Verantwoording methodologie (Engels)

VERANTWOORDING METHODOLOGIE (ENGELS)

 

This guideline was developed using the GRADE methodology (Grades of Recommendation, Assessment, Development and Evaluation Working Group). All necessary steps towards creating recommendations for clinical practice are described below.

First, already existing guidelines were extracted from guideline-databases (GIN, NICE, IPOG, ASCO) and those were evaluated for applicability and direct implementation.

In the absence of an applicable, usable guideline for children with cancer, then,, together with a multidisciplinary guideline panel, clinical questions were defined.

 

1. Clinical questions:

The purpose of this guideline is to provide recommendations for children with cancer, receiving anti-cancer treatment with curative intent. This accounts for all of the following patient groups. The guideline was not intended to provide recommendations for palliative care settings.

1) Platelet transfusions (disease or clinical-status related)

PICO (1A)
P =       Children with any type of cancer (aged 28 days-18 years), receiving anti-cancer treatment
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer?

PICO (1B)
P =       Neonates (aged 0-28 days)* with any type of cancer
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

* A 28-day boundary was unanimously determined by the guideline panel as age for neonates.

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer?

 

PICO (2A)
P =       Children (aged 28 days-18 years) with acute myeloid leukemia (AML)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with AML?

 

PICO (2B)
P =       Neonates (aged 0-28 days) with AML
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with AML?

PICO (3A)
P =       Children (aged 28 days-18 years)  with acute promyelocytic leukemia (APL)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with APL?

 

PICO (3B)
P =       Neonates (aged 0-28 days) with APL
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes1 in neonates with APL?

PICO (4A)
P =       Children (aged 28 days-18 years) with acute lymphoblastic leukemia (ALL)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with ALL?

PICO (4B)
P =       Neonates (aged 0-28 days) with ALL
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-   cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with ALL?

 

PICO (5A)
P =       Children (aged 28 days-18 years) with cancer who suffer from septicemia (author-defined)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who suffer from septicemia?

 

PICO (5B)
P =       Neonates (aged 0-28 days) with cancer who suffer from septicemia (author- defined)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events,  transfusion-related complications, anti-
            cancer treatment-related complications, morbidity, mortality, admission to hospital, costs,
            quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who suffer from septicemia?

2) Platelet transfusions (procedure-related)

PICO (6A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo a lumbar puncture for the
            purpose of diagnosis
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo a lumbar puncture for the purpose of diagnosis?

 

PICO (6B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo a lumbar puncture for the purpose
            of diagnosis
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo a lumbar puncture for the purpose of diagnosis?

PICO (7A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo a lumbar puncture for
            therapeutic/treatment related purposes
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo a lumbar puncture for therapeutic/treatment-related purposes?

PICO (7B)
P =       Neonates (aged 0-28 days)  with cancer who need to undergo a lumbar puncture for
            therapeutic/treatment-related purposes
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo a lumbar puncture for therapeutic/treatment-related purposes?

PICO (8A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo a nasogastric tube insertion  
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Hemorrhagic events (mild or severe), transfusion-related complications, procedure-related
            complications, anti-cancer treatment related complications, morbidity, mortality, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo a nasogastric tube insertion?

 

PICO (8B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo a nasogastric tube insertion  
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Hemorrhagic events (mild or severe), transfusion-related complications, procedure-related
            complications, anti-cancer treatment related complications, morbidity, mortality, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo a nasogastric tube insertion?

PICO (9A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo a bone marrow aspiration or biopsy  
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes transfusion in children with cancer who need to undergo a bone marrow aspiration or biopsy ?

 

PICO (9B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo a bone marrow aspiration or biopsy  
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes transfusion in neonates with cancer who need to undergo a bone marrow aspiration or biopsy ?

PICO (10A)
P =       Children (aged 28 days-18 years)  with cancer who need to undergo neurosurgery
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo neurosurgery?

PICO (10B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo neurosurgery
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo neurosurgery?

 

PICO (11A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo ocular surgery/procedures
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-    cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo ocular surgery/procedures?

PICO (11B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo ocular surgery/procedures
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo ocular surgery/procedures?

PICO (12A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo minor surgery (bone
            biopsy, skin biopsy, lymph node biopsy, insertion of gastrostomy catheter, ultrasound-guided
            biopsy)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

 

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo minor surgery?

PICO (12B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo minor surgery (bone biopsy,
            skin biopsy, lymph node biopsy, insertion of gastrostomy catheter, ultrasound-guided biopsy)

I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival
 
What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo minor surgery?


PICO (13A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo major cancer-related
            surgery such as tumor resection or debulking
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival
 
What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo major surgery?

 

PICO (13B)
P =       Neonates (aged 0-28 days)  with cancer who need to undergo major cancer-related surgery
            such as tumor resection or debulking
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo major surgery?

PICO (14A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo a bronchoalveolar lavage
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo a bronchoalveolar lavage?

 

PICO (14B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo a bronchoalveolar lavage
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo a bronchoalveolar lavage?

PICO (15A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo line insertion or removal
            (central venous line, PICC line )
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo line insertion or removal?


PICO (15B)
P =       Neonates (aged 0-28 days) with cancer with who need to undergo line insertion or removal
            (central venous line, PICC line)
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival
 
What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo line insertion or removal?

PICO (16A)
P =       Children (aged 28 days-18 years) with cancer who need to undergo other (minimally) invasive
            procedure such as enemas, urinary catheter insertions
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-    cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in children with cancer who need to undergo other (minimally) invasive procedures?

PICO (16B)
P =       Neonates (aged 0-28 days) with cancer who need to undergo other (minimally) invasive
            procedure such as enemas, urinary catheter insertions
I =        Prophylactic platelet transfusion (at any threshold)
C =       (No prophylactic platelet transfusion or transfusion at any other threshold)
O =      Mild hemorrhagic events, severe hemorrhagic events, transfusion-related complications, anti-
            cancer treatment related complications, procedure-related complications, morbidity, mortality,
            admission to hospital, delay of procedure, influence, on outcome material, success-rate
            procedure, quality of life, event-free survival

What is the effect of prophylactic platelet transfusion on hemorrhagic events and other outcomes in neonates with cancer who need to undergo other (minimally) invasive procedures?

2. In- and exclusion criteria
Population:

Outcomes:

Type of studies:
            - Firstly, RCTs are preferred. Then, if these studies provide not enough evidence,
            other controlled studies can be included 
            - Case series and case reports will be excluded
            - No language resection
            - No year restriction
            - Databases: PubMed, Embase, Cochrane CENTRAL

 

3. Search strategy
Together with a medical librarian, an extensive literature search was created and performed (see Appendix 3). We searched for all terms regarding platelet transfusions in pediatric oncology patients, as defined in the clinical questions. PubMed, Embase and Cochrane CENTRAL were searched, with a total of 7486 results (most recently: December 2020). The entire in- and exclusion process is shown in Appendix 4).

 

Additionally, an extra search was performed by researcher DS. A search was made with entry terms ‘children with cancer’, ‘thrombocyte’ and ‘bleed’. Through this search, we aimed to find additional evidence from observational studies which reported bleeding in children with a specific platelet count. In total, 2167 unique entries were found. After title and abstract selection, 0 articles were eligible for inclusion for the development of this guideline.

Then, thirdly, in order to collect additional evidence from other guidelines, various established guideline databases were searched (i.e. GIN, NICE etc). Then after critically evaluating 11 additional guidelines, three of them (ASCO (3), NICE (2), FMS (1)) were eligible for inclusion and therefore were added as additional evidence. These three guidelines were chosen because of their methods and evidence-based approach. The applicable guidelines are mentioned per clinical question. For some, the single studies that were cited in those guidelines, were also individually assessed.

4. Quality of single studies

4.1 Evaluating methodological quality of included RCTs

Bias evaluation was performed according to the Cochrane handbook. (5)

4.2 Evaluating methodological quality of included non-RCTs
The methodology for Risk of Bias assessment had to be adjusted for the non-RCT studies. We combined the Risk of Bias tool for observational studies, as described in the IGHG Handbook (6), with a couple of aspects of the RCT tool as described earlier. By combining these tools, we aimed to have the best possible tool to assess the Risk of Bias in our types of studies. The tool that we used is shown in Table 2.


Table 2: Adjusted Risk of Bias criteria

Selection bias

Is the study group representative? Cases and controls were selected based on comparable patient characteristics (i.e. age, gender and tumor type)

 

Low risk if: no significant differences between cases and controls with respect to age, gender and tumor type

High risk if: cases and controls differ with respect to age, gender and tumor type (baseline imbalances caused by selection)

 

Attrition bias

Is complete outcome data for all the participants available in this study? Is the follow up adequate?

Low risk if: no missing data, reasons for missing data not related to outcome, missing data balanced across groups, proportion missing or plausible effect size nog enough to have a clinically relevant effect
High risk if: imbalance in numbers or reasons, proportion missing or plausible effect size enough to have a clinically relevant effect, inappropriate use of imputation, ‘as treated’ analysis with substantial departure from allocation

 

Detection bias

Are the outcome assessors blinded for important determinants related to the outcome?


Low risk if: the outcome assessors were blinded for important determinants related to the outcome

High risk if: no blinding or broken blinding and measurement likely to be influenced

 

Reporting bias

Is the report complete? Are the outcomes that were planned to be measured also reported?

High risk if: Outcomes not reported as pre-specified or expected or outcomes reported incompletely so they cannot be entered in meta-analysis

 

Confounding bias

Are the analyses adjusted for important confounding factors?

 

Low risk if: important prognostic factors (i.e. age, gender, diagnosis and risk stratification) were taken adequately into account
High risk if: important prognostic factors (i.e. age, gender, diagnosis and risk stratification) were inadequately or not taken into account

 

Other bias

The following list of other potential sources of bias in a clinical study may aid detection of further problems.

High if:

  • The conduct of the study is affected by interim results (e.g. recruiting additional participants from a subgroup showing more benefit).
  • There is deviation from the study protocol in a way that does not reflect clinical practice (e.g. post hoc stepping-up of doses to exaggerated levels).
  • There is pre-randomization administration of an intervention that could enhance or diminish the effect of a subsequent, randomized, intervention.
  • Inappropriate administration of an intervention (or co-intervention).
  • Contamination (e.g. participants pooling drugs).
  • Occurrence of ‘null bias’ due to interventions being insufficiently well delivered or overly wide inclusion criteria for participants (Woods 1995).
  • An insensitive instrument is used to measure outcomes (which can lead to under-estimation of both beneficial and harmful effects).
  • Selective reporting of subgroups.
  • Fraud.
  • Baseline imbalances for other reasons than through selection.
  • Other

 

 

4.3 Dual appraisal

All relevant steps (study identification, data extraction and management, assessment of risk of bias in included studies) were performed by two review authors (DS, DK), independently. Discrepancies will be resolved by consensus.

 

4.4 Summary of findings tables

For each clinical question a summary of findings table of the body of evidence will be completed. A summary of findings table provides key information of every single study about the main patient characteristics, the magnitude of effects for the defined outcomes and determinants, and the quality of that study.

5. Total body of evidence

5.1 Importance of outcomes
According to the GRADE methodology, the outcomes were defined as ‘low important, important or critical’. The importance of outcomes and its hierarchy were discussed in the guideline panel meeting. Based on consensus, the following hierarchy of importance was determined by the guideline panel:

 

Table 3: Importance of outcomes social restrictions

Critical

9

Severe hemorrhagic events
Mortality

8

 

7

Transfusion-related complications
Anti-cancer treatment-related complications
Morbidity
Event-free survival
Quality of life

Important

6

Mild hemorrhagic events
Admission to hospital
Influence on outcome material
Success rate procedure

5

 

4

Costs
Delay of procedure

Low importance

3



2

 

1

 

 

5.2 Grading the quality of the body of evidence (GRADE)
Then, the quality of the body of evidence per outcome is assessed. According to the GRADE methodology, a randomized controlled trial starts at a high quality evidence level, whereas a cohort study or other type of study starts at a lower quality evidence level. Then, the following considerations can lower the quality of evidence: inconsistency (degree of consistency of effect between or within studies), imprecision (the precision of the results), indirectness (the generalizability of population and outcomes from each study to the population of interest), publication bias or other study limitations.

Some factors might increase the quality of the evidence: for example, a large magnitude of effect or a dose-response gradient.

 

A total GRADE score for the total body of evidence will be appointed per outcome:

⊕⊕⊕⊕ High quality evidence

⊕⊕⊕⊖ Moderate quality evidence

⊕⊕⊖⊖ Low quality evidence

⊕⊖⊖⊖ Very low quality evidence

 

6. Translate evidence into recommendations – Evidence-to-Decision Framework

Results of literature studies were used to formulate recommendations. If no studies were identified, we carefully considered expert consensus.

 

According to the GRADE methodology, an evidence-to-decision (EtD) framework was used to translate evidence into recommendations. Below examples of the questions in such a EtD framework are shown. These questions were answered by the guideline panel to help form a recommendation.

 

7. Terminology in recommendations
We used the GRADE terminology for evidence-based guidelines, such as ‘we suggest’ or ‘we recommend’. For our expert evidence recommendations, we used the terminology from the following article: “Lexicon for guidance terminology in pediatric hematology/oncology: A White Paper” (7). For example, we used ‘we believe’, to emphasize that these recommendations are based on expert opinion and group consensus, and not on a relevant body of identified studies. For further information about this terminology, we refer to this specific paper.

 

General remarks applicable to all recommendations:
1) The purpose of this guideline is to provide recommendations for children with cancer, receiving anti-cancer treatment with curative intent. The guideline was not intended to provide recommendations for palliative care settings.

2) No evidence was found for neonates.