to analyze genetic profiles, more precise risk can be assigned, and appropriate treatment given. Further, this analysis allows for understanding the evolution of tumor genetics as relapse and progression occurs.

Gudrun Schleiermacher from France presented on a study of numerical and segmental chromosome alterations in neuroblastoma tumors. This subject was a matter of interest at ANR in Stockholm as well, and this abstract was also presented at ASCO in June.[1]  This topic has been the subject of many abstracts at recent meetings, and several recent publications confirm the importance of this work [2-6].

Prior publication in 2009 from this French group included  a comprehensive overview of the genetic alterations of neuroblastoma and clinical significance. A series of 493 neuroblastoma samples was investigated by array-based comparative genomic hybridization and the analysis identified several types of profiles:

Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.[2]

Caren and collegues (Sweden) also concurred that these studies have:

implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment. [5]

Schleiermacher and colleagues analyzed 394 neuroblastoma tumors with array-based comparative genomic hybridization and linked the results to clinical data for outcomes. The tumor samples included all risk groups, and analysis was performed again in the event of relapse to discover changes in the tumor profile. The study confirmed that neuroblastoma tumors are characterized by two distinct genetic profiles — either numerical or segmental chromosome alterations.

Tumors were first divided into five groups based on genomic aberrations: numerical only, segmental only, MYCN amplified, numerical and segmental, MYCN and numerical. The tumors with only numerical alterations had the best prognosis. No breakpoint pattern was observed in the segmental-only group which contained up to 1000 breakpoints. Seven or more breakpoints portended a worse prognosis, and was an independent factor in multivariate analysis. More breakpoints were correlated with higher age at diagnosis, higher stage of disease, and higher risk of relapse.

Tumors with only numerical alterations at diagnosis frequently acquired segmental alterations upon relapse. This could not be strictly attributed to chemotherapy since tumors treated with surgery only had acquired segmental aberrations. The authors concluded that tumor progression is directly linked to an accumulation of segmental alterations.

References

1. J Clin Oncol. 2010 Jul 1;28(19):3122-30. Epub 2010 Jun 1. Accumulation of Segmental Alterations Determines Progression in Neuroblastoma. PMID: 20516441

2. J Clin Oncol. 2009 Mar 1;27(7):1026-33. Epub 2009 Jan 26.  Overall genomic pattern is a predictor of outcome in neuroblastoma. PMID: 19171713

3. British Journal of Cancer (2007) 97, 238–246.  Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. [free fulltext]

4. Am J Pathol. 2010 Jun;176(6):2616-25. Epub 2010 Apr 15. 2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics. PMID: 20395439

5. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4323-8. Epub 2010 Feb 9.  High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. [free fulltext]

6. N Engl J Med 2005; 353:2243-2253.  Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. [free fulltext]

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Swedish researchers share the prize at SIOP for winning posters on neuroblastoma

Drs Fredrik Hedborg (Uppsala University) and Catarina Trägar (Karolinska Institute) shared the top prize for neuroblastoma research poster at SIOP 2010.

PH036 Age dependent genotypes in high-risk neuroblastoma: MYCN amplification is a fast track to aggressive disease whereas segmental deletion of 11q implies a more complex, multi-step tumor evolution (p. 896)

Dr Hedborg and colleagues explored the age-dependence of the genetics of aggressive disease in 30 high-risk and 4 intermediate-risk children. MYCN amplification was present in all but one of the 12 youngest children (mean age 29.6 months, range 4 – 30 months) and MYCN amplification was absent in all but one of the 11 oldest (mean age 65.6 months, range 57 – 169 months), and 12/18 of these had 11q loss. This age differential was confirmed by the Swedish Childhood Cancer Registry where mean ages at diagnosis were 29.4 months for MYCN amplified (n=65)  and 54.8 months for MYCN-non-amplified (n=46). Significantly more segmental chromosome aberrations were noted in older children with 11q loss, and this data suggest that two major pathways exist in the development of aggressive neuroblastoma. MYCN-amplification tumors in younger children result from fewer but rapid genetic events, whereas tumors in older children with 11q loss are the result of a slower, multi-step process.

PH038 Differences in biological features and survival improvement between genetic subsets of high-risk neuroblastoma indicate the need of adapted treatment (p. 897)

Dr Trägar and colleagues also looked at Swedish registry data and noted older age for 34 children with 11q deletion (median age 41 months) and longer median survival of 40 months compared to children with MYCN-amplified tumors (median age 22.5 months, median survival 16 months), but both groups had similar 8 year overall survival rate of ~35%.

Survival data were reported as follows:
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The researchers concluded that 11q-deletion tumors present later than MYCN-amplified tumors, but noted that prognosis is similar, and suggest further consideration is needed for therapeutic approaches for 11q-deleted tumors since prognosis has not improved for this group since the 1980s.

Both research teams have contributed to increased understanding concerning the relationship between age and biology of neuroblastoma high-risk tumors.

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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“Meet the Experts” session

Drs Huib Caron (The Netherlands) and Suzanne Shusterman (Boston Childrens/DFCI) presented on MIBG therapy in “Meet the Experts” session Friday Oct 22 and Saturday Oct 23, 2010 at the SIOP meeting in Boston.

Completed and ongoing studies

Dr Caron covered the therapeutic considerations, and Dr Shusterman spoke about the practical and logistic issues surrounding the design of MIBG therapy rooms and handling the radioactive material.

MIBG (meta-iodobenzylguanidine) is a synthetic analogue to norepinephrine, developed in the 1970s at University of Michigan as a potential agent for use in hypertension. It is taken up by 90% of neuroblastomas. The compound (also called iobenguane) is useful for both imaging with I-123 isotope which has a shorter half-life of 13 hours and produces better resolution images, and radiation therapy with I-131 which has a longer half-life of 8 days.

The compound with a radioactive isotope of iodine attached (I-131) is taken up in the NB cell but is not lethal to that cell. The beta particles from I-131 decay kills cells up to 2 mm away, and gamma radiation from decay (as in imaging) reaches 2 m or greater distance, but is not lethal to cells in that path. The resulting beta particle decay “cross-fire” is why MIBG radiation therapy appears to be more effective in clumps of disease rather than in diffuse or trace disease. Dr Caron commented in his presentation that this is why he believes using MIBG radiation therapy at the end of induction with minimal or undetectable disease will have questionable efficacy, and why studies in the Netherlands have used double MIBG treatments at the beginning of induction (1989-1999 in 41 children).[1]   Dr Maris countered in a later conversation that there is evidence of efficacy from a double MIBG therapy study where children who respond completely to the first MIBG therapy receive a second MIBG treatment and do well. He also mentioned that it is very common to see much more disease in a post-MIBG therapy scan, revealing that often the imaging dose of MIBG does not show as much disease, and therefore using MIBG therapy at the end of induction even in children with negative MIBG scans may successfully treat undetectable or trace disease. This question (as well as feasibility) will be addressed by the new frontline pilot study now open in several centers using MIBG at the end of induction with CEM transplant for 49 newly diagnosed high-risk NB (see previous article). The German group GPOH is using MIBG therapy in frontline therapy in the ongoing NB2004 study a the end of induction for children who have remaining MIBG positive primary uptake. This study plan is to accrue 360 children.[2]

Other completed and ongoing studies were reviewed, including an ongoing study using MIBG upfront with topotecan in 15 children, a GPOH study using MIBG + gemcitabine phase I/II for refractory and relapsed NB and should finish within the year. The NANT 2007-03 phase I MIBG + vorinostat trial is based on the fact vorinostat (an HDAC inhibitor) increases the norepinephrine transporter expression, and in mice the combination results showed improved response. In 2006 Matthay et al published in JCO the results of the phase I MIBG + CEM transplant in 24 children where the 3-year event-free survival (EFS) was 30% and the 3-year overall survival (OS) was 60% for primary refractory disease. The dose levels from this study were used in the phase II which was recently completed and preliminary results were presented at ANR in June 2010 in Stockholm by Dr Greg Yanik (OR58). MIBG has been tested at 8 to 18 mCi in various trials. In 2007 a Phase II was published in JCO showing promising effectiveness in 164 relapsed or refractory patients with a median of 3 prior regimens (range 1 – 13).[3]  A study in the UK planned to use topotecan with MIBG for relapsed or refractory NB closed before it accrued. Another NANT phase I study N2004-06 used MIBG with irinotecan and vincristine, and results are pending. In Sweden a study using haploidentical donor transplant with MIBG was completed in 5 children.[4] In France a study is ongoing using topotecan with MIBG in relapsed and refractory children.

Approval status for 131-I MIBG

131-I MIBG is made by Draximage (a division of Draxis Health) in Canada, and another company Molecular Insights makes Azedra (Ultratrace MIBG with no cold contaminants). 131-I MIBG is approved for treatment of neuroblastoma in Europe, but still an investigational new drug (IND) in the US.

Future focus

Conclusions drawn from this session include the fact that MIBG therapy is obviously an important agent in the treatment of neuroblastoma, with a long history of studies completed since the 1980s. An important challenge for all researchers involved is figuring out the optimum way to use this agent. An excellent review published in 2008 by Drs Matthay and Dubois provides more information.[5]

References

1. Eur J Cancer. 2008 Mar;44(4):551-6. Epub 2008 Feb 11. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. PMID: 18267358

2.  Randomized Study of Standard Induction Chemotherapy Versus Topotecan Hydrochloride-Containing Induction Chemotherapy Followed by Myeloablative Autologous Stem Cell Transplantation and Consolidation Therapy With Isotretinoin in Pediatric Patients With High-Risk Neuroblastoma GPOH-NB2004-HR

3. J Clin Oncol. 2007 Mar 20;25(9):1054-60. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. PMID: 17369569

4. Biol Blood Marrow Transplant. 2009 Sep;15(9):1077-85. Epub 2009 Jul 8. High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma. PMID: 19660720

5. Q J Nucl Med Mol Imaging. 2008 Dec;52(4):403-18. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. PMID: 19088694

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Dr Frank Saran from The Royal Marsden in the UK presented on neuroblastoma during the Paediatric Radiation Oncology Society (PROS) education session Wednesday October 20 at the SIOP meeting in Boston. Prior to his presentation we heard from other specialists on the challenges of using radiation for poor-prognosis brain tumors, particularly high-grade glioma. Other brain tumors discussed were ependymoma, supratentorial primitive neuroectodermal tumors (sPNET), and the emerging use of proton radiation. The difficulty of minimizing neurocognitive damage and the grim prognosis for some of these tumors are very sobering. There was no discussion in this session of treatment for brain metastases for non-CNS tumors. There was also a presentation on radiation for Wilm’s tumor.

Dr Saran gave a short history of studies showing why today radiation is a part of standard therapy for high-risk neuroblastoma (but use of TBI was not discussed). Local failure accounted for a large percentage of relapses when chemo-only regimens were used. In unpublished data supplied by Dr Andrew Pearson,  40% of all stage 4 over 1 year relapsed at the primary site in the ENSG5 study. By contrast in 2001 Memorial-Sloan Kettering (MSKCC) published a series of 99 children with only 10% local failure rate. MSKCC uses hyperfractionated radiation 21 Gy in 14 fractions, usually given in two fractions per day to primary sites and additional radiation to some metastases.  The current SIOP NB trial uses 21 Gy in 14 fractions given over 3 weeks.

Dr Saran also listed current efforts to determine the optimum way to give 131-I MIBG radiation. Some investigations address maintaining oxygenation, fractionating treatment, using radiosensitizers, use of carrier-free (Ultratrace), and adding chemotherapy. A recent European trial showed good results when MIBG radiation therapy was given concurrently with topotecan. Several combination trials (chemo with MIBG) are ongoing in the US and in Europe.

Travel to this meeting was supported by:

• Lighthouse Laboratories

• Max’s Ring of Fire

• Magic Water

• Friends of Will

• Solving Kids’ Cancer

• Children’s Neuroblastoma Cancer Foundation