Oligometastasering
Uitgangsvraag
Wat is de rol van lokale behandeling (chirurgische metastasectomie, SBRT, ablatieve technieken) bij patiënten met a) synchrone oligometastasen / b) metachrone oligometastasen?
Aanbeveling
Bespreek de voor- en nadelen (uitstel systemische behandeling, mogelijke overlevingswinst versus invasieve behandeling oligometastasen) met de patiënt van de lokale behandeling van oligometastasen.
Overweeg focale therapieën wanneer die een bijdrage kunnen leveren aan een curatieve behandeling en/of verlichting van klachten. Hierbij dient de conditie en comobiditeit van patient, localisatie van metastasen, aantal metastasen en lokale beschikbaarheid en expertise meegenomen te worden in de keuze voor behandeling en soort therapie.
Aanbeveling-subgroep metachrone oligometastasen
Overweeg metastasectomie bij patiënten met metachrone oligometastasen op basis van mogelijke overlevingswinst, klachtenverlichting en eventueel uitstel van systemische therapie. Bespreek hierbij met de patiënt de voor- en nadelen van een invasieve behandeling in vergelijking met een afwachtend beleid.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
De werkgroep heeft een literatuurstudie verricht naar welke behandeling ( metastasectomie, SBRT/SABR, ablatieve therapie) het beste kan worden toegepast bij patiënten met synchrone oligometastasen / metachrone oligometastasen.
1. Metastasectomie
Er werd één systematische review (Hsieh, 2021) gevonden met daarin acht relevante observationele studies over het effect van metastasectomy (Alt, 2011; Ishihara, 2020; Kwak, 2007; Li, 2018; Russo, 2007; Sun, 2018; You, 2016; Yu, 2015). Daarnaast werden er nog zeven andere observationele studies over metastasectomy gevonden (Dragomir, 2020; Fares, 2019; Kim, 2019; Shin, 2021; Suzuki, 2021; Thomas, 2016; Tornberg, 2018).
De bewijskracht voor de cruciale uitkomstmaat ‘overall survival’ werd beoordeeld als zeer laag vanwege methodologische beperkingen door de retrospectieve studie opzet en heterogeniteit tussen de studies. Voor de cruciale uitkomstmaat ‘ziektevrije overleving’ werd geen bewijs gevonden. Dit leidt tot een zeer lage overall bewijskracht. Ook voor de belangrijke uitkomstmaten ‘kwaliteit van leven’, ‘complicaties’ en ‘uitstel van systeemtherapie’ werd geen bewijs gevonden of was de bewijskracht zeer laag door methodologische beperkingen en het lage aantal deelnemers. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten.
2. SBRT/SABR
Eén observationele studie over het effect van radiotherapie werd gevonden (Liu, 2021). De bewijskracht voor de cruciale uitkomstmaat ‘overall survival’ werd beoordeeld als zeer laag vanwege methodologische beperkingen door de retrospectieve studie opzet .Voor de cruciale uitkomstmaat ‘ziektevrije overleving’ en de belangrijke uitkomstmaten ‘kwaliteit van leven’,
‘complicaties’ en ‘uitstel van systeemtherapie’ werd geen bewijs gevonden. Dit leidt tot een zeer lage overall bewijskracht. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten.
Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over welke behandeling (metastasectomie, SABR, ablatie) het beste kan worden toegepast bij patiënten met synchrone oligometastasen / metachrone oligometastasen.
In de dagelijkse praktijk wordt SABR bij patienten met oligometasen met enige regelmaat toegepast. Dit kan een reden zijn om systemische therapie uit te stellen. In twee prospectieve studies waarbij patienten werden behandeld met SABR in plaats van systemische therapie, resulteerde dit in een 1-jaars systemische therapie-vrije overleving van 82-91% (C. Tang, et al, Lancet Oncol, 2021 R. Hannan et al, European Urology Oncology 2022).
Veiligheid van de behandeling werd bevestigd in de specifieke populatie van patiënten met oligometastasen in een recente meta-analyse met goede resultaten voor wat betreft lokale controle van behandeling middels SABR (E.J. Lehrer, JAMA Oncol, 7 (2021). De SABR-ORCA meta-analyse rapporteerde over 28 studies en 623 patiënten met 2733 extracraniële metastasen van RCC behandeld met SABR, waarbij de lokale controle en OS na 1 jaar 89.1% en 86.8%, respectievelijk is. Behandeling—gerelateerde bijwerkingen waren minimaal met slechts 0.7% graad 3–4 bijwerkingen (N.G. Zaorsky, et al, Eur Urol Oncol, 2 (2019)). De grote beperking van deze meta-analyse is dat het een heterogene populatie betreft met oligometastatische, oligoprogressieve en polymetastastische patiënten die behandeld worden met SABR alleen, of gecombineerd met systemische therapie.
Ook lokale behandeling middels percutane ablatie is een regelmatig toegepaste methode. Verschillende (retrospectieve) studies hebben aangetoond dat de behandeling veilig en effectief is. Technisch succes van de behandeling ligt bijvoorbeeld rond de 95-98% (Aurilio, 2023; Welch, 2014) en de beschreven complicatiekans tussen 2 en 20% (afhankelijk van de locatie van de lesie en gebruikte techniek, welch, aurilio), waarbij veruit het grootste deel zelf-limiterende bloedingen betreft. Ook de beschreven lokale recurrence rate is laag (7-7,9%, welch, aurilio) en de gemiddelde overal survival lijkt vergelijkbaar met lokale behandeling middels resectie of radiotherapie. Echter, ook hier gaat het om retrospectieve series met inherente (selectie) bias. Resultaten dienen dus met voorzichtigheid te worden geinterpreteerd.
Het is derhalve belangrijk dat toekomstig onderzoek zich richt op de lange termijn uitkomsten van deze behandelmodaliteiten, passende klinische parameters en biomarkers voor een betere patiënten selectie.
Daarnaast is het belangrijk om de behandeling van oligometastasen middels metastatectomie, percutane ablatie en SABR ook uit te zetten tegen active surveillance (AS). In een recent gerapporteerde prospectieve observationele studie worden patiënten met een oligo-gemetastaseerd RCC die geen behandeling krijgen vergeleken met patiënten die direct starten met systemische behandeling. Resultaten laten zien dat in deze beschreven, geselecteerde groep, AS een veilig en gepast alternatief is voor het direct starten met systemische behandeling; een deel van deze patienten kreeg echter tijdens de AS ook metastase gerichte lokale behandeling. (Harrison, 2021).
Een prospectieve fase III studie is essentieel om de rol en waarde van lokale behandeling middels percutane ablatie, SBRT/SABR en metastastactomie in de setting van oligo-gemetastaseerde patiënten te onderzoeken.
Waarden en voorkeuren van patiënten (en evt. hun verzorgers)
De werkgroep heeft op grond van beschikbare literatuur geen verschil kunnen vinden tussen de behandeling middels metastatectomie, percutane ablatie of SABR voor oligo-gemetastaseerde ziekte voor wat betreft overleving. Verdere prospectief gerandomiseerde studies zijn nodig om het toegevoegde effect van lokale therapie (ablatie, metastatectomie en SABR) te vergelijken met active surveillance of systemische therapie en om te identificeren welke patiënten hier het meeste voordeel van hebben. Hierbij is het ook belangrijk om patiënt gerapporteerde uitkomsten mee te nemen.
Als er sprake is van beperkte metastasen (1-5) dient men lokale behandeling te overwegen versus start met systemische behandeling of active surveillance. In de setting van één metastase bij patiënten in een goede conditie, waarbij nog geen weefsel bevestiging is voor wat betreft gemetastaseerde ziekte, heeft het vaak de voorkeur om een radicale metastatectomie of ablatie (met biopsie) te verrichten als de locatie dit toelaat. Bij patiënten in een goede conditie met 2-5 metastasen kan SABR overwogen worden als niet invasieve behandeling in 1-5 sessies. In deze patientengroep is een percutane ablatie ook vaak een optie, afhankelijk van de locatie van de lesie(s). Meestal worden per sessie maximaal 3 lesies behandeld. Hierbij is het belangrijk mee te nemen dat bijwerkingen gerelateerd aan de behandeling beperkt zijn met een grote kans op lokale controle van de ziekte.
Als men behandeld wordt middels systemische therapie en er is sprake van oligoprogressieve ziekte, dat wil zeggen een metastase groeit of gaat weer groeien, kan
lokale behandeling overwogen worden met als doel uitstel van switch naar een tweede lijn systemische behandeling. Vaak wordt hierbij percutane ablatie of SABR overwogen. Het voordeel van SABR is het niet-invasieve aspect.
Kosten (middelenbeslag)
De kosten effecten van metastatectomie, SABR en percutane ablaties zijn onvoldoende onderzocht. Ten opzichte van start met systemische behandeling is de verwachting dat lokale behandeling middels metastatectomie, SABR en percutane ablatie goedkoper is.
Aanvaardbaarheid, haalbaarheid en implementatie
Er zijn in Nederland enkele ziekenhuizen waar ervaring is met het uitvoeren van zowel metastatectomie, percutane ablatie en SABR. Ziekenhuizen die niet over deze ervaring of mogelijkheden beschikken dienen patiënten met oligo-gemetastaseerde ziekte te bespreken in een MDO met een centrum dat deze behandelingen aanbiedt, zodat voor alle patiënten een weloverwogen advies wordt geformuleerd waarbij langdurige (lokale) ziekte controle waarbij curatie de intentie kan zijn, of uitstel van systemische behandeling of uitstel van switch naar een tweede lijn systemische behandeling het uitgangspunt is en patiënten de kans krijgen om in expertise centra behandeld te worden. Door patiënten te bespreken vindt er verspreiding van kennis plaats en wordt er meer naar eenduidig beleid gestreefd.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Het effect van zowel metastasectomie als percutane ablatie en stereotactische radiotherapie op overleving is in vergelijking met geen/incomplete verwijdering van oligometastasen erg onzeker. Het level of evidence is namelijk zeer laag. Voor ablatie zijn er geen vergelijkende studies gevonden die de zoekvraag beantwoorden. Over het effect op ziektevrije overleving, complicaties en uitstel van systemische therapie is geen uitspraak te doen door gebrek aan gegevens. De rol die systemische therapie of immunotherapie hierbij speelt is tevens erg onzeker, hetgeen de plaatsbepaling en sequentie hiervan bemoeilijkt.
De keuze tussen metastatectomie, (percutane) ablatieve technieken zoals RFA, MWA, cryoablatie en SABR voor de behandeling van oligometastasen dient te worden gemaakt op basis van tumor karakteristieken (zoals aantal metastasen en locatie van de metastasen), patiëntenkarakteristieken (zoals conditie van de patiënt, co-morbiditeit), het moment van ontstaan van de metastasen en de voorkeur van de patiënt, waarbij afwachten of starten met systemische behandeling meegenomen moet worden.
Aanbeveling-subgroep metachrone oligometastasen
In subgroep analyse lijkt er mogelijk een voordeel in overleving voor metastasectomie in patienten met metachrone oligometastasen, echter is het level of evidence erg laag en daarmee het effect onzeker.
Onderbouwing
Achtergrond
Voor patiënten met oligometastasen (≤5 in ≤2 organen) kan zowel in de synchrone als in de metachrone setting, definitieve metastase-gerichte lokale therapie aangeboden worden zoals een metastasectomie, ablatieve therapie zoals RFA, cryo- of microwave ablatie (MWA) als ook hooggedoseerde radiotherapie (stereotactische ablatieve radiotherapie, SABR). Het is onduidelijk wat de optimale timing is van inzet van een van deze lokaal ablatieve behandelingen. Ook is niet duidelijk welke therapie het beste ingezet kan worden, die mogelijk afhankelijk is van de locatie van de metastasen. Het doel van definitieve metastase-gerichte lokale therapie kan zijn: langdurige (lokale) ziekte controle waarbij curatie de intentie kan zijn, of uitstel van systemische behandeling of uitstel van switch naar een tweede lijn systemische behandeling, echter het effect hiervan op overleving is nog niet duidelijk.
We houden hierbij aan dat synchrone oligometastasen zijn ontstaan binnen 6 maanden na diagnose van de primaire tumor en metachrone oligometastasen 6 maanden na diagnose van de primaire tumor zijn ontstaan, zonder het geven van systemische behandeling in die periode. Van oligoprogressieve ziekte is sprake als er groei of opnieuw groei is van een metastase onder systemische behandeling.
Conclusies / Summary of Findings
1. Metastasectomy
|
Very low GRADE |
The evidence is very uncertain about the effect of metastasectomy on overall survival when compared with no or incomplete removal in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases.
Sources: Kwak, 2007; Russo, 2007 |
|
No GRADE |
No evidence was found regarding the effect of metastasectomy on disease-free survival, quality of life, complications, and postponement of systemic therapy when compared with no or incomplete removal in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases. |
Synchronous metastases
|
Very low GRADE |
The evidence is very uncertain about the effect of metastasectomy on overall survival when compared with no or incomplete removal in patients with renal cell carcinoma and synchronous oligometastases.
Sources: Shin, 2020; Thomas, 2016 |
|
No GRADE |
No evidence was found regarding the effect of metastasectomy on disease-free survival, quality of life, complications, and postponement of systemic therapy when compared with no or incomplete removal in patients with renal cell carcinoma and synchronous oligometastases. |
Metachronous metastases
|
Very low GRADE |
The evidence is very uncertain about the effect of metastasectomy on overall survival when compared with no or incomplete removal in patients with renal cell carcinoma and metachronous metastases.
Sources: Shin, 2020; Thomas, 2016 |
|
No GRADE |
No evidence was found regarding the effect of metastasectomy on disease-free survival, quality of life, complications, and postponement of systemic therapy when compared with no or incomplete removal in patients with renal cell carcinoma and metachronous metastases. |
Subgroup: additional use of targeted therapy/immunotherapy
|
Very low GRADE |
The evidence is very uncertain about the effect of metastasectomy (with targeted therapy/immunotherapy) on overall survival when compared with no or incomplete removal (and targeted therapy/immunotherapy) in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases.
Sources: Dragomir, 2020; Ishihara, 2020; Kim, 2019; Li, 2018; Sun, 2018; Suzuki, 2022; You, 2016; Yu, 2015 |
|
Very low GRADE |
The evidence is very uncertain about the effect of metastasectomy (with targeted therapy/immunotherapy) on complications when compared with no or incomplete removal (and targeted therapy/immunotherapy) in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases.
Source: Suzuki, 2022 |
|
Very low GRADE |
The evidence is very uncertain about the effect of metastasectomy (with targeted therapy/immunotherapy) on postponement of systemic therapy when compared with no or incomplete removal (and targeted therapy/immunotherapy) in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases.
Source: Dragomir, 2020; Tornberg, 2018 |
|
No GRADE |
No evidence was found regarding the effect of metastasectomy (with targeted therapy/immunotherapy) on disease-free survival and quality of life when compared with no or incomplete removal (and targeted therapy/ immunotherapy) in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases. |
2. (stereotactic) radiotherapy
|
Very low GRADE |
The evidence is very uncertain about the effect of stereotactic radiation therapy (with tyrosine kinase inhibitors) on overall survival when compared with no or incomplete removal (and tyrosine kinase inhibitors) in patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases.
Source: Liu, 2021 |
|
No GRADE |
No evidence was found regarding the effect of stereotactic radiation therapy (with tyrosine kinase inhibitors) on disease-free survival, quality of life, complications, and postponement of systemic therapy when compared with no or incomplete removal (and tyrosine kinase inhibitors) on patients with renal cell carcinoma and synchronous oligometastases and metachronous metastases. |
Samenvatting literatuur
1. Metastasectomy
Description of studies
Kwak (2007) performed a retrospective study to determine the efficacy of metastasectomy after nephrectomy in patient with metastatic renal cell carcinoma who had not received systemic therapy. Patients who had not undergone radical nephrectomy or metastasectomy was incomplete were excluded. In total, 21 patients received metastasectomy and 41 patients did not receive metastasectomy. Groups were not comparable. Patients in the non-metastasectomy group had a higher ECOG performance status, had more poor prognostic factors, and had more multiple metastases. The outcome of interest was overall survival.
Russo (2007) performed a retrospective study to examine the effect of cytoreductive nephrectomy alone or in conjunction with nephrectomy and complete metastasectomy. It was not reported whether these patients received prior immunotherapy or whether they were naieve to systemic treatment. Patients who underwent a nephrectomy in the face of metastatic disease and patients who underwent a complete metastasectomy prior to, during, or subsequent to the nephrectomy were included. In total, 61 patients had removal of the kidney and all metastatic sites (nephrectomy/complete metastasectomy), and 30 patients had cytoreductive nephrectomy alone without resection of all metastatic sites. It is unclear if groups were comparable, since patient characteristics were not reported separately for both groups. The outcome of interest was overall survival.
Results
1. Disease-free survival
Not reported.
2. Overall survival
Kwak (2007) reported that patients who received metastasectomy had a median overall survival of 36.5 months (range: 4.0 to 182.7 months) as compared to 8.4 months (range: 0.9 to 63.7 months) for patients who did not undergo metastasectomy (p<0.001).
Russo (2007) reported that patients who underwent complete metastasectomy had a median overall survival of 30 months as compared to 12 months for patients who had incomplete or no metastasectomy.
3. Quality of life
Not reported.
4. Complications
Not reported.
5. Postponement of systemic therapy
Not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of observational studies starts at low.
The level of evidence regarding the outcome measure overall survival was downgraded to very low because of limitations regarding the study design (-1, risk of bias; groups most likely not comparable) and the optimal information size was not achieved (-1, imprecision).
The level of evidence regarding the outcome measures disease-free survival, quality of life, complications and postponement of systemic therapy could not be assessed with GRADE since it was not reported in the included studies.
Subgroup: synchronous and metachronous metastatic renal cell carcinoma
Results reported separately for these subgroups
Patient population might have additional use of targeted therapy/immunotherapy
Description of studies
Shin (2020) performed a retrospective study to analyze and identify prognostic factors for survival of metastatic renal cell carcinoma to the pancreas (PM-RCC) with a focus on the role of surgical resection on the prognosis. Patients who had PM-RCC at first mRCC diagnosis or at the initiation of first-line systemic therapy were included and patients with RCC involvement in the pancreas by disease progression following the first-line therapy and beyond were excluded. In this study, patients from both before and after introduction of the tyrosine kinase inhibitors were included. In total, 104 patients had synchronous PM-RCC of which 24 patients received no surgery, 14 patients received only nephrectomy and 66 patients received both nephrectomy and metastasectomy. Groups were not comparable. Patients who received metastasectomy were younger and had less diabetes mellitus, while patients who received no surgery had a higher T stage. Besides, 196 patients had metachronous PM-RCC of which 64 patients had no metastasectomy and 132 patients had a metastasectomy. Groups were not comparable. Patients who received metastasectomy were younger and had less diabetes mellitus but a higher nuclear grade. The outcome of interest was overall survival.
Thomas (2016) performed a retrospective study to determine whether metastasectomy has any survival benefit in patients with metastatic renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) treated with radical nephrectomy. Patients with RCC and sarcomatoid features with nephrectomy were included. Exclusion criteria were patients diagnosed with sRCC subsequent to nephrectomy (i.e., at time of metastasectomy), with no metastatic disease, with sarcomatoid percentage of 100%, in unreported clinical trials, with history of other metastatic malignancy, or with incomplete follow-up information. It was not reported whether these patients received immunotherapy prior or whether they were naieve to systemic treatment. In total, of patients with synchronous metastasis at diagnosis, 30 patients underwent metastasectomy and 26 patients had no metastasectomy. Groups were not comparable. Patients who received metastasectomy had a lower percentage of sarcomatoid component in sRCC. For patients with asynchronous metastasis at diagnosis, 10 patients underwent metastasectomy and 14 patients had no metastasectomy. Groups were not comparable. Patients in the no-metastasectomy group had a higher BMI and all received systemic therapy at any time. The outcome of interest was overall survival.
Results
Synchronous metastases
1. Disease-free survival
Not reported.
2. Overall survival
Shin (2020) reported that the median overall survival for synchronous PM-RCC was 23.7 months (range: 12.2 to 59.3 months) for patients who received metastasectomy and nephrectomy, 18.1 months (range: 9.3 to 69.5 months) for patients who received only nephrectomy, and 16.8 months (range: 8.8 to 25.1 months) for patients who received no surgery (p=0.121).
Thomas (2016) reported the overall survival for synchronous sRCC was 8.4 months for patients who received metastasectomy and 8.0 months for patients who had no metastasectomy (p=0.35)
3. Quality of life
Not reported.
4. Complications
Not reported.
5. Postponement of systemic therapy
Not reported.
Metachronous metastases
1. Disease-free survival
Not reported.
2. Overall survival
Shin (2020) reported that the median overall survival for metachronous PM-RCC was 53.7 months (range: 25.3 to 83.4 months) for patients who received metastasectomy as compared to 45.1 months (range: 20.4 to 67.8 months) for patients who received no metastasectomy (p=0.012).
Thomas (2016) reported that the overall survival for asynchronous sRCC was 36.2 months for patients who received metastasectomy as compared to 13.7 months for patients who had no metastasectomy (p=0.29).
3. Quality of life
Not reported.
4. Complications
Not reported.
5. Postponement of systemic therapy
Not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of observational studies start at low.
Synchronous oligometastases
The level of evidence regarding the outcome measure overall survival was downgraded to very low because of limitations regarding the study design (-1, risk of bias) and the optimal information size was not achieved (-1, imprecision).
The level of evidence regarding the outcome measures disease-free survival, quality of life, complications and postponement of systemic therapy could not be assessed with GRADE since it was not reported in the included studies.
Metachronous metastases
The level of evidence regarding the outcome measure overall survival was downgraded to very low because of limitations regarding the study design (-1, risk of bias) and the optimal information size was not achieved (-1, imprecision).
The level of evidence regarding the outcome measures disease-free survival, quality of life, complications and postponement of systemic therapy could not be assessed with GRADE since it was not reported in the included studies.
Subgroup: additional use of targeted therapy/immunotherapy
Patient population consists of both synchronous and metachronous renal cell carcinoma metastases (data not reported for these subgroups separately)
Dragomir (2020) performed a retrospective study to assess the impact of complete metastasectomy in metastatic renal cell carcinoma (mRCC). Patients diagnosed with mRCC with prior nephrectomy were included, while patients receiving a first incomplete metastasectomy were excluded. 12% of the patients had first-line targeted treatment prior to matching date. No subanalysis was performed for this group. In total, 229 patients underwent complete metastasectomy (28.8% with synchronous metastases) and were matched with 803 patients not treated with metastasectomy (30.4% with synchronous metastases). Besides, these patients were matched on specific variables such as the usage of first-line targeted treatment. Groups were comparable at baseline after matching. The outcome of interest was overall survival and time to first-line targeted treatment.
Fares (2019) performed a propensity score-matched analysis to determine overall survival benefit of complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC). Patients with clear cell histology and absence of sarcomatoid or rhabdoid features who underwent previous nephrectomy. Besides, patients who underwent CM and patients treated without metastasectomy and with targeted therapy alone who fit inclusion criteria were included. No subgroup analysis was performed for the targeted therapy group. In total, 37 patients underwent CM (37% with synchronous metastases) and 37 patients had no metastasectomy (19% with synchronous metastases). Groups were not comparable. All patients who did not underwent metastasectomy had systemic therapy at first line as compared to 25 of the 37 patients (68%) who underwent CM. The outcome of interest was overall survival.
Ishihara (2020) performed a retrospective study to determine survival following metastasectomy for renal cell carcinoma (RCC) in the postcytokine therapy era. Patients diagnosed with metastatic RCC (mRCC) were included. Exclusion criteria were those who were registered on clinical trials, those who had undergone maintenance dialysis, those who had a kidney transplant, those who were administered first-line ipilimumab and nivolumab as systematic therapy and those with missing eligible data. In total, 45 patients underwent complete metastasectomy (cMS; 17.8% with synchronous metastases), 53 patients underwent incomplete metastasectomy (icMS; 50.9% with synchronous metastases), and 216 patients had no metastasectomy (nonMS; 58.3% with synchronous metastases). Groups were not comparable. These three groups were different in age (nonMS group was older), the frequency of sarcomatoid differentiation (nonMS group had higher frequency), IMDC risk (nonMS group had more often a poor risk), frequency of prior nephrectomy (nonMS group had less often prior nephrectomy), metastasis status (nonMS group more synchronous metastases), frequency of systemic therapy (cMS group lower frequency) and follow-up (nonMS group had a lower follow-up period). The outcome of interest was overall survival.
Kim (2019) performed a retrospective study to determine the effects of metastasectomy to those of non-metastasectomy regarding overall survival and progression-free survival in metastatic renal cell carcinoma (mRCC). Exclusion criteria were a non-complete history of survival outcomes in the National Cancer Registry Database, non-complete surgical records concerning metastasectomy or nephrectomy, or age <19 years. In total, 83 patients underwent metastasectomy (44.6% with synchronous metastases) and 190 patients had no metastasectomy (65.3% with synchronous metastases). The choice of targeted agents was at the discretion of the treating urologist (JC) according to each patient’s pathology and coverage by the Health Insurance. It was not reported how many patients received targeted therapy, which targeted therapy and whether this was prior or after the metastasectomy. Groups were not comparable. Patients in the metastasectomy group were younger, had a lower clinical T stage, had a higher rate of favorable- and intermediate-risk groups, and had less synchronous metastases. In addition, patients in the metastasectomy group had a higher rate of bone, brain, and pancreas metastases and a lower rate of liver metastases and received more often cytoreductive nephrectomy and radiation therapy than patients in the non-metastasectomy group. The outcome of interest was overall survival.
Li (2018) performed a retrospective chart-review analysis to assess the clinical impact of local interventions after receiving targeted therapies. Consecutive metastatic renal cell carcinoma patients who had received at least one line of targeted treatment were included. Exclusion criteria were incomplete data or loss of follow-up. In total, 26 patients received complete resection, 23 patients underwent incomplete resection, and 75 patients did not receive metastasectomy. Seventy-five patients (60.5%) received targeted therapies only, twenty-six patients received complete resection, while the final 23 received incomplete local interventions for their metastatic lesions. Groups were not comparable. Patients who only received targeted therapy had a higher percentage of poor MSKCC risk, had more often more than one metastatic site, and had a shorter targeted treatment duration and median follow-up. The outcome of interest was overall survival.
Sun (2018) performed a retrospective study to determine the use of metastasectomy for metastatic renal cell carcinoma (mRCC) at diagnosis in the targeted therapy era. All patients >18 years old with a primary diagnosis of mRCC who underwent a cytoreductive nephrectomy were included. Some of the included patients received targeted therapy. It was not reported how many patients received targeted therapy, which targeted therapy and whether this was prior or after the metastasectomy. Post-propensity matched survival analyses were performed. In total, 1695 patients who underwent metastasectomy were matched to 1695 patients who did not receive metastasectomy. Groups were comparable. The outcome of interest was overall survival.
Suzuki (2022) performed a retrospective study to determine the therapeutic efficacy of surgical metastasectomy in patients with solitary metastasis of renal cell carcinoma (RCC). Patients with a history of nephrectomy for primary site of RCC who had been treated for solitary metastasis of RCC were included. Some of the included patients received targeted therapy. It was not reported how many patients received targeted therapy, which targeted therapy and whether this was prior or after the metastasectomy. In total, 29 patients underwent surgical metastasectomy and 44 patients did not undergo metastasectomy. Groups were not comparable. The duration from primary nephrectomy to occurrence of metastasis was shorter for patients who did not undergo metastasectomy. Besides, 11 of the 18 patients who underwent metastasectomy had systemic therapy prior to the metastasectomy, while it is unclear whether patients who did not undergo metastasectomy received any systemic therapy. The outcome of interest was overall survival.
Tornberg (2018) performed a retrospective study to determine the outcome of metastasectomy in mRCC in the era of targeted therapies as a primary endpoint. Patients with sporadic mRCC treated by surgery for adrenal or lymph node metastases and whose primary tumor was inevitably treated by surgery were included. In addition, patients treated by either radical or cytoreductive intention in the initial operation, nephrectomy or nephrectomy combined with simultaneous metastasectomy for RCC were included. Exclusion criteria were patients who received palliative treatment alone for metastases and patients with coincidentally encountered lymph node involvement or minimal findings in the adrenal gland. In total, 46 patients underwent complete metastasectomy and 51 patients underwent non-complete metastasectomy. Besides, systemic treatment was administered in both groups. A medical oncologist was consulted regarding the suitability of targeted therapies when a relapse without any reasonable prospect of surgical treatment was observed. 55 patients underwent first line therapy, and 43 underwent second line therapy. It was not reported whether this targeted therapy was prior or after the metastasectomy. It is unclear if groups were comparable, since no patient characteristics were reported for both groups separately. The outcome of interest was postponement of systemic therapy.
You (2016) performed a retrospective study to assess the value of metastasectomy in patients treated with targeted therapy for metastatic renal cell carcinoma (mRCC). Patients with mRCC without prior systemic therapy were included, while patients who underwent consolidation metastasectomy after targeted therapy were excluded. It was not reported whether these patients received targeted therapy prior or whether they were naieve to systemic treatment. In total, 33 patient underwent complete metastasectomy (cMS; 15.2% with synchronous metastases), 29 patients received incomplete metastasectomy (icMS; 51.7% with synchronous metastases)
and 263 patients did not receive metastasectomy (nonMS; 60.8% with synchronous metastases). Groups were comparable, except for age (nonMS patients were older), history of nephrectomy (cMS patients all received nephrectomy), type of metastasis (nonMS patients had more synchronous metastases), IMDC risk groups (cMS patients had more favorable risk), histology (nonMS patients had more non-clear cell histology), and bone metastases (cMS patients had less bone metastases). The outcome of interest was overall survival.
Yu (2015) performed a retrospective study to determine the efficacy of surgery in the treatment of metastatic renal cell carcinoma (mRCC). Patients diagnosed with metastatic renal cell carcinoma who had oligometastasis and a Karnofsky Performance Scale not less than 80 were included. Exclusion criteria were no previous nephrectomy, incomplete data concerning survival time, pathology, metastatic sites, and detailed record of surgery. In total, 31 patients received complete metastasectomy, 11 patients received incomplete metastasectomy and 54 patients did not receive metastasectomy. It was not reported whether these patients received targeted therapy prior or whether they were naieve to systemic treatment. Groups were comparable except that patients who received metastasectomy had more often only one metastatic organ. The outcome of interest was overall survival.
Results
1. Disease-free survival
Not reported.
2. Overall survival
Ten studies reported overall survival (table 1). When survival was expressed in years, this was converted into months.
Table 1. Overview of studies reporting overall survival (in months)
|
Study |
Metastasectomy |
No or incomplete resection |
P-value and HR (if reported) |
|
Dragomir, 2020 |
81 months (IQR: 58 to NR) (n=229) |
61 months (IQR: 26 to NR) (n=803) |
- |
|
Fares, 2019 |
98.3 months (n=37) |
40.5 months (n=37) |
HR=0.24, 95%CI 0.11 to 0.53 |
|
Ishihara, 2020 |
NR (121.9 to NR) (n=45)
|
No: 28.1 months (22.6 to 41.5) (n=216)
Incomplete: 81.5 months (44.6 to NR) (n=53) |
P<0.0001 |
|
Kim, 2019 |
32.0 months (n=83) |
12.8 months (n=190) |
P<0.001 |
|
Li, 2018 |
60.6 months (n=26) |
No: 42 months
Incomplete: 28.8 months (n=75) |
p=0.024 |
|
Sun, 2018 |
24.1 months (n=1695) |
18.9 months (n=1695) |
p<0.001 |
|
Suzuki, 2022 |
NR (n=29) |
62.9 months (n=44)
|
P=0.002 |
|
You, 2016 |
92.5 months (n=33) |
No: 23.5 months (n=263)
Incomplete: 29.6 months (n=29) |
P<0.001 |
|
Yu, 2015 |
52 months (95% CI: 26.8 to 77.2) (n=31)
|
No: 22 months (95% CI: 17.6–26.4) (n=54)
Incomplete: 16 months (95% CI: 9.5 to 22.5) (n=11) |
P=0.001 |
Abbreviations: HR=hazard ratio; IQR=Interquartile range; NR=not reached
1. Quality of life
Not reported.
2. Complications
Suzuki (2022) reported perioperative complications. No serious perioperative complications were demonstrated for patients who underwent surgical metastasectomy.
3. Postponement of systemic therapy
Dragomir (2020) reported that patients without prior exposure to systemic therapy had a median time to first-line targeted treatment during follow-up of 49 months (IQR: 14 to NR) and 38 months (IQR: 11 to 66) for patients receiving complete metastasectomy and patients not treated with metastasectomy, respectively (p=0.0057).
Tornberg (2018) reported time from diagnosis to oncological treatment. For patients with non-complete metastasectomy the median interval was 19 months (IQR: 1-71 months), while this was not achieved for patients with complete metastasectomy.
Level of evidence of the literature
According to GRADE, the level of evidence of observational studies start at low.
The level of evidence regarding the outcome measure overall survival was downgraded to very low because of limitations regarding the study design (-1, risk of bias) and the indirectness (-1, variation in patient population between studies, thus pooling of data not possible).
The level of evidence regarding the outcome measure complications was downgraded to very low because of limitations regarding the study design (-1, risk of bias) and the indirectness (-1, variation in patient population between studies, thus pooling of data not possible).
The level of evidence regarding the outcome measure postponement of systemic therapy was downgraded to very low because of limitations regarding the study design (-1, risk of bias) and the optimal information size was not achieved (-1, imprecision).
The level of evidence regarding the outcome measures disease-free survival and quality of life could not be assessed with GRADE since it was not reported in the included studies.
2. (stereotactic) radiotherapy
Subgroup: additional use of targeted therapy/immunotherapy
Patient population consists of both synchronous and metachronous renal cell carcinoma metastases (data not reported for these subgroups separately)
Description of studies
Liu (2021) performed a retrospective study to determine the survival outcomes of patients receiving stereotactic body radiation therapy (SBRT) plus tyrosine kinase inhibitors (TKIs) versus TKIs alone. Patients aged ≥ 18 years who received TKI treatment for metastatic renal cell carcinoma were included. Exclusion criteria were patients treated with conventionally fractionated radiotherapy or received immunotherapy as first-line treatment. In total, 85 patients received SBRT and TKI (48.2% with synchronous metastasis) and 105 patients received TKI alone (53.3% with synchronous metastasis). Groups were comparable except that patients who received SBRT and TKI were older and more likely to have bone metastases. The outcome of interest was overall survival.
Results
1. Disease-free survival
Not reported.
2. Overall survival
Liu (2021) reported that patients who received stereotactic radiotherapy and tyrosine kinase inhibitors had a median overall survival of 63.2 months as compared to 29.8 months for patients who received tyrosine kinase inhibitors alone (p<0.001).
3. Quality of life
Not reported.
4. Complications
Not reported.
5. Postponement of systemic therapy
Not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of observational studies start at low.
The level of evidence regarding the outcome measure overall survival was downgraded to very low because of limitations regarding the study design (-1, risk of bias) and the optimal information size was not achieved (-1, imprecision).
The level of evidence regarding the outcome measures disease-free survival, quality of life, complications and postponement of systemic therapy could not be assessed with GRADE since it was not reported in the included studies.
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question:
| P (Patients): | Patients with renal cell carcinoma and a) synchronous- / b) metachronous oligometastatic disease |
| I (Intervention): |
Ablation, (stereotactic) radiotherapy, metastasectomy |
| C (Control): |
No or incomplete removal/treatment |
| O: (Outcome measure): |
Disease-free survival, overall survival, quality of life, complications, postponement of systemic therapy |
Relevant outcome measures
The guideline development group considered disease-free survival and overall survival as critical outcome measures for decision making; and quality of life, complications, and postponement of systemic therapy as important outcome measures for decision making.
A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.
The working group defined a relative risk (RR) or hazard ratio (HR) <0.80 or >1.25 as a minimal clinically (patient) important difference for dichotomous or survival variables, and >0.5 SD for continuous variables.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2000 until April 12th 2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 1094 hits. Studies that met the following criteria were eligible for selection: studies reporting original data, systematic reviews, randomized controlled trials (RCTs) and observational comparative studies reporting on ablation, (stereotactic) radiotherapy or metastasectomy with no or incomplete removal in patients with renal cell carcinoma and synchronous oligometastases or metachronous metastases. Twenty-eight studies were initially selected based on title and abstract screening. After reading the full text, nineteen studies were excluded (see the table with reasons for exclusion under the tab Methods), and nine studies (1 systematic review containing 8 observational studies and 8 other observational studies) were included.
Results
Nine studies were included in the analysis of the literature. One systematic review was included (Hsieh, 2021). Since the systematic review was of poor quality, the eight suitable studies were individually included in the literature analysis (Alt, 2011; Ishihara, 2020; Kwak, 2007; Li, 2018; Russo, 2007; Sun, 2018; You, 2016; Yu, 2015). All these studies examined the effect of metastasectomy. Besides, eight observational studies were included (Dragomir, 2020; Fares, 2019; Kim, 2019; Liu, 2021; Shin, 2021; Suzuki, 2021; Thomas, 2016; Tornberg, 2018). Seven of these studies examined the effect of metastasectomy and one study was about (stereotactic) radiotherapy. No studies about ablation were included.
A subgroup analysis was performed on studies that reported data about synchronous and metachronous metastases separately. In addition, in some studies, patients received additional treatment with targeted therapy or immunotherapy, which were also analyzed as a subgroup. 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.
The module is structured as follows:
1. Metastasectomy
- No subgroup
- Subgroup about synchronous and metachronous metastases
- Subgroup about additional use of targeted therapy or immunotherapy
2. (stereotactic) radiotherapy
- Subgroup about additional use of target therapy or immunotherapy
Referenties
- 1 - Alt AL, Boorjian SA, Lohse CM, Costello BA, Leibovich BC, Blute ML. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011 Jul 1;117(13):2873-82. doi: 10.1002/cncr.25836. Epub 2011 Jan 10. PMID: 21692048.
- 2 - Dragomir A, Nazha S, Wood LA, Rendon RA, Finelli A, Hansen A, So AI, Kollmannsberger C, Basappa NS, Pouliot F, Soulières D, Heng DYC, Kapoor A, Tanguay S. Outcomes of complete metastasectomy in metastatic renal cell carcinoma patients: The Canadian Kidney Cancer information system experience. Urol Oncol. 2020 Oct;38(10):799.e1-799.e10. doi: 10.1016/j.urolonc.2020.07.021. Epub 2020 Aug 7. PMID: 32778475.
- 3 - Fares AF, Araujo DV, Calsavara V, Saito AO, Formiga MN, Dettino AA, Zequi S, da Costa WH, Cunha IW. Complete metastasectomy in renal cell carcinoma: a propensity-score matched by the International Metastatic RCC Database Consortium prognostic model. Ecancermedicalscience. 2019 Oct 14;13:967. doi: 10.3332/ecancer.2019.967. PMID: 31921338; PMCID: PMC6834380.
- 4 - Harrison MR, Costello BA, Bhavsar NA, Vaishampayan U, Pal SK, Zakharia Y, Jim HS, Fishman MN, Molina AM, Kyriakopoulos CE, Tsao CK. Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC). Cancer. 2021 Jul 1;127(13):2204-12.
- 5 - Hsieh PY, Hung SC, Li JR, Wang SS, Yang CK, Chen CS, Lu K, Cheng CL, Chiu KY. The effect of metastasectomy on overall survival in metastatic renal cell carcinoma: A systematic review and meta-analysis. Urol Oncol. 2021 Jul;39(7):422-430. doi: 10.1016/j.urolonc.2021.02.026. Epub 2021 Apr 29. PMID: 33934963.
- 6 - Ishihara H, Takagi T, Kondo T, Fukuda H, Tachibana H, Yoshida K, Iizuka J, Kobayashi H, Ishida H, Tanabe K. Prognostic impact of metastasectomy in renal cell carcinoma in the postcytokine therapy era. Urol Oncol. 2021 Jan;39(1):77.e17-77.e25. doi: 10.1016/j.urolonc.2020.08.011. Epub 2020 Aug 28. PMID: 32863124.
- 7 - Kwak C, Park YH, Jeong CW, Lee SE, Ku JH. Metastasectomy without systemic therapy in metastatic renal cell carcinoma: comparison with conservative treatment. Urol Int. 2007;79(2):145-51. doi: 10.1159/000106329. PMID: 17851285.
- 8 - Kim SH, Park WS, Park B, Pak S, Chung J. A Retrospective Analysis of the Impact of Metastasectomy on Prognostic Survival According to Metastatic Organs in Patients With Metastatic Renal Cell Carcinoma. Front Oncol. 2019 May 22;9:413. doi: 10.3389/fonc.2019.00413. PMID: 31179242; PMCID: PMC6538800.
- 9 - Li JR, Ou YC, Yang CK, Wang SS, Chen CS, Ho HC, Cheng CL, Yang CR, Chen CC, Wang SC, Lin CY, Hung SC, Hsu CY, Chiu KY. The Impact of Local Intervention Combined with Targeted Therapy on Metastatic Renal Cell Carcinoma. Anticancer Res. 2018 Sep;38(9):5339-5345. doi: 10.21873/anticanres.12861. PMID: 30194186.
- 10 - Liu Y, Zhang Z, Han H, Guo S, Liu Z, Liu M, Zhou F, Dong P, He L. Survival After Combining Stereotactic Body Radiation Therapy and Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma. Front Oncol. 2021 Feb 22;11:607595. doi: 10.3389/fonc.2021.607595. PMID: 33692951; PMCID: PMC7937906.
- 11 - Russo P, Synder M, Vickers A, Kondagunta V, Motzer R. Cytoreductive nephrectomy and nephrectomy/complete metastasectomy for metastatic renal cancer. ScientificWorldJournal. 2007 Feb 19;7:768-78. doi: 10.1100/tsw.2007.145. PMID: 17619759; PMCID: PMC5901325.
- 12 - Shin TJ, Song C, Jeong CW, Kwak C, Seo S, Kang M, Chung J, Hong SH, Hwang EC, Park JY, Lee H. Metastatic renal cell carcinoma to the pancreas: Clinical features and treatment outcome. J Surg Oncol. 2021 Jan;123(1):204-213. doi: 10.1002/jso.26251. Epub 2020 Oct 12. PMID: 33047324.
- 13 - Sun M, Meyer CP, Karam JA, de Velasco G, Chang SL, Pal SK, Trinh QD, Choueiri TK. Predictors, utilization patterns, and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy. Eur J Surg Oncol. 2018 Sep;44(9):1439-1445. doi: 10.1016/j.ejso.2018.05.026. Epub 2018 Jun 5. PMID: 29935840.
- 14 - Suzuki K, Hara T, Terakawa T, Furukawa J, Harada K, Hinata N, Nakano Y, Fujisawa M. The Efficacy of Surgical Metastasectomy for Solitary Metastasis of Renal Cell Carcinoma. Urol Int. 2022;106(4):397-403. doi: 10.1159/000516679. Epub 2021 Jun 16. PMID: 34134119.
- 15 - Thomas AZ, Adibi M, Slack RS, Borregales LD, Merrill MM, Tamboli P, Sircar K, Jonasch E, Tannir NM, Matin SF, Wood CG, Karam JA. The Role of Metastasectomy in Patients with Renal Cell Carcinoma with Sarcomatoid Dedifferentiation: A Matched Controlled Analysis. J Urol. 2016 Sep;196(3):678-84. doi: 10.1016/j.juro.2016.03.144. Epub 2016 Mar 29. PMID: 27036304; PMCID: PMC5014677.
- 16 - Tornberg SV, Visapää H, Kilpeläinen TP, Taari K, Järvinen R, Erkkilä K, Nisen H, Järvinen P. Surgery for metastases of renal cell carcinoma: outcome of treatments and preliminary assessment of Leuven-Udine prognostic groups in the targeted therapy era. Scand J Urol. 2018 Oct-Dec;52(5-6):419-426. doi: 10.1080/21681805.2018.1553893. Epub 2019 Jan 20. PMID: 30663485.
- 17 - You D, Lee C, Jeong IG, Song C, Lee JL, Hong B, Hong JH, Ahn H, Kim CS. Impact of metastasectomy on prognosis in patients treated with targeted therapy for metastatic renal cell carcinoma. J Cancer Res Clin Oncol. 2016 Nov;142(11):2331-8. doi: 10.1007/s00432-016-2217-1. Epub 2016 Aug 23. PMID: 27553579.
- 18 - Yu X, Wang B, Li X, Lin G, Zhang C, Yang Y, Fang D, Song Y, He Z, Zhou L. The Significance of Metastasectomy in Patients with Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy. Biomed Res Int. 2015;2015:176373. doi: 10.1155/2015/176373. Epub 2015 Oct 11. PMID: 26568955; PMCID: PMC4619757.
Evidence tabellen
Evidence table for intervention studies
Research question: Which treatment (surgical metastasectomy, SBRT, ablation) is best applied to patients with a) synchronous oligometastases / b) metachronous oligometastases?
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
Alt, 2011 |
Type of study: Retrospective study
Setting and country: Mayo Clinic, US
Funding and conflicts of interest: Source of funding not reported. The authors made no disclosures for conflicts of interest
|
Inclusion criteria Patients who underwent radical nephrectomy for pathologically confirmed RCC who were diagnosed with multiple metastases either at the time of or after nephrectomy
Exclusion criteria Not reported
N total at baseline: Intervention: 125 Control: 762
Important prognostic factors2: Median age (range) I: 62 (41-85) C: 63 (21-92)
Sex: I: 69.6% M C: 69.5% M
Synchronous metastases I:73 (58.4%) C: 426 (55.9%)
Groups not comparable |
Complete surgical resection |
No complete surgical resection |
Length of follow-up: Up to 10 years
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Median overall survival (converted to months) I: 48 months C: 15.6 months P<0.001 |
Author’s conclusion The current results indicated that complete resection of multiple RCC metastases may be associated with longterm survival and should be considered when technically feasible in appropriate surgical candidates.
Remarks
|
|
Dragomir, 2020 |
Type of study: Retrospective study
Setting and country: Canadian Kidney Cancer information system database (multicentre collaboration of 16 academic hospitals in 6 Canadian provinces)
Funding and conflicts of interest: Source of funding and conflicts of interest not reported.
|
Inclusion criteria: Patients diagnosed with metastatic renal cell carcinoma with prior nephrectomy
Exclusion criteria: Patients receiving a first incomplete metastasectomy
N total at baseline: Intervention: 229 Control: 803
Important prognostic factors2: Median age (IQR) I: 62 (55-68) C: 63 (57-70)
Sex: I:78.2 % M C: 75.2% M
Synchronous metastases I: 28.8% C: 30.4%
After matching, baseline characteristics were well balanced between groups |
Complete metastasectomy: surgical resection of all visible metastases present at the time of surgery
|
No metastasectomy: resection of part of the metastases without a curative intent
|
Length of follow-up: 5 years
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Overall survival (median and IQR) I: 81 months (58 to NR) C: 61 months (26 to NR) P=0.0001
Time to first-line targeted treatment during (median and IQR) I: 49 months (14-NR) C: 38 months (11-66) P=0.0057 |
Author’s conclusion: Patients who underwent complete metastasectomy have a longer overall survival and a longer time to initiation of targeted therapy compared to patients not receiving metastasectomy. These findings should support aggressive resection of metastasis in selected patients.
Remarks: - Selection bias
|
|
Fares, 2019 |
Type of study: Retrospective study (propensity score-matched analysis)
Setting and country: AC Camargo Cancer Center, Brazil
Funding and conflicts of interest: No financial support was necessary for this study. None of the authors have any conflicts of interest.
|
Inclusion criteria: - Patients with clear cell histology and absence of sarcomatoid or rhabdoid features who underwent previous nephrectomy - Patients who underwent complete metastasectomy and patients treated without metastasectomy and with targeted therapy alone
Exclusion criteria: Not reported.
N total at baseline: Intervention: 37 Control: 37
Important prognostic factors2: Mean age (SD) I: 55.92 (11%) C: 57.38 (11%)
Sex: I: 68% M C: 76% M
Synchronous metastases I: 14 (37%) C: 7 (19%)
Groups not comparable |
Complete metastasectomy |
No metastasectomy |
Length of follow-up: Median of 70.4 months
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Overall survival I: 98.3 months C: 40.5 months HR=0.24, 95%CI 0.11–0.53 |
Author’s conclusion After matching for age, gender and IMDC, we found CM impacts on OS and also diminishes the need for systemic treatment. Survival benefit was confirmed for favourable/intermediate IMDC but not for the poor IMDC prognostic model.
Remarks: - Retrospective, non-randomised nature
|
|
Ishihara, 2020 |
Type of study: Retrospective study
Setting and country: Tokyo Women’s Medical University, Japan
Funding and conflicts of interest: This study did not receive any funding. Tsunenori Kondo received honoraria from Pfizer, Novartis, and Ono Pharmaceutical. All other authors have no conflict of interest to declare.
|
Inclusion criteria Patients diagnosed with metastatic RCC (mRCC)
Exclusion criteria - Registered on clinical trials - Undergone maintenance dialysis - Kidney transplant - Administered first-line ipilimumab and nivolumab as systematic therapy - Missing eligible data
N total at baseline: Intervention: 45 Control: C1 Incomplete: 53
Important prognostic factors2: Median age (IQR) C1: 61 (55.5−65) C2: 66.0 (57.3−72.0)
Sex: I: 73.3% M C1: 71.7% M C2: 66.7% M
Synchronous metastases I: 8 (17.8) C1: 27 (50.9%) C2: 126 (58.3%)
Groups not comparable |
Complete metastasectomy |
Incomplete metastasectomy
Without metastasectomy |
Length of follow-up: Median of 25.3 months
Loss-to-follow-up: Patients lost to follow-up were censored at the time of last contact.
Incomplete outcome data: Patients with missing data were excluded.
|
Overall survival I: NR (121.9 to NR) C1: 81.5 months (44.6 to NR) C2: 28.1 months (22.6 to 41.5) P<0.0001 |
Author’s conclusion MS, especially cMS improved survival in selected patients with mRCC in the postcytokine therapy era. In addition, MS still plays a significant role in the current systemic therapy.
Remarks: - Small sample size - Patients who underwent MS could have inherently favourable outcome - Relatively short follow-up duration |
|
Kim, 2019 |
Type of study: Retrospective study (propensity score-matched analysis)
Setting and country: AC Camargo Cancer Center, Brazil
Funding and conflicts of interest: No financial support was necessary for this study. None of the authors have any conflicts of interest.
|
Inclusion criteria: Patients with metastatic renal cell carcinoma
Exclusion criteria: - Non-complete history of survival outcomes in the National Cancer Registry Database - Non-complete surgical records concerning metastasectomy or nephrectomy - Age <19 years
N total at baseline: Intervention: 83 Control: 190
Important prognostic factors2: Median age (range) I: 52 (22–78) C: 58 (10–76)
Sex: I: 80.7% M C: 79.0% M
Synchronous metastases I: 37 (44.6%) C: 124 (65.3%)
Groups not comparable |
Metastasectomy |
No metastasectomy |
Length of follow-up: Median of 143.3 months
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Overall survival I: 32.0 months C: 12.8 months P<0.001
|
Author’s conclusion The study showed a significantly beneficiary role of metastasectomy according to various metastatic states in survival gains with regards to mRCC and found that liver metastasis was the most unfavorable factor in metastasectomy in mRCC.
Remarks: - Retrospective, single-center design - Low number of cases - Lack of consideration of the number of metastatic lesions within the metastatic organs, and the sizes or total sum of the metastatic lesions, representing the overall tumor burden - Derivation of results over an extended period - Baseline general performance status and underlying disease were not considered thoroughly
|
|
Kwak, 2007 |
Type of study: Retrospective study
Setting and country: Korea
Funding and conflicts of interest: Source of funding and conflicts of interest not reported.
|
Inclusion criteria Patients with metastatic RCC who had not received immunotherapy (all patients did not meet the criteria for receiving immunotherapy or refused receiving immunotherapy)
Exclusion criteria - Not undergone radical nephrectomy - Metastasectomy was incomplete
N total at baseline: Intervention: 21 Control: 41
Important prognostic factors2: Median age (range) I: 60 (38–79) C: 61 (31–79)
Sex: I: 90.5 % M C: 82.9% M
Groups not comparable at baseline. |
Metastasectomy |
Nonmetastasectomy |
Length of follow-up: I: 36.5 months (4.0 to 182.7 months) C: 8.4 months (0.9 to 63.7 months)
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Median overall survival I: 36.5 months (4.0 to 182.7 months) C: 8.4 months (0.9 to 63.7 months) P<0.001
|
Author’s conclusion Our findings suggest that for the management of metastatic renal cell carcinoma, complete surgical resection of the metastatic lesions may prolong survival even in patients with some poor prognostic factors who cannot or are not willing to receive systemic therapy.
Remarks: - Clinical experience one centre - Data depends on medical records - Observer bias |
|
Li, 2018 |
Type of study: Retrospective chart-review analysis
Setting and country: Taichung Veterans General Hospital, Taiwan
Funding and conflicts of interest: This research was supported by the Ministry of Science and Technology of the Republic of China, Grant number MOST 105-2628-B-075A-001-MY3. All authors declare no conflicts of interest regarding this study.
|
Inclusion criteria Consecutive metastatic renal cell carcinoma patients who had received at least one line of targeted therapy
Exclusion criteria Incomplete data or loss to follow-up
N total at baseline: Intervention: 26 Control:
Important prognostic factors2: Median age (IQR) C1: 56.0 (0.6-62) C2: 58.0 (59.5-68)
Sex: I: 65.4% M C1: 87.0% M C2: 65.3% M
Groups not comparable |
Complete resection |
Incomplete resection
Without resection (only targeted therapy) |
Length of follow-up: I: 41.9 months (23.8-63.2 months) C1: 41.3 months (24.9-50.7) C2: 13.4 months (8.3-31.8 months)
Loss-to-follow-up: Patients loss to follow-up were excluded
Incomplete outcome data: Patients with incomplete data were excluded
|
Overall survival (converted to months) I: 60.6 months C1: 42 months C2: 28.8 months
|
Author’s conclusion Complete resection of metastatic sites for MRCC patients, combined with targeted therapy, could provide better overall survival rates than targeted therapy alone. Poor MSKCC risk is still correlated to a poor outcome in the current targeted therapy era.
Remarks - Selection bias - Small patient numbers - Targeted treatment not identical |
|
Liu, 2021 |
Type of study: Retrospective study
Setting and country: Sun Yat-sen University Cancer Center, China
Funding and conflicts of interest: Source of funding was not reported. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
|
Inclusion criteria Patients aged ≥ 18 years who received tyrosine kinase inhibitor treatment for metastatic renal cell carcinoma.
Exclusion criteria Patients treated with conventionally fractionated radiotherapy or received immunotherapy as first-line treatment.
N total at baseline: Intervention: 85 Control: 105
Important prognostic factors2: Median age (range) C: 54 (18–83)
Sex: I: 78.8% M C: 76.2% M
Synchronous metastasis I: 41 (48.2) C: 56 (53.3)
Groups were comparable except that patients who received SBRT and TKI were older and more likely to have bone metastases. |
Stereotactic body radiation therapy plus tyrosine kinase inhibitor |
Tyrosine kinase inhibitor |
Length of follow-up: At least three months up to 10 years
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported |
Median overall survival I: 63.2 months C: 29.8 months P<0.001
|
Author’s conclusion Combining SBRT with TKIs is tolerable and associated with longer OS in selected patients, such as those with oligometastasis and favorable or intermediate risk.
Remarks - Retrospective design - SBRT delivered at various timepoints for different purposes - Cannot control for type and sequence of targeted regimens - Conducted at high-volume cancer center and results might be difficult to replicate in smaller centers. |
|
Russo, 2007 |
Type of study: Retrospective study
Setting and country: Renal tumor database, Memorial Sloan Kettering Cancer Center, New York, US
Funding and conflicts of interest: Not reported
|
Inclusion criteria: Patients who underwent a nephrectomy in the face of metastatic disease and patients who underwent a complete metastasectomy prior to, during, or subsequent to the nephrectomy.
Exclusion criteria: Not reported.
N total at baseline: Intervention: 61 Control: 30
Important prognostic factors2: Not reported
Unclear if groups were comparable. |
Removal of the kidney and all metastatic sites (nephrectomy/complete metastasectomy) |
Cytoreductive nephrectomy alone without resection of all metastatic sites |
Length of follow-up: Median: 43 months I: 30 months C: 12 months
Loss-to-follow-up: Not reported
Incomplete outcome data: Missing data about preoperative laboratory values more frequent in complete metastasectomy group
|
Overall median survival I: 30 months C: 12 months |
Author’s conclusion This surgical experience provides a contemporary foundation as new targeted therapeutic agents are integrated into the neoadjuvant or adjuvant treatment of locally advanced and metastatic renal cancer.
Remarks - Selection bias |
|
Shin, 2020 |
Type of study: Retrospective study
Setting and country: Korean Renal Cancer Study Group (University of Ulsan, Seoul National University, Sungkyunkwan University, National Cancer Center, Catholic University, Chonnam National University, and Korea University)
Funding and conflicts of interest: Source of funding not reported. The authors declare that there are no conflict of interests.
|
Inclusion criteria: Patients who had PM-RCC at first mRCC diagnosis or at the initiation of first-line systemic therapy.
Exclusion criteria: Patients with RCC involvement in the pancreas by disease progression following the first-line therapy and beyond.
N total at baseline: Synchronous PM-RCC Intervention: 66 Control:
Metachronous PM-RCC Intervention: 132 Control: 64
Important prognostic factors2: Synchronous PM-RCC Mean age ± SD I: 53.9 ± 14.2 C1: 62.3 ± 9.7 C2: 60.2 ±10.7
Sex: I: 63.5% M C1: 75% M C2: 85.7% M
Metachronous PM-RCC Mean age ± SD I: 58.7 ± 11.1 C: 65.3 ± 9.6
Sex: I: 72.7% M C: 64.1% M
Groups not comparable |
Synchronous PM-RCC: Metastasectomy and nephrectomy
Metachronous PM-RCC: Metastasectomy |
Synchronous PM-RCC: - No surgery - Only nephrectomy
Metachronous PM-RCC: No metastasectomy |
Length of follow-up: Median follow‐up of 25 months (IQR: 53.3 to 83.0)
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Overall survival Synchronous PM-RCC I: 23.7 months (12.2 to 59.3 months) C1: 16.8 months (8.8 to 25.1 months) C2: 18.1 months (9.3 to 69.5 months) P=0.121
Metachronous PM-RCC I: 53.7 months (25.3 to 83.4 months) C: 45.1 months (range: 20.4 to 67.8 months) P=0.012
|
Author’s conclusion Compared to the other mRCC, PM‐RCC demonstrated a favorable prognosis. Pancreas metastasectomy was associated with prolonged survival in the metachronous PM‐RCC with a long progression‐free period.
Remarks: - Small number of participants |
|
Sun, 2018 |
Type of study: Retrospective study
Setting and country: National Cancer Database, US
Funding and conflicts of interest: Funded in part by the Trust family, Loker Pinard, and Michael Brigham Funds for Kidney Cancer Research (to T.K. Choueiri) at Dana-Farber Cancer Institute, the Dana- Farber/Harvard Cancer Center Kidney Cancer Program, and the Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE P50 CA101942-01. None of the authors have any conflicts of interest to declare.
|
Inclusion criteria All patients >18 years old with a primary diagnosis of mRCC who underwent a cytoreductive nephrectomy
Exclusion criteria Not reported
N total at baseline: Intervention: 1695 Control: 1695
Important prognostic factors2: Mean age (STE) I: 60.1 (0.232) C: 60.1 (0.244)
Sex: I: 70.6% M C: 70.7% M
Groups were comparable |
Metastasectomy |
No metastasectomy |
Length of follow-up: Up to 5 years
Loss-to-follow-up: Patients that did not have follow-up data were excluded
Incomplete outcome data: Not reported
|
Median overall survival I: 24.1 months C: 18.9 months |
Author’s conclusion MSX-treated patients may benefit from an improved overall survival compared to non-MSX treated patients. Good patient selection and a proper risk stratification strategy are still very important considerations.
Remarks - Selection bias - Unclear which targeted therapy
A total of 1976 patients underwent MSX (28.3%). Of those, 849 patients received targeted therapy (43.0%). Of note, 2581 (36.9%) received targeted therapy without MSX, whereas 2437 (34.8%) did not receive targeted therapy nor did they undergo MSX. Overall utilization rate of MSX increased significantly from 24.9% in 2006 to 31.4% in 2013 (EAPC: +2.18%, 95% CI: 0.35 to 4.04, p=0.03, Figure 1). In sub-analyses, we found that the increase was mainly driven by patients treated with MSX alone (EAPC: +3.78%, 95% CI: 1.00-6.64, p=0.015). Patients treated with MSX and targeted therapy did not observe a statistically significant increase over time (EAPC: 0.68%, 95% CI: -3.27-4.80, p=0.69). |
|
Suzuki, 2022 |
Type of study: Retrospective study
Setting and country: Kobe University Hospital in Japan
Funding and conflicts of interest: The authors have not received any external funding for this study. The authors declare no conflicts of interest.
|
Inclusion criteria Patients with a history of nephrectomy for primary site of RCC who had been treated for solitary metastasis of RCC
Exclusion criteria Not reported
N total at baseline: Intervention: 29 Control: 44
Important prognostic factors2: Median age (range) I: 68 (40–84) C: 68 (45–83)
Sex: I: 75.9% M C: 81.8% M
Groups not comparable |
Surgical metastasectomy |
No surgical metastasectomy |
Length of follow-up: Not reported
Loss-to-follow-up: Not reported.
Incomplete outcome data: Not reported. |
Overall survival I: Not reached C: 62.9 months P=0.002
Perioperative complications I: None C: Not reported |
Author’s conclusion If resection is feasible, surgical metastasectomy may be beneficial for patients with solitary metastasis of RCC, and we showed the possibility that presurgical targeted therapy prior to surgical metastasectomy may be effective for avoiding recurrence after surgical metastasectomy.
Remarks - Retrospective study with small number of patients à selection bias - Unevaluated confounders and missing data (e.g. tumor size and distance from vital organs) |
|
Thomas, 2016 |
Type of study: Retrospective study
Setting and country: The University of Texas MD Anderson Cancer Center, Houston, Texas, US
Funding and conflicts of interest: The Biostatistics Resource Group is supported by the NIH/NCI under award number P30CA016672. Conflicts of interest not relevant to the current manuscript.
|
Inclusion criteria: Patients with RCC and sarcomatoid features with nephrectomy.
Exclusion criteria: Patients diagnosed with sRCC subsequent to nephrectomy (i.e., at time of metastasectomy) - No metastatic disease, with sarcomatoid percentage of 100%, in unreported clinical trials, with history of other metastatic malignancy, or with incomplete follow-up information
N total at baseline: Synchronous sRCC Intervention: 30 Control: 26 Asynchronous sRCC Intervention: 10 Control: 14
Important prognostic factors2: Synchronous sRCC Median age (IQR) I: 54 (47 to 64) C: 55 (49 to 63)
Sex: I: 67% M C: 54% M
Asynchronous sRCC Median age (IQR) I: 52 (48 to 60) C: 54 (49 to 58)
Sex: I: 70% M C: 36% M
Groups not comparable |
Metastasectomy |
No metastasectomy |
Length of follow-up: Not reported.
Loss-to-follow-up: Censored on date of last contact
Incomplete outcome data: Patients with unknown or missing values are not included in the comparison |
Overall survival Synchronous sRCC I: 8.4 months C: 8.0 months P=0.35
Asynchronous sRCC I: 36.2 months C: 13.7 months P=0.29
|
Author’s conclusion In the current study, there was no clear evidence of benefit for patients with sRCC undergoing metastasectomy after nephrectomy. Particularly, the group of patients with pathological LN positive disease at nephrectomy has a considerably worse survival.
Remarks: - Retrospective nature and long study time period, during which surgical and systemic treatment strategies have changed. - Small sample size |
|
Tornberg, 2018 |
Type of study: Retrospective study
Setting and country: Helsinki University Kidney Tumour Register
Funding and conflicts of interest: This study was financially supported by the Competitive State Research Financing of the Expert Responsibility area of Helsinki University Hospital. No conflicts of interest to declare or no relevant conflict of interest (outside submitted work)
|
Inclusion criteria: - Patients with sporadic mRCC treated by surgery for adrenal or lymph node metastases - Primary tumor was inevitably treated by surgery - Patients treated by either radical or cytoreductive intention in the initial operation, nephrectomy or nephrectomy combined with simultaneous metastasectomy for RCC
Exclusion criteria: - Patients who received palliative treatment alone for metastases - Patients with coincidentally encountered lymph node involvement or minimal findings in the adrenal gland.
N total at baseline: Intervention: 46 Control: 51
Important prognostic factors2: Not reported
Unclear if groups were comparable. |
Complete metastasectomy |
Non-complete metastasectomy |
Length of follow-up: 12 years
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
5-year overall survival I: 59% C: 45% P=0.002
Interval time from diagnosis to oncological treatment I: not achieved C: 19 months (1-71 months) |
Author’s conclusion Metastasectomy is an option for selected patients with mRCC. Complete resection should be attempted when feasible.
Remarks: - Number of patients with metastases fit for surgery remained low
|
|
You, 2016 |
Type of study: Retrospective study
Setting and country: Asan Medical Center, Korea
Funding and conflicts of interest: Source of funding not reported. All authors declare that they have no conflict of interest.
|
Inclusion criteria: Patients presented with mRCC but without prior systemic therapy
Exclusion criteria: Patients who underwent consolidation metastasectomy after targeted therapy
N total at baseline: Intervention: 33 Control:
Important prognostic factors2: Mean age (SD) I: 56.1 (8.9) C1: 53.6 (10.3) C2: 59.3 (12.1)
Sex I: 75.8% M C1: 55.2% M C2: 71.1% M
Synchronous metastases I: 5 (15.2%) C1: 15 (51.7%) C2: 160 (60.8%)
Groups not comparable. |
Complete metastasectomy followed by targeted therapy |
Incomplete metastasectomy followed by targeted therapy
Non-metastasectomy (only targeted therapy) |
Length of follow-up: Up to 16 months
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Overall survival I: 92.5 months C1: 29.6 months C2: 23.5 months |
Author’s conclusion Complete metastasectomy performed before targeted therapy might improve progression-free and overall survivals in patients with mRCC.
Remarks - Retrospective nature: confounding variables - Small number of participants
|
|
Yu, 2015 |
Type of study: Retrospective study
Setting and country: Peking University First Hospital, China
Funding and conflicts of interest: Source of funding not reported. The authors declare that there is no conflict of interests regarding the publication of this paper.
|
Inclusion criteria - Patients diagnosed with metastatic renal cell carcinoma - Oligometastasis - Karnofsky Performance Scale not less than 80
Exclusion criteria - No previous nephrectomy
N total at baseline: Intervention: 31 Control:
Important prognostic factors2:
Sex I: 90.3% M C1: 81.8% M C2: 75.9% M
Age (65 or more) I: 29% C1: 27% C2: 26%
Groups not comparable. |
Complete metastasectomy |
Incomplete metastasectomy
No metastasectomy |
Length of follow-up: Median of 45 months (range 2 to 112 months)
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Overall survival I: 52 months (95% CI: 26.8–77.2) C1: 16 months (95% CI: 9.5–22.5) C2: 22 months (95% CI: 17.6–26.4) P=0.001
|
Author’s conclusion In the era of targeted therapy, complete metastasectomy can improve overall survival. Complete metastasectomy, T stage > 3, disease free interval <12 months, and multiorgan involvement are independent prognostic factors.
Remarks - Bias due to retrospective design - Small number of participants - Incomplete records on specific targeted therapy usage |
Risk of bias table for interventions studies (cohort studies based on risk of bias tool by the CLARITY Group at McMaster University)
|
Author, year |
Selection of participants
Was selection of exposed and non-exposed cohorts drawn from the same population?
|
Exposure
Can we be confident in the assessment of exposure? |
Outcome of interest
Can we be confident that the outcome of interest was not present at start of study? |
Confounding-assessment
Can we be confident in the assessment of confounding factors? |
Confounding-analysis
Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these confounding variables? |
Assessment of outcome
Can we be confident in the assessment of outcome? |
Follow up
Was the follow up of cohorts adequate? In particular, was outcome data complete or imputed?
|
Co-interventions
Were co-interventions similar between groups? |
Overall Risk of bias |
|
Alt, 2011 |
Probably yes
Reason: Participants were selected from same hospital.
|
Probably yes
Reason: Probably derived from medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of patients were provided. |
Probably yes
Reason: Multivariate analysis was performed. |
Probably yes
Reason: Probably derived from death certificates. |
Probably yes
Reason: No missing data. |
Probably no
Reason: The use of systemic therapy differed between both groups. |
Some concerns |
|
Dragomir, 2020 |
Definitely yes
Reason: Participants were selected from the same database. |
Definitely yes
Reason: Derived from patient’s medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival). |
Definitely yes
Reason: Obtained by patient survey and medical record review.
|
Probably yes
Reason: Exposed and unexposed were matched on specific variables. |
Probably yes
Reason: Derived from database. |
Probably yes
Reason: No missing data. |
Probably yes
Reason: Targeted therapy was balanced between groups
|
Low |
|
Fares, 2019 |
Probably yes
Reason: Participants were selected from the same biobank.
|
Probably yes
Reason: Derived from biobank. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided by electronic medical chart.
|
Probably yes
Reason: Exposed and unexposed are matched and balanced. |
Probably yes
Reason: Derived from biobank. |
Probably yes
Reason: No missing data. |
Probably no
Reason: Systemic treatment was different in both groups. |
Some concerns |
|
Ishihara, 2020 |
Probably yes
Reason: Participants were selected from the same institution.
|
Probably yes
Reason: Derived from electronic database and patient medical records.
|
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided by electronic database and patient medical records.
|
Probably yes
Reason: Multivariable analysis was performed. |
Probably yes
Reason: Derived from electronic database and patient medical records.
|
Probably no
Reason: Follow-up was relatively short. |
Probably no
Reason: Systemic treatment was different in both groups. |
Some concerns |
|
Kim, 2019 |
Probably yes
Reason: Participants were selected from the same registry database.
|
Probably yes
Reason: Derived from registry database. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided by medical records.
|
Probably yes
Reason: Multivariable analysis was performed. |
Probably yes
Reason: Derived from medical records |
Probably yes
Reason: No missing data. |
Probably no
Reason: Cytoreductive nephrectomy, readiation therapy and embolization different between groups.
|
Some concerns |
|
Kwak, 2007 |
Probably yes
Reason: Participants selected from medical records.
|
Probably yes
Reason: Derived from patient’s medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Multivariate analysis was performed. |
Probably yes
Reason: Derived from patient’s medical record. |
Probably yes
Reason: No missing data. |
Probably yes
Reason: No other interventions provided. |
Low |
|
Li, 2018 |
Probably yes
Reason: Participants selected from same hospital.
|
Probably yes
Reason: Derived from chart-review. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Multivariate analysis was performed. |
Probably yes
Reason: Derived from chart-review. |
Probably yes
Reason: Patients with incomplete data were excluded. |
Probably no
Reason: Targeted therapy was not identical. |
Some concerns |
|
Liu, 2018 |
Probably yes
Reason: Participants selected from same center.
|
Probably yes
Reason: Derived from medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Multivariate analysis was performed. |
Probably yes
Reason: Derived from chart-review. |
Probably yes
Reason: No missing data. |
Probably yes
Reason: Other intervention (nephrectomy) similar between groups. |
Low |
|
Russo, 2007 |
Probably yes
Reason: Participants selected from same database.
|
Probably yes
Reason: Database was queried to identify exposed patients.
|
Definitely yes
Reason: Outcome of interest could not be present at the start (survival). |
Probably yes
Reason: Characteristics of participants were provided. |
Probably no
Reason: No adjustment for confounders. |
Probably yes
Reason: Derived from database. |
Probably yes
Reason: No missing data for outcome of interest. |
Probably yes
Reason: No other interventions provided. |
Some concerns |
|
Shin, 2020 |
Definitely yes
Reason: Participants were selected from the same database.
|
Probably yes
Reason: Derived from database. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Multivarate analysis was performed. |
Probably yes
Reason: Derived from database. |
Probably yes
Reason: No missing data. |
No information
Unclear how targeted therapy was administered in both groups |
Some concers |
|
Sun, 2018 |
Probably yes
Reason: Participants were selected from the same database.
|
Probably yes
Reason: Derived from database. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Exposed and unexposed were matched. |
Probably yes Reason: Derived from database. |
Probably yes
Reason: No missing data. |
No information
Unclear how targeted therapy was administered in both groups |
Some concerns |
|
Suzuki, 2022 |
Probably yes
Reason: Participants were selected from the same hospital.
|
Probably yes
Reason: Derived from medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided from medical records.
|
Probably no
Reason: Some multivariate analyses were performed, but also unevaluated confounders. |
Probably yes
Reason: Derived from medical records. |
Probably yes
Reason: No missing data. |
No information
Unclear if non-metastasectomy group also received systemic therapy. |
High |
|
Thomas, 2016 |
Probably yes
Reason: Participants were selected from the same database.
|
Probably yes
Reason: Derived from database. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Exposed and unexposed are matched. |
Probably yes
Reason: Derived from database. |
Probably yes
Reason: Missing values not included in the comparison. |
Probably no
Reason: Systemic therapy different between groups |
Some concerns |
|
Tornberg, 2018 |
Definitely yes
Reason: Participants were selected from the same register.
|
Probably yes
Reason: Derived from register. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival). |
Probably no
Reason: No characteristics presented for patients with complete/non-complete metastasectomy.
|
Probably yes
Reason: Multivarate analysis was performed. |
Probably yes
Reason: Derived from patient registry. |
Probably yes
Reason: No missing data. |
No information
No data presented for complete/non-complete metastasectomy
|
Some concerns |
|
You, 2016 |
Probably yes
Reason: Participants were selected from the same medical center.
|
Probably yes
Reason: Derived from medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival). |
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Multivariate analysis was performed. |
Probably yes
Reason: Derived from medical records. |
Probably yes
Reason: No missing data. |
Probably yes
Reason: No other interventions. |
Low |
|
Yu, 2015 |
Probably yes
Reason: Participants were selected from the same hospital.
|
Probably yes
Reason: Probably derived from medical records. |
Definitely yes
Reason: Outcome of interest could not be present at the start (survival).
|
Probably yes
Reason: Characteristics of participants were provided. |
Probably yes
Reason: Multivariate analysis was performed. |
Probably yes
Reason: Derived from medical records. |
Probably yes
Reason: No missing data. |
Probably no
Reason: Unclear which targeted therapy was administered. |
Some concerns |
Table of excluded studies
|
Reference |
Reason for exclusion |
|
Alt AL, Boorjian SA, Lohse CM, Costello BA, Leibovich BC, Blute ML. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011 Jul 1;117(13):2873-82. doi: 10.1002/cncr.25836. Epub 2011 Jan 10. PMID: 21692048 |
Included in systematic review of Hsieh 2021 |
|
Dabestani S, Marconi L, Hofmann F, Stewart F, Lam TB, Canfield SE, Staehler M, Powles T, Ljungberg B, Bex A. Local treatments for metastases of renal cell carcinoma: a systematic review. Lancet Oncol. 2014 Nov;15(12):e549-61. doi: 10.1016/S1470-2045(14)70235-9. Epub 2014 Oct 26. PMID: 25439697. |
More recent systematic review with overlap in included studies available |
|
Haque W, Verma V, Butler EB, Teh BS. Utilization of Stereotactic Radiosurgery for Renal Cell Carcinoma Brain Metastases. Clin Genitourin Cancer. 2018 Aug;16(4):e935-e943. doi: 10.1016/j.clgc.2018.03.015. Epub 2018 Apr 3. PMID: 29680768. |
Wrong comparison: stereotactic radiosurgery versus whole brain radiation therapy |
|
Ishihara H, Takagi T, Kondo T, Fukuda H, Tachibana H, Yoshida K, Iizuka J, Kobayashi H, Ishida H, Tanabe K. Prognostic impact of metastasectomy in renal cell carcinoma in the postcytokine therapy era. Urol Oncol. 2021 Jan;39(1):77.e17-77.e25. doi: 10.1016/j.urolonc.2020.08.011. Epub 2020 Aug 28. PMID: 32863124. |
Included in systematic review of Hsieh 2021 |
|
Kwak C, Park YH, Jeong CW, Lee SE, Ku JH. Metastasectomy without systemic therapy in metastatic renal cell carcinoma: comparison with conservative treatment. Urol Int. 2007;79(2):145-51. doi: 10.1159/000106329. PMID: 17851285. |
Included in systematic review of Hsieh 2021 |
|
Kim DY, Karam JA, Wood CG. Role of metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy. World J Urol. 2014 Jun;32(3):631-42. doi: 10.1007/s00345-014-1293-6. Epub 2014 Apr 18. PMID: 24744223. |
Wrong study design: narrative review |
|
Li JR, Ou YC, Yang CK, Wang SS, Chen CS, Ho HC, Cheng CL, Yang CR, Chen CC, Wang SC, Lin CY, Hung SC, Hsu CY, Chiu KY. The Impact of Local Intervention Combined with Targeted Therapy on Metastatic Renal Cell Carcinoma. Anticancer Res. 2018 Sep;38(9):5339-5345. doi: 10.21873/anticanres.12861. PMID: 30194186. |
Included in systematic review of Hsieh 2021 |
|
Liu Y, Long W, Zhang Z, Zhang Z, Mai L, Huang S, Han H, Zhou F, Dong P, He L. Metastasis-directed stereotactic body radiotherapy for oligometastatic renal cell carcinoma: extent of tumor burden eradicated by radiotherapy. World J Urol. 2021 Nov;39(11):4183-4190. doi: 10.1007/s00345-021-03742-1. Epub 2021 May 27. PMID: 34043023; PMCID: PMC8571216. |
Wrong intervention: among the patients receiving SBRT, systemic therapies were initiated after SBRT in 5 patients. The remaining patients started systemic therapy before SBRT. Some patients in both groups also received metastasectomy. |
|
Lyon TD, Thompson RH, Shah PH, Lohse CM, Boorjian SA, Costello BA, Cheville JC, Leibovich BC. Complete Surgical Metastasectomy of Renal Cell Carcinoma in the Post-Cytokine Era. J Urol. 2020 Feb;203(2):275-282. doi: 10.1097/JU.0000000000000488. Epub 2019 Aug 8. PMID: 31393812. |
Wrong comparison: also, nonsurgical therapy |
|
Masini C, Iotti C, De Giorgi U, Bellia RS, Buti S, Salaroli F, Zampiva I, Mazzarotto R, Mucciarini C, Vitale MG, Bruni A, Lohr F, Procopio G, Caffo O, Nole F, Morelli F, Baier S, Buttigliero C, Ciammella P, Timon G, Fantinel E, Carlinfante G, Berselli A, Pinto C. Nivolumab in Combination with Stereotactic Body Radiotherapy in Pretreated Patients with Metastatic Renal Cell Carcinoma. Results of the Phase II NIVES Study. Eur Urol. 2022 Mar;81(3):274-282. doi: 10.1016/j.eururo.2021.09.016. Epub 2021 Oct 1. PMID: 34602312. |
Wrong population: second- and third-line mRCC patients |
|
Onal C, Hurmuz P, Guler OC, Yavas G, Tilki B, Oymak E, Yavas C, Ozyigit G. The role of stereotactic body radiotherapy in switching systemic therapy for patients with extracranial oligometastatic renal cell carcinoma. Clin Transl Oncol. 2022 Aug;24(8):1533-1541. doi: 10.1007/s12094-022-02793-z. Epub 2022 Feb 4. PMID: 35119653. |
No comparison: only SBRT |
|
Ouzaid I, Capitanio U, Staehler M, Wood CG, Leibovich BC, Ljungberg B, Van Poppel H, Bensalah K; Young Academic Urologists Kidney Cancer Working Group of the European Association of Urology. Surgical Metastasectomy in Renal Cell Carcinoma: A Systematic Review. Eur Urol Oncol. 2019 Mar;2(2):141-149. doi: 10.1016/j.euo.2018.08.028. Epub 2018 Sep 24. PMID: 31017089. |
Included studies were retrospective and non-comparative |
|
Staehler MD, Kruse J, Haseke N, Stadler T, Roosen A, Karl A, Stief CG, Jauch KW, Bruns CJ. Liver resection for metastatic disease prolongs survival in renal cell carcinoma: 12-year results from a retrospective comparative analysis. World J Urol. 2010 Aug;28(4):543-7. doi: 10.1007/s00345-010-0560-4. Epub 2010 May 4. PMID: 20440505. |
Included in systematic review of Hsieh 2021, but wrong comparison (partial resection versus no surgery; control group refused surgery) |
|
Sun M, Meyer CP, Karam JA, de Velasco G, Chang SL, Pal SK, Trinh QD, Choueiri TK. Predictors, utilization patterns, and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy. Eur J Surg Oncol. 2018 Sep;44(9):1439-1445. doi: 10.1016/j.ejso.2018.05.026. Epub 2018 Jun 5. PMID: 29935840. |
Included in systematic review of Hsieh 2021 |
|
Verbiest A, De Meerleer G, Albersen M, Beuselinck B. Non-Surgical Ablative Treatment of Distant Extracranial Metastases for Renal Cell Carcinoma: A Systematic Review. Kidney Cancer 2018; 2(1), 57-67. |
C does not match PICO |
|
Verbiest A, Roussel E, Tosco L, Joniau S, Laenen A, Clement P, Beuselinck B. Long-term outcomes in clear-cell renal cell carcinoma patients treated with complete metastasectomy. Kidney Cancer 2020; 4(4), 177-183. |
Wrong comparison: systemic therapy |
|
You D, Lee C, Jeong IG, Song C, Lee JL, Hong B, Hong JH, Ahn H, Kim CS. Impact of metastasectomy on prognosis in patients treated with targeted therapy for metastatic renal cell carcinoma. J Cancer Res Clin Oncol. 2016 Nov;142(11):2331-8. doi: 10.1007/s00432-016-2217-1. Epub 2016 Aug 23. PMID: 27553579 |
Included in systematic review of Hsieh 2021 |
|
Yu X, Wang B, Li X, Lin G, Zhang C, Yang Y, Fang D, Song Y, He Z, Zhou L. The Significance of Metastasectomy in Patients with Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy. Biomed Res Int. 2015;2015:176373. doi: 10.1155/2015/176373. Epub 2015 Oct 11. PMID: 26568955; PMCID: PMC4619757. |
Included in systematic review of Hsieh 2021 |
|
Zaid HB, Parker WP, Safdar NS, Gershman B, Erwin PJ, Murad MH, Boorjian SA, Costello BA, Thompson RH, Leibovich BC. Outcomes Following Complete Surgical Metastasectomy for Patients with Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. J Urol. 2017 Jan;197(1):44-49. doi: 10.1016/j.juro.2016.07.079. Epub 2016 Jul 26. PMID: 27473875. |
More recent systematic review with overlap in included studies available |
Verantwoording
Beoordelingsdatum en geldigheid
Publicatiedatum : 14-04-2026
Beoordeeld op geldigheid : 14-04-2026
Algemene gegevens
De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.
Samenstelling werkgroep
Voor het ontwikkelen van de richtlijnmodule is in 2021 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten met nierkanker en een vertegenwoordiger namens de patiëntenvereniging.
Werkgroep
- Dr. A. (Axel) Bex, uroloog, Antoni van Leeuwenhoek, Amsterdam, NVU (voorzitter)
- Dr. R.F.M. (Rob) Bevers, uroloog, Leids Universitair Medisch Centrum, Leiden, NVU
- Dr. J.F. (Hans) Langenhuijsen, uroloog, Radoudumc, Nijmegen, NVU
- Dr. A.P. (Paul) Hamberg, internist-oncoloog, Franciscus Gasthuis en Vlietland Ziekenhuis, Rotterdam, NIV/NVMO
- Dr. J.V. (Hans) van Thienen, internist-oncoloog, Antoni van Leeuwenhoek, Amsterdam, NIV/NVMO
- J. (Jolanda) Bloos-van der Hulst, verpleegkundig specialist, Antoni van Leeuwenhoek, Amsterdam, V&VN
- Dr. A.M.E. (Anna) Bruynzeel, radiotherapeut-oncoloog, Amsterdam Medisch Centrum, NVRO
- Dr. L. (Linda) Kerkmeijer, radiotherapeut-oncoloog, Radboudumc, Nijmegen, NVRO
- Drs. E. (Else) Wolak, belangenbehartiger Kwaliteit van zorg, Patiëntenvereniging Blaas- of Nierkanker
- Dr. M.A.J. (Mark) Meier, interventieradioloog, Isala Ziekenhuis, Zwolle, NVvR / NVIR
Met ondersteuning van
- Drs. D.A.M. (Danique) Middelhuis, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. M.H.D. (Majke) van Bommel, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. M. (Mohammadreza) Abdollahi, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. J.H. (Hanneke) van der Lee, senior-adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. I.M. (Irina) Mostovaya, senior-adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Linda Niesink, medisch informatie specialist, Kennisinstituut van de Federatie Medisch Specialisten
- Esther van der Bijl, medisch informatie specialist, Kennisinstituut van de Federatie Medisch Specialisten
Belangenverklaringen
De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.
Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.
|
Werkgroeplid |
Functie |
Nevenfuncties |
Gemelde belangen |
Ondernomen actie |
|
Bex (voorzitter) |
Uroloog AVL Amsterdam. Afdelingshoofd in het Specialist Centre of Kidney Cancer, Royal Free London NHS Foundation Trust, Professor of Urology, UCL Division of Surgery and Investigational Science. |
Alle nevenfuncties zijn onbetaald: |
- Restricted educational grant van Pfizer tbv een neoadjuvante studie (sponsor is het NKI-AvL). - Steering committee op twee internationale adjuvante fase 3 studies van BMS en Roche. - Lid van medical steering committee van twee patientenorganisaties (Kidney Cancer Association en IKCC). - Financier BMS: randomised phase 3 trial of adjuvant nivolumab plus ipilimumab versus placebo in high risk RCC. - Financier Roche: randomised phase 3 trial of adjuvant atezolizumab versus placebo in high risk RCC. - Financier Pfizer: single-arm phase 2 trial of neoadjuvant avelumab plus axitinib in high risk RCC (funded by restricted educational grant) |
Geen restricties |
|
Bevers |
Uroloog LUMC Leiden |
Geen |
Geen |
Geen restricties |
|
Langenhuijsen |
Uroloog Radboudumc Nijmegen |
Invited speaker Update Urology (Astra Zeneca), vergoeding+reiskosten |
Financier: ZonMW Voorbereidende studie Doelmatigheidsonderzoek, Pentixafor PET vs veneuze sampling bij primair hyperaldosteronisme - Financier: PentixaPharm GmbH, CASTUS trial. |
Geen restricties |
|
Hamberg |
Oncoloog Franciscus Gasthuis en Vlietland Rotterdam |
voorzitter WIN-O nier (onbetaald) bestuurslid Pro RCC (onbetaald) |
- Adviesraden meerdere farmaceutische bedrijven actief binnen RCC zorg - lokale hoofonderzoeker van aantal adjuvante nierkanker studies (Farma sponsored). Tevens ook van studies (farma sponsored) naar medicamenteuze interventies bij gemetastaseerde ziekte (oa RCC) |
Geen restricties |
|
Van Thienen |
Internist-oncoloog NKI-AvL Amsterdam |
Alle nevenfuncties zjn onbetaald: - Inhoudelijk/vice voorzitter Medisch Inhoudelijke Standpunten (MIS) groep van DRCG - Lid wetenschappelijke adviesraad Stichting PRO-RCC |
Pfizer Neoadjuvant axitinib en avelumab bij niercelcarcinoom (projectleider); BMS Checkmate 914 Adjuvant immunotherapy in high-risk renal cancer (onderzoeker); Eisai CLEAR study: levantinib and everolimus or pembrolizumab vs sunitinib in mRCC (onderzoeker); Goethe University Frankfurt am Main Sunniforecast (nivolumab+ipilimumab vs sunitinib in non-clear cell mRCC)(onderzoeker); Roche Adjuvant atezolizumab in high risk renal cancer (onderzoeker) |
Geen restricties |
|
Bloos-van der Hulst |
Verpleegkundig specialist uro-oncologie AVL Amsterdam |
Geen |
Geen |
Geen restricties |
|
Kerkmeijer |
Radiotherapeut-oncoloog, Radboudumc Nijmegen. Plaatsvervangend keteneigenaar Urologische Oncologie Radboudumc Nijmegen |
Alle nevenfuncties zjn onbetaald: - DUOS bestuurslid - Raad van Advies Tie Ribbon - Associate Editor Frontiers in oncology - Radiotherapeut-oncoloog UMC Utrecht (gastaanstelling) |
KWF subsidie FLAME studie prostaatcarcinoom |
Geen restricties |
|
Wolak |
Belangenbehartiger kwaliteit van zorg Patiëntenvereniging blaas- of nierkanker (PBNK) |
Patiëntenvereniging blaas- of nierkanker |
Werkzaam bij patiëntenorganisatie Leven met blaas- of nierkanker, geen boegbeeldfunctie |
Geen restricties |
|
Meier |
Interventieradioloog Isala Zwolle Voorzitter RVE Medische Beeldvorming, Isala Zwolle |
|
Geen |
Geen restricties |
|
Bruynzeel |
Radiotherapeut-oncoloog, Amsterdam UMC |
Geen |
ViewRay Inc: Een onderzoek naar hoge en precieze bestraling (stereotactische ablatieve radiotherapie) bij patiënt |
Geen restricties |
Inbreng patiëntenperspectief
Er werd aandacht besteed aan het patiëntenperspectief door uitnodigen van de Patiëntenvereniging blaas- of nierkanker (PBNK) voor de schriftelijke knelpunteninventarisatie en afvaardiging namens PBNK in de werkgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen (zie per module ook “Waarden en voorkeuren van patiënten”). De conceptrichtlijn is tevens voor commentaar voorgelegd aan Patiëntenvereniging blaas- of nierkanker (PBNK) en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.
Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz
Bij de richtlijnmodule is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).
Module |
Uitkomst raming |
Toelichting |
|
Module Oligometastasering |
geen financiële gevolgen |
Uitkomst 1 |
De kwalitatieve raming volgt na de commentaarfase.
Werkwijze
AGREE
Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 3.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).
Knelpuntenanalyse en uitgangsvragen
Tijdens de voorbereidende fase inventariseerde de werkgroep de knelpunten in de zorg voor patiënten met nierkanker. Tevens zijn er knelpunten aangedragen door de NVU (Nederlandse Vereniging voor Urologie) en NVRO, NVVR en Patiëntenvereniging blaas- of nierkanker (PBNK) via een schriftelijke knelpuntenanalyse.
Op basis van de uitkomsten van de knelpuntenanalyse zijn door de werkgroep concept-uitgangsvragen opgesteld en definitief vastgesteld.
Uitkomstmaten
Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.
Methode literatuursamenvatting
Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.
Beoordelen van de kracht van het wetenschappelijke bewijs
De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).
GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).
|
GRADE |
Definitie |
|
Hoog |
|
|
Redelijk |
|
|
Laag |
|
|
Zeer laag |
|
Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).
Overwegingen (van bewijs naar aanbeveling)
Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.
Formuleren van aanbevelingen
De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.
In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.
|
Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers |
||
|
|
||
|
|
Sterke aanbeveling |
Zwakke (conditionele) aanbeveling |
|
Voor patiënten |
De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet. |
Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet. |
|
Voor behandelaars |
De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen. |
Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren. |
|
Voor beleidsmakers |
De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid. |
Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen. |
Organisatie van zorg
In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.
Commentaar- en autorisatiefase
De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.
Literatuur
Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.
Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.
Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.
Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.
Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.
Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html
Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.
Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.
Zoekverantwoording
Algemene informatie
|
Richtlijn: Herziening Niercelcarcinoom |
|
|
Uitgangsvraag: Welke behandeling (chirurgische metastasectomie, SBRT, ablatie) kan het beste worden toegepast bij patiënten met a) synchrone oligometastasen / b) metachrone oligometastasen? |
|
|
Database(s): Medline (OVID), Embase |
Datum: 12-04-2022 |
|
Periode: >2000 |
Talen: Engels, Nederlands |
|
Literatuurspecialist: Linda Niesink |
|
|
BMI zoekblokken: voor verschillende opdrachten wordt (deels) gebruik gemaakt van de zoekblokken van BMI-Online https://blocks.bmi-online.nl/ Bij gebruikmaking van een volledig zoekblok zal naar de betreffende link op de website worden verwezen. |
|
|
Toelichting:
→ Voor deze vraag is gezocht op de elementen (oligo)metastasen (in het groen), niercelcarcinoom (in het blauw), en metastasectomie, radiotherapie en/of ablatie (in het oranje).
→ Resultaten staan in Rayyan. |
|
|
Te gebruiken voor richtlijnen tekst: In de databases Embase (via embase.com) en Medline (via OVID) is op 12-04-2022 met relevante zoektermen gezocht naar systematische reviews, RCT’s en observationele studiedesigns over metastasectomie, radiotherapie en/of ablatie bij patiënten met synchrone of metachrone (oligo)metastasen bij niercelcarcinoom. De literatuurzoekactie leverde 1094 unieke treffers op. |
|
Zoekopbrengst
|
|
EMBASE |
OVID/MEDLINE |
Ontdubbeld |
|
SRs |
114 |
91 |
143 |
|
RCTs |
222 |
71 |
253 |
|
|
510 |
501 |
698 |
|
Totaal |
846 |
663 |
1094 |
Zoekstrategie
|
Database |
Zoektermen |
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Embase
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Medline (OVID)
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1 exp Carcinoma, Renal Cell/ or exp Kidney Neoplasms/ or (('kidney' or 'renal' or nephroid or hypernephroid or 'collecting duct') adj3 (cancer* or carcinoma* or adenocarcinoma* or neoplasm* or tumor* or tumour* or mass*)).ti,ab,kf. or (grawitz* adj3 (tumor* or tumour*)).ti,ab,kf. or hypernephroma*.ti,ab,kf. or (RCC or MRCC or nccrcc or ncrcc).ti,ab,kf. (113711) 2 exp Neoplasm Metastasis/ or (advanced or metasta* or oligometasta* or synchron* or metachron* or mrcc).ti,ab,kf. (1186195) 3 exp Metastasectomy/ or exp Radiofrequency Ablation/ or exp Radiotherapy/ or (ablation or metastasectom* or metastectom*).ti,ab,kf. or (metastasis adj3 (resect* or excision*)).ti,ab,kf. or (microwave adj3 (ablation or therap* or thermotherap*)).ti,ab,kf. or (stereotactic adj3 (radiation or radiotherap* or radiosurger* or therap*)).ti,ab,kf. (325116) 4 1 and 2 and 3 (2243) 5 limit 4 to ((english or dutch) and yr="2000 -Current") (1713) 6 5 not (comment/ or editorial/ or letter/ or ((exp animals/ or exp models, animal/) not humans/)) (1643) 7 (meta-analysis/ or meta-analysis as topic/ or (metaanaly* or meta-analy* or metanaly*).ti,ab,kf. or systematic review/ or cochrane.jw. or (prisma or prospero).ti,ab,kf. or ((systemati* or scoping or umbrella or "structured literature") adj3 (review* or overview*)).ti,ab,kf. or (systemic* adj1 review*).ti,ab,kf. or ((systemati* or literature or database* or data-base*) adj10 search*).ti,ab,kf. or ((structured or comprehensive* or systemic*) adj3 search*).ti,ab,kf. or ((literature adj3 review*) and (search* or database* or data-base*)).ti,ab,kf. or (("data extraction" or "data source*") and "study selection").ti,ab,kf. or ("search strategy" and "selection criteria").ti,ab,kf. or ("data source*" and "data synthesis").ti,ab,kf. or (medline or pubmed or embase or cochrane).ab. or ((critical or rapid) adj2 (review* or overview* or synthes*)).ti. or (((critical* or rapid*) adj3 (review* or overview* or synthes*)) and (search* or database* or data-base*)).ab. or (metasynthes* or meta-synthes*).ti,ab,kf.) (585374) 8 (exp randomized controlled trial/ or randomized controlled trials as topic/ or random*.ti,ab. or rct?.ti,ab. or ((pragmatic or practical) adj "clinical trial*").ti,ab,kf. or ((non-inferiority or noninferiority or superiority or equivalence) adj3 trial*).ti,ab,kf.) not (animals/ not humans/) (1366536) 9 Case-control Studies/ or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or comparative study/ or control groups/ or controlled before-after studies/ or controlled clinical trial/ or double-blind method/ or historically controlled study/ or matched-pair analysis/ or single-blind method/ or (((control or controlled) adj6 (study or studies or trial)) or (compar* adj (study or studies)) or ((control or controlled) adj1 active) or "open label*" or ((double or two or three or multi or trial) adj (arm or arms)) or (allocat* adj10 (arm or arms)) or placebo* or "sham-control*" or ((single or double or triple or assessor) adj1 (blind* or masked)) or nonrandom* or "non-random*" or "quasi-experiment*" or "parallel group*" or "factorial trial" or "pretest posttest" or (phase adj5 (study or trial)) or (case* adj6 (matched or control*)) or (match* adj6 (pair or pairs or cohort* or control* or group* or healthy or age or sex or gender or patient* or subject* or participant*)) or (propensity adj6 (scor* or match*))).ti,ab,kf. or (confounding adj6 adjust*).ti,ab. or (versus or vs or compar*).ti. or ((exp cohort studies/ or epidemiologic studies/ or multicenter study/ or observational study/ or seroepidemiologic studies/ or (cohort* or 'follow up' or followup or longitudinal* or prospective* or retrospective* or observational* or multicent* or 'multi-cent*' or consecutive*).ti,ab,kf.) and ((group or groups or subgroup* or versus or vs or compar*).ti,ab,kf. or ('odds ratio*' or 'relative odds' or 'risk ratio*' or 'relative risk*' or aor or arr or rrr).ab. or (("OR" or "RR") adj6 CI).ab.)) (5129254) 10 6 and 7 (91) – SRs 11 (6 and 8) not 10 (71) - RCTs 12 (6 and 9) not (10 or 11) (501) – observationele studies 13 10 or 11 or 12 (663) |