Interview with the Canadian Cancer Research Alliance (CCRA)
In September 2013, the Canadian Cancer Research Alliance (CCRA) published a report on the “Investment in Research on Childhood and Adolescent Cancers, 2005-2010”. According to their website, the “purpose of the Canadian Cancer Research Alliance is to foster the development of partnerships amongst cancer research funding agencies in Canada, to promote the development of national cancer research priorities and strategies, to report back to donors and the public on the nature and impact of the investment in cancer research funding in Canada, and to work together to achieve the overarching goals of effective and timely cancer control in Canada.”
In October 2013, Neuroblastoma Canada sent a list of interview questions to Kimberly Badovinac, the lead author of the CCRA report. The purpose of the interview was to seek additional information about the report in general and to also understand more about the impact of cancer investment in Canada on neuroblastoma. The interview questions were answered by Ms. Badovinac with significant support from Kathy Brodeur-Robb, the executive director of the C17 Council (children’s cancer and blood disorders). C17 is a consortium of 17 institutions across Canada that provides pediatric oncology, hematology, and stem-cell transplant programs. C17 focuses on a number of initiatives that include research, education, guideline creation, advocacy, and partnership development.
The CCRA report provides commentary on pediatric cancer in Canada, the state of investment into childhood cancer research, and where money is being targeted for various forms of research. The purpose of the interview was to ask questions about the report that pertained to neuroblastoma in particular, to try and learn more information about the state of investment into neuroblastoma research, and to better understand some of the issues related to this report.
1. According to the table on page 6, Neuroblastoma is listed as the fifth most common cancer; however, in all of the medical literature, it is cited as the third most common cancer. Can you comment? In addition, one interesting point for neuroblastoma that is not illustrated in this table is that neuroblastoma is the most common cancer diagnosed in the first year of life.
From Neuroblastoma Canada:
There was a great deal of discussion about this question which ultimately highlighted a number of challenges in the gathering and interpretation of pediatric cancer data and statistics in Canada. The following is a summary of this discussion and additional commentary from Neuroblastoma Canada.
The CCRA report provides a table (table 1.1.1) that illustrates the most prevalent pediatric cancers according to four age groupings. This table was a significant source of discussion over the course of the interview since it differed from other reported statistics, especially for neuroblastoma. Table 1.1.1 from the report is provided as follows :
|0 to 4 years*||5 to 9 years||10 to 14 years||15 to 19 years|
|1. Acute lymphocytic leukemia
3. Kidney and renal pelvis
5. Soft tissue
|1. Acute lymphocytic leukemia
3. Non-Hodgkin’s Lymphoma
4. Bones and joints
5. Kidney and renal pelvis
2. Hodgkin’s disease
3. Acute lymphocytic leukemia
4. Bones and joints
5. Non-Hodgkin’s lymphomas
|1. Hodgkin’s disease
4. Non-Hodgkin’s lymphomas
5. Bones and joints
* IMPORTANT NOTE: This is the table found in the CCRA report. They use data based on “anatomy” and this differs from MOST other systems used to capture incidence.
This table in the report was constructed using the Canadian Socioeconomic Information Management (CANSIM) database from Statistics Canada. The CANSIM database is a robust resource that contains a wide variety of data, including cancer incidence rates in Canada. In the CANSIM database, cancers are classified according to the site that they are found in the body (i.e., breast, colon, etc.). This type of classification system is beneficial for adult cancers; however, it does not work well for pediatric cancers. This is especially the case for neuroblastoma since the disease can have primary sites in different parts of the body (i.e., renal, abdominal, thoracic, spinal, etc.). For pediatric cancers, it is more appropriate and accurate to define the cancer by its type and not by its site in the body. As a comparison to how cancer statistics are collected, in the United States the Surveillance, Epidemiology, and End Results Program (SEER) of the National Cancer Institute (NCI) data defines pediatric cancers by type and by site.
In the CCRA report, the table that illustrates pediatric cancer incidence rates across different age groups was constructed using only the CANSIM database. For neuroblastoma in particular, it was associated with the “other endocrine” category for only the 0-4 age group. When compared against data from the Canadian Cancer Society (CCS) and the SEER data, the “most common cancers among children” table in the CCRA report presents a very different ordering of the prevalence rates of pediatric cancer than what is commonly understood. The CCS report constructs their table using data this is slightly older (2000-2004); however, incidence rates do not fluctuate dramatically for pediatric cancer. The following is a representation of the information from CCS in their 2008 Statistics report:
|0-4 Years Old||5-9 Years Old||10-14 Years Old|
4. Renal tumours
4. Soft tissue
4. Bone tumours
The following is a summary of Canadian neuroblastoma prevalence statistics:
- Neuroblastoma is the most common cancer diagnosed in the first year of life.
- Between the ages of 0-4 years old, neuroblastoma is the 2nd most common cancer.
- Within the age group of 0-14 years old, neuroblastoma is the 3rd most common cancer (when Leukemia and Lymphoma are grouped in the same category) ,,.
- Neuroblastoma has the highest rate of metastasis present at the time of diagnosis, compared with any other pediatric cancer (55%).
- Cancer related mortality from neuroblastoma is approximately 11%.
There are also challenges with how data is collected for different age groups, especially for young adults. “In Canada the health system for children with cancer can be a children’s hospital, a children’s wing in an adult hospital, or a cancer centre – and the age cut-off may be different” says Kathy Brodeur-Robb. In addition, “because health is also a provincial responsibility, there is actually no national database that is inclusive. While there are provincial cancer registries, many children are not seen in cancer centres, they are seen in children’s hospital. And then the 15-19 year olds may be seen in children’s hospital, cancer centres or local cancer clinics. There are also issues around “benign” tumours being counted or not counted. So we collect data from our C17 centres (which is all the peds onc programs) but it is never completely comprehensive (ie. a 14 year old with melanoma may not arrive at the clinic; some brain tumours get only surgery and don’t see ped onc MDs at some centres). I also know that there have always been discrepancies between the various data sets – the cancer registry is also not complete” says Kathy Brodeur-Robb, and adds that “the data is not always consistently available.”
2. Are there statistics on the most relapsed cancers?
“No, we do not have solid data on relapsed cancers, other than estimates of percentages. One initiative that C17 started in January 2012 is a Relapse Registry Log at 8 of the largest centres in Canada. Once a month data is collected on the number of relapse patients, the diagnosis and if a research study is offered. The survey is being updated for January 2014 to capture better data on the relapse number, and better defining refractory/progressive disease and the research options that are offered.
“The Cancer in Young People surveillance database, an initiative of Public Health Agency of Canada and C17, will provide more complete information on all patients age 0-14 years diagnosed with cancer. This database will include data on relapses and survival for all patients in Canada. CYP-C is currently retrospectively collecting data for all patients age 0-14 years diagnosed and treated at a Canadian pediatric institution from 2000-2012. Prospective data collection was also started in 2012 to collect data for all patients moving forward. The data is currently being checked and monitored for patients from 2000-2006; it is expected that the data will be available in 2014. The date of 2006 was chosen to establish 5-year survival data as the first data set. “
From Neuroblastoma Canada:
For neuroblastoma in particular, there is a challenge in distinguishing refractory disease from new relapse/recurrence (post response). This is a challenge which is more difficult for neuroblastoma versus other pediatric cancers. It is possible that neuroblastoma will continue to be under reported due to this issue.
3. Using the “overall five-year observed survival” statistics does hold value and that 5 year mark is often considered to be the time when a patient is finally deemed to be “in remission”. However, I believe that only presenting the 5 year survival rate is becoming a less valuable statistic. Many childhood cancers, like neuroblastoma, can be fought for well over 5 years, and even treated like a chronic condition in some cases. Would it be possible to look at the statistics from a 10 year perspective?
“While the 5-year survival data is often considered the “gold standard” in many areas of cancer, many of the research protocols actually collect data on patients for 10 years. The Children’s Oncology Group established a registry protocol to enroll as many patients as possible at all COG centres; and to collect long term survival data for patients, including past the age of majority (when they are approached to reconsent to being in the registry). For many studies, a relapse also establishes a new point of entry, with a 5 or 10 year follow-up. For this reason, while we may not get complete population data, we will get good research data as we treat and follow these patients.”
From Neuroblastoma Canada:
There are challenges with looking only at 5 year survival numbers, particularly for neuroblastoma. This is because:
- Some patients with neuroblastoma can live with disease for extended periods of time. This is especially the case for older patients who may have a more “indolent” type of disease that is slower growing in comparison to other disease patterns. In neuroblastoma, “overall survival” is typically the statistic used instead of “event-free survival”.
- In some low and intermediate risk cases of neuroblastoma, the tumour may not be fully removed by surgery; however, additional treatment may not be necessary with a “wait and see approach”. In this case, the disease can be difficult to classify as “remission”.
4. I greatly appreciated that you included information on late-effects and the findings from the CCSS. It was also very valuable to include information on the increased risk of psychological distress for pediatric cancer patients. There is quite a bit of literature that deals with the impact of a pediatric cancer diagnosis on parents and siblings; however, this is not necessarily within the direct scope of your report.
“Research into late effects of cancer treatment is an area of expertise and considerable research funding in Canada. In 2011, the Canadian Institutes of Health Research, in collaboration with C17, Pediatric Oncology Group of Ontario, the Garron Family Institute, and others provided $12.5 million in funding 4 projects over 5 years in Canada.
“The C17 Research Network has also funded numerous quality of life and late effect research studies. The studies that we fund and the publications that result can be found on the www.c17.ca website.
“The data shows that late effects of variable degree and severity, probably affect a majority of childhood cancer patients.”
5. The information provided on survivorship is very well presented. The following quote was one that I had not seen before: “Furthermore, given the World Health Organization definition of cost-effectiveness (i.e., the ratio of the cost required to avert one disability-adjusted life year to the annual per capita GDP), the treatment of childhood and adolescent cancer is a highly cost-effective undertaking” (pg. 9). Are there any additional comments that you can provide in relation to this?
“Because childhood cancer is so rare, and because we can cure quite a large number of patients with chemotherapy drugs that are widely available, the economic arguments have been used to provide solid justification and rationale for investing in curing children with cancer, beyond providing healthcare to children. As pediatric programs have been expanded to developing countries, where healthcare dollars are scarce with many competing diseases, it is important to prove that it is cost-effective way to use scarce health care resources to cure children with cancer.”
6. For a future report would you consider looking at the cost of treating the different pediatric cancers and how that relates to research funding? It is certainly sobering to see the financial impact on the family (pg. 9); however, when that is coupled with an estimated cost of treatment within the medical system, it may further help to reinforce the point being made. The 2008 Canadian Cancer Society report (pg. 10) discusses how neuroblastoma is one of the most expensive pediatric cancers to treat. This may also be interesting to consider in comparison to adult cancers.
“Establishing actual costs in the Canadian healthcare system can be difficult, not just in pediatrics or cancer. Because much of the research in Canada in pediatric oncology is done as academic cooperative group research protocols, the costs of research vs the cost of clinical treatment is going to be similar. Most new patients diagnosed with cancer will be treated on a research protocol or treated by following the standard care and treatment outlined in a protocol, so the costs for the “research” part may be incremental.
“The costs of both options (research and clinical) are often similar; but unfortunately we do not have good data for either. Many centres, faced with pressure to ensure costs are not escalating too fast, are facing more questions about this; and pressure to not conduct studies that cannot provide funding to cover the extra “research” costs. This may be a good area to study in the future.
“Many of the high costs associated with treatment are when new drugs are used – either marketed drugs used in adults or for a different cancer that may have costs that may not be covered by standard hospital budgets, or in the some of the new investigational drugs, such as monoclonal antibodies or drugs targeted to very small patient populations.”
7. It was somewhat surprising to see the statistic that only 27% of newly diagnosed patients seen in pediatric cancer centres are being enrolled in clinical trials (pg. 11). Even though this is much higher than adult patients, I would have expected this number to be larger. Is it possible to know what the percentage is for neuroblastoma patients in terms of how many typically enroll in a clinical trial? Is there information on what percentage of neuroblastoma patients enroll in a clinical trial at the time of relapse?
“The percentage is up to 30% this year, and we hope that it will continue to increase because we are opening up more studies and developing some Canadian developed and led studies.
“The number of patients who enroll in a clinical trial when there is a trial open and available to them is much higher. Because “childhood cancer” is a very broad category, there are not clinical trials always open for rarer cancers. The number of patients who follow a protocol treatment arm, but not being officially enrolled in a trial, is also quite high. The reason that this is important is that there is evidence to suggest that standardizing treatments under a protocol (research or clinical) gives better outcomes.
“The figure of 27% is not a percentage of new diagnoses, it is a ratio of all patients enrolled in a [therapeutic] trial against the number of new patients diagnosed. So, a patient could be enrolled in more than one trial in the year, and they might be enrolled in a trial not in their year of diagnosis. The CYP-C database is hoped to provide more detail at the patient specific level, where we will be able to track at the individual (anonymous) patient level when and how many times a patient enrolls in a trial.
“Because neuroblastoma has had several research studies open over much of the past decade, it is likely that a much higher percentage of them have had the opportunity to be a part of a research study.
“The data on patients who enroll in a biology study is very high. In some years over 60% of patients will be enrolled in a study where their tissue samples will be analyzed and potentially included in a bio-bank. In scenarios where a trial may not have been available for a patient, there are many whose treatment will be guided by a participating in a research biology study, and many of these samples continue to be available to researchers who need many samples to try and figure out what is driving the tumours.”
From Neuroblastoma Canada:
There are times when patients are treated “as per” a protocol – where a patient is not formally enrolled on a protocol; however, they follow the treatment process used in the protocol that recently closed. This happens when a study may not be open for a particular patient group so the “standard arm” of the protocol of the most recent study is followed, still giving the patient the best possible care until the results of the study are available. For neuroblastoma in particular, it is very rare that a newly diagnosed neuroblastoma patient is not enrolled in a study.
8. Does the analysis stop at year 2010 simply because this is all that is available in the database? How often is the survey administered? What does the survey look like? Who does it go out to? What is the response rate like?
“We are in the process of collecting 2012 data and are somewhat behind with reporting 2011 because of the number of publications we produced this year. Data are collected from the 40 contributing organizations every year. All respond. A list of contributors is provided in the Acknowledgements section of the report.”
“The Canadian Partnership Against Cancer (CPAC), the Canadian Cancer Research Alliance (CCRA), the Canadian Cancer Society (CCS) all put efforts into collecting, analyzing and publishing data. Pediatric, adolescents and young adults have all been the focus of various types of publications over the past decade.”
9. It is understandable that the report can only include data in the analysis that is detailed to a particular level of quality. However, reporting that the actual investment numbers could be 33% higher than what is presented in the report is a significant amount of money. Is there a way to still include this data in a separate compendium report to get an idea of what a more inclusive investment landscape might look like? Is there anything that can be done in the future to try and get more accurate information from the people who fill out the survey?
“As provided in the table on page 19, not all of these funders are Canadian and not all are government and charitable organizations. We gather this information to help us ballpark what the total research investment may be. We do not have the details on the individual research projects involved in these estimates. The survey database is based on details about individual research projects provided by our 40 Canadian-based government and charitable research funding organizations.”
“We have also tried to get some estimates on “other funding” from our pediatric centres – for instance centres get funding for participating in each of the cooperative group studies, and for taking on roles such as a Study Chair. There are probably 10 different cooperative groups working in Canada. There is some pharmaceutical funding in Canada in childhood cancer, but not a large amount. We try to get estimates, but we only have limited resources.
“Tracking investment dollars in this category is probably not as important – there are other ways to gather data about what other clinical trials research is being conducted in Canada. For instance, all clinical trials must be registered on clinicaltrials.gov and they list the sites in Canada participating. This data is also made available through the CPAC website on the cancerview.ca portal.”
10. In terms of the research investment not captured in the report, seeing SickKids, the BC Childrens’ Hospital, Coast to Coast, and others listed was rather surprising. What efforts are made to try and close the data quality gap with these important organizations to try and include their information in your report?
“We have made attempts to get some of these data. Obtaining detailed project-level data is difficult and may not be the way that monies are dispensed.”
“Many local foundations fund research and special projects at each of their centres. There is very little detailed information beyond the formal grant competitions about what is truly “research”. Local foundations may fund research staff, academic research positions at a university, summer students, lab projects, etc. Defining what research is will be a challenge if we try to get more detailed reports.”
11. Is it correct that a total of $72.5 million was invested as a total over the six years reported?
“As detailed in the appendices (pages 39 and 40), the total is $72.7M.”
12. In 2010, was there a specific federal initiative that accounted for the significant increase in funding into pediatric cancer research? Has this been maintained and/or repeated since then?
“If you are referring to the CIHR plus partners initiative, “Late Effects of Childhood Cancer Treatment,” the funding started to flow in 2011. The latest investments are detailed on pages 12 and 13 and will be captured in future reports. At this point, I am unaware of any additional federal initiatives.”
“The Late Effects are 5 year grants. There was also a large 1 year Genome Canada partnered grant that will probably lead to some additional funding opportunities. Other opportunities may be developed, but there are no large competitions specific to pediatric oncology right now.”
13. Is it accurate to compare the amount of research money a province receives with the number of pediatric cancer patients they treat (pg. 24)? For example, Ontario sees the greatest number of patients diagnosed and patients from other provinces might travel to Ontario for part (or possibly all) of their treatment (e.g. stem cell transplant). Do the numbers presented account for this? Is the BC value accurate on this graph considering they didn’t take part in the survey? Isn’t it possible that institutions in some provinces do not conduct particular kinds of research due to the smaller number of diagnoses that are made in the province overall?
“Again, this is a way to ballpark where research activity (as gauged by research funding) is happening and to identify where funding organizations may need to raise the level of investment in order to address the level of burden (in this case, new cancer cases). I would agree that all the issues that you identified are caveats with this figure.”
“Ontario sees the most, they have the most number of centres, and SickKids is one of the largest centres in all of North America. SickKids also has the largest number of researchers. Research grants are also awarded to a single researcher, and their province of origin is what is being tracked. It doesn’t mean that no research is being conducted in the other provinces. For example, most of our C17 grants are multicentre – even if the investigator comes from Ontario, other centres participate.”
14. Could you please provide a little more context on the following statement: “At 18% of the investment, however, cancer control, survivorship & outcomes represented a much greater proportion than that found for the overall cancer research investment” (pg. 25)?
“This means that the investment in the CSO category “Cancer control, survivorship & outcomes” represented a higher proportion of the overall research investment in childhood and adolescent cancers than this same category did for the total cancer research investment. In 2010, 10% of the total cancer research investment was in the CSO category ‘Cancer control, survivorship & outcomes.’”
15. Is it possible to get an idea of what types of projects were funded for neuroblastoma during the 2005-2010 time period, when $4.2M was awarded? It is mentioned that 45% of the $4.2M invested into neuroblastoma research is targeted towards treatment; what are these projects in particular?
“See titles of projects in the table below (sorted alphabetically). These projects were in part or in whole focused on neuroblastoma.
- A Pre-clinical Evaluation of Two Oncolytic Viruses for the Treatment of High Risk Neuroblastoma
- Apoptin-based peptidomimetics as novel anti-cancer agents
- Assessment of AEG35156 (XIAP antisense) in mouse models of neuroblastoma
- Combined telomerase inhibition and drug screen as novel therapies for tumor initiating cells in pediatric nervous system tumors
- Dequalinium as a novel therapeutic agent in neuroblastoma: efficacy and mechanism in a tumor-initiating cell model
- Exhaustion of tumour initiating cells by targeting their self-renewal capacity with telomerase inhibition
- Factors promoting multidrug resistance and tumor progression in failure of pediatric cancer therapy
- Gene therapy mediated by histone H2A and its application to the treatment of murine neuroblastoma
- MRP mediated multidrug resistance
- Modulation of p73 by cyclo-oxygenase inhibitors in neuroblastoma
- Next Generation Carbohydrates Based Vaccines Against Cancer and Microbial Diseases
- P73 signalling in cancer: roles of modulatory proteins in apoptosis and chemosensitivity
- Reversing the malignant phenotype: the neuroblastoma model
- Role of HIF2a in chemoresistance of cancer cells
- Role of p53 family in the treatment of neuroblastoma with COX inhibitor and chemotherapy
- Study of the structure-activity relationships between Ganglioside GD2 and its ligands
- The Utility of Oncolytic Virus Therapy as Novel Treatment for Neuroblastoma
- Use of zebrafish to identify inhibitors of leukemic oncogenes”
From Neuroblastoma Canada:
It is important to know that many granting agencies ask researchers to select the cancer that is being researched from an established list. This list is typically categorized by anatomy, which is beneficial for adult cancers; however, it does not work well for pediatric cancers. Researchers might have to select “other” or make another choice like “brain” or “CNS” which poorly identifies research as being neuroblastoma related. Because of this, it is highly possible that neuroblastoma research projects are underrepresented.
16. Is the statistic on neuroblastoma cancer deaths correct? It is described in medical journal publications as accounting for about 15% of all childhood cancer related deaths.
This is based on Canadian statistics reported by the Canadian Cancer Society. There were 71 deaths from neuroblastoma out of 962 cancer deaths for the 0-19 age group (which works out to 7.4%).
From Neuroblastoma Canada:
According to the 2013 statistics from the Canadian Cancer Society, the mortality rate for neuroblastoma is 11% for the 0-14 age group. The statistics mentioned above by the CCRA come from the 2011 Canadian Cancer Society statistics report. Instead of looking at the number of deaths in a certain time period, it is more valuable to look at the Observed Survival Proportion (OSP) rates. It shows that neuroblastoma continues to have a disappointing survival rate, much like other pediatric cancers such as bone and CNS cancers.
17. Referring to the graphs on page 30, is it correct that the largest amount of money invested into neuroblastoma is directed towards treatment? This certainly suggests a lack of understanding on how to treat the disease. Is this now greater than Hodgkins Lymphoma (from previous report)?
“The title for this graph has a typo – this refers to the 2009 to 2010 period and not the full six years. I have provided a graph and table below to give you a more comprehensive picture of the data over the three time periods for neuroblastoma. The figure for Hodgkin’s Lymphoma (HL) in the previous report was due to a single, large project which ended in 2005. There was actually no funding in the Treatment category for HL in 2009-2010.”
|Early Detection, Diagnosis and Prognosis||$25,987||$0||$0||$25,987|
|Cancer Control, Survivorship, and Outcomes||$12,974||$621,388||$689,236||$1,606,873|
18. Who are the funding agencies for neuroblastoma research during the 2005-2010 time period? Is research money provided by “The James Fund for Neuroblastoma Research” included in this report?
“There was one “James Birrell Neuroblastoma Fund – CIHR Fellowship” project included (Zhang, Libo, A model of neuroblastoma metastasis based on chemokine interactions, dated April 1, 2006 to March 31, 2008).”
The following chart was provided by CCRA to Neuroblastoma Canada:
19. Is it possible to get an idea of the number of trainees that are in the particular cancer types (i.e., figure 3.4.3)? In particular, how many would be for neuroblastoma?
“For the entire six year period, there were 26 trainees involved in neuroblastoma projects at the following levels: 2 undergraduates; 11 graduate; and 13 post-graduate.”
20. When do you hope to publish the next version of this report? Will it be something that is published every 3 years or so?
“There will likely be an updated analysis on this topic in a few years.”
Neuroblastoma Canada would like to thank Kathy Brodeur-Robb and Kimberley Badovinac for their time and efforts associated with this interview. This post was reviewed by Dr. Meredith Irwin from the Hospital for Sick Children (SickKids, Toronto Ontario). Neuroblastoma Canada greatly appreciates Dr. Irwin’s expertise and professionalism in editing this post.
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