Van meerdere studies met immuuntherapie heeft slechts een studie met adjuvant pembrolizumab een verbetering van DFS en OS laten zien en is inmiddels door de EMA geregistreerd. In het TKI-tijdperk heeft van meerdere studies alleen een studie met sunitinib een verbetering van DFS getoond maar werd niet door de EMA geregistreerd.

Adjuvant Tyrosine kinase inhibitors versus placebo

Overall survival

Disease-free survival

All-cause adverse event (AE) of any grade

All-cause adverse event (AE) of grade ≥3

Treatment-related adverse events (trAEs) of any grade

Treatment-related adverse events (trAEs) of grade ≥3

Quality of life

Nivolumab with or without + ipilimumab versus placebo

Overall survival

Disease-free survival

All-cause adverse event (AE) of any grade

All-cause adverse event (AE) of grade ≥3

Treatment-related adverse events (trAEs) of any grade

Treatment-related adverse events (trAEs) of grade ≥3

Quality of life

Pembrolizumab versus placebo

Overall survival

Disease-free survival

All-cause adverse event (AE) of any grade

All-cause adverse event (AE) of grade ≥3

Treatment-related adverse events (trAEs) of any grade

Treatment-related adverse events (trAEs) of grade ≥3

Quality of life

Atezolizumab versus placebo

Overall survival

Disease-free survival

All-cause adverse event (AE) of any grade

All-cause adverse event (AE) of grade ≥3

Treatment-related adverse events (trAEs) of any grade

Treatment-related adverse events (trAEs) of grade ≥3

Quality of life

Adjuvant Tyrosine kinase inhibitors versus placebo

Description of studies

Riaz, 2021 performed a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating risk-benefit for adjuvant postoperative treatments in high-risk renal cell carcinoma by assessing reported disease-free survival (DFS), overall survival (OS), toxicity, and quality of life. A literature search was performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials to identify relevant RCTs (from database inception through May 15, 2018). The results of the ATLAS trial were published while writing this manuscript, and the manuscript was updated accordingly. Four phase 3 clinical trials with a total of 4820 patients were included in qualitative analysis and meta-analysis.

Results

Both disease free survival (DFS) and overall survival (OS) did not benefit from adjuvant tyrosine kinase inhibitors (TKIs). The highest-risk patients demonstrated no benefit in DFS in the subgroup analysis of either risk category. However the definition of highest risk varied across trials.

Therapy with TKI resulted in a higher risk of all-cause adverse event (AE) of any grade and all-cause adverse event (AE) of grade ³3 compared to the placebo.

1. Overall survival

TKI monotherapy offers no benefit in Overall survival (OS) (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) and is not considered clinically relevant.

2. Disease-free survival

TKI monotherapy offers benefit in disease-free survival (DFS) (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) but this difference is not considered clinically relevant.

3. All-cause adverse events

TKI monotherapy offers no benefit in all-cause adverse event (AE) of any grade (hazard ratio, 1.07; 95% CI, 1.02 to 1.12, high certainty) and is not considered clinically relevant.

4. All-cause adverse event (AE) of grade ≥3

TKI monotherapy offers no benefit in all-cause adverse event (AE) of grade ≥3 (hazard ratio, 2.44; 95% CI, 2.17 to 2.76, high certainty) and is considered clinically relevant.

5. Treatment-related adverse events TKI monotherapy offers no benefit in treatment-related adverse events (trAEs) of any grade
(hazard ratio, 1.45; 95% CI, 1.15 to 1.83, high certainty) and is considered clinically relevant.

6. Treatment-related adverse events (trAEs) of grade ≥3treatment-related adverse events (trAEs) of grade ≥3 TKI monotherapy offers no benefit in treatment-related adverse events (trAEs) of grade ≥3

(hazard ratio, 5.25; 95% CI, 3.10 to 8.88, high certainty) and is considered clinically relevant.

7. Quality of life

The PROTECT, S-TRAC, and ASSURE trials included some measure of QoL as a study outcome. The PROTECT trial used the Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19) questionnaire to assess QoL, and although significantly greater deterioration in QoL from baseline was seen in the TKI group compared with placebo (adjusted mean change in total FKSI-19 score at 1 year: −4.49 v −0.47, P , .01), this was not considered clinically relevant and QoL scores in both groups returned to baseline after treatment cessation. Similarly, in S-TRAC, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores favored placebo, but the difference was not clinically meaningful. The ASSURE trial collected patient-reported data on a quality-of-life (QoL) assessment for fatigue, called PROMIS Fatigue-SF1, but these results are yet to be published.

Level of evidence of the literature

Overall survival (OS)

The level of evidence regarding the outcome measure Overall Survival started at high (RCT) and was not downgraded.

Disease-free survival (DFS)

The level of evidence regarding the outcome measure Disease-free survival started at high (RCT) and was not downgraded.

All-cause adverse event (AE) of any grade

The level of evidence regarding the outcome measure all-cause adverse event (AE) of any grade started at high (RCT) and was not downgraded.

All-cause adverse event (AE) of grade ≥3

The level of evidence regarding the outcome measure all-cause adverse event (AE) of grade ≥3 started at high (RCT) and was not downgraded.

Treatment-related adverse events (trAEs) of any grade

The level of evidence regarding the outcome measure Treatment-related adverse events (trAEs) of any grade started at high (RCT) and was downgraded by 1 level to moderate because of number of included patients (imprecision, overlap of boundary of clinical relevance).

Treatment-related adverse events (trAEs) of grade ≥3

The level of evidence regarding the outcome measure treatment-related adverse events (trAEs) of grade ≥3 started at high (RCT) and was not downgraded.

Quality of life

The level of evidence regarding the outcome measure quality of life started at high (RCT) and was downgraded by 1 level to moderate because of applicability (bias due to indirectness: different measurement tools are used thus pooling of results is not possible).

Nivolumab with or without + ipilimumab versus placebo

Description of studies

Motzer, 2013 reported a double-blind, randomised, trial (CheckMate 914 ). Patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4–12 weeks before random assignment were included.Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 2 weeks, and treatment could be continued until week 36, allowing for treatment delays. 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female.

Results

1. Overall survival

The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group).

2. Disease-free survival

With a median follow-up of 37·0 months (IQR 31·3–43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71–1·19; p=0·53).

3. All-cause adverse events

In the all-treated population, 392 (97%) of 404 patients who received nivolumab plus ipilimumab and 361 (89%) of 407 patients who received placebo had at least one adverse event of any grade and of any cause. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo.

4. All-cause adverse event (AE) of grade ≥3

In total, 154 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had an adverse event of grade 3–5. The most common adverse events of any cause in the two arms were pruritus (32% with nivolumab plus ipilimumab and 17% with placebo), fatigue (30% with nivolumab plus ipilimumab and 27% with placebo), and diarrhoea (27% with nivolumab plus ipilimumab and 21% with placebo).

5. Treatment related adverse events

A total of 359 (89%) of 404 patients treated with nivolumab plus ipilimumab and 231 (57%) of 407 patients treated with placebo had at least one treatment-related adverse event of any grade. Treatment-related adverse events of any grade led to the discontinuation of nivolumab plus ipilimumab in 117 (29%) of 404 treated patients and of placebo in four (1%) of 407 treated patients

6. Treatment-related adverse events (trAEs) of grade ³3treatment-related adverse events (trAEs) of grade ≥3

28% of patients treated with nivolumab plus ipilimumab experienced a treatment-related adverse event of grade 3 or 4 as compared to 2% of patients treated with placebo.

7. Quality of life

Not reported.

Level of evidence of the literature

Overall survival (OS)

The level of evidence regarding the outcome measure Overall Survival started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Disease-free survival (DFS)

The level of evidence regarding the outcome measure Disease-free survival started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

All-cause adverse event (AE) of any grade

The level of evidence regarding the outcome measure all-cause adverse event (AE) of any grade started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

All-cause adverse event (AE) of grade ≥3

The level of evidence regarding the outcome measure all-cause adverse event (AE) of grade  ³3 started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Treatment-related adverse events (trAEs) of any grade

The level of evidence regarding the outcome measure Treatment-related adverse events (trAEs) of any grade started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Treatment-related adverse events (trAEs) of grade ≥3

The level of evidence regarding the outcome measure treatment-related adverse events (trAEs) of grade ³3 started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Quality of life

This outcome was not reported and could not be graded.

Pembrolizumab versus placebo

Description of studies

A total of three publications, describing one study reported a double-blind, randomised, trial (Keynote 564): Choueiri, 2021; Choueiri, 2024 and Powles 2022. A fourth publication updating overall survival was published after the literature search and shall be discussed in “Overwegingen – van bewijs tot aanbeveling” at the end of this chapter to support the recommendation. Patients with localised clear cell renal cell carcinoma with an increased risk of recurrence were included. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. The risk of disease recurrence was classified according to protocol-defined criteria as intermediate to high (tumor stage T2 with nuclear grade 4 or sarcomatoid features, or tumor stage T3; no regional lymph node or distant metas tasis present), high (tumor stage T4 with no regional lymph node or distant metastasis, or any tumor stage with the presence of regional lymph-node involvement), or stage M1 NED (no evidence of disease). Patients were randomly assigned to pembrolizumab 200 mg (n=496) or placebo (n=498) intravenously every 3 weeks for up to 17 cycles or until a new malignancy or any progression or recurrence of the malignancy under study occurred, the participant or physician decided to discontinue treatment, or any occurrence of pregnancy, intercurrent illness, or recurrent grade 2 or worse pneumonitis. Dose modifications for pembrolizumab were not permitted. Some patients had metastases and randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region.

Choueiri, 2021 reported the outcomes at the median time from randomization to the data-cutoff date of 24.1 months.

Powles reported long-term follow-up outcomes. The median follow-up (time from randomisation to the data cutoff date of June 14, 2021) was 30·1 months (IQR 25·7−36·7). The median number of treatment cycles administered was 17 (IQR 9–17) in the pembrolizumab group and 17 (16–17) in the placebo group. Among participants who received at least one dose of study treatment, 298 (61%) of 488 in the pembrolizumab group and 366 (74%) of 496 in the placebo group completed all 17 planned cycles of treatment.

Choueiri, 2024 reported the health-related quality of life (HRQoL) compared between treatment and placebo group. This was assessed by the European Organization for Research and Treatment of Cancer core quality of life questionnaire, (EORTC QLQ-C3)0 global health status/quality of life (GHS/QoL) and physical functioning scale scores and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index—Disease-Related Symptoms (FKSI-DRS).

Results

1. Overall survival

Chioueri, 2021 reports a total of 51 deaths (18 in the pembrolizumab group and 33 in the placebo group). The median overall survival was not reached in either group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96).

Powles, 2022 reports similar results: overall survival was better with pembrolizumab compared with placebo (HR 0.52 ( 95% CI 0.31–0.86). At 30 months follow up also median overall survival was not reached in either group. At 30 months, the estimated proportion of participants who were alive was 95.7% (95% CI 93.3–97.2) in the pembrolizumab group and 91.4% (88.3–93.7) in the placebo group.

2. Disease-free survival

Chioueri, 2021 reports that as of the data-cutoff date, 260 events of disease recurrence or death had occurred (109 events in the pembrolizumab group and 151 in the placebo group). The median disease-free survival was not reached in either group. The risk of disease recurrence or death was 32% lower with adjuvant pembrolizumab therapy than with placebo (hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P=0.002 [two-sided]).

Powles, 2022 reports similar results: disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]) in the intention-to-treat population. Median disease-free survival was not reached in either group.

3. All-cause adverse events

Chioueri, 2021 reports that in the as-treated population, 96.3% of the patients who received pembrolizumab and 91.1% of those who received placebo had at least one adverse event of any grade and of any cause.

Powles, 2021 reports that the adverse event profile of pembrolizumab was in line with those reported for this study previously, with no new safety signals.

4. All-cause adverse event (AE) of grade ≥3

Chioueri, 2021, describes that in total, 32.4% of the patients who received pembrolizumab and 17.7% of those who received placebo had an adverse event of grade 3 to 5. There were two deaths in the pembrolizumab group, which were due to multiple organ dysfunction syndrome and pneumonia (in one patient each), and one death in the placebo group, which was due to intracranial hemorrhage,Powles, 2021 states that Grade 3 or worse adverse events of any cause were reported in 157 (32%) of 488 participants in the pembrolizumab group and 88 (18%) of 496 participants in the placebo group. The most common grade 3 or worse adverse events of any cause were hypertension (in 14 [3%] participants) and increased alanine aminotransferase (11 [2%] participants) in the pembrolizumab group and hypertension (13 [3%] participants) in the placebo group.

5. Treatment related adverse events

Chioueri repoerted that a total of 386 patients (79.1%) who received pembrolizumab and 265 (53.4%) who received placebo had at least one adverse event of any grade that was attributed to pembrolizumab or placebo by the investigator, including an event of grade 3 or 4 in 18.9% of the patients who received pembrolizumab and 1.2% of those who received placebo.

Powles, 2022 did not report treatment related adverse events specifically.

6. Treatment-related adverse events (trAEs) of grade ³3treatment-related adverse events (trAEs) of grade ≥3

Chioueri, 2021 describes that no deaths that were attributed to either pembrolizumab or placebo occurred. At least one treatment-related serious adverse event occurred in 12.1% of the patients who received pembrolizumab and in 0.2% of those who received placebo.

Powles, 2022 similarly states that no deaths from treatment-related adverse events occurred in either study group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. The most common serious treatment-related adverse events (≥1% incidence) in the pembrolizumab group were adrenal insufficiency (six [1%] participants), colitis (six [1%]), and diabetic ketoacidosis (five [1%])

7. Quality of life

Chioueri, 2024 reported that adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (–2.5; 95% CI –5.2 to 0.1), EORTC QLQ-C30 physical functioning (–0.87; 95% CI –2.7 to 1.0), and FKSI-DRS (–0.7; 95% CI –1.2 to –0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%).

Level of evidence of the literature

Overall survival (OS)

The level of evidence regarding the outcome measure Overall Survival started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers, confidence interval crossing border for clinical relevance).

Disease-free survival (DFS)

The level of evidence regarding the outcome measure Disease-free survival started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers, confidence interval crossing border for clinical relevance).

All-cause adverse event (AE) of any grade

The level of evidence regarding the outcome measure all-cause adverse event (AE) of any grade started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers) and heterogeneity.

All-cause adverse event (AE) of grade ≥3

The level of evidence regarding the outcome measure all-cause adverse event (AE) of grade ≥3 started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Treatment-related adverse events (trAEs) of any grade

The level of evidence regarding the outcome measure Treatment-related adverse events (trAEs) of any grade started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers) and heterogeneity.

Treatment-related adverse events (trAEs) of grade ≥3

The level of evidence regarding the outcome measure treatment-related adverse events (trAEs) of grade ≥3 started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers) and heterogeneity.

Quality of life

The level of evidence regarding the outcome measure Overall Survival started at high (RCT) and was downgraded by two levels to low due to imprecision (wide confidence intervals).

Atezolizumab versus placebo

Description of studies

Pal, 2022 reported a double-blind, randomised, trial (IMmotion010 ). Eligible patients were patients aged 18 years or older with renal cell carcinoma with a clear cell or sarcomatoid component and increased risk of recurrence. After nephrectomy with or without metastasectomy, patients were randomly assigned (1:1) to receive atezolizumab (1200 mg) or placebo (both intravenous) once every 3 weeks for 16 cycles or 1 year. Patients with metastases were eligible for inclusion. Stratification factors were disease stage (T2 or T3a vs T3b–c or T4 or N+ vs M1 no evidence of disease), geographical region (north America [excluding Mexico] vs rest of the world), and PD-L1 status on tumour-infiltrating immune cells. 778 patients were enrolled; 390 (50%) were assigned to the atezolizumab group and 388 (50%) to the placebo group. The median follow-up duration was 44.7 months (IQR 39·1–51·0).

Results

1. Overall survival

At data cutoff, the overall survival was immature and patients alive were censored. There were 107 deaths, 54 (14%) in the atezolizumab group and 53 (14%) in the placebo group. There was no evidence of a reduced risk of death from any cause with adjuvant atezolizumab compared with placebo (HR 0.97, 95% CI 0.67–1.42). The 3-year overall survival rate was 90.3% (95% CI 87.3–93.3) in the atezolizumab group and 89.8% (86.6–92.9) in the placebo group.

2. Disease-free survival

332 events of investigator-assessed disease-free survival occurred (164 [42%] events in the atezolizumab group and 168 [43%] in the placebo group. Median disease-free survival (investigator assessment) was 57·2 months (95% CI 44.6 to not estimable) in the atezolizumab group and 49.5 months (47.4 to not estimable) in the placebo group (HR 0.93, 95% CI 0.75–1.15; p=0·50). 3-year disease-free survival was 59.4% (95% CI 54.4–64.5) in the atezolizumab group and 59.0% (54.0–64.0) in the placebo group. The corresponding percentages at 1 year were 77.4% (73.2–81.6; atezolizumab) and 74.1% (69.7–78.5; placebo), and 67.3% (62.6–72.1; atezolizumab) and 65.0% (60.2–69.9; placebo) at 2 years.

3. All-cause adverse events

Adverse events of any grade were reported in 373 (96%) patients who received atezolizumab and 341 (89%) patients who received placebo. Adverse events that occurred in at least 15% of patients who received atezolizumab were fatigue in 109 (28%) patients, diarrhoea in 87 (22%), arthralgia in 78 (20%), and pruritus in 74 (19%), whereas those occurring in at least 15% of patients who received placebo were fatigue in 93 (24%) and diarrhoea in 79 (21%).

4. All-cause adverse event (AE) of grade ≥3

Grade 3–4 adverse events occurred in 106 (27%) patients who received atezolizumab and 81 (21%) patients who received placebo.

There were four deaths due to adverse events in the study, one among patients who received atezolizumab and three among patients who received placebo. One patient who received atezolizumab died due to acute myeloid leukaemia. Among patients who received placebo, deaths due to adverse events resulted from respiratory failure, sepsis, and unknown cause.

5. Treatment related adverse events

296 patients (76%) who received atezolizumab and 203 (53%) who received placebo experienced at least one adverse event deemed by investigators as related to atezolizumab or placebo. Adverse events related to treatment that occurred in more than 10% of patients in the atezolizumab group were fatigue in 77 (20%) patients, pruritus in 56 (14%), hypothyroidism in 52 (13%), and diarrhoea in 45 (12%); those occurring in more than 10% of patients in the placebo group were fatigue in 69 (18%) patients, pruritus in 40 (10%), and diarrhoea in 39 (10%).

6. Treatment-related adverse events (trAEs) of grade ³3treatment-related adverse events (trAEs) of grade ≥3

Grade 3–4 adverse events related to treatment occurred in 55 (14%) patients who received atezolizumab and 18 (5%) who received placebo. The most common grade 3–4 adverse events were hypertension (seven [2%] patients who received atezolizumab versus 15 [4%] patients who received placebo), hyperglycaemia (ten [3%] vs six [2%]), and diarrhoea (two [1%] vs seven [2%]). There were no deaths attributed to treatment.

7. Quality of life

Not reported.

Level of evidence of the literature

Overall survival (OS)

The level of evidence regarding the outcome measure Overall Survival started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Disease-free survival (DFS)

The level of evidence regarding the outcome measure Disease-free survival started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

All-cause adverse event (AE) of any grade

The level of evidence regarding the outcome measure all-cause adverse event (AE) of any grade started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

All-cause adverse event (AE) of grade ≥3

The level of evidence regarding the outcome measure all-cause adverse event (AE) of grade ≥3 started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Treatment-related adverse events (trAEs) of any grade

The level of evidence regarding the outcome measure Treatment-related adverse events (trAEs) of any grade started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Treatment-related adverse events (trAEs) of grade ≥3

The level of evidence regarding the outcome measure treatment-related adverse events (trAEs) of grade ³3 started at high (RCT) and was downgraded by two levels to low due to imprecision (low event numbers).

Quality of life

This outcome was not reported and could not be graded.

A systematic review of the literature was performed to answer the following question:

What are the (un)desirable effects of adjuvant therapy compared to no adjuvant therapy in patients with non-metastatic renal cell carcinoma?

Relevant outcome measures

The guideline development group considered survival and progression-free survival a critical outcome measure for decision making; and quality of life as an important outcome measure for decision making.

The working group followed the definitions of the outcome measures as described in the included literature.

The working group used the GRADE default boundaries for clinical relevance (0.80-1.25) for all outcome measures as minimal clinically (patient) important differences.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 25-04-2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 37 hits. Studies were selected based on the following criteria: systematic reviews, RCT’s and observational studies. Studies were initially selected based on title and abstract screening. After reading the full text, 36 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 1 study was included. The search was updated on the 22nd of December 2023. The updated literature search yielded another 529 hits. After reading the full text, out of 14 studies a total of 10 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 4 additional studies were included in the literature analysis.

Thus the literature analysis contains 5 studies in total.

Results

5 of studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.