Monday January 16, 2023
Retinoblastoma research is vital to understand how this cancer behaves; treatment benefits, side effects, and risks; and impacts throughout life. Findings help guide medical and supportive care for the child patient, survivor, and family. Rb Survivor, Abby White explores different types of medical research; their goals, benefits, and limitations; and opportunities to overcome the current challenges.
Research Guides the Best Care and Outcomes
Research is vital to improve cancer care and cure. Different kinds of research add to our knowledge and understanding of retinoblastoma, how it impacts children, adult survivors, and their families, and the best ways to provide care.
Research helps us:
- Document incidence and cancer stage at diagnosis.
- Uncover genetic factors in retinoblastoma care.
- Diagnose retinoblastoma and second cancers earlier.
- Understand tumour growth and treatment response.
- Improve current therapies and develop new therapies.
- Identify and monitor treatment risks, safety issues, and concerns.
- Monitor patient and family outcomes, and track outcome trends over time.
- Understand social factors influencing decisions and outcomes.
- Establish patient, survivor and family needs, and develop supports.
- Determine appropriate care at each stage of the lifelong retinoblastoma journey.
Medical research often takes years to progress from the first hypothesis to standard medical care. Research can be complicated and confusing, and is often misunderstood by families and survivors. This article explains the main types of research in the context of retinoblastoma care, some of the challenges to effective research, and key ways these obstacles can be overcome to improve outcomes for more patients, survivors and families.
Understanding the patterns, causes, and effects of a specific disease on patients is vital to improving care. This is the focus of clinical epidemiology studies. Researchers are particularly interested in understanding how screening, diagnosis, genetic risk, and medical and supportive care affect physical and mental health outcomes.
Clinical epidemiology occurs primarily through analysis of disease registries and pooled data from multiple treatment centres, systematic reviews, and meta-analyses. Systematic reviews and meta-analysis are overlapping, but different research concepts.
A systematic review uses a clearly defined systematic process to gather, assess, and combine all available evidence to answer a specific question.
A meta-analysis is the statistical process of analyzing and combining data from several similar studies, and forms part of a wider systematic review.
Within retinoblastoma research, clinical epidemiology can help researchers identify trends over time. For example:
- How many children develop retinoblastoma, and any causative factors;
- Lag time between first observation of signs / symptoms, and diagnosis;
- How many babies Inherit the RB1 pathogenic allele, and how it affects them;
- Life and vision survival following diagnosis;
- Treatment effectiveness, risks, late effects, and other impacts;
- Long term physical and mental health concerns;
- Why many survivors develop second cancers, and what increases that risk; and
- The different kinds of second cancer, and when they are more likely to occur.
These findings can improve patient care by driving the development of:
- Education and screening programs for early diagnosis;
- Patient and health professional education and decision aids;
- National and international evidence-based care guidelines;
- Patient-centred point-of-care databases, and collaborative registries;
- New basic science, clinical, and ethnographic research studies.
Playing with medical and research equipment was a popular activity among children attending the One Rb World 2017 child life program in Washington D.C.
Also called Basic Science, pre-clinical research involves laboratory experiments. This research is conducted for many different reasons. For example, to:
- Gather foundational information about how cancer behaves;
- Identify genetic changes that cause cancer or influence its growth;
- Develop and test new ways to diagnose cancer, and predict treatment response;
- Test theories about new treatments and methods of delivering treatment; and
- Assess the efficiency, toxicity and action of new therapies and delivery methods.
The data guides researchers to prioritize a particular test or treatment for clinical investigation.
Clinical Trials / Clinical Research Studies
Research is done to identify improved ways to control retinoblastoma, with fewer side effects, risks, and life impacts. When this research involves patients, it is called a clinical trial or clinical research study.
Clinical trials evaluate:
- Value of existing treatments;
- Modifications to reduce toxicity;
- Potentially promising new diagnostic tools and treatments; and
- New approaches to delivering and assessing treatments.
Clinical research is conducted in phases, each with aims and objectives that help answer questions or hypotheses posed by the investigators. Each phase is treated as a separate clinical trial. Randomized clinical trials compare a standard treatment to a new therapy or a modified version of the standard treatment. This is gold standard research.
Retinoblastoma is rare. Many important clinical research studies are being conducted, but often with very small groups of children, limited in their ability to effectively evaluate therapies.
Most peer-reviewed journals will only publish the results of a clinical trial if it is registered in the Clinical Trials Database of the US National Institutes of Health (NIH).
Professionals, parents and adult survivors should carefully review and assess registered trials for relevance and value to children with retinoblastoma, survivors, and their families.
Read More: Clinical trials in Retinoblastoma Care.
Clinical research is vital to advance vision- and life-saving retinoblastoma treatment. Understanding the human experience of childhood eye cancer can impact how we provide medical and supportive care.
Ethnography is a type of qualitative research that helps us learn more about people’s personal experiences by talking with, listening to, and observing them in their natural environment and everyday life.
The goal is to gather perspectives and experiences in the real-world context. Studying the collected data deepens understanding of what individuals and groups of people think and feel; how they act, react, and interact with the world around them; and the things that influence their decisions and experience.
Ethnographic studies can gain important insights into patient, family, survivor, and medical professional experience, with great potential to enhance care worldwide. For example, findings can lead to:
- More effective retinoblastoma awareness campaigns in diverse cultures;
- Reduced lag time from first signs of retinoblastoma to referral and diagnosis;
- Reduced stage of disease at diagnosis and chance of cure;
- Improved communication between professionals, caregivers, and decision-makers;
- Appropriate and consistent medical and psychosocial care;
- Greater uptake and completion of appropriate treatment and follow-up;
- Better coping and mental health for child patients, families, and survivors; and
- Relevant support provided by the family’s community.
A breakout group at One Rb World 2017, Washington D.C., including parents, survivors and professionals.
Qualitative and Quantitative Research
“Qualitative” and “quantitative” describe different scientific approaches to investigating a subject.
Quantitative research is highly structured, and designed to prove or disprove a theory using facts, numbers and statistics. These studies:
- Have a narrow focus;
- Test a pre-defined hypothesis;
- Rely on facts, numbers, and statistics;
- Use surveys and questionnaires* with closed questions and specified responses such as “YES/NO”, checklist boxes and multiple choice options, agreement scales such as “Terrible, Poor, Average, Good, Excellent”, and numbers such as age ranges or percentages.
Qualitative research is semi-structured and flexible, designed to answer a question and understand the human perspective, using direct observation. These studies:
- Are broad in focus;
- Develop a theory;
- Collect participant experiences, opinions, and views, and researcher observations;
- Use surveys and questionnaires* with open questions that ask respondents to use their own words rather than choosing a set response;
- Facilitate and observe focus groups;
- Use structured interviews and unstructured conversations; and
- Observe participants in their routines and activities of daily life.
*A questionnaire is a set of questions posed to research participants. It is one part of a survey – the scientific process of gathering, studying, and interpreting data from all participants. A questionnaire collects data; a survey aims to understand the subject.
Interventional and Observational Research
Medical research studies can be described as interventional and observational.
Interventional studies test a specific treatment, delivery method, procedure, diagnostic process, medical device, or therapeutic activity – in patients. All phase 1, 2, and 3 clinical trials are interventional studies.
Observational studies monitor and assess the current experience without modification, and describe the effects and outcomes. Epidemiological and ethnographic studies are usually observational. Phase 4 clinical studies are observational. Once a new therapy or system has been approved for general use, monitoring of its effectiveness and impacts may continue for years at Phase 4.
Research Informed Consent
Before participating in any research study, individuals or their parents will be asked to give informed consent. This usually involves signing a consent form that summarises the purpose of the research, what activities the participant is agreeing to, their potential benefits and risks. Clinical Trial consent will also include summary information about the treatment and its potential side effects, which are detailed in full in the research protocol.
Informed consent means you:
- Have received and reviewed all relevant information;
- Understand your child’s medical condition;
- Understand all options, including and in addition to the research study;
- Understand the potential benefits, risks, and side effects of your decision;
- Understand the possible short, medium, and long-term impacts of your decision;
- Have had appropriate opportunity to ask questions;
- Make this decision freely, without coercion; and
- Agree to the research activities / treatment described.
Read More: Clinical Trial Informed Consent
Challenges to Retinoblastoma Research
Rarity and Global Distribution
Retinoblastoma is rare. The number of diagnosed children is small, and patients are widely distributed around the world, many in remote and low resource communities.
Only 10% of affected children live in developed countries, where most retinoblastoma clinical research takes place and the main focus is saving sight.
90% of affected children live in developing countries, where clinical research is difficult due to limited resource. Most of these children have advanced cancer and the priority is life-saving treatment and palliative care.
This makes it difficult to conduct rigorous clinical research that effectively answers key questions with potential to improve life and vision outcomes for many.
Variations in “Standard” Treatment
Chemotherapy is globally recognized as the best non-surgical treatment for retinoblastoma. However, there are multiple ways to deliver chemotherapy, and no internationally agreed-to regimen for any of these. Accurate comparison of outcome from those diverse regimens is currently not possible.
There is also no universal agreement on pathological findings that indicate need for post-enucleation therapy. As a result, there is no standard treatment for retinoblastoma confined to the eye, or for high risk post-operative care.
Single Centre Research
Numerous single centre studies are investigating promising therapies. However, many children receiving a treatment under investigation have already received different treatments at that centre or elsewhere.
These differing treatment histories make it difficult to evaluate toxicity and extract meaningful conclusions about the treatment’s efficiency. The numbers of children enrolled are also very small, due to the rarity and global distribution of this cancer.
These studies cannot validate therapies, but they do provide important information about potential risks. They also put forward new ideas that could be studied effectively with collaborative multicentre research.
Lack of Randomization
The small numbers of children enrolled in individual research studies prevents randomization. Retinoblastoma is particularly difficult for randomization, since there are very many factors to be considered: numbers of tumours, one or both eyes affected, genetics, prior therapies, and social and economic factors.
Without standard therapy comparison, investigators cannot demonstrate how valuable an experimental therapy is. They cannot evaluate risk, or predict efficiency in treating a particular stage of disease.
In medical research, “bias” refers to factors that skew the study process, leading to conclusions differing from the reality. This is a universal challenge in all forms of research. Researchers may intentionally create a bias to reach certain conclusions, or the bias may be unintentional and unseen by the investigators.
Research bias relates to the study’s validity, and accuracy of its results. It does not describe a human characteristic, or imply fraudulent activity.
Many types of bias can influence all stages of research, from hypothesis or question and study design to analysis and interpretation of results. These biases cannot be accommodated during data analysis – the influencing factors must be addressed directly to minimise the risk of bias happening.
In retinoblastoma, some of the biggest bias concerns are:
- Cognitive Bias: Personal opinions, prejudices, preferences, and choices of the investigators;
- Systematic Bias: the methodology is not appropriate in the study’s context;
- Selection/Sampling bias: inappropriate criteria for recruiting participants, and small participant numbers;
- Measurement bias: using a data collection process that is not designed for the target population;
- Procedural Bias: participants are not given enough time or support to complete the requested tools such as questionnaires.
- Analysis bias: processing data to confirm the researcher’s hypothesis.
- Competition among treatment centres;
- Publication Bias: selective reporting of outcomes – this is particularly influenced by publication criteria, institutional competition, and funding from sources with vested interest in the results.
Barriers to Parent and Survivor Participation
Survivor participation in retinoblastoma research is key to understanding the long-term impacts of this cancer, and to improving care for survivors, children in treatment and families. But many barriers to participation hinder this research.
Many research tools use technology that may be inaccessible to an individual who is visually impaired or blind. When research tools are not independently accessible, the portion of our community most affected by this cancer are unable to participate effectively, with significant implications for the individual, and for the validity of research findings.
Survivors and family members also often find it difficult to revisit the memories and traumatic experiences encountered during treatment. While highly familiar to many people in the retinoblastoma community, this emotional aspect is often not considered when designing research studies. Many of us value research, but the unearthing of our experiences is so painful that we prefer to let it rest. This makes it very difficult to develop studies that truly capture psychosocial experiences and needs at different stages of the retinoblastoma lifetime journey.
Many survivors with sight loss are wary of divulging their personal psychological experience in a medical setting. When harmful perspectives already exist in the professional setting regarding individuals with disability, experiences can be misinterpreted, with serious consequences for a patient. Trust among individuals with disabilities has been significantly tested in this arena.
Read More: Retinoblastoma Clinical Research
Overcoming Challenges through Collaborative Research
Currently, retinoblastoma research benefits about 6% of children in the world with eye cancer. International multicentre clinical trials are the only effective way to test existing and new approaches to retinoblastoma care, and improve experiences and outcomes for the majority of children with eye cancer.
The best cancer outcomes are led by objective, unbiased research. Multicentre studies with larger participant numbers, and collaboration with survivors and families from the early hypothesis and design stage can help overcome many of the bias challenges that currently influence findings.
Awareness campaigns, medical and supportive care based on clear scientific evidence will dramatically improve children’s chances of survival with minimal negative effects, and lifelong survivor care and quality of life.
World Eye Cancer Hope encourages a collaborative global research community that challenges the rarity of this cancer. The One Retinoblastoma World conference unites researchers, medical professionals, parents, survivors, and children to address key issues in patient care, discuss research progress, and nurture collaborations to overcome obstacles to high quality evidence based care.
This article is only a brief summary of retinoblastoma research approaches, challenges, and solutions. We hope it helps clarify the most common misunderstandings, and highlights our greatest needs as a small global community fighting a rare childhood cancer with lifelong implications for many.
Later this year, we will bring you some more research focused articles, including bias in research and decision-making, opportunities for multicentre collaboration, and how research funding works.
Let’s work together to advance care and cure for all children with retinoblastoma, survivors, and their families!
About the Author
Abby’s father was diagnosed with bilateral retinoblastoma in Kenya in 1946. Abby was also born with cancer in both eyes. She has an artificial eye and limited vision in her left eye that is now failing due to late effects of radiotherapy in infancy.
Abby studied geography at university, with emphasis on development in sub-Saharan Africa. She co-founded WE C Hope with Brenda Gallie, responding to the needs of one child and the desire to help many in developing countries. After receiving many requests for help from American families and adult survivors, she co-founded the US chapter to bring hope and encourage action across the country.
Abby enjoys listening to audio books, creative writing, open water swimming and long country walks.