2. Introduction – Thyroid Cancer
2.1 Scope and Purpose
2.1.1 Objective and Key Questions
The aim of the S3 guideline "Thyroid Cancer" is to provide physicians who deal with thyroid diseases and affected patients with an evidence-based and accepted decision-making aid for the diagnosis and treatment of thyroid cancer that is tailored to the care situation in Germany in order to offer curative and optimal treatment to as many patients as possible and to enable follow-up care with a high quality of life.
The creation of the S3 guideline "Thyroid Cancer" will summarize and evaluate the current evidence for the entire course of treatment of the disease.
The recommendations for action drawn up on this basis are intended to bring about a qualitative improvement in medical treatment as well as in the care of affected patients
2.1.2 Target Audience
The guideline is aimed at the members of the following medical specialties or professional groups as well as those working in the fields mentioned, including those in training who aspire to a corresponding medical specialty or professional title or activity (in alphabetical order):
- General medicine
- General and visceral surgery
- Endocrinology
- Hematology and medical oncology
- Human genetics
- Internal medicine
- Pediatric endocrinology and diabetology
- Medical physics
- Nuclear medicine
- Oncological rehabilitation and social medicine
- Pediatric oncology and hematology
- Palliative medicine
- Pathology
- Phoniatrics and pediatric audiology
- Psycho-oncology
- Radiology
- Radiologic oncology
The guideline also provides information on good medical practice for:
- Medical-scientific societies, professional associations,
- Patient representatives and self-help groups, as well as
- Quality assurance bodies and institutions at federal and state level, such as
- the Federal Office for Radiation Protection (BfS),
- the German Medical Association (BÄK),
- Medical bodies (in accordance with Section 128 of the Radiation Protection Ordinance)
- the National Association of Statutory Health Insurance Physicians (KBV),
- the Central Institute for Statutory Health Insurance Physician Care in Germany (ZI),
- the Federal Joint Committee (GBA),
- the Institute for Quality and Efficiency in Health Care (IQWIG),
- the Institute for Quality and Transparency in Health Care (IQTIG),
- the Robert Koch Institute (RKI) and
- the Society of Epidemiologic Cancer Registries in Germany (GEKID),
- Certification bodies (e.g. OnkoZert),
- Cost bearers.
2.1.3 Validity and Update Process
The S3 guideline is valid until the next update; the estimated period of validity is five years. Regular updates are planned; if urgent changes are required, these will be published separately. Comments and suggestions for the updating process are expressly welcome and can be addressed to the offices of the lead specialist societies.
2.2 Methodology
The methodological procedure for the preparation of the guideline is set out in the guideline report. This is freely available on the Internet, e.g. on the websites of the German Guideline Program in Oncology and the AWMF (see Chapter 1.9).
2.2.1 Levels of Evidence (LoE) According
The evidence classification for questions addressed by Evidence-based Medicine | Cochrane Haematology (Prof. Dr. Nicole Skoetz) was carried out according to the scheme of the Oxford Centre for Evidence-based Medicine 2009 for intervention and prognostic studies (see table below). For nine recommendations, the endpoint-based assessment according to GRADE was used (see table "Scheme of evidence assessment according to GRADE"). Details can be found in the evidence report.
For drug-related questions that were processed by the GGPO Office, the quality of the evidence was assessed according to the GRADE methodology.
For drug-related questions that were dealt with in an evidence-based manner by the guideline group, the level of evidence was assessed according to the Oxford 2009 scheme following a critical evaluation of the study quality.
|
Level |
Therapy/Prevention, Etiology/Harm |
Prognosis |
Diagnosis |
|
1a |
SR (with homogeneity*) of RCTs |
SR (with homogeneity*) of inception cohort studies; CDR validated in different populations |
SR (with homogeneity*) of Level 1 diagnostic studies; CDR with 1b studies from different clinical centers |
|
1b |
Individual RCT (with narrow Confidence Interval”¡) |
Individual inception cohort study with > 80% follow-up; CDR" validated in a single population |
Validating** cohort study with good" " " reference standards; or CDR" tested within one clinical center |
|
1c |
All or none§ |
All or none case-series |
Absolute SpPins and SnNouts" " |
|
2a |
SR (with homogeneity*) of cohort studies |
SR (with homogeneity*) of either retrospective cohort studies or untreated control groups in RCTs |
SR (with homogeneity*) of Level >2 diagnostic studies |
|
2b |
Individual cohort study (including low quality RCT; e.g., <80% follow-up) |
Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR" or validated on split-sample§§§ only |
Exploratory** cohort study with good" " " reference standards; CDR" after derivation, or validated only on split-sample§§§ or databases |
|
2c |
"Outcomes" Research; Ecological studies |
"Outcomes" Research |
|
|
3a |
SR (with homogeneity*) of case-control studies |
SR (with homogeneity*) of 3b and better studies |
|
|
3b |
Individual case-control study |
Non-consecutive study; or without consistently applied reference standards |
|
|
4 |
Case-series (and poor quality cohort and case-control studies§§) |
Case-series (and poor quality prognostic cohort studies***) |
Case-control study, poor or non-independent reference standard |
|
5 |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
|
* By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a "-" at the end of their designated level. " Clinical Decision Rule. (These are algorithms or scoring systems that lead to a prognostic estimation or a diagnostic category). "¡ See note above for advice on how to understand, rate and use trials or other studies with wide confidence intervals. § Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it. §§ By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed to identify or appropriately control known confounders. §§§ Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into "derivation" and "validation" samples. " " An "Absolute SpPin" is a diagnostic finding whose specificity is so high that a Positive result rules-in the diagnosis. An "Absolute SnNout" is a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis. "¡"¡ Good, better, bad and worse refer to the comparisons between treatments in terms of their clinical risks and benefits. " " " Good reference standards are independent of the test, and applied blindly or objectively to applied to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study. " " " " Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and the same or more expensive. ** Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are 'significant'. *** By poor quality prognostic cohort study we mean one in which sampling was biased in favor of patients who already had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded, non-objective way, or there was no correction for confounding factors. **** Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (for example 1-6 months acute, 1 - 5 years chronic |
|||
Table 4:
Schema der Evidenzbewertung nach GRADE
| Bezeichnung | Erläuterung |
|---|---|
| ⊕⊕⊕⊕ | High quality of evidence according to GRADE = There is a lot of confidence that the true effect lies close to that of the estimated effect. |
| ⊕⊕⊕⊝ | Moderate quality of evidence according to GRADE = There is moderate confidence in the estimated effect: The true effect is likely to be close to the estimated effect, but there is a possibility that it is substantially different. |
| ⊕⊕⊝⊝ | Low quality of evidence according to GRADE = There is limited confidence in the estimated effect: The true effect might be substantially different from the estimated effect. |
| ⊕⊝⊝⊝ | Very low quality of evidence according to GRADE = There is very little confidence in the estimated effect: The true effect is likely to be substantially different from the estimated effect. |
2.2.2 Grades of Recommendation (GoR)
The guideline development methodology of the German Guideline Program in Oncology is based on the processes for S3 guidelines defined in the AWMF guidelines (Version 2.1 of 05.09.2023).
With regard to the strength of the individual recommendations, a distinction is being made between three recommendation grades, which are also reflected in the specific wording of the recommendations (see table "Scheme of recommendation grading").
In principle, the evidence-based recommendations were based on the strength of the available evidence, i.e. a high level of evidence (e.g. meta-analyses/systematic reviews of RCTs or several methodologically high-quality RCTs), i.e. a high level of certainty regarding the results should generally also lead to a strong recommendation (recommendation grade A, "shall").
In addition, further criteria were taken into account when selecting the level of recommendation. The following criteria taken into account could lead to an upward or downward deviation in the strength of recommendation:
Consistency of the study results
Example: The effect estimates of the study results go in different directions and do not show a uniform trend.
Clinical relevance of the endpoints and effect sizes
Example: Although there are studies with results in one direction, the significance of the selected endpoints and/or effect sizes is not considered relevant.
Benefit-risk ratio
Example: The proven benefit of an intervention is offset by a relevant aspect of harm which speaks against an unrestricted recommendation.
Ethical obligations
Example: Downgrading: For ethical reasons, an intervention with proven benefits cannot be offered without restriction. Upgrading: Strong recommendation based on e.g. case-control studies, as an RCT is not feasible for ethical reasons.
Patient preferences
Example: An intervention with proven benefit is not strongly recommended because it is rejected by patients as burdensome or impractical.
Applicability, feasibility in care
Example: An intervention with proven positive effects cannot be recommended because it cannot be offered in the regional care system for structural reasons.
The recommendation grades were determined within the framework of structured consensus conferences moderated by AWMF-certified neutral persons. As part of these processes, the recommendations were formally agreed by the voting mandate holders (see "Authors of the guideline").
The neutral moderation was carried out by employees of the AWMF (Dr. Nothacker) and the Office of the German Guideline Program in Oncology (Dr. Follmann, Mr. Langer, Mr. Wenzel).
The recommendations and statements adopted in this way are presented in separate boxes in the guideline, indicating the level of recommendation and the strength of consensus. In the case of evidence-based recommendations or statements, the underlying evidence and its respective evidence class is also indicated.
The results of the respective votes (strength of consensus) are assigned to the recommendations according to the categories in the following table 6.
Table 5:
Schema der Empfehlungsgraduierung
| Bezeichnung | Erläuterung |
|---|---|
| A | Strong recommendation for or against für a measure - expression used = shall/shall not |
| B | Recommendation for or against a measure - expression used = should/should not |
| 0 | Open recommendation (option) for a measure - expression used = can |
Table 6:
Festlegungen hinsichtlich der Konsensstärke
| Bezeichnung | Erläuterung |
|---|---|
| Strong consensus | > 95% approval from those eligible to vote |
| Consent | > 75-95% approval from those eligible to vote |
| Majority approval | > 50-75% approval from those eligible to vote |
| No majority approval | < 50% approval from those eligible to vote |
2.2.3 Statements
Statements are statements or explanations of specific facts or issues without a direct call for action. They are adopted as part of a formal consensus procedure in line with the procedure for recommendations and can be based either on study results or on expert opinions.
2.2.4 Expert Consensus
Expert consensus refers to recommendations for which no systematic search for relevant literature has been carried out. As a rule, these recommendations address procedures of good clinical practice for which no scientific studies exist or can be expected. No symbols or letters were used for the grading of expert consensus; the strength of the recommendation is determined by the wording used (shall/should/can) according to the grading in table 6 (see above).
2.2.5 Independence and Disclosure of Possible Conflicts of Interest
This guideline was funded by the German Cancer Aid as part of the German Guideline Program in Oncology. This funding was used in particular for personnel costs (guideline secretariat, evidence research) and the consensus conferences. The guideline was developed in editorial independence from the funding organization.
During the guideline process, all members of the guideline group submitted a declaration of any existing conflicts of interest via the AWMF portal "Declaration of Interests Online".
Participants who did not submit a such declaration were excluded from the consensus processes. The submitted declarations of interest were evaluated by the guideline coordinator and the steering group; those of the guideline coordinator and steering group were in turn evaluated by members of the guideline group and the commissioned methodologists.
The consequences of the declarations of interest submitted were agreed by consensus in each case. Minor conflicts of interest did not lead to any restrictions on collaboration. In the case of moderate conflicts, participation in the preparation of the guideline text was only tolerated if the members with moderate conflicts of interest were in the minority. Furthermore, abstention from voting was required for the recommendations concerned.
The topic of conflicts of interest was discussed in the guideline group and also addressed in all consensus conferences. The affected members of the guideline group abstained from the votes in which they had a corresponding conflict of interest. Abstentions were documented in the minutes. The disclosed relationships and circumstances are presented in the guideline report.