1. health and fitness
2. disease
3. cancer

Annals of Oncology 15 (Supplement 4): iv319 – iv328, 2004
doi:10.1093/annonc/mdh946
Current treatment of renal cell carcinoma
P. H. M. De Mulder1, C. M. L. van Herpen1 & P. A. F. Mulders2
1
Department of Medical Oncology and 2Department of Urology, University Medical Center Nijmegen, Nijmegen, the Netherlands
Hormonal treatment and chemotherapy
Renal cell carcinoma (RCC) accounts for 3% of all malignancies in man and is the third most common urological cancer
after prostate and bladder cancer. The incidence of RCC is
increasing with about 31 500 new cases annually in the USA
and 20 000 in Europe. The annual death rate due to metastatic
disease (mRCC) is 12 000 and 8 000 in the USA and Europe,
respectively.
The accidental diagnosis of RCC has increased due to the
extensive use of ultrasonography, leading to an earlier diagnosis and probably better prognosis. Today about 70 –80% of
patients present with localized disease of whom approximately
50% will develop metastatic disease. According to the Surveillance, Epidemiology and End Results (SEER) data, the 5-year
survival of localized disease is 89% (54% of all patients),
61% in regionally advanced disease and only 9% in the case
of metastatic disease [1]. The tumour mainly affects adults
aged 50 –70 years with a male to female ratio of 1.6:1 [2].
Several risk factors have been described for RCC. Tobacco
smoking doubles the risk of RCC and there is a positive linear
relation between body weight and the risk for RCC, especially
in women. Other factors associated with higher risk for RCC
are exposure to asbestos or chemicals, thiazide and urinary
tract infections.
The majority of RCC is adenocarcinomas originating from
the proximal tubular cells, but malignant tumours can also
arise from other structures such as the collecting duct and the
epithelium of the pyelum. Most adenocarcinomas are of the
clear cell type and are considered the most sensitive subtype
for systemic therapy.
At the onset of RCC there are only a few early warning
signs. The classical triad of Virchow [2a], consisting of an
abdominal mass together with flank pain and macroscopic
haematuria, is nowadays only seen in approximately 5% of
patients with RCC. At presentation, the disease may be
accompanied by non-specific signs such as fatigue, weight
loss, malaise, fever and/or night sweats. The primary treatment
consists of a radical nephrectomy and in selected cases a partial nephrectomy. The role of nephrectomy in metastatic
patients will be discussed later
The occurrence of spontaneous regressions is considered
very low, i.e. less than 1%. Two recently published studies
indicate that sometimes these figures may be as high as 7%
[3, 4].
This paper provides an overview of the systemic treatment
of RCC.
It is well established that RCC expresses receptors for oestrogen, progesterone and testosterone. Therefore, hormonal
manipulation has been part of the early treatment of this
tumour. Although response rates have been described in recent
randomized trials, their efficacy regarding both response and
survival is inferior compared with cytokine-based therapy
[5, 6] and hormones are at present not considered appropriate
as systemic therapy.
The normal proximal tubular cells contain the p-glycoprotein phenotype, which plays a role in the active transportation of toxic molecules over the cell membrane. In cancer
this phenotype is associated with resistance to certain cytotoxic agents and this may be the explanation that, in general,
chemotherapy induces low responses in RCC [7– 9].
Drugs with some activity are vinblastine, 5-fluorouracil
(5-FU) and gemcitabine. Single agent gemcitabine and combinations with gemcitabine were recently reviewed by Stadler
et al. [10]. The survival of 153 patients with mRCC treated in
one phase I and four phase II studies with gemcitabine/5-FUbased regimens was superior compared with historical
controls. One control arm included interferon-a (INF-a) and
interleukin-2 (IL-2) and one was a combination with thalidomide. Of these patients, 55% were pretreated with immunotherapy and 74% had undergone a tumour nephrectomy. The
majority had a clear cell subtype. The median survival of
these 153 patients was 12.5 months (confidence interval, CI
10.7–15.2 months) and was very similar to the survival seen
with cytokine-based therapy. These data suggest that the combination of gemcitabine plus 5-FU might have some activity
in this disease. However, there are no data from randomized
studies to support the information obtained from this pooled
retrospective analysis.
Capecitabine is an orally administered fluoropyrimidine
carbamate, which is activated to 5-FU. In a phase II study 7%
complete responses (CR) and 27% partial responses (PR) were
seen in 30 patients with a median duration of 9 and 8 months,
respectively. Tolerance was good and treatment was generally
completed without dose modifications [11]. These data suggest
activity in this disease and capecitabine may be considered as
a compound to be used in combination.
q 2004 European Society for Medical Oncology
Role of surgery in metastatic disease
The role of surgery in the treatment of mRCC is essential
but limited. If the patient presents with metastatic disease,
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Introduction
iv320
Cytokine therapy
In patients with mRCC the course of the disease is variable.
Sometimes a rapid progression is seen, but also long-lasting
stabilization or spontaneous remissions of metastases are
described. Therefore it is assumed that immune mechanisms
may play a role. Many approaches have been investigated of
which IFN-a and IL-2 are the most extensively studied. In
Europe both drugs are registered for treatment of mRCC.
Interferon-a
In 1957 the interferons were first described as a family of proteins produced by cells after exposure to viruses [22]. Three
types are recognized: IFN-a, IFN-b and IFN-g. IFN-a is most
extensively investigated and shows activity in mRCC. Potential mechanisms of action are the direct inhibition of tumour
cell proliferation, the augmentation of the lytic activity of
natural killer (NK) cells and an increased expression of the
human leukocyte antibody (HLA) class I on tumour cells. As
a consequence tumour cells are better recognized and killed
by cytotoxic T-cells [23].
IFN-a can be administered subcutaneously, intramuscularly
or intravenously. The response rate is independent of the route
of administration [24]. The best schedule and dose-intensity
have not been established in a randomized trial. In the
very low dose range there is a dose–response relationship.
The minimal effective dose lies between 20 106 and
40 106 units/week. Higher dosages give more toxicity without higher response rates. In the published studies the frequency of administration varies between twice a week to daily
and seems not to be a critical issue [25–28].
In 1985 Kirkwood et al. described the first responses in
mRCC with IFN-a [29]. Since then many phase II studies
with small numbers of patients have been published but there
are very few phase III randomized studies. The studies differ
in many aspects, including the route of administration and the
dosage schedule of IFN-a. IFN-a administered as a single
agent in mRCC gives a response rate between 8% and 26%.
One-third of the responses are CRs [24, 25, 30 –33]. The
median duration of a PR is 10 months. In rare cases very
long-lasting complete remissions are described. Also a stabilization of disease occurring in approximately 30% of the
patients can continue for a few months. Responses are most
frequently seen in the lung and, to a lesser degree, in the
lymph nodes. Anecdotal responses in almost all sites have
been reported. Patients with brain metastases were generally
excluded from studies with IFN, because the brain is considered to be a non-responsive site. The interval between the
start of treatment and the occurrence of a clinical response is
usually 1–3 months, but can occur even after 6 months [30].
If an objective response or stabilization of disease occurs,
treatment is continued for 1 year in most of these phase II
studies. The median overall survival with IFN-a therapy is
approximately 13 months [25, 34– 36].
The number of randomized studies is limited. One study
comparing IFN-a with medroxyprogesterone acetate revealed
a significant improvement in median (8.5 and 6 months,
respectively) and 1-year survival (43% and 31%) for the
IFN-a-treated group [5]. In another study, vinblastine was
compared with IFN-a plus vinblastine. Median survival was
67.6 weeks for the 79 patients receiving IFN-a plus vinblastine and 37.8 weeks for the 81 patients treated with vinblastine
alone (P = 0.0049). Overall response rates were 16.5% for
patients treated with the combination therapy and 2.5% for
patients treated with single agent vinblastine (P = 0.0025).
Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters,
but no toxic deaths were reported [37].
Side-effects may be acute or delayed. Acute side-effects
are fever, chills, headache and myalgia; delayed side-effects
are nausea, vomiting, fatigue and anorexia. During treatment the acute side-effects tend to diminish. Neutropenia,
neurotoxicity, depression, hyper- or hypothyroidism and a
rise of liver enzymes are less frequently seen. At the start
of therapy, acetaminophen is usually given to reduce
’flu-like symptoms with interferon or other compounds with
some activity in this disease.
Interleukin-2
In 1976 IL-2 was first described as the most important
growth factor and activator of T-lymphocytes and NK-cells.
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a tumour nephrectomy can be considered when there is symptomatic disease, such as pain, haematuria, malaise and hypercalcaemia. In the majority of patients relief of symptoms is
observed [12].
A recent, randomized study in 246 patients [with a performance status (PS) of 0–1] showed a survival benefit in the
patients treated with a nephrectomy prior to IFN-a compared
with those immediately treated with IFN-a without nephrectomy [13]. The 1-year survival was 50% versus 37% and the
median survival was 12.5 versus 8.1 months, respectively. The
response on IFN-a was the same in both groups and was very
low (4% and 3%, respectively).
Another study with a limited number of patients showed the
same results [14]. The combined analysis of the two studies
(n = 331) further emphasized the role of nephrectomy in good
prognostic patients eligible for cytokine-based therapy [15].
The median survival was 13.6 versus 7.8 months in favour of
the combined arm.
Another consideration in favour of nephrectomy is the
occurrence of spontaneous remission of metastatic disease.
This in itself is not an indication for nephrectomy, because
this is generally thought not to extend survival for the group
as a whole without the addition of cytokine-based therapy.
In carefully selected patients with limited volume metastases, usually in the lung, resection can give rise to longstanding survival [16, 17]. Also a metastasectomy after a
partial response on immunotherapy can be advisable.
Adjuvant therapy with INF-a, IL-2 and autologous tumour
vaccine has no proven impact on overall survival and cannot
be recommended outside clinical trials [18–21].
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haematological toxicity, i.e. anaemia and thrombocytopenia are
frequently seen [52, 53]. Almost all toxicity disappears fast
after stopping IL-2. In general, patients with cardiovascular
illness or severe renal dysfunction should not be treated with
IL-2.
Combinations with IFN-a and/or IL-2
IFN-a and IL-2
The combination of IFN-a and IL-2 has been investigated
extensively. A wide variety of routes, doses and schedules have
been used but rarely in a randomized study. Many phase II
studies showed a response rate of 11% –27%, which is approximately in the same range as with both cytokines alone; toxicity
was acceptable [54– 59]. In a large phase III study with
425 patients, the combination was compared with single agent
IL-2 c.i.v. or IFN-a. The response rates were 18.6%, 6.5% and
7.5%, respectively. The combination therapy showed a significantly higher response than both single agent treatments. The
disease-free survival was higher in the combination arm
(20%, 15% and 12%, respectively); the overall survival of 17,
12 and 13 months was not significantly different [35].
There seems to be no strong arguments to give IL-2 after
failing IFN-a or vice versa, because of a very low response
rate (2% and 4.8%, respectively) [59].
Immunochemotherapy
The most frequently used combination of IFN-a and a cytostatic agent is with vinblastine. Vinblastine gives no additional
beneficial effect in randomized studies. Also, other cytostatic
agents, such as cyclophosphamide, epirubicin, floxuridin, ifosfamide and mitomycin, have no clear additional effect on the
response rate in combination with INF-a, although most
studies were small and therefore meaningful differences may
not have been detected [10, 59 –64].
Atzpodien et al. described a combination of s.c. IFN-a, s.c.
IL-2 and i.v. 5-FU in 120 patients with a response rate of
39%, of which 11% were CR [65, 66]. Until now this is the
most effective schedule in a phase II study. This schedule is
repeated by a number of investigators with response rates of
11–39% with 0–9% CRs [67–70]. The combination of IFNa, IL-2 and 5-FU has also been used in other schedules. The
most important differences are that either IL-2 was given as a
continuous intravenous infusion and/or the drugs were administered all three concomitantly. The response rates
varied between 2% and 39% [71–76].
A randomized study, in which this schedule is compared
with s.c. IFN-a is ongoing in a combined European Organization for research and Treatment of Cancer (EORTC) and
Medical Research Council (MRC) study.
Other combinations
A phase III study showed no improvement of survival with
the addition of 13-cis-retinoic acid to IFN-a [77]. A second
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This effect on the cellular immune response is the proposed
anti-tumour mechanism of IL-2 [38].
Basically, three ways of administration are used: a short
intravenous (i.v.) infusion with high- or low-dose IL-2; a continuous i.v. infusion (c.i.v.); or a subcutaneous (s.c.) administration. These schedules have been developed in the past in an
attempt to maintain efficacy and diminish side-effects. Many
variations are known.
In 1985 Rosenberg et al. described the first responses in
mRCC after treatment with a high-dose short i.v. infusion of
IL-2 [39]. Since then several studies have been published. The
response rate is 7%–23% and in approximately one-third of
patients a CR is observed [24, 40–46]. The median duration
of a PR is 12 –19 months. In a variety of studies the median
duration of the CR had not been reached, the longest being
more than 84 months.
The median survival in a phase III study was 12 months
[35]. The duration of treatment in the case of response is
usually 3–4 months. Sometimes a maintenance therapy is
given until progression, but this is not a definite guideline
[47]. The addition of lymphokine-activated killer cells has no
proven value [48, 49].
There is no randomized study comparing IL-2 versus best
supportive care. There is one randomized study comparing
high-dose i.v. versus low-dose i.v. versus s.c. IL-2. This study
was started in 1991 and the results were reported in 2003, the
third arm was added in 1993 [42]. A total of 156 patients
were randomly assigned to high-dose i.v. IL-2, and 150
patients to low-dose i.v. IL-2. Toxicities were less frequent
with low-dose i.v. IL-2 (especially hypotension), but there
were no IL-2-related deaths in any arm. There was a higher
response proportion with high-dose i.v. IL-2 (21%) versus
low-dose i.v. IL-2 (13%; P = 0.048) but no overall survival
difference. The response rate of s.c. IL-2 (10%, partial response and complete response) was similar to that
of low-dose i.v. IL-2 and different from high-dose i.v.
(P = 0.033). Response duration and survival in patients with
CR was superior with high-dose i.v. compared with low-dose
i.v. therapy (P = 0.04). The latter observation will prolong the
debate of efficacy versus toxicity with no definite answer.
In a retrospective analysis [50], 103 patients with s.c. IL-2
were compared with 225 patients treated with low-dose c.i.v.
No difference was seen in overall survival, response rate and
response duration. The toxicity was significantly less with the
s.c. route.
The administration of lymphokine-activated killer (LAK)cells in combination with IL-2, mainly by c.i.v., is extensively
investigated in mRCC. The response rate of IL-2, with or
without LAK-cells, is similar in both groups but the toxicity
seems to be higher with LAK-cells [48, 49].
The toxicity of IL-2 is higher than that of IFN-a [31].
The toxicity is dependent on dose and schedule. Toxicity is
similar to that for IFN-a but IL-2 can also cause a capillary
leak syndrome with oliguria, hypotension and an increase
in serum creatinine [51]. Cardiopulmonary toxicity (rhythm
disturbances and myocardial infarctions) are sometimes seen;
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EORTC study with the same combination has recently been
completed, but data are not yet available.
IFN-a is also combined with other compounds, such as
acetylcystein, cimetidine and melatonin [25, 78, 79]. IL-2 is
combined with indomethacine and ranitidine [80]. These combinations are investigated only in small studies and their value
is not clear.
The isolation of tumour-infiltrating lymphocytes (TIL-cells)
is complicated; the few studies applying this technology in
combination with IL-2 do not show a promising effect [81].
In a phase I study granulocyte macrophage colony stimulating factor (GM-CSF) was combined with IL-2 and IFN-a,
and showed promising results [82]. However, these results
were not confirmed in a phase II study [83].
Other cytokines, such as IL-4 and IL-12, have been administered in phase I and II studies. As single agents they do not
show meaningful activity [84 –87].
Allogenic stem cell transplantation
A new and effective form of adoptive cellular therapy against
various haematological malignancies is allogenic stem cell
transplantation (allo-SCT) with or without donor lymphocyte
infusions (DLI). In the setting of allo-SCT, T-cell reactivity
against minor histocompatibility antigens is the suggested
mechanism of action both causing graft-versus-host disease
(GVHD) and anti-tumour effect [88]. This method has also
been explored in mRCC. In two comparable studies safety,
feasibility and clinical results of allo-SCT after non-myeloablative chemotherapy were evaluated [89, 90]. Both trials
show that a graft-versus-tumour effect can be induced with
objective response rates of 53% and 33%, respectively. However, substantial toxicity due to GVHD occurred and a transplantation-related mortality of 33% and 12% was observed in
the two trials, respectively. T-cell depleted bone marrow may
facilitate graft take while preventing GVHD and subsequent
DLI may give rise to an anti-tumour effect, which does not
necessarily parallel GVHD [91]. These observations are the
basis of ongoing clinical studies.
Dendritic cells
With the increased knowledge of tumour immunology, the
recognition of immunogenic tumour proteins and development
antibodies, new treatment options with increased specificity
and subsequently fewer side-effects can be explored.
Dendritic cells (DC) have been identified as the most potent
antigen presenting cells (APC) of the immune system [92].
This has led to the initiation of several clinical trials, e.g. in
melanoma [93], B-cell lymphoma [94], prostate carcinoma
[95] and RCC [96, 97]. In these trials, monocyte-derived DC,
cultured in vitro in the presence of IL-4 and GM-CSF have
been used. The collective results of these early trials show the
safety and feasibility of DC-based vaccines in the management of mRCC. However, as clinical benefits are minimal,
Monoclonal antibodies
The concept of selective tumour targeting with antibodies is
based on the avid interaction between the antibody and an
antigen that is expressed on malignant cells, but not on normal
tissues. This specificity can be employed to guide toxic substances or radionuclides to the tumour. Alternatively, effector
functions such as antibody-dependent cellular cytotoxicity
(ADCC), which are intrinsically present in antibodies, may
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New developments
optimalization is needed. For the further development of
effective DC-based vaccines two aspects are important: (a)
knowledge of potentially immunogenic structures and (b) the
type of DC used.
First, despite compelling evidence that RCC is an immunogenic tumour, until recently only a few cyctotoxic T-cell clones
(CTC) specific for autologous RCC have been identified [98 –
102]. Unfortunately, these antigens are expressed in a minority
of primary RCC. In the absence of defined antigens that can
serve as CTL targets, vaccinations of tumour lysate pulsed DC
[96, 97] or DC-tumour cell hybrids [103] have been used in
clinical trials. This circumvents the requirement of identified
tumour-specific antigens. Furthermore, multi-antigen loaded
DC are likely to give poly- or oligoclonal expansion of T cells,
which might provide an enhanced anti-tumour effect compared
with peptide-pulsed DC that are monoclonal of origin.
Recently, the RCC-associated antigen G250 was identified
[104]. G250 is present in 85% of all RCC-types and in virtually
all of the clear-cell subtype RCC. Moreover, no expression
could be detected in the tissue of normal kidney. The
expression is highly restricted and limited to large bile ducts
and gastric epithelium [105]. Recently, a G250-derived peptide
was found which was recognized by HLA-A2.1 restricted CTL
and a helper peptide recognized by HLA-DR restricted Thelper cells [105 –107]. This finding, together with the high
prevalence of G250 in RCC make these peptides potential tools
for peptide-based vaccines to induce both CD4+ and CD8+
T-cells. A clinical trial is ongoing to test the potency of these
peptide-loaded DC to induce T cell responses.
The second important aspect in DC-based vaccination is the
type of DC that is used. For adequate cellular anti-tumour
responses the activation of the Th1 pathway is required. Thus,
DC need to be able to polarize T cells into the Th1 pathway.
Mature DC (mDC) stimulate this polarization most adequately. In contrast, immature DC (iDC) show superior ability
to capture antigens effectively [108– 110]. Based on this
hypothesis a clinical trial was performed at our institution confirming the safety and feasibility of a vaccine of iDC loaded
with autologous tumour lysate in patients with mRCC [96].
Although prolonged stabilisation of mRCC was seen, no significant immunological or clinical reactions were observed.
Recent literature points out that in vitro cultured mDC, with
superior migration characteristics, can initiate more powerful
anti-tumour responses [111, 112]. This is also reflected by the
results presented by Holtl et al. [97] describing both immunological and clinical responses following vaccination of ex vivo
matured DC pulsed with tumour lysate.
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New targets
Angiogenesis
Angiogenesis is crucial for the growth and spread of cancer
cells. It is well established that vascular endothelial growth
factor A (VEGF-A) is an important angiogenic cytokine with
a critical role in tumour angiogenesis. VEGF-A is a multifunctional cytokine that is widely expressed by tumour cells and
that acts through receptors (VEGFR-1, VEGFR-2 and neuropilin) that are expressed on vascular endothelium and on some
other cells. It increases microvascular permeability, induces
endothelial cell migration and division, reprogrammes gene
expression, promotes endothelial cell survival, prevents senescence and induces angiogenesis. Recently, VEGF-A has also
been shown to induce lymphangiogenesis. Measurements of
circulating levels of VEGF-A may have value in estimating
prognosis, and VEGF-A and its receptors are potential targets
for therapy. Recognized as the single most important
angiogenic cytokine, VEGF-A has a central role in tumour
biology and is therefore an important target for cancer therapy
[117].
The enthusiasm felt by many investigators in the field
comes from the potential advantages of such agents compared
with standard chemotherapy in treating cancer. These include
the easy access to targets within the vasculature, independence of tumour cell resistance mechanisms and the broad
applicability of this therapy in many tumour types. Because
angiogenesis is infrequent in the adult, there is the potential to
develop very specific therapies with minimal toxicities, except
during times of wound healing, inflammation, ovulation, pregnancy or ischaemia. An understanding of these various processes and their regulation might lead to differential targeting
[118]. Vessels within tumours can be inhibited by blockade of
the endothelial growth factor receptors through false ligands,
by receptor proteine kinase inhibitors or by neutralization of
the ligand by means of mAbs.
RCC is clinically recognized as a highly vascularized
tumour. VEGF mRNA expression correlates with RCC vascularization and VEGF is overexpressed in up to 70% of RCC
mutations in the Von Hippel Lindau gene (VHL) are found in
75% of sporadic RCC and wild-type VHL is a tumour suppressor gene that inhibits accumulation of hypoxia inducible
mRNAs, including VEGF.
In several studies the potential of this approach is shown.
Yang et al. [119] found in a randomized phase II study
comparing placebo versus low- and high-dose bevacizumab, a
monoclonal antibody against vascular endothelial growth factor, a significant prolongation in the time to progression for
the high-dose regimen. The probability of being progressionfree at 8 months was 14% for the low- and high-dose group
combined versus 5% for the placebo group. There was no
difference in overall survival.
Thalidomide, initially used to treat morning sickness and
subsequently banned for its teratogenic effects, has recently
been used in the field of oncology for its anti-angiogenic properties. In a recent review, a response rate of 7% (range 0 –
17%) was found in nine single agent phase II studies and
stabilization of their disease was observed in 31% of the
patients. Side-effects included constipation, lethargy, neuropathy and trombo-embolic complications [120]. Based on
these results, thalidomide is combined with other agents with
some activity in this disease such as IL-2, IFN, gemcitabine
and 5-FU. No randomized data are available to give a conclusion on the role of this agent in mRCC.
Other anti-angiogenic agents with potential are: neovastat,
a naturally occurring multifunctional anti-angiogenic agent
[121]; SU011248, an oral multitargeted receptor tyrosine
kinase inhibitor (anti-PDGFR, VEGFR, Kit, and Flt3) [122];
and PTK/ZK, an oral selective inhibitor of VEGFR-1,
VEGFR-2, and VEGFR-3 tyrosine kinases [123]. With all
these compounds, activity has been seen in mRCC and these
agents are currently under study in this disease.
Miscellaneous
The epidermal growth factor receptor is known to be overexpressed in mRCC. This makes this receptor or its ligand a
target for therapy. To date the clinical results are disappointing [124, 125].
Other pathways of relevance in mRCC are the Raf-kinase
and mammalian target of rapamycin (mTOR); specific inhibitors are Bay 43 –9006 [126] and CCI 779 [127], for which
clinical studies are ongoing.
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lead to tumour cell kill. Currently, several monoclonal antibodies (mAb) have been approved by the Food and Drug
Administration (FDA), e.g. for the treatment of non-Hodgkin’s
lymphoma [113] and breast cancer [114]. In RCC the chimeric
monoclonal antibody G250 (WX-G250) has been identified
and developed for both therapeutic and diagnostic purposes
[115]. In total, approximately 200 patients with RCC have
received radiolabelled WX-G250. A protein dose escalation
study with 131I-WX-G250 in 16 patients with primary RCC
showed that the radiolabelled antibody accumulated very efficiently in RCC. An activity dose escalating study in patients
with metastasized RCC showed that doses as high as
60 mCi/m2 can be administered safely to patients [115]. In
two out of eight patients receiving high activity doses of this
radiolabelled antibody (45–75 mCi/m2) a partial response
was observed. An extended phase I clinical trial to establish
the maximal tolerated dose and therapeutic efficacy of
two serial injections of 131I-WX-G250 has recently been
completed.
A study with the unconjugated WX-G250 has been performed in 36 patients with mRCC. The weekly schedule of
i.v. WX-G250 was safe and well tolerated. One objective
response, one minor response and a substantial number of durable disease stabilisations were observed. Together with a
median survival after study entry of 15 months, this suggests
that WX-G250 has the capacity to modulate the natural history
of mRCC [116]. Phase-II trials optimizing treatment schedules
with both the conjugated and the unconjugated WX-G250 in
combination with cytokines have been initiated.
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Prognostic groups
_ 1)
Bad PS (World Health Organization >
Based on the number of risk factors, patients have been
divided into prognostic groups.
Palmer and Jones separated patients treated with IL-2 into
four or three groups, respectively [130, 45]. They compared
these patients with historical controls treated with chemotherapy matching the same inclusion criteria. This was the
first retrospective analysis that suggested that IL-2 lengthened
the survival in patients with mRCC. It was noticeable that
patients with good prognostic factors had a bigger survival
advantage than those with intermediate factors. In patients
with bad prognostic factors immunotherapy did not induce a
survival advantage (see Table 2).
Fossa et al. made a similar analysis but their patients were
treated with IFN-a [132]. They also compared the survival of
their patients with those treated with chemotherapy in the
study of Elson et al. [129]. In this study, it was shown again
that patients with good prognostic factors, i.e. a PS of 0, a
DTI of more than 24 months and only one MS, gained most
by treatment with IFN-a. The survival of these patients treated
with IFN-a was comparable with those treated with c.i.v. IL-2
(see Table 2). It is obvious that this does not imply that both
treatments are equally effective. Motzer [131] identified five
prognostic factors for predicting survival and used to categorize patients with mRCC into three risk groups, for which the
median survival times were separated by 6 months or more.
These risk categories can be used in clinical trial design and
interpretation, and in patient management. An attempt is currently being made to come to one internationally accepted
prognostic model.
Patients with rapidly progressive disease are probably not
suitable candidates for second-line therapy. Motzer [131] analysed the survival in previously treated patients with mRCC
who were candidates for clinical trials of new agents in secondline therapy. Median survival of the 251 patients was 10.2
Short disease-to-treatment interval (<2 years)
More than one metastatic site
Loss of weight (>10% in last 6 months)
Metastasis in liver, bone or brain
No nephrectomy (possible)
_ 70 mm/h; LDH > 280 U/l; neutrophils > 6109/l;
Sedimentation rate >
low haemoglobin level, corrected serum calcium <6.3 mmol/l
Prognostic factors in mRCC
It is well recognized that a number of factors can predict survival in the patient with mRCC. Patient-related factors are PS,
weight loss, time from initial diagnosis to the start of systemic
treatment [disease-to-treatment interval (DTI)] and various
laboratory parameters such as sedimentation rate, white blood
count, lactate dehydrogenase (LDH) and haemoglobin. Also
localization and number of metastatic sites (MS) are relevant
(see Table 1) [35, 40, 128–130].
The most important predictive factors for response on
immunotherapy are PS and number of MS [35, 40]. Fyfe et al.
[40] described patients, who were treated with high-dose bolus
i.v. IL-2, with a PS of 0, had a response rate that was twice as
high as patients with a PS of 1 (17% versus 9%). In this study
11 of the 12 CR were seen in patients with a PS of 0.
The most prognostic and/or predictive factors for longer
survival after immunotherapy are a PS of 0, a long DTI (±24
months) and only one MS [129, 130]. Other bad prognostic
factors in univariate analysis were the presence of metastases
in brain, liver or bone [129]. In 1999, Motzer et al. presented
their prognostic analysis [131]. The relationship between pretreatment clinical features and survival was studied in 670
patients with advanced RCC, treated in Memorial Sloan-Kettering Cancer Center clinical trials between 1975 and 1996.
Clinical features were first examined univariately. A stepwise
modelling approach based on Cox proportional hazards
regression was then used to form a multivariate model. The
median survival time was 10 months (95% CI, 9–11 months).
Fifty-seven of 670 patients remain alive and the median follow-up time for survivors was 33 months. Pretreatment features associated with a shorter survival in the multivariate
analysis were low Karnofsky PS (<80%), high serum LDH
(greater than 1.5 times the upper limit of normal), low haemoglobin (less than the lower limit of normal), high
‘corrected’ serum calcium (>10 mg/dl) and absence of prior
nephrectomy. These were used as risk factors to categorize
patients into three different groups. The median time to death
in the 25% of patients with zero risk factors (favourable risk)
was 20 months. Fifty-three percent of the patients had one or
two risk factors (intermediate risk) and the median survival
time in this group was 10 months. Patients with three or more
risk factors (poor risk) (22% of the patients) had a median
survival time of 4 months.
Table 2. Comparison of the survival of prognostic groups of patients with
mRCC treated with immunotherapy or chemotherapy. Prognostic groups
are defined as the sum of the number of points of three prognostic factorsa
[41, 125, 126]
Prognostic groups
(total points)
Median survival (in days) after treatment with
IL-2
(n = 327)
IFN-a
(n = 231)
Chemotherapy
(n = 350)
Good (0 of 1)
570
652
352
Intermediate (2)
320
315
202
Poor (3)
177
193
158
a
Prognostic factors were: (a) PS of 0 (fully active; able to carry on all
pre-disease activities without restriction) = 0 points; PS of 1 (restricted
in physically strenuous activity but ambulatory and able to carry out work
of light or sedentary nature) = 1 point; (b) disease to treatment interval
_ 24 months and 1 if <24 months; (c) number of metastatic
(DTI): 0 if >
sites (MS): 0 if one localization and 1 if more than one localization.
PS = performance status according to the World Health Organization.
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Table 1. Risk factors for a short survival in patients with MRCC
iv325
months and differed according to year of treatment: patients
treated after 1990 had a longer survival. In this group, the
median overall survival time was 12.7 months. Pretreatment
features associated with a shorter survival in multivariate analysis were low Karnofsky performance status, low haemoglobin
level, and high corrected serum calcium. These were used as
risk factors to categorize patients into three different groups.
The median time-to-death in patients with no risk factors was
22 months. The median survival in patients with one of these
prognostic factors was 11.9 months. Patients with two or three
risk factors had a median survival of 5.4 months. These risk
factors were very similar to those seen in first-line treatment.
Conclusions
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