University of Groningen

Perfect pitstopsLoeffen, Erik

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Citation for published version (APA):Loeffen, E. (2019). Perfect pitstops: Towards evidence-based supportive care in children with cancer.[Groningen]: Rijksuniversiteit Groningen.

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CHAPTER 1GENERAL INTRODUCTION

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1.1 GENER AL INTRODUCTION

“There is no cure for leukemia; treatment is directed at prolonging life and relieving

symptoms. […] Without any treatment the average duration of life is approximately four

to five months. When transfusions and antibiotics are given, the life expectancy increases

to eight months; with a combination of folic acid antagonists, 6-M.P., and steroids given

in sequence children live an average of one year.” - Handbook of Pediatrics, Silver et

al., 1961.[1]

It is hard to imagine that these lines were published less than 60 years ago. In fact, in the

1961 “Handbook of Pediatrics” the chapter “Neoplastic diseases” only comprised 12 of

the total of 576 pages and contained various prognosis paragraphs similar to the one

quoted above. Nevertheless, the first signs of the upcoming treatment regimens that

would improve survival rates dramatically are already emerging: folic acid antagonists,

6-mercaptopurine and steroids are currently still used in the treatment of acute

lymphoblastic leukemia.

In the 60 years since the handbook was published, cure rates have improved to the

point that currently four out five children diagnosed with cancer in high-income countries

will be cured.[2] Nowadays it is almost hard to imagine that the quote above is about

acute lymphoblastic leukemia, as this is one of the types of childhood cancer with the

most dramatic improvement in survival rates (see Figure 1.1). This shows how much this

field of medicine has changed over the last decades.

Figure 1.1. Overall survival of children diagnosed with acute lymphoblastic leukemia who were enrolled in Children’s Cancer Group and Children’s Oncology Group clinical trials, 1968 to 2009. Source: Hunger et al.[3] Reproduced with permission from New England Journal of Medicine, Copyright Massachusetts Medical Society.

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GENERAL INTRODUCTION

A major factor in the increase in survival rates is the introduction of multimodal, intensive

treatment strategies comprising chemotherapy, radiotherapy, and/or surgery.[2] However

these intensive treatments come at a price, as they are associated with several side

effects, ranging from mild to potentially life-threatening. Children undergoing anti-cancer

therapy suffer from these side effects, which reduce quality of life. In addition, there is a

portion of children that die due to these side effects. Supportive care is the care focusing

on preventing and treating the side effects of anti-cancer therapy.

There should be a focus on improving supportive care. Because with the ongoing

improvement of childhood cancer survival rates, it is not only important if a child survives

cancer (although this naturally remains the main concern), but also, and increasingly so,

how a child survives cancer. To improve supportive care, and thus reduce treatment-

related morbidity and –mortality, development and implementation of evidence-based

guidelines is of the utmost importance, as this contributes to informed treatment

decisions and uniform care.

1.2 CHILDHOOD CANCER

INCIDENCE AND SURVIVALEach year approximately 550 children in the Netherlands are diagnosed with cancer.

This is in line with the European incidence rate, which is 14 per 100.000 children (aged

0-14 years).[4] Even though the aforementioned major advances have been made in

the treatment of childhood cancer, it remains an important cause of death in children

in high-income countries. For instance, in 2015 in the Netherlands, neoplasms were

responsible for 43 out of 158 deaths (27%) in children aged one to 10 years, and was

therefore the primary cause of death in this age group.[5] In children aged 10-18 years

external causes were the primary cause of death, followed by neoplasms with 23% of

deaths. For children younger than one year, cancer is only the cause of death in 1% of all

deaths, with the majority of deaths being due to conditions originating in the perinatal

period and congenital anomalies.

Cancer in children differs to great extent to cancer in adults. For one, a child is

growing and developing, which might affect treatment options and choices. In addition,

the distribution of cancer types is substantially different in children as compared to adults.

[2] Adults mainly suffer from solid malignancies, with carcinomas being the predominant

type. In children however, carcinomas only account for 1.5% of all malignancies.

Hematological malignancies, with leukemia occurring most frequently, have the highest

incidence in childhood cancer, covering nearly half of all diagnosed malignancies in

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children. Tumors of the central nervous system are also relatively common (23% of all

malignancies), as are embryonal tumors (25% of all malignancies). The distribution of the

types of cancer is highly dependent of age. For example, retinoblastoma accounts for

almost one in 10 cancer diagnoses under the age of one year, but occurs rarely above

the age of four years.

All tumor types have different treatment regimens, which are often designed as

trial protocols that are adhered to in a national or international manner. In this way,

with each protocol update a new treatment approach or adjustment that builds upon

the previous findings can be trialed. Treatment protocols can comprise one or more

treatment modalities, which are mostly chemotherapy, radiotherapy, surgery and/or

immunotherapy. The duration of treatment depends on the type of tumor and various

other factors (such as gene variations), and ranges from very short, for example one

surgical procedure for some types of germ cell tumors, to very long, for example three

years of chemotherapeutical treatment for some types of leukemia.

Although the overall survival in high-income countries has surpassed 80%, there is still

great variation in the prognosis of different types of cancer. There are tumor types with an

excellent prognosis, such as acute lymphoblastic leukemia (see Figure 1.1). Nevertheless

there are also tumors that remain very difficult to treat, such as stage 4 neuroblastoma

(10-year overall survival of 38%) or diffuse intrinsic pontine glioma (currently incurable).[6]

TREATMENT-RELATED MORBIDITY AND MORTALITYChildren who undergo treatment for cancer can be confronted with an array of side

effects, as each treatment modality has its own side effects profile. Chemotherapy can

lead to early toxicities such as nausea and vomiting, neuropathic pain, and/or bone

marrow suppression (which on its turn increases the risk of serious infections).[7] But

also late effects of chemotherapy occur, such as cardiotoxicity or infertility.[8] Each

chemotherapeutic drug has its own profile of side effects, of which the severity can differ

from individual to individual. Another widely used treatment modality, radiotherapy, is also

associated with both early toxicities (e.g. skin blistering) and late toxicities (e.g. cognitive

decline), depending on area and dose of irradiation.[9] Novel treatment modalities are

naturally aimed at improving survival, but might also be aimed at decreasing these side

effects. For instance, early cognitive outcomes in children irradiated to the brain using

proton radiation therapy, a relatively novel treatment modality, show superior results as

compared to traditional (photon) radiation therapy.[10]

Morbidity is naturally not limited to the direct somatic toxicities. In fact, when

parents were asked what they believed their children found the most bothersome

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GENERAL INTRODUCTION

cancer treatment-related adverse effects, the most prevalent symptoms were mood

swings, fatigue, and disappointment at missing activities with friends/peers.[11] All these

treatment-related adverse effects can severely decrease quality of life of a child and his/

her family.

In addition, as the side effects of cancer treatment can be very severe, there is a

portion of children that die due to these adverse effects. As the anti-cancer treatments

are becoming more and more intensive and the total number of children that die from

cancer is decreasing, preventing treatment-related deaths is crucial to further increase

survival rates.[12]

1.3 SUPPORTIVE CARE IN CHILDHOOD CANCER

Supportive care is aimed at reducing side effects of childhood cancer treatment in the

broadest sense. The Canadian clinician B. Page was among the first to define supportive

care in 1994 and did this in both a comprehensive and comprehensible manner: “[..] In

other words, supportive care is anything one does for the patient that is not aimed directly

at curing his disease but rather is focused at helping the patient and family get through

the illness in the best possible condition.”.[13]

Thus, supportive care is an extremely broad field, ranging from topics as medication

for reducing nausea and vomiting to distraction techniques for reducing procedural

pain, and from providing psychosocial support for a child and his/her family to treating

graft-versus-host disease, and so on.

Optimal supportive care is of the utmost importance as it has the potential to reduce

or even prevent early and late adverse effects of anti-cancer treatment, hereby increasing

quality of life and potentially even reducing mortality.

1.4 EVIDENCE-BASED MEDICINE

In 2007 the BMJ, one of the most important and influential peer-reviewed medical

journals, let readers vote on the world’s greatest medical milestones since the mid-19th

century.[14] Sanitation was the clear winner, but at number seven of these most important

advances was “evidence-based medicine”.

The term evidence-based medicine (EBM) was introduced to a wide audience in a

1992 publication by Gordon Guyatt from the Canadian McMaster University, still one of

the driving forces behind EBM developments today.[15] Guyatt was part of a medical

movement that gained momentum in the 1980s, and that argued that medical decisions

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should be based on the best available scientific knowledge and good arguments. This

was inspired by a feeling that medical decisions were too often based on seniority,

individual physician habits or successful marketing of pharmaceutical companies.

Since the introduction of EBM, the definition has expanded, stating that healthcare

practice should be “based on integrating knowledge gained from the best available

research evidence, clinical expertise, and patients’ values and circumstances.”.[16] Several

methods to facilitate EBM have been introduced, of which systematic reviews and meta-

analyses are among the most important. The body of medical scientific literature is

expanding at a speed impossible to keep up with as an individual practitioner. In fact,

the MEDLINE database, one of the largest databases with biomedical literature in the

world, indexed over 750.000 citations per year in the last 10 years.[17] This corresponds

to nearly 90 new medical papers being published every hour. Focusing on childhood

cancer, a relatively small clinical area, a simple MEDLINE search for studies published

in the last five years using “child AND cancer” resulted in 37.433 citations.[18] This still

corresponds to over 20 new childhood cancer studies published per day, an unattainable

rate to keep up with for an individual clinician.

Systematic reviews aim to summarize and critically appraise the available scientific

knowledge for a clinical question and are therefore a welcome aid for clinicians who

practice EBM. In 1993, an international network was formed that aimed to produce high-

quality systematic reviews in a collaborative manner.[19] This network was entitled The

Cochrane Collaboration, in memory of Archibald Cochrane, a Scottish epidemiologist

that is regarded as one of the founders of EBM and an early advocate for the importance

of randomized clinical trials. Presently, The Cochrane Collaboration is the largest

international organization involved in medical evidence syntheses and its methods are

considered as the standard reference for high-quality systematic reviews. Within the field

of childhood cancer, Cochrane Childhood Cancer plays an important role in identifying,

appraising, and synthesizing the available evidence on relevant clinical questions. The

editorial base of Cochrane Childhood Cancer is located in the Princess Máxima Center

for Pediatric Oncology in Utrecht, the Netherlands.

Conclusions from a systematic review can be used to develop evidence-based

guidelines. These guidelines recommend on care by combining the best available

scientific knowledge (systematic review conclusions) with other factors such as a

treatment’s acceptability, feasibility, and resource use. When using these guidelines

for clinical-decision making, patient relevant factors such as personal wishes and values

naturally also play an important role.

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GENERAL INTRODUCTION

EBM thus stimulated the connection between science and practice by asking structurized

clinical questions and developing evidence-based guidelines, and is pivotal to improving

care and clinical outcomes. A striking example of this importance is the estimation that

if research into preventing and treating AIDS had not been put into practice, currently

more than 50% of hospital beds in the US would be filled with AIDS patients.[16] This

makes EBM so crucial, as without it new insights would not be implemented in practice

and patients would not benefit from the medical scientific advances.

1.5 CLINICAL PR ACTICE GUIDELINES

DEFINITIONAs there are multiple interpretations of how an evidence-based guideline should be

composed, and more importantly when it is considered truly based on evidence, there

was a need for a more precise term and definition. In 2011 the Institute of Medicine

(IoM) published a document entitled “Clinical Practice Guidelines We Can Trust“, in

which the term Clinical Practice Guidelines (CPG) is defined as: “Statements that include

recommendations intended to optimize patient care that are informed by a systematic

review of evidence and an assessment of the benefits and harms of alternative care

options.”.[20]

There are various crucial factors in this definition. First; ‘intended to optimize

patient care’. Although this seems logical and perhaps even at first sight somewhat

condescending, it is important to stress this. Optimizing patient care should always be

the underlying main motivator of guideline development. Second; ‘systematic review of

evidence’. The CPG should be informed by a thorough and systematic evaluation and

appraisal of the existing literature. This comprises searching multiple databases, using

a priori developed comprehensive search strategies and search filters, with the results

appraised by multiple independent, trained appraisers. Third and final; ‘assessment of

the benefits and harms of alternative care options’. Naturally it is important to review

the treatment option the CPG is focusing on, but this should always be put in the

contemporary context. For example, are there more effective treatments? Are there

treatments that are evenly effective but more patient friendly or more cost-effective?

Guideline panels should not be fixated at merely studying the treatment they are focusing

on, but also assess alternative care options in a systematic and transparent manner.

Although the definition is quite comprehensive, there are various other factors that

are considered important parts of CPGs that lack in the IoM definition. Bulkier, but also

more comprehensive, the definition of CPGs could be rephrased to: “Statements that

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include recommendations intended to optimize patient care that are 1) informed by a

protocol-driven systematic review of evidence, 2) formulated by a representative panel of

professionals and patient representatives, and 3) include an assessment of the benefits,

harms, and other relevant outcomes of the care option and alternative care options.”.

EFFECTS OF CPGSAn important effect of CPGs is the reduction of practice variation, as uncertainty about

the most effective treatment has been found to be one of the most important causes

of practice variations.[21] Variation in practice implies one of the centers is not advising

the most effective treatment. Furthermore, being advised a specific treatment in one

hospital and a completely other treatment in another hospital can also be confusing and

frustrating for patients and their families. Thus in addition to contributing to uniform care,

CPGs might also increase the confidence of patients in the provided care.

Reduction of practice variations is important, as it has been shown to be related to

better health outcomes. For instance, in a study in children with asthma, variations in

practice were associated with worse outcomes as compared to outcomes in children

receiving uniform care.[22] With the care for children with cancer in the Netherlands

being centralized in 2018 in the new Princess Máxima Center for Pediatric Oncology

(Utrecht), care for all these children is coordinated from one center. This creates a unique

opportunity to implement CPGs and reduce practice variations (see Figure 1.2).

Figure 1.2. With the Dutch situation changing from seven primary pediatric oncology hospitals to one primary pediatric oncology hospital and several shared care centers, there is a unique oppor-tunity to facilitate uniform care, by going from the ‘classic’ situation (all centers use their internally developed protocols, see left panel) to the ‘desired’ situation (the Princess Máxima Center for Pediatric Oncology endorses supportive care CPGs and disseminates these to the shared care centers, see right panel).

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GENERAL INTRODUCTION

It has repeatedly been shown that care in line with recommendations from CPGs has

improved patient outcomes, in addition to facilitating a more efficient care delivery.

[23,24] For instance, multiple studies have shown that guideline-consistent anti-emetic

care was associated with a significant reduction of chemotherapy-induced nausea and

vomiting in adults.[25,26] The effect of guideline-consistent care can go even further, as

it was found that adherence to a CPG in relation to initiating antibiotic therapy in adult

low-risk febrile neutropenia was associated with decreased mortality.[27] The effect of

guideline adherence on outcomes in supportive care in children with cancer is an area

of research that deserves attention but is yet to be explored.

Besides contributing to better health outcomes and uniform care, CPGs have

additional benefits. They help clinicians to absorb the rapidly changing scientific state-

of-art in a clinical relevant matter, they can improve the knowledge and awareness of

patients (through educational materials), they can contribute to changes in public policy,

and they expose gaps of evidence for which future studies need to be initiated.[24]

EXISTING GUIDELINES IN SUPPORTIVE CARE IN CHILDHOOD CANCERCurrently the number of CPGs focused on topics in childhood cancer supportive care is

limited. Thankfully, for some important topics there are already recent CPGs available.

These topics comprise for instance nausea and vomiting, febrile neutropenia, mucositis

and fatigue.[7,28-33] Nevertheless, there are numerous important supportive care topics

for which evidence-based guidance is lacking. As the field of supportive care is very

broad, it is important to first develop CPGs for topics for which there is a high clinical

demand for guidance.

An important recent development is the initiation of the International Pediatric

Oncology Guidelines in Supportive Care Network (iPOG Network).[34] This is an

international, multidisciplinary network of healthcare professionals with an interest

in childhood cancer supportive care guideline development. By using international

collaboration, the effort that the development of a CPG takes can be shared, and by

informing one another on current projects, duplication of work is prevented. In addition,

the iPOG network plays a role in educating and supporting individuals or organizations

that aim to developed childhood cancer supportive care guidelines.

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1.6 DEVELOPMENT OF CPGS

Throughout the years, there have been various methods to developing an evidence-

based guideline. In an effort to create uniform, sensible, and transparent methods

for developing CPGs, the Grading of Recommendations Assessment, Development

and Evaluation (GRADE) working group was formed in 2000.[35] This working group

specifically focused on developing an approach to grade quality of evidence (or: certainty

of effect estimate) and strength of recommendations. Currently, the GRADE approach

is the world-leading standard for CPG development. Various organizations also provide

local guidance to guideline development (often incorporating the GRADE approach),

such as the Dutch National Health Care Institute with the AQUA directory on quality

standards.[36]

There are various phases in the development of a CPG, which will briefly be discussed:

1) startup, 2) clinical questions, 3) evidence search and selection, 4) data extraction and

quality appraisal, 5) summarizing evidence, 6) formulating recommendations, 7) writing

the CPG. An overview of the complete process can be found in Figure 1.3.

In phase one, the startup phase, the topic is selected and a comprehensive guideline

development panel (with multiple working groups if applicable) is composed. Also a

systematic search is carried out to identify existing, relevant guidelines. If multiple

guidelines on the desired topic are identified, the quality should be assessed and

concordances and discordances between recommendations should be evaluated.

In the case of concordant recommendations, it should be determined if there is

sufficient supporting evidence to support these recommendations. For the discordant

recommendations (and naturally for topics for which there is a lack of recommendations),

clinical questions can be composed.

During phase two, clinical questions are composed by the complete guideline

development panel. These should be composed using the PICO structure, an acronym

that stands for Patient (who is your target population?), Intervention (which treatment

do you want to study?), Control (which treatment do you want to compare it to?), and

Outcomes (on which benefits and harms do you want information?). It is important to

decide beforehand on the hierarchy of outcomes. In accordance to GRADE, outcomes

can be critical for decision making, important but not critical for decision making,

or not important for decision making.[37] This is scored by all panel members on a

9-point scale. Deciding this hierarchy a priori will facilitate the process of formulation of

recommendations later on in the process.

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GENERAL INTRODUCTION

When the PICO(s) are finalized, electronic search strategies can be designed. It

is becoming increasingly popular to have these search strategies peer reviewed for

correctness and applicability, e.g. by a librarian or a medical information specialist. In

addition, at this point the eligibility criteria for the study should be determined.

Hereafter, in phase three, the literature search is performed and the selection of

relevant citations can commence. This should be done by at least two independent

reviewers, whereby discrepancies should be discussed and solved by consensus or by use

of a third party arbiter. Usually, this selection is performed in multiple rounds depending

on number of citations, for instance first selection based upon titles and abstracts, then

based on full-text articles. It is advised to pilot the selection process to identify sub-

optimally defined criteria or other chances for optimization.

Phase four is performed in a similar dual, independent fashion as phase 3. In this

phase the data is extracted from the relevant studies, and the studies are evaluated for

their methodological quality. For the data extraction a purpose-build data extraction

form should be used (and piloted), that facilitates unambiguous extraction of relevant

data. The quality appraisal should be performed by using an appropriate and established

instrument for the specific study type. A well-known example is the Cochrane Risk of Bias

Tool for evaluating the quality of randomized controlled trials (RCTs).

When the study qualities are determined, the quality of the body of evidence per

outcome can be summarized using the GRADE system.[35] For this purpose all the

included studies per outcome are combined and the quality of the body of evidence is

graded as high, moderate, low, or very low. The classification is dependent upon multiple

factors: the initial study design (e.g. RCTs start as high quality, observational studies

as low quality), factors that require upgrading (dose response effect, large magnitude

of effect), and factors that require downgrading (study limitations, inconsistency,

indirectness, imprecision, or publication bias).

In phase five all findings are summarized in Summary of Findings tables, including

conclusions of evidence with an overall level of evidence (corresponding to the lowest

level of evidence of included critical outcomes). The Summary of Findings tables facilitate

guideline development panel members to have a structured and comprehensive overview

of the information needed to base recommendations upon. These tables are discussed

and finalized in accordance with the entire panel.

In phase six the guideline development panel will discuss the evidence and formulate

recommendations. These recommendations can be classified as strong or weak and

can be for or against an intervention. Strong recommendations, phrased as “we

recommend…”, imply that most informed patients would want to have that treatment,

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and most clinicians would want to prescribe that treatment. Weak recommendations,

phrased as “we suggest…”, imply that a large portion of informed patients would want

that treatment, but also many would not, and puts more focus on identifying individual

patient needs to base a joint decision upon.

In 2016 the GRADE working group introduced Evidence-to-decision (EtD) tables, which

facilitate the process of discussing the important factors for basing a recommendation

upon.[38,39] The EtD framework comprises 11 questions in six domains, i.e. problem,

benefits and harms, resource use, equity, acceptability, and feasibility. After discussing

and answering the questions, the panel then decides on the balance of desirable and

undesirable consequences on a 5-point scale. After this a recommendation strength

is chosen and the recommendation is formulated. This is supplemented with a short

justification, subgroup considerations, implementation considerations, monitoring and

evaluation considerations, and future research priorities. This systematic and transparent

approach to formulating recommendations not only helps the guideline development

panel, it also makes their choices and considerations insightful for users of the CPG.

When the formulations are finalized the CPG can be written (phase seven). The final

document should be reviewed and agreed upon by all guideline development panel

members, and can then be send out for external review by stakeholders.

IMPLEMENTATIONAs bringing a CPG development to a successful end is a lot of work, it might be tempting

to then breathe a sigh of relief and shift focus to another project. This would however

be a mistake, as the recommendations of a finalized CPG still have to be made aware to

clinicians and patients. It has proven to be challenging to implement a CPG successfully.

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GENERAL INTRODUCTION

Figure 1.3. An overview of the CPG development process, following GRADE methodology. Source: GRADE Handbook.[40]

Various factors have been identified that are potential barriers to successful guideline

implementation, for instance unfamiliarity with guidelines, reluctance of physicians

to change their approach, and practical barriers (e.g. availability of recommended

treatment).[41,42]

Multiple studies have evaluated the effectiveness of implementation strategies,

which proved to be a difficult concept to measure.[41,43] Although there is no gold

standard yet for implementation, there are various interventions identified that increase

the chance of a successful CPG implementation. Besides interventions specifically

tailored to the guideline recommendations (e.g. making the recommended treatment

more easily available), these comprised use of computerized decision-making systems,

formal training, active engagement of clinicians, and, perhaps most importantly, use of

multifaceted implementation strategies combining the aforementioned interventions.

[41,43,44]

A method to evaluate the implementation of guidelines, is to use indicators.

Indicators are measurable items that can evaluate structure of care (settings in which

care occurs), process of care (processes that belong to giving and receiving care), and

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outcome of care (states of health or events that follow care).[45] The aim of developing

and implementing indicators is to monitor, evaluate, and improve the quality of patient

care and care deliverance.

Recently, interest in indicators is growing. Several sets of indicators to evaluate quality

of care in multiple subdomains of adult oncology have been published and implemented.

[46-48] Also the effect of implementing indicators to improve quality of care has been

studied, for which it was found that feedback reports are among the most effective

implementation strategies.[49] In childhood cancer supportive care, development

and implementation of indicators is an underexposed area of research that should be

explored, as it has the potential to improve quality of care.

1.7 AIMS AND OUTLINE OF THIS THESIS

The aim of the research described in this thesis is to improve childhood cancer supportive

care, by developing and implementing supportive care CPGs for topics for which there

is a high need for guidance. The research can be divided in three parts: preparation,

development, and implementation.

PART I. PREPAR ATION FOR GUIDELINE DEVELOPMENTFirstly, we wanted to explore for which supportive care topics there was a high clinical

need for guidance. Thus in Chapter 2 we asked a multidisciplinary group of professionals

to prioritize topics for guideline development. This was done in a two-round Delphi survey

were side effects were first scored for prevalence, severity, and adequate treatment

options, and subsequently for importance to develop a CPG.

We also wanted to explore the views of patients and parents on supportive care,

use of guidelines, and shared decision making. Therefore, in Chapter 3 we report on

a qualitative study in which we held traditional focus group meetings with parents and

online asynchronous focus group meetings with children aged 12-18 years.

In Chapter 4 we explored the current state of supportive care practice in the

Netherlands, focusing on concordances and discordances between supportive care

practice in the then primary pediatric oncology hospitals. We also evaluated if current

practice was in line with recommendations from existing supportive care CPGs.

The preparation phase culminated in a plea (Chapter 5) for the development and

implementation of CPGs for childhood cancer supportive care, in which we argue why

these guidelines are desperately needed.

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GENERAL INTRODUCTION

PART II . DEVELOPMENT OF CLINICAL PR ACTICE GUIDELINESIn Chapter 6 we present the methodology for the development of a CPG we developed

from scratch, focused on assessment and management of pain in children with cancer.

In this chapter also the overall results of the inclusion and appraisal of evidence are

discussed. As this CPG is very extensive, encompassing 22 clinical questions that we

aimed to answer, we opted to publish this guideline in three parts. In Chapter 7, one

of these parts is presented, i.e. the part that focused on the pharmacological, physical,

and psychological treatment of procedure-related pain and distress in children with

cancer. The other two parts focused on assessment of pain in children with cancer, and

pharmacological, physical, and psychological treatment of tumor- and toxicity-related

pain in children with cancer.

Another approach to develop a CPG is to use an existing high-quality evidence

synthesis and update its findings, whereafter these can be discussed by the guideline

development panel and recommendations can be formulated. In Chapter 8 we present

such an approach, that we used to develop a CPG in which we provided recommendations

on the infusion duration of anthracycline chemotherapy agents in children with cancer.

PART III . IMPLEMENTATION OF CLINICAL PR ACTICE GUIDELINESTo evaluate how guidelines can be implemented we explored various approaches. In

Chapter 9 we aimed to put an existing CPG for pediatric palliative care more firmly

into practice, as it was previously proved to be underused. We did this by developing

and piloting a functional individualized pediatric palliative care plan that covers

physical, psychological, spiritual and social functioning, and puts great emphasis on

the recommendations from the CPG, advance care planning and patients’ and parents’

preferences and desires.

In Chapter 10 we explored how we could develop and use indicators to measure

the current state of care, more specifically to evaluate the implementation of a nationally

endorsed febrile neutropenia guideline, and to produce baseline measurements on local

quality of febrile neutropenia care.

Not all topics lend itself for indicator development, as sometimes there is not

sufficient information available to define these indicators upon. Therefore, in Chapter 11

we tried to define grounds for indicators for treatment-related mortality by exploring in

a cohort of over 1750 children with cancer how many children died, how many deaths

were treatment-related, and if we could identify risk factors for treatment-related death.

In Chapter 12 the findings of all studies are summarized and discussed, and future

perspectives are presented.

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1.8 REFERENCES

[1] Silver HK, Kemp CH, Bruyn HB. Handbook of Pediatrics. 4th edition. Los Altos,

California, United States of America: Lange Medical Publications; 1961. p301-302.

[2] Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010 Jun;36(4):277–85.

[3] Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. Longo DL,

editor. N Engl J Med. 2015 Oct 15;373(16):1541–52.

[4] Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh J-W, Lacour B,

et al. Geographical patterns and time trends of cancer incidence and survival

among children and adolescents in Europe since the 1970s (the ACCIS project): an

epidemiological study. Lancet. 2004 Dec;364(9451):2097–105.

[5] Statistics Netherlands. CBS Statline - Deaths; underlying cause of death

[Internet] . 2018 [cited 2018 Oct 8] . Available from: http://statline.cbs.nl/

Statweb/publication/?DM=SLEN&PA=705 2eng&D1=a&D2=0&D3=1-4&D4=65&

LA=EN&HDR=G1,G2,G3&STB=T&VW=T

[6] Berthold F, Spix C, Kaatsch P, Lampert F. Incidence, Survival, and Treatment of

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preparation for guideline development

PART 1