Dabestani S, Marconi L, Hofmann F, Stewart F, Lam TB, Canfield SE, Staehler M6, 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.
This is the final draft, after peer-review, of a manuscript published in The
Lancet. The definitive version, detailed above, is available online at
www.thelancet.com
Systematic Review of Local Therapies for Metastases of Renal Cell Carcinoma
Saeed Dabestani, Lorenzo Marconi, Fabian Hofmann, Fiona Stewart, Thomas B L
Lam, Steven Canfield, Michael Staehler, Thomas Powles, BörjeLjungberg, Axel Bex
* Saeed Dabestani, MD, Department of Urology, Skåne University Hospital, Jan
WaldenstömsGata 7, 20502, Malmö, Sweden
* Lorenzo Marconi, MD, Department of Urology, CoimbraUniversityHospital, Coimbra,
Portugal
* Fabian Hofmann, MD, Department of Urology, SunderbyHospital, Sunderby,
Sweden
* Fiona Stewart, MSc, Academic Urology Unit, University of Aberdeen, Aberdeen,
United Kingdom
* Thomas B. L. Lam, MD, Academic Urology Unit, University of Aberdeen, Aberdeen,
United Kingdom
* Steven E. Canfield, MD, Division of Urology, University of Texas Medical School at
Houston, Houston, Texas, USA
2
* Michael Staehler, MD,, Urologische Klinik, Klinikum der Ludwig-Maximilians
Universitaet, Munich, Germany.
*Thomas Powles, MD, professor,Barts Cancer Institute, Queen Mary University of
London, St Bartholomew's Hospital, London, UK.
* BörjeLjungberg, MD, professor, Department of Surgical and Perioperative Sciences,
Urology and Andrology, UmeåUniversity, Umeå, Sweden.
* Axel Bex, MD, Department of Urology, The Netherlands Cancer Institute, Antoni
van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Correspondence to:
Axel Bex, MD, PhD.The Netherlands Cancer Institute, Antoni van Leeuwenhoek
Hospital, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121,
1066 CX Amsterdam, The Netherlands.
Tel: +31 20 512 2553; Fax: +31 20 512 2554. E-mail address: a.bex@nki.nl (A. Bex).
Keywords: Renal cell carcinoma; Metastasis; Metastasectomy; Radiotherapy;
Stereotactic radiotherapy; Surgery; Targeted therapy;
Word count = 4507 words [including the summary but excluding the references,
figures and tables (journal word-count limit = 5000 words)]
3
Unstructured summary (word count = 200)
Local therapy of metastases such as metastasectomy or radiotherapy remains
controversial in the treatment of metastatic renal cell carcinoma (mRCC). To
investigate the benefits and harms of various local therapies, a systematic review was
conducted in accordance with Cochrane review methodology, including all types of
comparative studies on local treatment of RCC metastases in any organ. To address
whether local therapy of RCC metastases is beneficial, and what the best options are,
databases were searched from 1st January 2000 to 30th September 2013. Interventions
included metastasectomy, radiotherapy modalities, and no local treatment. The
outcomes were survival (overall, cancer-specific and progression-free), local symptom
control, and adverse events. Of 2180 studies retrieved, 16 retrospective comparative
studies recruiting a total of 2350 patients were eligible for inclusion, covering local
treatment of metastases to various organs and lymph nodes. The results suggest a
survival benefit with complete metastasectomy versus either incomplete or no
metastasectomy, and symptom control, including pain relief in bone metastases.
Nevertheless, the evidence base was marred by high risks of bias and confounding
across all studies. Whilst the findings should be interpreted cautiously, the identified
4
knowledge gaps should provide guidance for clinicians and researchers in terms of
improving the evidence base.
5
Introduction
Renal cell carcinoma (RCC) frequently leads to synchronous or metachronous
metastases (mRCC)1,2 and has an estimated age-standardised mortality in Europe of
2·6%.3 For synchronous mRCC, cytoreductive nephrectomy (CN) in combination with
interferon alpha resulted in a significant improvement in median overall survival (OS)
over interferon alone, but in the era of targeted therapy its role is ill defined. 4 With
current targeted drugs objective response rates (ORR) of 20-40% are achieved, but
complete responses have been reported in only 1-3% of patients in pivotal studies.5-7
Data from population-based analysis suggest that a plateau is being reached in terms
of median OS which ranges between 9-40 months depending on clinical risk scores.8
Therefore, with the exception of rare but durable responses following high-dose
interleukin-2, removal of all synchronous or metachronous lesions, when technically
feasible and clinically appropriate, provides the only potentially curative treatment
alternative. However, the benefits of local therapeutic options for metastases from
RCC are controversial. Despite retrospective data suggesting consistently that
complete resection of solitary or oligometastatic mRCC is a favourable prognostic
factor, independent of race or geographical location,9 uncertainty exists as to whether
this is due to a relatively favourable tumour biology, or to the role of metastasectomy,
or both. Less disputed benefits include palliation of symptoms, and delay or withdrawal
of systemic therapy, thereby avoiding associated toxicities.
RCC metastases are common in lung, bone, liver and brain, but can occur at any
anatomical site.10,11For surgical resection,
accessibility,
resectability,
patient
performance and co-morbidities have to be considered.12 Radiotherapy modalities may
provide valid local non-invasive treatment alternatives to surgery. For brain
metastases, these include whole brain radiotherapy (WBRT) or stereotactic
6
radiosurgery (SRS). In contrast to WBRT, SRS delivers highly collimated radiation to
a precisely defined target area, minimizing the radiation dose to surrounding areas.13
For other sites, including bone, conventional radiotherapy (CRT) or stereotactic body
radiotherapy (SBRT) are options. CRT is fractionated radiotherapy primarily applied to
treat painful metastases, while SBRT shares the qualities of SRS to deliver high-dose
single or multi-fraction radiation.14
Until now, no systematic review (SR) on the outcome of different local treatment
options for RCC metastases has been performed, and there is a need to determine
potential benefits of such an approach. Therefore the objective of this SR was to
address the question whether integration of local therapy of metastases into the
management of mRCC is beneficial, and if so, what the best treatment modalities are.
Methods
Search strategy and selection criteria
The review was performed according to PRISMA guidelines.15 The
search was
conducted in accordance with the principles outlined in the Cochrane Handbook for
Systematic Reviews of Interventions.16Studies were identified by searching electronic
databases and relevant websites. Highly sensitive electronic searches were conducted
to identify reports of randomized controlled trials (RCTs) or non-randomised
comparative studies of local treatment for mRCC. The search strategy excluded
studies published before 1st January 2000 and there were no language restrictions.
The databases searched were MEDLINE (1946 to 30th September 2013), MEDLINE
In-Process (30th September 2013), Embase (1974 to 30th September 2013), Cochrane
Central Register of Controlled Trials (The Cochrane Library, Issue 8, 2013) and Latin
7
American and Caribbean Center on Health Sciences Information (LILACS) (up to 30th
September 2013). The search was complemented by additional sources, including the
reference lists of included studies which were hand searched, and additional reports
identified by an expert panel (European Association of Urology Renal Cell Carcinoma
Guideline Panel). The search strategy has been described elsewhere (EAU RCC
Guideline 201317); the present review represents an update of the original search.
The inclusion criterion was comparative studies only, and these included RCTs,
prospective
non-randomised
comparative
interventional
studies,
prospective
observational studies with a comparator arm, and retrospective comparative studies.
Studies with no comparator group (e.g. single-arm case series), non-effectiveness
studies (e.g. prognostication or nomogram studies), reviews, or studies with less than
ten patients per arm, were excluded. If appropriate, some of these excluded studies
were retained for discussion. The study population included patients with mRCC to any
organ, except those with synchronous metastases to the ipsilateral adrenal gland or
retroperitoneal lymph nodes only. There were no restrictions regarding prior treatment
with cytoreductive nephrectomy, systemic or targeted therapy. The types of
interventions included metastasectomy with or without intended complete resection of
metastases in any organ, WBRT, CRT,SRS, SBRT, Cyberknife radiotherapy, hypofractionated radiotherapy, and no local treatment. The primary outcomes were overall
survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS).
Local tumour control, quality of life, symptom control and adverse events or toxicity
were considered as secondary outcomes.
Data extraction and risk of bias assessment
8
Two reviewers (S.D., L.M.) independently screened titles and abstracts of all citations
identified by the search strategies. Full text copies of all potentially relevant reports
were obtained and independently assessed by two reviewers to determine whether
they met the pre-defined inclusion criteria. Any disagreements were resolved by
consensus or arbitration by a third person (T.L.). A data extraction form was developed
specifically for the purpose of this assessment to collect information on study design,
characteristics of participants, characteristics of interventions, and outcome measures.
Two reviewers (S.D., L.M.) independently assessed the risk of bias (RoB) of individual
studies. The standard Cochrane Collaboration RoB tool16 was used to assess the RoB
in RCTs, whilst for non-randomised comparative studies, the RoB tool recommended
by the Cochrane Non-Randomised Studies Methods Group was used.16 In addition,
for non-randomised comparative studies, the main confounders were identified a priori
by the expert panel, for the primary (i.e. oncological) outcomes. A study was
considered to be at high RoB if any of the confounders were imbalanced. The main
confounders identified included age, gender, Fuhrman grade, size or volume of
metastases, previous treatment prior to local treatment, performance status (PS),
different sites treated in the same study, and tumour histology. The confounders were
assessed on the following four criteria: (a) whether the confounder was considered by
the study author; (b) precision of measurement; (c) baseline imbalance between the
intervention and comparator group(s); and (d) quality of adjustment for imbalance in
studies with various treatment sites.18 The assessment of the quality of evidence using
the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) approach was planned for outcomes in which the data synthesis involved
RCTs or non-randomised comparative studies with low RoB.19
9
Data synthesis and analysis
For data analysis, descriptive statistics were used to summarise baseline
characteristics data. The main results were summarized in a summary of findings table.
A quantitative synthesis (i.e. meta-analysis) was planned for RCTs only, due to the
inherent clinical and methodological heterogeneity present in non-randomised studies.
In instances when pooling of data was not performed, where appropriate the results
were presented in Forest plots to allow a visual comparison of the effects of
interventions between studies. Both fixed effects and random effects models were
used to derive the appropriate test statistic. For time-to-event data, hazard ratios and
95% confidence intervals (CIs) obtained directly from studies or indirectly from
presented Kaplan-Meier survival curves were used to compare results.20In analysing
dichotomous outcomes, relative risk with 95% CIs were used, whilst for continuous
outcomes, means and standard deviations or median and range were used to
summarise the data, and weighted mean difference and 95% CIs were used to
compare interventions. Statistical heterogeneity between studies was assessed by
visual inspection of plots of the data, the chi-square test for heterogeneity, and the
I2statistic.21 Analysis was performed using Cochrane RevMan version 5·2 software.
Where meta-analysis was not feasible, a narrative synthesis was provided instead.22
Role of the funding source
There was no funding source for this study. The corresponding author had full access
to all the data in the study and had final responsibility for the decision to submit for
publication.
10
Results
The literature search identified 2180 studies (Figure1). Of these, 189 were selected for
full text screening. Non-English language articles (n = 6) were translated. 16 studies
reporting on 2350 patients were eligible for final inclusion. Of studies not meeting the
inclusion criteria, 34 were retained for discussion, to put into clinical context the
relevance and implication of the review findings.
All 16 included studies were retrospective comparative studies. Neither RCTs nor any
prospective non-randomised comparative studies were identified. Eight studies
concerned local therapies of RCC-metastases in various organs.12,23-29 Various organs
was defined as metastases to any single organ or multiple organs of which major sites
were lung, bone, liver and brain. Minor sites included pancreas, adrenal gland, lymph
nodes, thyroid gland, spleen, ethmoid sinus and skin. Three studies concerned local
therapies of RCC-metastases in bone including the vertebrae,30-32 two in the brain33,34
and one each in the liver,35 lung,36 and pancreas.37 Three studies26,28,36 were abstracts
only. Baseline characteristics of included studies are outlined in Table 1 and the
summary of findings in Table 2. The heterogeneity of data did not allow for any metaanalysis. A narrative synthesis of the evidence is presented instead. There was great
variation in the type and distribution of systemic therapies and in their reporting across
studies (Table 1 and 2). Generally, systemic therapy consisted of cytokines and VEGFinhibitors. Eight studies27-29,31-34,36contained no information on systemic therapies;
three studies12,26,30 did not specify type of systemic therapies. Three studies25,35,37 used
therapy after and one study23 used therapy prior to metastasectomy. One study24
reported systemic treatment was not used.
Complete vs no/incomplete metastasectomy
11
All of the eight studies12,23-29 concerning RCC-metastases in various organs reported
on complete metastasectomy versus no and/or incomplete metastasectomy. However,
in one study25 complete resection was achieved in only 45% of the metastasectomy
cohort which was compared with no metastasectomy. No other focal treatment
modalities were applied. Six of the eight studies12,24-26,28,29 observed a significantly
longer median OS or CSS following complete metastasectomy (median figure for
median OS or CSS 40·75 months, range 23 – 122 months) compared with incomplete
and/or no metastasectomy (median figure for median OS or CSS 14·8 months, range
8·4 – 55·5 months). Of the two remaining studies, one study23 showed no significant
difference in CSS between complete metastasectomy and no metastasectomy (58
versus 50 months, [p =0·223]), however only 18 and 16 patients were assessed in the
respective study arms. The other study27 reported a longer median OS for the
metastasectomy group (30 versus 12 months) but the p-value was not provided. Figure
2 is a Forest plot showing the hazard ratios (HR) for OS and/or CSS in studies
comparing incomplete or no metastasectomy with complete metastasectomy for
mRCC to various organs. It demonstrates a clear survival benefit for complete over
incomplete or no metastasectomy, in patients with metastases to various organs.
Regarding metastasectomy at specific organs, three studies were found concerning
RCC-metastases to lung,36 liver,35 and pancreas37 respectively. The lung study
showed significantly higher median OS for metastasectomy compared with both target
therapy and immunotherapy (36·3, 30·4, and 18·0 months respectively, [p <0·05]). The
liver study showed significantly higher median OS for metastasectomy compared with
no metastasectomy (142 months versus 24 months, [p<0·001]). The pancreas study
showed a significantly higher 5-year OS rate compared with no metastasectomy (88%
versus 77%, [p = 0·0263]).
12
Local therapies for RCC bone metastases
Three studies were identified. One study32 compared single-dose image guided
radiotherapy (IGRT) (n = 59) with hypofractionated IGRT (n = 46) in patients with RCC
bone metastases at various locations. Single-dose IGRT (≥24 Gray) had a significantly
better 3-year actuarial local PFS rate (88% versus 17% [p =0·001]), which was also
shown with a Cox regression analysis (p = 0·008). Another study30 compared
metastasectomy/curettage and local stabilization (n = 33) with no surgical treatment (n
= 27) of solitary RCC bone metastases in various locations. A significantly higher 5year CSS rate was observed in the intervention group (36% versus 8% [p = 0·007]),
even when adjusting for adjuvant local radiotherapy. A multivariate analysis, adjusting
for prior nephrectomy, gender and age, still favoured metastasectomy/curettage and
stabilization (p = 0·018). A third study31 compared the efficacy and durability of pain
relief between single-dose SBRT (n = 76) and CRT (n = 34) in patients with RCC bone
metastases to the spinal column (C1-sacrum); no significant difference in pain ORR
(CRT 68% versus SBRT 62% [p = 0·67]), time to pain relief (CRT 0·6 weeks versus
SBRT 1·2 weeks [p = 0·29]), nor duration of pain relief (CRT 1·7 months versus SBRT
4·8 months [p = 0·095]) was found.
Local therapies for RCC brain metastases
Two studies on RCC brain metastases were included. One 3-armed study33 compared
SRS (n = 51) versus WBRT (n = 20) versus the combination of SRS + WBRT (n = 17).
Of note, all patients in the WBRT and combination groups had ≥2 brain metastases,
whereas such patients accounted for 17·6% of the SRS group. Each group was further
13
subdivided into recursive partitioning analysis (RPA) classes I to III (I favourable, II
moderate and III poor patient status). Two-year OS and intracerebral control were
equivalent for SRS and SRS + WBRT groups; both were superior to WBRT alone
(p<0·001), in the general study population and in the RPA subgroup analyses
(p<0·001). Comparing SRS with SRS + WBRT in a subgroup analysis of RPA class I
revealed significantly better 2-year OS and intracerebral control for the combination
group based on only three participants. The other study34 compared fractionated
stereotactic radiotherapy (FSRT) (n = 10) with metastasectomy + CRT (MTS + CRT)
(n = 11) or CRT alone (n = 12). Only six patients after MTS + CRT and four patients
after CRT were followed with imaging. Several of the patients in all groups underwent
alternative surgical and non-surgical treatments after initial treatment. Survival rates at
1, 2 and 3-years were 90%, 54%, 40·5% for FSRT, 63·6%, 27·3% and 9·1% for MTS
+ CRT, and 25%, 16·7% and 8·3% for CRT, respectively. No p-value was reported for
survival rates. FSRT did not have a significantly better 2-year local control rate
compared with MTS +CRT (p = 0·61).
Risk of bias and confounding assessment
Figure 3 summarises the RoB and confounding assessment for all included studies.
All included studies were of retrospective non-randomised comparative nature,
resulting in high RoB associated with non-randomisation, attrition, and selective
reporting. With the exception of one study12 all other studies were significantly
underpowered.
Regarding confounding, most studies reported adequate data on age and gender.
Systemic treatment type and the frequency of their use were heterogeneous. Although
the majority of studies had included PS in their baseline characteristics, there was
14
heterogeneity in the classification of PS. There was a moderate to high risk of
confounding regarding previous treatment, tumour histology, grade, and size/volume,
especially in studies on local therapies of RCC bone and brain metastases.30-34
Concerning different sites treated in the same study, there was generally a moderate
to high risk of confounding, especially for studies pertaining to therapies of metastases
at various sites12,24,25,27,29 as it was often unclear if these confounders were adjusted.
Finally, assessment of quality of evidence by GRADE was not performed because of
the nature of the included studies (i.e. retrospective comparative studies), and the high
RoB across the studies.
Discussion
The results of this SR indicated a survival benefit with complete metastasectomy
versus either incomplete or no metastasectomy for RCC metastases to parenchymal
organs. There was also some evidence in favour of local treatment in terms of symptom
control, such as pain relief in patients with bone metastases. The great variation in type
and distribution of systemic therapy and its response being reported in only a subset
of studies prevents any conclusion on the role and impact of targeted therapy in the
setting of complete metastasectomy. However, in a non-comparative report, the
majority of patients who had a complete response following a combination of targeted
therapy and local therapy stopped systemic treatment. After a median follow up of 322
days, 48% were still without progression which suggests that local therapy may have
a role in delaying systemic treatment and associated toxicity.38
The main strength of the review lies in its robust methodology, which adheres to strict
criteria which are rigorous, transparent and reproducible. It represents the best
15
available contemporary evidence base, from which some conclusions can indeed be
made, and identified knowledge gaps which can only be addressed through well
designed, prospective comparative studies in this field.
However, several limitations can be identified. All included studies were retrospective
comparative studies, involving small numbers of patients; there were neither RCTs nor
any prospective non-randomised comparative studies. There were generally high risks
of bias across all included studies, across most domains, including a significant risk of
confounding. As a result, only a narrative synthesis of the evidence was presented; a
meta-analysis would have been contraindicated due to the above limitations. In
addition, the search was pragmatically limited to studies published from 2000 onwards;
earlier publications may have been missed, although a scoping exercise of the
available literature prior to 2000 did not reveal any RCTs. The retrieved indicators of
poor quality of the evidence base imply that there is significant uncertainty in regard to
the findings, and therefore, caution is required in interpreting them. For instance, it
cannot be ruled out that the observed benefit is largely due to an indication bias based
on differences in tumour aggressiveness. Potentially, patients with oligometastasis and
long metachronous interval are more likely to be candidates for metastasectomy, while
those with high volume metastasis, rapid progression, and reduced performance status
may often not undergo resection. The dynamic of the disease may be more important
than any intervention, and several non-comparative studies support this assumption.
Low tumour grade39 and long metachronous intervals with repeat resection are
associated with long survival40 No reliable data exist on the proportion of patients with
mRCC who would be eligible for local therapy of their metastases. Depending on age
at diagnosis, 57-65% of patients with metastatic RCC have single sites.10 Estimates
suggest that 25% of patients with metachronous metastasis may be candidates for
16
local therapy.12 Regarding synchronous metastatic disease this proportion may be less
than 10%.
41
Most studies identified in this SR acknowledge that patient selection for
local therapy of metastases is complex due to the heterogeneous course of mRCC,
surgical resectability and anatomical access.
There is general consensus that a number of clinical and pathological factors such as
PS, disease-free interval, burden and site of metastases, as well as histological
subtype and Fuhrman grade, affect to a large extent the prognosis and management
of mRCC.42 Most of the data on metastasectomy exist for patients with clear-cell RCC
and little is known for other subtypes such as papillary RCC.43 Accurate information on
prognosis is of utmost importance for treatment decisions. The Memorial Sloan
Kettering Cancer Centre (MSKCC) risk score is one of the most commonly used
prognostic models and establishes favourable, intermediate and poor risk from
Karnofsky performance status (KS), time from diagnosis to treatment, serum
hemoglobin, calcium and lactate dehydrogenase.44 Surprisingly we identified only two
studies which reported the MSKCC score.29,35 For patients receiving targeted therapy,
MSKCC and the validated Database Consortium (DCM) model share concordance
indices of 0·66 to 0·65 to assess prognosis.8,45,46 In one of the studies included in the
SR, a more favourable risk category and metastasectomy were each independently
associated with better survival.29 However, median survival of 6 months for poor risk
patients suggests they do not live long enough to derive benefit from metastasectomy.
Other more site-specific clinical factors which may have prognostic value for local
therapy of metastases are recognized and are in part discussed in the studies included
in the SR.
Most data exist for the common lung metastases. Large non-comparative case series
not included in the SR reported 5-year survival rates of 37-54% for completely resected
17
solitary
or
oligometastatic
pulmonary
metastases.47-53
Multivariate
analyses
consistently identified a pattern of prognostic factors (Table 3). A higher number of
pulmonary metastases removed12,51,54, concomitant mediastinal nodal metastasis47,5153
or incomplete resection was associated with poorer 5-year survival rates of 0-
24·4%.12,48,51-54 In addition, a short disease-free interval after nephrectomy or
synchronous metastasis was associated with a poor outcome48,51,52,54 as well as size
of lung metastases.47,52,55Recently a lung-specific prognostic score including these
factors was developed from 200 consecutive patients with pulmonary metastases and
requires external validation.56
Interpretation of the identified studies for bone and brain metastases reporting on
radiotherapy or comparing radiotherapy to surgery is specifically problematic. During
the long period of 6-15 years represented by the included studies, considerable
advances were made in radiotherapy, including changes in dosage and modalities. In
addition, location, size, and soft-tissue involvement of metastases varied substantially
and were inconsistently reported. This prevented a direct comparison of results.
Although this SR suggests prolonged disease-free survival after SBRT or
metastasectomy of single and multiple bone metastases, no recommendations can be
made as to the best treatment modality. However, a RCT in patients with bone
metastasis from various malignancies, including RCC, demonstrated that immediate
decompressive surgery and postoperative radiotherapy is superior to radiotherapy
alone for patients with spinal cord compression.57 A further small non-comparative
study suggests the effectiveness of SRS for RCC spinal lesions with regard to absence
of progression and pain.58 In addition to general prognostic factors, peripheral location
of bone metastases was reported as a favourable factor.12,59-62
18
Only 2 studies were identified comparing different radiotherapy modalities, including
combination with surgery, for RCC brain metastases. This precludes recommendation
of a specific treatment modality. Additional studies on non-RCC brain metastases,
however, suggest a prognostic score-related approach. With SRS, craniotomy has
been largely abandoned except for brain metastases >3 cm and rapidly symptomatic
lesions with midline shift.63,64 RCC brain metastases were mostly evaluated collectively
with cerebral lesions from other malignancies. Recommendations for radiotherapy
follow the Radiation Therapy Oncology Group (RTOG) recursive partition analysis
(RPA) developed from brain metastases irrespective of the primary tumour site.65 (RPA
class I: KS >70%, age < 65, primary tumour controlled, no extracranial sites; class II:
KS > 70% with absence of ≥ one of the other factors; class III: KS < 70%). Most
patients (70% to 80%) belong to RPA class II.63,66 A retrospective non-comparative
study evaluated 85 RCC patients with brain metastases who underwent SRS.63 Median
metastatic volume was 1·2cm (range: 0·1 - 14·2cm) and 65% had multiple cerebral
metastases. Following SRS median OS was 11 months with a local control rate of 94%.
The majority (78%) died of extracranial progression. Median OS for RPA classes I, II
and III was 24·2 months, 9·2 months, and 7·5 months, respectively. A study including
RCC brain metastases among 4295 patients identified KS and number of brain
metastases as significant prognostic factors.67Patients with a KS of 90-100% and a
single brain lesion had a median OS of 14·8 months versus 3·3 months for those with
a KS <70% and >3 metastases. Current data suggest that WBRT is adequate for
patients with poor performance requiring palliation for multiple lesions. SRS can
provide effective local control comparable to surgery, even for multiple and recurrent
metastases and is recommended for patients with RPA I and II.68
19
For liver and pancreatic metastases, a potential benefit needs to be balanced against
morbidity and mortality of local therapy. In the study included in this SR, liver
metastasectomy was associated with significant morbidity in 20·1%35 with no benefit
for patients with high-grade RCC and synchronous metastases.In contrast,a noncomparative retrospective analysis of 43 patients reported low morbidity and mortality,
resulting in a 3-year OS of 62·1% and a median recurrence-free survival of 15·5
months.69 Alternatively, ablative techniques and SRS have resulted in effective local
control of small liver metastases.70,71,72
Cumulative data suggest that pancreatic metastasectomy may be beneficial in patients
with good PS and a single metastatic site.73 However, a 2·8% in-hospital mortality rate
after extensive surgery with pancreatico-duodenectomy in 35·8% and total
pancreatectomy in 19·9%, suggest that morbidity and mortality may outweigh the
potential benefit. In view of the overall low quality of the data and the significant surgical
morbidity, patients with a short interval to pancreatic metastasis following nephrectomy
may be best treated with systemic therapy.
Despite lymph nodes being the third metastatic site with 21.8% 10 we identified few
studies reporting on only subgroups who underwent nodal metastasectomy compared
to either no or incomplete resection. Isolated metachronous nodal metastases are rare
and most patients harbour additional extensive metastatic disease at multiple sites74
precluding complete metastasectomy which may explain the low number of
comparative retrospective studies retrieved.
In conclusion, this is the first SR to determine the evidence base regarding the role of
local treatment of RCC metastases. The results consistently point towards a benefit of
complete metastasectomy in terms of OS and CSS. With the exception of brain and
20
possibly bone metastases, metastasectomy remains by default the most appropriate
local treatment for most sites. As for secondary outcomes, there is some evidence for
local control benefits such as pain relief for bone metastases. Due to the relatively poor
quality of included studies, it remains unresolved whether the observed survival benefit
is a consequence of local therapy or a selection bias of those patients whose tumour
biology allowed them to proceed to metastasectomy,or both. An additional conclusion
is that future prospective studies, preferably with randomized design and larger
populations, are needed in order to increase the quality of evidence regarding local
treatment of RCC metastases. Finally from a clinical perspective, the possible survival
and symptom control benefits in mRCC patients eligible for local treatment should be
discussed in multi-disciplinary boards in order to tailor therapies individually. Despite
consistent prognostic factors associated with a favourable outcome following
metastasectomy, no general therapeutic guideline can be given, due to the large
uncertainties that exist in the evidence base. Careful patient selection is of paramount
importance, and the decision to resect metastases has to be taken for each site, and
on a case-by-case basis. PS, risk profiles, patient preference and alternative
techniques to achieve local control, such as SRS or ablation, will have to be
considered. There may also be a role for local therapy of metastases in terms of
delaying systemic treatment and associated toxicity.
21
Contributors
S.D., L.M., F.H., F.S., T.L. and A.B. contributed to study design, literature search,
figures, data collection, data analysis, data interpretation, presentation of results,
manuscript writing. T.L. and A.B. provided additional critical comments and
supervision.
M.S. contributed data and to their interpretation and provided expert comments
T.P., S.C. and B.L: data analysis and interpretation, providing expert and critical
comments. All authors approved the final version of the report
Conflict of interest:
Saeed Dabestani: None
Lorenzo Marconi: None
Fabian Hofmann: None
Fiona Stewart: None
Thomas Lam: None
Steven Canfield: has received honoraria as speaker for Amgen, Bayer and Genomic
Health.
Michael Staehler has received honoraria and research grants from: Pfizer, GSK,
Novartis, Astellas, Roche, Bayer, Imatics
Thomas Powles: has received research grants and honoraria for advisory board
participation and as speaker for Pfizer, GSK, Novartis and Astellas.
22
BorjeLjungberg: has received honoraria for advisory board participation from Bayer,
Novartis, GSK, Roche, Pfizer
Axel Bex : has received honoraria for advisory board participation and as speaker for
Pfizer, GSK, Novartis and Astellas. He is the PI of the EORTC 30073 SURTIME trial
which is supported by a research grant from Pfizer to the EORTC.
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29
Figure legends
Figure 1. PRISMAflow diagram showing the screening process by which included
studies were identified.
Table 1. Baseline characteristics of all included studies.
Table 2.Summary of results regarding comparative effectiveness and harms for all
included studies.
Table 3. General and site-specific factors for lung, bone and brain associated with a
favourable outcome after local treatment of RCC metastases. * Other sites follow the
general factors.
Figure 2. Forest plot of hazard ratios for overall survival/cancer-specific survival in
studies comparing incomplete or no metastasectomy versus complete
metastasectomy.*Cancer specific survival; Inc = incomplete; MTS = metastasectomy.
Figure 3. Risk of bias and confounding assessment summary. . Green circle = low
risk of bias/confounding; Red circle = high risk of bias/confounding; Yellow circle
=unclear risk of bias.
30
Abstracts and titles identified
through database searching
(n = 2085)
Abstracts identified from
other sources
(n = 95)
Abstracts and titles screened
(n = 2180)
Screening
Identification
Figure 1.PRISMAflow diagram
Eligibility
Articles identified for
full text screening
(n =189)
Articles full text
screened
(n = 189)
Included
Studies included in
systematic review
(n = 16)
-
Treatment site:
- Various (n=8)
- Lung (n = 1)
- Bone (n=3)
- Brain (n=2)
- Liver (n=1)
- Pancreas (n=1)
Records excluded
(n = 1991)
Exclusion criteria:
Publication year before 1
January 2000, review studies,
basic science studies, genetic or
epidemiologic studies, case
series or case reports, local
recurrence only studies, tumour
thrombosis of the Vena Cava
studies, non-comparative
studies, experimental treatment
studies, systemic treatment only
studies, number of participants
in any arm (intervention or
comparison) less than ten,
localised treatments for primary
kidney cancer.
Full text articles excluded
(n = 173)
34 studies retained for
discussion
Table 1: Baseline characteristics of all included studies
Study ID; design;
country; recruitment
period
Site of
treatment
Amiraliev 2012;36
Retrospective
comparative study
(Abstract only);
Russia;
1998 – 2010
Alt 2011;12 USA;
Retrospective
comparative study;
1976-2006
Lung
Various
(39% lung
only; 40%
lung +
various)
Petralia 2010;26
Italy & Austria:
Retrospective
comparative study;
(abstract only)
1984-2006
Staehler 2010;35
Retrospective
comparative study;
Germany;
1995-2006
Various
(% lung NR)
Staehler
2009;28Germany;
Retrospective
comparative study;
(abstract only)
1995-2006
Eggener 2008;29
USA;
Retrospective
comparative study;
1989-2007
Zerbi 2008;37
Retrospective
comparative study;
Various
(67% lung)
Interventions
N
Age in years:
mean (SD),
median [range]
Complete MTS
90
NR
Performance
status (as
stated by
author)
NR
FU (months)
mean (SD),
median
[range]
NR
Tumour
grade
(% Fuhrman
≥3)
NR
Tumour
histology
(% clear cell
carcinoma)
NR
Metastatic burden
Treatment
before/ after
intervention
NR
NR
Immunotherapy
(interferon-α)
Targeted therapy
41
NR
NR
NR
NR
NR
NR
NR
21
NR
NR
NR
NR
NR
NR
NR
Complete MTS
125
62 [41, 85]
37.2 [0, 334.4]
For all
participants:
76.9%
For all
participants:
90.2%
75% with ≥3 mets
Incomplete MTS
762
62 [21, 92]
Complete MTS
35
Prior CN/RN.
28% received
various SysT
Prior CN/RN.
48.5% received
various SysT
Prior CN/RN.
Other 3 groups
(incomplete MTS,
No MTS, AdjSysT)
143
For all
participants:
60 [27, 87]
ECOG 0-1 =
89.3% of
participants
ECOG 0-1 =
81.0% of
participants
NR
Complete MTS
68
No MTS (refused
surgery)
20
Complete MTS
183
NR
MSKCC score
≥intermediate
= 94%
MSKCC score
≥intermediate
= 95%
NR
No MTS (refused
surgery)
57
NR
NR
MTS (91%
complete MTS)
No MTS
44
85
For all
participants:
61.7 [52.7, 70.8]
For all
participants:
KS ≥80% =
106 (82%)
Complete MTS
23
64 (NR)
NR
Outcomes
measured
OS
(Sunitinib+Sorafenib)
Liver
Various
(64% lung)
Pancreas
For all
participants
58 [17, 78]
NR
31.2 [0, 182.4]
21 [1, 235]
92% with ≥3 mets
For all
participants:
56.2%
NR
NR
NR
NR
Prior CN/RN.
21% received
AdjSysT.
28%
88%
62% with ≥2 mets
0%
55%
70% with ≥2 mets
NR
NR
NR
Prior CN.
81% received
AdjSysT.
Prior CN.
80% received
AdjSysT.
Prior CN/RN
NR
NR
NR
Prior CN/RN
NR
NR
For all
participants:
80%
100% with 1
metastases
NR
NR
NR
17.4% with ≥2 mets
Prior RN in 123
patients (95%)
6 patients (5%)
had a partial
nephrectomy.
Prior RN.
35% received
AdjSysT
26 [1, 187]
26 [1, 187]
NR
31 [12, 98]
OS, CSS
CCS for MTS
vs. the 3
other groups.
OS
OS
OS
OS
32
Study ID; design;
country; recruitment
period
Site of
treatment
Italy;
1998-2006
Brinkmann 2007;23
Germany;
Prospective
comparative study;
1997-2004
Various
(85% lung)
Kwak 2007;24
Retrospective
comparative study;
Korea;
1990-2004
Various
(48% lung)
Russo 2007;27
Retrospective
comparative study;
USA;
1989-2003
Various
(48% lung)
Lee 2006;25
Retrospective
comparative study;
Korea;
1999-2003
Various
(63% lung)
Zelefsky 2012;32
Retrospective
comparative study;
USA;
2004-2010
Hunter 2012;31
Retrospectivecompar
ative study
USA;
2002-2010
Bone
(various
locations)
Bone
(spine C1
to sacrum)
Interventions
N
Age in years:
mean (SD),
median [range]
No MTS
13
65.9 (NR)
Complete MTS
18
61 [43, 75]
No MTS
16
64 [39, 76]
Complete MTS
21
60 [38, 79]
No MTS
41
61 [31, 79]
Complete MTS
61
For all
participants:
61 [52, 68]
No MTS or
incomplete MTS
30
MTS
(45% complete
MTS) +SysT
No MTS +SysT
20
Single dose IGRT.
59
For all
participants:
58 [31, 77]
37
NR
Performance
status (as
stated by
author)
NR
ECOG 0-1 =
78% of
participants
ECOG 0-1 =
81% of
participants
ECOG 0-1 =
100% of
participants
ECOG 0-1 =
43.9% of
participants
KS ≥80% =
89% of
participants
KS ≥80% =
84% of
participants
ECOG 0-1 =
100% of
participants
ECOG 0-1 =
79% of
participants
FU (months)
mean (SD),
median
[range]
Tumour
grade
(% Fuhrman
≥3)
NR
Tumour
histology
(% clear cell
carcinoma)
NR
NR
NR
NR
NR
NR
NR
36.5 [4, 182.7]
61.9%
8.4 [0.9, 63.7]
Metastatic burden
46.1% with ≥2 mets
Treatment
before/ after
intervention
Outcomes
measured
85.7%
>50% with 2 or more
organ systems with
metastases
>50% with 2 or more
organ systems with
metastases
33.3% with ≥2 mets
Prior RN.
100% received
AdjSysT.
Prior CN in 94%.
100% received
Neo-adjSysT.
Prior CN in 75%.
100% received
Neo-adjSysT.
Prior CN
56.1%
78.0%
70.7% with ≥2 mets
Prior CN
NR
90%
28.0% with ≥2 mets
Prior CN
NR
97%
53.0% with ≥2 mets
Prior CN
NR
NR
NR
75% with ≥2 mets
CSS, PFS
NR
NR
NR
95% with ≥2 mets
Prior RN or CN.
100% received
AdjSysT
Prior RN or CN.
100% received
AdjSysT
NR
NR
85% pelvic or spine
mets.
NR
Local PFS
67% pelvic or spine
mets.
59% with multiple
sites treated
NR
CSS
OS
OS
43 [Range NR]
NR
12 [1, 48]
Hypofractionated
IGRT
Single dose SBRT
46
NR
NR
NR
NR
76
57 [41, 80]
KS
(median =80%,
range 50-90)
NR
NR
CRT
34
62 [43,81]
KS
(median =70%,
range 20-100)
NR
NR
4.3 [0.2,38]
24% with multiple
sites treated
Prior radiation
to spine: 16%
Palliative
surgery : 0%
Prior radiation
to spine: 18%,
Palliative
surgery: 23%
Symptom
control
33
Study ID; design;
country; recruitment
period
Site of
treatment
Interventions
N
Fuchs 2005;30
Retrospective
comparative study;
Switzerland
1976-1999
Bone
(various
locations)
MTS/local
stabilization
non-surgical
treatment
33
Fokas 2010;33
Retrospective
comparative study;
Germany;
1996-2006
Brain
SRS
51
59% ≥ 63 years
WBRT
20
80% ≥ 63 years
SRS + WBRT
17
48% ≥ 63 years
Ikushima 2000;34
Retrospective
comparative study;
Japan;
1983-1998
Brain
FSRT
10
10% ≥ 60 years
MTS + CRT
11
18% ≥ 60 years
CRT alone
12
8.3% ≥ 60 years
27
Age in years:
mean (SD),
median [range]
For all
participants:
mean 67 (range
38 – 85)
Performance
status (as
stated by
author)
NR
NR
RPA I = 33% of
participants
RPA I = 5% of
participants
RPA I = 17% of
participants
ECOG 0-1 =
100% of
participants
ECOG 0-1 =
82% of
participants
ECOG 0-1 =
50% of
participants
FU (months)
mean (SD),
median
[range]
21 [1, 76]
NR [9, 95]
Tumour
grade
(% Fuhrman
≥3)
For all
participants:
26.7%
Tumour
histology
(% clear cell
carcinoma)
NR
NR
Metastatic burden
Treatment
before/ after
intervention
Outcomes
measured
73% appendicular
mets.
78% appendicular
mets.
No treatment
15%, CN 60% or
RN 25%. 20% of
all patients
received SysT.
CSS
NR
17.6% with ≥2 mets
OS, Symptom
control
NR
NR
100% with ≥2 mets
NR
NR
100% with ≥2 mets
NR
NR
NR
NR
NR
NR
10% with >1 mets
90% with
extracranialmets
36% with >1 mets
82% with
extracranialmets
50% with >1 mets
100% with
extracranialmets
No treatment
or RN or CN for
all participants.
Salvage therapy
= surgical
resection
No treatment,
RN or CN for all
participants.
NR
5.2 [0.5,68]
Adj = adjuvant; CN= Cytoreductive nephrectomy; CRT = Conventional radio therapy; CSS= Cancer-specific survival; ECOG = Eastern Cooperative Oncology Group performance status; EBRT= External beam
radiotherapy; FSRT = Fractionated stereotactic radiotherapy; HR = Hazard ratio with 95% confidence interval; KS = Karnofsky performance status; Mets = metastases; MSKCC = Memorial Sloan-Kettering Cancer
Center; MTS= Metastasectomy; NR= Not reported; ORR = Overall response rate (of symptom control); OS= Overall survival; PR = Pain relief; RN=radical nephrectomy; RPA = Recursive partition analysis (class I-III);
SBRT= Single fraction stereotactic body radiation therapy; SysT = Systemic therapy; WBRT= Whole brain radiotherapy.
CSS, local
control
34
Table 2.Summary of results regarding comparative effectiveness and harms of all included studies
Study ID
Amiraliev 201236
(abstract only)
Site of
treatment
Lung
Intervention
Immunotherapy
(interferon-α)
Complete MTS
Targeted therapy
Complete MTS
(Sunitinib+Sorafenib)
Alt 201112
Petralia 201026
(abstract only)
Staehler
201035
Various
(39% lung
only; 40%
lung +
various)
Various
(% lung NR)
Incomplete MTS
Other 3 groups
(incomplete MTS,
No MTS, SysT)
Various
(64% lung)
No MTS
Zerbi 200837
Complete MTS
OS( median)
N at baseline
Int
Com
41
90
OS(median)
21
90
OS (median)
762
125
CCS (median)
762
125
OS HR
(adjusted)
CSS HR
(adjusted)
CSS (median)
762
125
762
125
143
35
CSS HR
(adjusted)
OS (median)
143
35
20
68
OS HR
(adjusted)
20
68
OS
(mean 5 yrs)
OS (median)
183
57
183
57
OS HR
(unadjusted)
183
57
OS (median)
85
Value
Int
Com
Reported P
values
18.0
months
36.3
months
<0.05
30.4
months
36.3
months
<0.05
15.6
months
15.6
months
48.0
months
57.6
months
<0.001
<0.001
HR 2.61 [1.99 – 3.42]
<0.001
HR 2.91 (2.17 – 3.90)
<0.001
14 months
30 months
MTS
(91% complete)
Complete MTS
HR 1.71 [1.09 – 2.69]
27 months
142 months
HR 2.23 [1.05 – 4.72]
Complete MTS
Pancreas
No MTS
Outcome
=0.02
Notes
Three arm study. Not
reported if SysT was
given to MTS group.
Type of SysT not
specified in study.
43.7% of all patients
also received radiation
therapy for ≥ 1 mets.
Type of SysT given not
specified in study.
Complete MTS
Various
(67% lung)
No MTS (refused
surgery)
Eggener 200829
Complete MTS
Liver
No MTS (refused
surgery)
Staehler 200928
(abstract only)
Comparator
35.3%
(±9.2)
55.5
months
57.8 %
(±5.9)
122.0
months
HR 2.14 [ 1.44 – 3.174]
44
21 months
=0.01
=0.004
=0.036
<0.001
<0.001
<0.001
45 months
<0.001
OS HR
(adjusted)
OS (2/5 year
rate)
85
44
13
23
HR 2.70 [1.6 – 4.5]
59%/47%
AdjSysT was
interferon-α and/or
interleukin-2. 6% of
patients received
multi-kinase inhibitors
Author contacted to
get study data.
Median OS and OS HR
based on statistical
analysis of acquired
data. Not reported if
SysT was given.
Not reported if SysT
was given.
<0.001
98%/88%
=0.0263
AdjSysT was
interferon-α and/or
interleukin-2. 5.5% of
35
Study ID
Brinkmann 200723
Site of
treatment
Intervention
Various
(85% lung)
Russo
Lee 200625
N at baseline
Int
Com
18
16
Value
Int
50 [18-104]
months
Com
Reported P
values
58 [9,104]
months
Complete MTS
Various
(48% lung)
No MTS
200727
Outcome
CSS (median)
No MTS
Kwak 200724
Comparator
=0.223
8.4 months
36.5 months
No MTS or
incomplete MTS
Complete MTS
Various
(63% lung)
No MTS + SysT
MTS (45%
complete) + SysT
41
21
OS HR
(adjusted)
OS (median)
41
21
30
61
12 months
30 months
NR
Not reported if SysT
was given.
CSS (median)
PFS (median)
CSS (median)
37
37
11
20
20
9
13 months
5 months
20 months
23 months
13 months
28 months
=0.1098
=0.0226
AdjSysT was a
combination of
Interferon-α,
Interleukin-2 and 5flourouracil. HR was
only available for
incomplete MTS
subgroup versus
complete MTS
subgroup.
<0.001
HR 2.57 [1.21 – 5.44]
=0.014
=0.2587
Incomplete MTS +
SysT
Zelefsky 201232
Bone
(various
locations)
Single dose IGRT
≥24 Gray/dose
Single dose IGRT.
Hunter 201231
Complete MTS+
SysT
Hypofractionated
IGRT
Hypofractionated
IGRT
Bone
(spine C1
to sacrum)
CSS HR
(unadjusted)
11
Local PFS
(3 year rate)
45
Local PFS HR
(adjusted)
59
Single dose SBRT
9
HR 3.47 [1.26 – 9.56]
46
88%
PR HR
(unadjusted)
Time to PR
(median)
Duration of
PR (median)
=0.016
17%
=0.001
46
HR 0.280 [0.11 – 0.72]
PR ORR
CRT
patients also received
thalidomide.
Neo-adjSysT was a
combination of
Interferon-α,
Interleukin-2 and 5flourouracil
Study only included
patients who had not
received any
immunotherapy.
OS (median)
Complete MTS
Various
(48% lung)
Notes
34
76
68%
62%
HR 1.28 [0.78 – 2.08]
25
54
=0.008
=0.67
= 0.33
0.6 weeks
1.2 weeks
=0.29
1.7 months
4.8 months
=0.095
High single dose
(≥24Gy) subgroup
N=45 compared to
hypofractionated IGRT
in 3 year PFS. HR for
PFS is for all
participants in
intervention arm.
Not reported if SysT
was given.
Not reported if SysT
was given. Unclear
degree of metastatic
burden.
36
Study ID
Fuchs 200530
Fokas 201033
Ikushima 200034
Site of
treatment
Intervention
Bone
(various
locations)
Brain
Brain
Comparator
Outcome
CSS (5 year
rate)
MTS/local
stabilization
N at baseline
Int
Com
33
27
Value
Int
36%
Com
Reported P
values
8%
non-surgical
treatment
=0.007
SRS
WBRT
51
20
40%
0%
<0.001
SRS + WBRT
WBRT
17
20
35%
0%
<0.001
SRS
SRS + WBRT
51
17
40%
35%
=0.703
SRS
RPA class I
SRS
RPA class II-III
SRS
RPA class II-III
SRS + WBRT
class II-III
SRS
SRS + WBRT
RPA class I
WBRT
RPA class II-III
SRS + WBRT
RPA class II-III
WBRT
RPA class II-III
WBRT
17
3
52%
60%
<0.001
34
20
24%
0%
<0.001
34
14
24%
21%
<0.001
14
20
21%
0%
<0.001
51
20
38%
0%
<0.001
SRS + WBRT
WBRT
17
20
29%
0%
<0.001
SRS
SRS +WBRT
51
17
38%
29%
=0.032
SRS
RPA class I
SRS
RPA class II-III
SRS
RPA class II-III
SRS + WBRT
class II-III
FSRT
SRS + WBRT
RPA class I
WBRT
RPA class II-III
SRS + WBRT
RPA class II-III
WBRT
RPA class II-III
MTS+CRT;
CRT alone
17
3
59%
100%
<0.001
34
20
27%
0%
<0.001
34
14
27%
21%
<0.001
14
20
21%
0%
<0.001
90%/ 54%
/40.5%
FRST
MTS + CRT
FRST
CRT alone
OS (2 year
rate)
Intracerebral
control
(2 year rate)
CSS (1,2 and 3
year rate)
10
11;
12
LC (2 year
rate)
LC (2 year
rate)
10
6
55.2%
63.6%/ 27.3%
/9.1%;
25%/16.7%
/8.3%
70%
10
4
55.2
NR
NR
=0.61
NR
Notes
Type of SysT given
only stated as
chemotherapy. 82% of
all patients also
received radiation
therapy for mets.
Three arm study. OS
and Intracerebral
control outcomes for
SRS or SRS + WBRT
versus WBRT alone for
RPA class I not in table
as the WBRT subgroup
for RPA class I = 0
patients. No specific
definition of symptom
control given. Not
reported if SysT was
given.
Three arm study.
Actuarial LC rates only
for patients that were
followed by imaging
studies. Not reported
if SysT was given.
37
Adj = Adjuvant; Com = comparator; CRT= Conventional radiotherapy; CSS= Cancer-specific survival; FSRT= Fractionated stereotactic radiotherapy; HR = Hazard ratio with 95% confidence interval; IGRT = Image guided
radiotherapy; Int = Intervention; LC = local control; MTS= Metastasectomy; N = Number of participants; NR= Not reported; ORR= Overall response rate (= complete pain relief response and partial pain relief response
in total); OS = Overall survival; P = Probability; PR = Pain relief; RPA = Recursive partitioning analysis; SBRT= Single fraction high dose stereotactic body radiation therapy; SRS= Stereotactic radio surgery; SysT =
Systemic therapy; WBRT= Whole body radiotherapy.
38
Figure 2. Forest plot of hazard ratios for overall survival/cancer-specific survival in studies comparing incomplete or no
metastasectomy versus complete metastasectomy.*Cancer specific survival; Inc = incomplete; MTS = metastasectomy.
Heterogeneity: Tau2= 0.00; Chi2= 3.62; df=6; P=0.73; I2= 0%
39
Figure 3. Risk of bias and confounding assessment for included studies.
40
41
Table 3: General and site-specific factors for lung, bone and brain associated with a favourable outcome after local treatment of
RCC metastases. *Other sites follow the general factors
General*

Patient factors

< 7 metastases
- good performance status
(Karnofsky, ECOG, WHO)

absence of mediastinal
lymph node
metastases
- MSKCC or Heng favourable
and intermediate risk

Extent of disease
- solitary or oligometastatic
lesions
- single organ site
- absence of nodal metastases

Lung
Course of disease
- metachronousmetastasis
- disease-free interval of > 2
years
- absence of progression to
therapy

metastases < 4cm

unilateral lung
involvement
Bone

peripheral
location of
metastases
Brain

RTOG-RPA class I:
- Karnofsky PS > 70 %
- age <65 years
- absence of
extracranial metastatic
sites
- control of the primary
tumour

Karnofsky PS 90100 % and single
lesion
42

Tumour biology
- absence of sarcomatoid
component
- clear-cell subtype
- low to moderate Fuhrman grade

Surgical factor
- complete resection