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									SURGICAL TREATMENT OF RENAL CELL CANCER
LIVER METASTASES; A POPULATION BASED
STUDY




Naam:                   Thony Ruys
Begeleider:             Prof. T.M. van Gulik
Facultair begeleider:   Dr. A.J.M Karthaus
Instituut:              Afdeling Chirurgie, AMC, Amsterdam,
Periode:                06-07-2009 – 16-11-2009
ABSTRACT (English)

INTRODUCTION
Renal cell cancer (RCC) has an incidence of 1200 new patients in the Netherlands each year
(12.5 per 100.000 inhabitants). Half of these patients ultimately develop metastases and
prognosis of this group is poor with a 1-year survival of 10%. According to literature, the
liver is involved in 20% of patients with metastatic RCC, however resection is feasible in only
a minority (2-4%) of patients due to concomitant widespread disease. Hence, little is known
about outcomes of surgical treatment in patients with resectable liver metastases of RCC .

AIM
To evaluate outcomes of surgical treatment in patients with hepatic metastases from RCC in
the Netherlands and to identify prognostic factors for survival after resection.

METHODS
Patients were retrieved from local databases of the Netherlands Task Force for Liver Surgery
(14 centres) and from the Dutch collective pathology database PALGA. From these national
registries, 33 patients were identified who underwent resection n=(32) or local ablation (n=4)
of hepatic metastases of RCC in the Netherlands, between 1990 and 2008. Patient and tumour
characteristics, survival and prognostic factors in this specific patient population were
analysed by Kaplan-Meier curves and logrank tests.

RESULTS
The overall 1-, 3- and 5-year survival rates were 78.6%, 45.1%, and 40.6%, respectively.
Median survival was 26.6 months. There was no operative mortality and morbidity was 18%.
At a median follow-up interval of 19.2 (3.45-188.9) months, 28 patients showed evidence of
recurrence with a median time to recurrence of 10 (0.89-54) months. Metachronous
metastases (n=23, p=0.04) and radical resection (n=24, p<0.001) were significant
prognosticators of long-term survival. Size <50mm (n=18, p=0.84), solitary metastases (n=19,
p=0.92) and surprisingly, presence of extrahepatic metastases (n=11, p=0.21) showed no
significant influence on survival.

CONCLUSION
The survival rates and low operative morbidity and mortality found in this nation-wide study
indicate that surgical treatment of patients with hepatic metastases of RCC can benefit from
radical resection with 5-year survival rate of 40.6%.




                                                                                               2
ABSTRACT (Nederlands)


INLEIDING
Niercel carcinoom (NCC) heeft een incidentie van 1200 nieuwe patiënten in Nederland per
jaar (12,5 per 100.000 inwoners). De helft van deze patiënten ontwikkelen uiteindelijk
metastasen en de prognose van deze groep is zeer slecht met een 1-jaars overleving van 10%.
Volgens de literatuur, is de lever betrokken bij 20% van de patiënten met gemetastaseerd
niercelcarcinoom, resectie is echter slechts haalbaar bij een minderheid (2-4%) van de
patiënten als gevolg van de vaak gelijktijdig wijdverbreide ziekte. Hierdoor is er weinig
bekend over de resultaten van chirurgische behandeling bij patiënten met resectable
levermetastasen van NCC.

DOEL
Evaluatie van de resultaten van chirurgische behandeling bij patiënten met levermetastasen
van NCC in Nederland en het identificeren van prognostische factoren voor overleving na
resectie.

METHODEN
Patiëntendata werd verzameld uit lokale databases van de werkgroep Leverchirurgie (14
centra) en van de Nederlandse collectieve pathologie database Palga. Uit deze nationale
registers, werden 33 patiënten geïdentificeerd die resectie (n = 32) of lokale ablatie (n = 4)
ondergingen van levermetastasen van NCC in Nederland, tussen 1990 en 2008. Patiënt en
tumor kenmerken, overleving en prognostische factoren in deze specifieke patiëntenpopulatie
werden geanalyseerd met behulp van Kaplan-Meier curves en logrank tests.

RESULTATEN
De algemene 1 -, 3 - en 5-jaars overleving was respectievelijk 78.6%, 45.1% en 40.6%. De
mediane overleving was 26.6 maanden. Er was geen operatieve mortaliteit en morbiditeit was
18%. Bij een mediane follow-up interval van 19.2 (3.45-188.9) maanden, vertoonden 28
patiënten tekenen van recidief met een mediane tijd tot recidief van 10 (0.89-54) maanden.
Metachrone metastasen (n = 23, p = 0.04) en radicale resectie (n = 24, p <0.001) waren
significante prognostische markers voor lange termijn overleving. Grootte <50mm (n = 18, p
= 0.84), solitaire metastasen (n = 19, p = 0.92) en verrassend genoeg, de aanwezigheid van
extrahepatische metastasen (n = 11, p = 0.21) toonden geen significante invloed op de
overleving.

CONCLUSIE
De overlevingskansen en lage operatieve morbiditeit en mortaliteit in dit landelijke onderzoek
geven aan dat chirurgische behandeling aan patiënten met levermetastasen van RCC een
voordeel kan bieden, met een 5-jaarsoverleving van 40.6%




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TABLE OF CONTENTS

 ABSTRACT (English) ........................................................................................................... 2
 ABSTRACT (Nederlands) ..................................................................................................... 3
 INTRODUCTION .................................................................................................................. 5
 MATERIALS AND METHODS ........................................................................................... 8
   Patients ............................................................................................................................... 8
   Primary tumour .................................................................................................................. 9
   Metastases .......................................................................................................................... 9
   Statistical Analysis ............................................................................................................. 9
 RESULTS............................................................................................................................. 11
   Operative data .................................................................................................................. 11
   Survival ............................................................................................................................ 11
   Disease-free survival ........................................................................................................ 12
   Univariate analysis of prognostic factors ......................................................................... 12
 DISCUSSION ...................................................................................................................... 14
 Appendix A .......................................................................................................................... 21
 Appendix B .......................................................................................................................... 22




                                                                                                                                           4
INTRODUCTION

Renal cancer is the 7th leading malignant condition among men and the 12th among women,
accounting for 2.6 percent of all cancers worldwide1. In the Netherlands 1200 people are
diagnosed with RCC each year. The incidence of RCC in the Netherlands is 12,5 per 100.000
inhabitants and is gradually rising due to the sharp rise in the ageing population.

The classic presentation of renal-cell carcinoma (RCC) includes the triad of flank pain,
hematuria and a palpable abdominal mass, however only 10% of patients present with these
classic symptoms. Most patients are identified because a renal mass is incidentally detected
on radiographic examination2. Ultrasound (US), chest radiography, computed tomography
(CT) and magnetic resonance imaging (MRI) are used for primary diagnosis and staging3.
Surgical excision is still the primary treatment for renal cell carcinoma. The surgical approach
is determined by the size and location of the tumor within the kidney and the TNM stage.
Total ‘en bloc’ nephrectomy used to be the gold standard, however nowadays this is no longer
the case for small tumors (less than 7 cm)4. In patients with small tumors, bilateral tumors and
bad kidney function a partial nephrectomy is currently considered as the appropriate
treatment5. In this selection of patients cryoablation of the tumour has also shown promising
results, however randomised controlled trials confirming these results are lacking6. In addition,
laparoscopic surgery has also been explored and shown good results7.
5-Years survival can be predicted by the TNM staging system and varies from 95% in T1
tumors to 20% in T4 tumors8 (figure 1).




Figure 1. TNM staging RCC; Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med
2005; 353:2477-2490.




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RCC is relatively little affected by radiotherapy9. Rates of response to chemotherapy alone are
very low and have not proven effective as an adjuvant therapy10. The immune responsiveness
of renal-cell carcinoma could possibly provide an opportunity for the development and
optimization of immune therapies1. Several immunomodulatory therapies are currently under
research including interferon alpha and interleukin-2, however multiple randomised trials
haven’t demonstrated any benefit11,12. Recently molecularly targeted therapy has become
available for advanced renal cell carcinoma and has until now shown promising results.
Sunitinib and sorafenib, two small molecule tyrosine kinase inhibitors allowing the blocking
of the vascular endothelial growth factor (VEGF) pathway, both showed overall survival
benefit in big multicentre trials13,14.

At presentation 25 to 30% of patients have distant metastases and another third of patients
develop metastatic recurrence after primary tumour resection15. The lung is most frequently
involved in patients with RCC, namely in 50-60% of patients with metastatic disease16.
Liver metastases develop in 30%–40% of patients with metastatic disease. Prognosis is poor
in patients with metastatic RCC, only 10% survive more than a year17. The development of
hepatic metastases is generally considered a poor prognostic factor and a frequent predictor of
more widespread disease18. Only 2% to 4% of patients have isolated metastases and are
candidates for radical surgery19. As a result, numbers of hepatic resections for RCC are small
for individual centres, complicating clinical studies in these patients.

Liver surgery for colorectal metastases has evolved over the last decades. When mortality
rates for liver surgery started to drop in the late 70’s, the indication for a liver resection
widened20. As a result, the once incurable patient with colorectal metastases to the liver
obtained a possibility of long-term survival. Over the following years large series have arisen
in literature describing a 5-year survival after resection of over 30% in highly selected patient
groups. Today, 5-year survival rates have been improved even more. For instance, Pawlik et
al recently reported a series with a 5-year survival of 47,3% in 1669 patients treated surgically
(resection +/- radiofrequency ablation) for colorectal liver metastasis. In addition, the
indication for treatment of hepatic metastases widened due to the development of new
techniques as portal vein embolisation21, RFA22, two-stage hepatectomy23, downsizing of
metastases with neoadjuvant chemotherapy24 and new systemic therapies25.

In contrast with the immense amount of studies and reports about surgical outcomes of
colorectal liver metastases, relatively little is known about surgical outcomes of hepatic
metastases originating from other organs. One valid argument for this phenomenon is the high
incidence of colorectal liver metastases in comparison with hepatic metastases from other
origin. Nevertheless, the lack of high-level evidence (i.e. prospective randomised clinical
trials) for surgical treatment of non-colorectal hepatic metastases is still remarkable.
Data about surgical outcomes of hepatic metastases originating from organs other than the
colon are often pooled in series with non-colorectal metastases. Due to the recognition that
patients with endocrine metastases are a unique group with a better prognosis, a sub-
classification of patients with non-colorectal non-endocrine tumours was formed. These
include metastases from genitourinary malignancies, sarcomas, breast cancer, melanoma and
other primary tumors. Tumour biology and clinical behaviour varies substantially among all
these different malignancies. Consequently, unfortunately, analysis of survival following
surgical treatment in this group of patients still suffers from a large heterogeneity of primary
tumours and limited numbers of patients. Adam et al recently reported the first large series
(more than 150 patients) about the outcomes of hepatic resection in 1452 patients with non-
colorectal non-endocrine metastases. Five-year survival rates in this study varied from 8% in


                                                                                               6
patients with primary lung carcinoma to 66% in patients with a primary tumour in an adrenal
gland. Hence, this illustrates the complexity of interpreting results from hepatic resection in
the heterogeneous group of patients with non-colorectal non-endocrine liver metastases.

In most studies published, patients with metastatic RCC to the liver are part of a larger group
of patients with liver metastases from non-colorectal and non-neuroendocrine tumors26.
Furthermore, RCC itself is characterized by large heterogeneity in clinical course (from
highly progressive to indolent and even regression), disease-free interval (synchronous to
more than 20 years from primary treatment) and pattern of dissemination (including rare
localisations i.e. pancreas, skin, muscle, thyroid).

Although relatively few patients (2-4% as described above) present with a metastatic disease
that is potentially curable by radical resection, long-term survival following hepatic resection
is described in literature. Adam et al reviewed the literature and identified 15 reports with
combined survival data of 64 patients with hepatic resections for RCC metastases18. In this
combined series 2-year mortality was 40%, which is substantially higher than 10% survival
after one year in patients with unresected renal cell metastases17,27. Therefore, Adam et al
concluded that liver resection should be offered to all these patients if a complete radical
resection is feasible.

The objective of this study was to determine patient and tumour characteristics, survival and
prognostic factors in patients with hepatic metastases from RCC in the Netherlands. This will
provide a better insight in several aspects of hepatic RCC metastases and will probably help
us in better selection of patients for surgery or local ablative techniques. In addition,
identification of patients at high risk of recurrence may guide adjuvant therapy using novel
systemic agents like sunitinib or sorafinib in the future.




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MATERIALS AND METHODS


Patients

For study data acquisition two methods were used. This study was conducted under the
direction of the Netherlands Liver Task Force and all members were sent a letter (appendix A).
In this letter the members were asked to check their local databases if they had surgically
treated patients with hepatic metastases from RCC in the past. A specific questionnaire
designed to
acquire a variety of patient, primary tumor, metastases, treatment and outcome variables was
attached to this letter. In addition, one of the investigators (ATR), visited a part of the
hospitals to acquire the data.

In order to identify a complete cohort of patients with hepatic metastases from RCC treated
surgically in the Netherlands a second method was used, a search in the nationwide
histopathology database PALGA was performed28. PALGA (‘Pathologisch Anatomisch
Landelijk Geautomatiseerd Archief’; Pathological Anatomy National Automated Archive) is a
nationwide network and archive that has been setup in the Netherlands in order to facilitate
the optimal use of histopathology and cytopathology data. PALGA has been available since
1971. The PALGA system is a highly automated pathology archiving and communication tool
that provides support to pathologists in their daily practices. As a result, the PALGA network
was joined by all 64 histopathology and cytopathology laboratories in The Netherlands. A
continuously expanding automated archive of excerpts of pathology reports with currently
about 42 million excerpts on nearly 10 million patients in the central databank was created28.

The patient information obtained by the search in the PALGA database was used to contact
the hospitals concerned and additional data was acquired by sending the previously described
questionnaire. Survival data were obtained from the local hospitals and updated, if necessary,
by contacting the primary care physicians.

Twenty patients were identified by the questionnaire, which was send to the members of the
Netherlands Liver Task Force. An additional seventeen patients were identified by the search
in the PALGA database28. The data from four of these patients could not be retrieved, as a
result of unavailability of the data in the hospitals concerned presumably as a consequence of
the long time period between treatment and retrieval of the data. The data of an additional
thirteen patients could be retrieved by the search in the PALGA database, resulting in a study
population of 33 patients (16 men, 17 women) with hepatic metastases from RCC, who were
surgically treated in the Netherlands. The median age was 61 (range 20-77) years. Data was
obtained from a total of 14 hospitals, including 7 academic and 7 referring hospitals (appendix
B). Patients with direct ingrowth of the primary tumour in the liver or ingrowth of peritoneal
metastases in the liver were excluded from this analysis because of expected different tumour
biology. Patients with nephroblastoma as primary tumour were excluded from this analysis as
well, because these patients have a much worse outcome18.




                                                                                             8
Primary tumour

Histopathology of the primary tumour could be retrieved in 28 (84%) patients and showed
clearcell-carcinoma in 21 (63%) patients, chromophobic carcinoma in 3 patients (9%),
papillar carcinoma in 3 patients (9%) and another type in 2 patients (6%). Primary tumour site
was the left kidney in 14 (42%) patients, the right kidney in 17 (52%) patients, bilateral in 1
(3%) patient and unknown in 1 (3%) patient. TNM staging at the time of primary tumour
removal of the primary tumour was unknown in 12 patients (36%), T1 in 1 patients (3%), T2
in 3 patients (9%), T3 in 7 patients (21%) and T4 in 11 patients (33%). Lymph node status
was unknown in 14 patients (42%), node negative (N0) in 17 patients (51%) and node
positive (N1) in 3 patients (9%). Distant metastases were present (M1) in 12 patients (36%),
absent (M0) in 10 patients (30%) and unknown in 11 patients (33%).


Metastases

Liver metastases were synchronous in 10 patients (30%), whereas 23 patients (70%) had
metachronous metastases. The median interval of metachronous metastases between
nephrectomy and diagnosis of liver metastases was 50 (range: 7-360) months. Liver
metastases were symptomatic in 11 patients (33%), asymptomatic in 9 patients (27%) and
unknown in 13 patients (39%). Symptoms described included: abdominal pain, a palpable
mass, malaise, fatigue and losing weight. Liver metastases in asymptomatic patients were
discovered by routine ultrasound or computed tomography for different reasons. Liver
metastases were solitary in 19 patients (57%) and multiple in 14 patients (43%). The median
number of metastases was 1 (range: 1-19). Median size of the hepatic metastases was 42
(range 3-150) millimetres. Metastases were localised in the left lobe of the liver in 10 patients
(33%), in the right lobe of the liver in 20 patients (60%), in both lobes of the liver in 2
patients (6%) and the localisation was not reported in 1 patient (3%). At the time of diagnosis
of the liver metastases there was evidence of extrahepatic disease in 11 patients. These
extrahepatic metastases included metastases to vagina, omentum, bile duct, diaphragm,
adrenal gland, gall bladder and lung. The patient with metastases to the bile duct was
previously described in the literature29.


Statistical Analysis

Data were analyzed using the SPSS software program. Survival was evaluated according to
the method of Kaplan and Meier. Prognostic variables related to the patient (sex and age),
primary tumour (side), hepatic metastases (number, size, metachronous or synchronous and
time between metastases and primary tumour), presence of extrahepatic disease and radicality
of resection were evaluated with regard to patient survival. Groups were compared by
univariate analysis with the log-rank test. The univariate tested variables tested were chosen
based on described variables from prior reports in metastatic renal cell carcinoma and studies
on colorectal liver metastases. A multivariate analysis was not feasible in this study, due to
the small sample size. P values of <0.05 were considered as statistically significant.




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Table I: Patient and tumour characteristics of patients with hepatic metastases from
renal cell carcinoma.

Factor                              Number of patients (N=33)             %
Sex
  Male                              16                                    48
  Female                            17                                    52
Age
  Median (range)                    61 (20-77)
Primary tumour
  Side
    Left                            14                                    44
    Right                           17                                    53
    Bilateral                       1                                     3
  T
    T1-T2                           4                                     18
    T3                              7                                     32
    T4                              11                                    50
  N
    N0                              17                                    85
    N1                              3                                     15
  M
    M0                              10                                    43
    M1                              13                                    57
Histology
  Clearcell                         21                                    64
  Chromofobic                       3                                     9
  Papillary                         3                                     9
  Other / Unknown                   6                                     18
Metastases
  Time
    Synchronous                     10                                    30
    Metachronous (interval range) 23 (7-360 months)                       70
  Symptomatic
    Yes                             9                                     45
    No                              11                                    55
  Size
    ≤50mm                           18                                    60
    >50mm                           12                                    40
  Number
    Solitary                        19                                    58
    Multiple (interval range)       14 (2-19)                             42
  Localisation
    Left liver lobe                 10                                    32
    Right liver lobe                20                                    62
    Bilateral lobes                 2                                     6
  Extrahepatic disease
    Yes                             11                                    33
    No                              22                                    67
Missing numbers are a result of unknown data.


                                                                                       10
RESULTS

Operative data
The surgical treatment performed in these patients included 8 metastasectomies (24%), 10
segmentectomies (30%), 4 left hemihepatectomies (12%), 6 right hemihepatectomies (18%),
one extended right hemihepatectomy and 4 radio frequency ablations (RFA). In 3 patients
RFA was performed in addition to a resection and in one patient RFA was the only treatment.
Resection of the metastases was margin negative in 24 patients (73%), as defined by removal
of all macroscopically detectable disease and microscopically clear resection margins or
adequate successful ablation in the case of RFA. All RFA procedures were performed after
laparotomy.
12 Patients received additional systemic treatment including chemotherapy, immunotherapy
(IFN and IL-2) and molecularly targeted therapy (sunitinib and sorafenib).

There was no operative mortality and postoperative complications developed in 6 patients
(18%). This operative morbidity included lung embolism in atrial fibrillation, haemorrhage,
reversible liver failure, pleural fluid and an intra-abdominal abscess. Re-intervention was
required in one patient as a result of intra-abdominal haemorrhage.


Survival
Complete survival data could be retrieved from all but three patients (9%), who were lost to
follow-up. At the end of the study seventeen patients (52%) had died. Of the sixteen patients
(48%) alive, 11 patients had evidence of recurrent disease (recurrence of liver metastases or
extrahepatic disease).
Overall 1-, 3- and 5-year survival rates were 78.6%, 45.1%, and 40,6%, respectively (Figure
2). The median survival was 26,6 (3,5-199) months.




Figure 2. Overall survival and disease-free survival of surgical treatment in patients with
hepatic metastases from RCC.


                                                                                              11
                                                As described above, 24 patients had free
                                                surgical margins (R0-resection). The 1-year, 3-
                                                year and 5-year survival rates of patients with a
                                                radical resection were 91,5%, 61,9% and
                                                55,7% respectively. These rates contrast
                                                sharply with the survival rates of patients with
                                                non-radical resection (R1), namely 44% 1-year
                                                survival and zero 3-year and 5-year survival.


                                                 Disease-free survival
                                                 The time to recurrence of disease, defined as
                                                 recurrence of liver metastases or evidence of
                                                 extrahepatic disease, ranged from 0,89 to 54
                                                 months with a median of 10 months. The 1-
                                                 year, 3-year and 5-year disease-free survival
                                                 (DFS) rates were 48,5%, 17,4% and 10,4%
                                                 respectively (Figure 2). None of the patients
 Figure 3. Overall survival according          with recurrent hepatic metastases underwent
 to resection margins (p=0.001)                repeat hemi-hepatectomy or other additional
                                               treatment for hepatic recurrence.
Median survival of patients with recurrent disease was 18,5 (3,45-198,9) months. One patient
was diagnosed with metastases to the lungs after 33 months. He survived two consecutive
metastasectomies of the lungs and is still alive after 199 months.




Figure 4. Overall survival according to the presence of extrahepatic disease (p=0,21) and
timing of metastases (p=0.04).

Univariate analysis of prognostic factors
In the univariate analysis two factors showed statistically significant influence on survival. As
described earlier, resection margins had a tremendous effect on outcome. None of the patients
with an irradical resection survived longer than 23 months, in contrast with patients with a


                                                                                              12
radical resection, who had a median survival of 83,9 months. This difference was highly
significant (P<0.0001). Patients with synchronous metastases had a significantly (P=0,04)
shorter survival (median survival of 17,3 months) than people with metachronous metastases
(median survival of 83,9 months). This effect slightly diminished when we compared the
patients with a disease-free survival of less than 24 months with more than 24 months
between primary tumour and hepatic metastases. The median survival of patients with a
disease-free survival of less than 24 months after the primary tumour (this obviously included
the synchronous metastases) was 22,1 months. Patients with a disease-free survival of more
than 24 months had a median survival of 83,9 months. This effect was not significant
(p=0,08). Age (patient ≤ 60 years of age versus > 60 years of age), sex and the side of primary
tumour had no significant influence on survival. Number of metastases and the size of the
largest metastasis had no significant influence on survival (table II). To our surprise patients
with extrahepatic disease had a longer median survival (median survival of 60 months)
compared to patients with no extrahepatic metastases (median survival of 26,6), although this
was not significant (P=0,213). The results of the univariate analysis are depicted in table II.

Table II. Univariate analysis of prognostic variables in patients with hepatic metastases from
renal cell carcinoma.
                                Nr of Patients    Median Survival (Months)         P value
Age
  ≤ 60 yr                             16                      26,6                   0,26
  > 60 yr                             17                        -
Sex
  Male                                16                      26,6                   0,38
  Female                              17                      33,3
Primary tumour side
  Left                                14                      33,3                   0,95
  Right                               17                      26,6
Liver metastases
  Timing
    Synchronous                       10                      17,3                 0,04 *
    Metachronous                      23                      83,9
  Disease-free interval
    ≤ 24 months                       17                     22,13                  0,084
    > 24 months                       16                      83,9
  Size of largest metastasis
    ≤ 50 mm                           18                      33,3                   0,84
    > 50 mm                           12                      24,4
  Number of metastases
    Solitary                          19                      26,6                   0,90
    Multiple                          14                      33,3
Extrahepatic disease
  Present                             22                      26,6                   0,21
  Absent                              11                      60,0
Resection margin
  Radical resection (R0)              24                      83,9                <0,001 *
  Irradical resection (R1/R2)          9                       9,2




                                                                                             13
DISCUSSION

Despite improvements in surgery and systemic therapy in the last decades the prognosis of
patients with metastasized renal cell carcinoma is still poor. Conventional systemic therapies
like chemotherapy, radiotherapy have shown little to no influence on survival in these patients.
Albeit, molecularly targeted therapy has shown hopeful results. Nevertheless, even though
these drugs give significant survival benefit, they do not provide possibility on long-term
survival.

The lungs are most commonly affected in metastatic RCC, namely in 50-60% of patients with
metastastic disease. The outcomes of surgery on RCC metastases to the lungs have been quite
well investigated. Several relatively large series, although retrospective and non-randomised,
emphasize survival benefit and possibility on long-term survival (up to 37% 5-year survival
rate30) after radical resection in selected patients with relatively few complications30-32.
Factors correlating with good prognosis found in these studies included solitary lesions,
metachronous presentation, greater disease-free interval and radical resection.

Liver metastases are less common in patients with metastatic RCC, but still occur in roughly
20% of patients with metastatic RCC. Patients with RCC metastases to the liver have a
particularly poor prognosis, which is even worse than patients with RCC metastases to other
organs, like lungs and bone33. In a series of Suppiah et al33, the median survival of 186
untreated patients with hepatic RCC metastases was only 7,8 months.

Data about the efficacy of surgical treatment in hepatic RCC metastases are still very rarely
reported. In addition to the fifteen reports reviewed by Aloia et al18, describing survival data
of 64 patients, two studies were published26,34. Thelen et al34 described their single institution
experience in 31 patients who underwent hepatic resection for RCC metastases. The overall 1-,
3- and 5-year survival rates reported in this study were 82.2%, 54.3%, and 38.9%,
respectively. As mentioned earlier Adam et al26 described a series of 1452 patients with non-
colorectal non-endocrine hepatic metastases. In this series 85 patients were enrolled with a
primary RCC. Overall median survival and 5-year survival rates reported in this study were
36 months and 38% respectively.

The present study had zero operative mortality and complication only occurred in 18% of the
patients. An explanation for this low operative mortality and morbidity is that a large
proportion of the resections were minor resections (metastasectomies and segmentectomies)
and only 48% of patients underwent a hemihepatectomy.

The reported survival rates in this study are superior to the results of older series reviewed by
Alioa et al and comparable to the recently published series from Adam and Thelen18,26,34. As
Thelen mentioned as well about their own series, the improved survival rate of our study
could well be explained by: advancements in imaging technology resulting in more adequate
staging and assessment of disease extend; better appreciation of tumour and patient
characteristics that influence prognosis resulting in an improved patient selection;
improvements in surgical technique including local ablative techniques and perioperative care
resulting in a safer approach to large resections.




                                                                                              14
We contacted all centres performing
liver surgery in the Netherlands.
Furthermore we did a search in the
nationwide histopathology database
PALGA, in which all data about
resection specimens in the Netherlands
is stored. By doing so we believe that
we retrieved nearly all patients who
underwent surgical treatment for
hepatic metastases from RCC in the
last 19 years in the Netherlands. This
fact addresses another interesting point     Figure5. Incidence and mortality of RCC in the
of this study. The number of new             Netherland in the period 1989-2003. Source: Nederlandse
patients diagnosed with RCC in the           kankerregistratie, http://cijfers.ikcnet.nl ).
Netherlands has been quite stable over
the last years around 1200 (figure 5).
Because we know that approximately 10% of patient with RCC ultimately develop liver
metastases16, we can make a rough estimation of the total patients with liver metastases from
RCC and the percentage who were surgically treated in this time period in the Netherlands. In
the last 19 years roughly 2280 (10% of 19x1200) patients were diagnosed with hepatic
metastases from RCC. In this particular time period we identified 33 patients who where
surgically treated, which signifies that approximately 1,5% of the patients received surgical
intervention. This number is in accordance with the percentage described by Dineen et al19.
This emphasises once more the remarkably small proportion of these patients who are treated
surgically.

Previous studies reported prognostic factors influencing survival aiming to establish selection
criteria for resection. Prognostic factors predicting long survival described in previous series
included male gender, a maximum metastasis diameter ≤ 5 cm, left primary tumour
localisation, disease-free interval >24 months, and margin negative resection margins. In our
series only metachronous metastases and radical resection had a positive impact on survival
rates in univariate analysis. To our surprise, patients with extrahepatic disease had a better
survival than patients with only hepatic metastases, although this was not significant. The
conclusion that extrahepatic disease improves survival would be ridiculous. Nonetheless in
our opinion these results strongly suggest that extrahepatic disease has no significant
influence on survival, which is in concordance with data from Alioa et al18. We assume that
hepatic metastases strongly dictate the survival rate above metastases to other organs. In other
words, these patients die from hepatic metastases before metastases to other organs start to
influence survival. This assumption would have huge impact on management in this particular
patient group, because this would implicate that potentially resectable extrahepatic disease is
not a contraindication for liver surgery. On the other hand, we realize that our data has limited
power to draw these strong conclusions.

Our study certainly has limitations. Data were obtained from a complete, but relatively small
group of patients, resulting in the impossibility of performing an adequate multivariate
analysis. Data was retrieved from a long study period (eighteen years), in which as described
before, many improved techniques in imaging, perioperative care and liver surgery were
introduced. Only an extremely small selection of patients, that is the patients eligible for
resection, was enrolled in the study resulting in an obvious selection bias. Data was
retrospectively retrieved resulting in the well-known problems of retrospectively obtained


                                                                                              15
data: incomplete data, selection bias and improved possibility of confounding factors. And
finally, data was retrieved from fourteen hospitals, including seven referral and seven
academic hospitals, all with different selection criteria. Hence, care must be taken in drawing
strong conclusions with the available data.

The survival-rates presented in this study and results from previous studies18,26,34 are well
comparable to results of hepatic resection for colorectal metastases. Survival rates are also
certainly not inferior to results after resection of pulmonal metastases in patients with RCC.
Please note that an aggressive surgical approach to these pulmonary metastases, in which a
radical resection can be reached, is currently considered as the appropriate treatment.
The future will tell us whether surgical treatment for hepatic RCC metastases will follow the
path of treatment for colorectal liver metastases, which started with small retrospective series
in highly selected patients in the seventies and advanced at present to a standard treatment in a
large portion of patients justified by large randomised controlled trials. The result of this study
in any case supports a much wider indication for liver resection in patients with RCC and
denies the suggestion that patients with hepatic metastases from RCC cannot be cured. Future
research should further define the role of sunitinib and sorafenib as (neo)adjuvant therapy.

In conclusion, surgical treatment for hepatic metastases from RCC is only performed in
roughly 1,5% of patients. Data from this study, in accordance with data from almost 150
patients reported in literature suggest that surgical treatment can provide reasonable survival
rates, with a 5-year survival of 40%. The data available today combined with the
unavailability of effective systemic therapy justifies an aggressive surgical approach in
patients with hepatic metastases from RCC when margin negative resection can be obtained.
In addition, our data suggests that extrahepatic disease is not a contraindication for surgical
intervention when radical resection of all tumor sites is feasible. Prognostic factors
influencing survival in literature are contradictory, with the exception of margin negative
resection, which is a prognosticator for long-term survival in all studies. Further research is
warranted and may provide selection criteria for these patients.




                                                                                                16
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Appendix A


Hospitals connected by the Netherlands Liver Task Force.

Academisch Medisch Centrum, Amsterdam
VU Medisch Centrum, Amsterdam
Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam
Universitair Medisch Centrum St Radboud, Nijmegen
Erasmus Medisch Centrum -Daniel den Hoed Kanker Centrum, Rotterdam
Universitair Medisch Centrum Groningen, Groningen
Universitair Medisch Centrum Utrecht, Utrecht
Maastricht Universitair Medisch Centrum, Maastricht
Deventer Ziekenhuis, Deventer
Isala klinieken, Zwolle
Leids Universitair Medisch Centrum, Leiden
Amphia Ziekenhuis, Breda
Maxima Medisch Centrum, Eindhoven
Gelre Ziekenhuizen, Apeldoorn
Medisch Centrum Haaglanden, Den Haag
Medisch Spectrum Twente, Enschede




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Appendix B

Hospitals participating in this study:

Academisch Medisch Centrum, Amsterdam
VU Medisch Centrum, Amsterdam
Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam
Universitair Medisch Centrum St Radboud, Nijmegen
Erasmus Medisch Centrum -Daniel den Hoed Kanker Centrum, Rotterdam
Universitair Medisch Centrum Groningen, Groningen
Maastricht Universitair Medisch Centrum, Maastricht
Leids Universitair Medisch Centrum, Leiden
Amphia Ziekenhuis, Breda
Maasland Ziekenhuis, Sittard
Maxima Medisch Centrum, Eindhoven
Gelre Ziekenhuizen, Apeldoorn
Medisch Centrum Haaglanden, Den Haag
Medisch Spectrum Twente, Enschede




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