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 I searched for meeting abstracts for unpublished results, and scrutinized the published results of trials.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!”

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[1] Huge gap in world cancer survival. BBC News, July 16, 2008. [link]

[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.