Further effects of thalidomide may be relevant to
clinical management of malignancy. Inhibition of polymorphonuclear leukocyte
chemotaxis has been reported in an in
vitro model (Faure et al, 1980). Thalidomide also inhibits neutrophil
chemotaxis (Dunzendorfer et al, 1997). Leukocyte migration to sites of
inflammation may be affected by downregulation of cellular adhesion molecules
(Settles et al, 2001). Thalidomide has been reported to decrease the ratio of
circulating T-helper cells to suppressor T cells in healthy subjects as the
result of a reduction in the production of helper cells and increase in
production of suppressor cells.
Another possible mode of action for thalidomide
involves modulation of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis
of prostaglandins (Fujita et al, 2001). COX-2 is highly expressed in various
human cancers including prostate cancer, and has been shown to be required for
angiogenesis in a rat corneal model (Yamada et al, 1999; Daniel et al, 1999).
The results are in keeping with the anti-angiogenic response of human prostate
cancer cells treated both in vitro
and in vivo with a COX-2 Inhibitor
(Kirschenbaum et al, 2001). Thalidomide has been demonstrated to inhibit COX-2
and subsequent prostaglandin-E2 biosynthesis in a dose dependant
manner (Fujita et al, 2001).
V. Prostate cancer
Prostate cancer is the most commonly diagnosed
malignancy affecting men beyond middle age in developed countries. Although
detection of early prostate cancer is increasing, many patients still present
with metastatic disease. Hormone treatment in the form of androgen deprivation
is an established therapeutic option for metastatic prostate cancer. In
patients who respond to hormone manipulation, subsequent clonal expansion of
hormone insensitive cancer cells results in loss of response with a mean time
to tumour progression of less than 18 months. Prostatic Specific Antigen (PSA)
is used as a clinical marker of tumour load and a serial increase in PSA values
after initial successful androgen ablation usually indicates clinical
progression to androgen independent prostate cancer (AIPC). Androgen-independence
can be defined as a rising PSA value of at least 20ng ml-1 on two
consecutive occasions after the nadir of response to androgen ablation therapy,
or a rise of at least 5ng ml-1 if the absolute PSA value was less
than 20 ng ml-1 (Bubley et al, 1999). Various agents have been
tested in an attempt to achieve second-line response in AIPC, including;
corticosteroids, diethylstilboestrol, tamoxifen, aminoglutethamide,
ketoconazole, suramin, estramustine, taxanes, mitozantrone and herceptin. Benefits
in terms of disease suppression and survival are uncertain. The prognosis for
patients with hormone refractory disease is poor; median overall survival is 12
-18 months.
A. Tumour
biology and angiogenesis
The role of angiogenesis in the growth and metastasis
of prostate cancer has been demonstrated by Weidner et al, (1993) who showed that increased microvessel density in
prostate cancer specimens can predict advanced tumour stage. Mean microvessel counts are significantly greater in the primary
tumours of patients with metastatic disease than in those without metastases,
and a correlation between microvessel density and increasing pathological grade
has been observed. Increased microvascularity also correlates with a
poorer prognosis (Lissbrant et al, 1997). Rogatsch et al (1997) investigated
whether the quantification of tumour microvessels can be reliably applied to
prostatic core biopsies, as a means of detecting likely local tumour extension
prior to radical prostatectomy. They observed a high degree of correlation
between microvessel density in biopsies and the subsequent prostatectomy
samples. The median microvessel density in core biopsies predicted the local
tumour stage.
Malignant prostatic epithelial
cells show increased expression of numerous angiogenic substances, including;
basic FGF, (Mansson et al, 1989; Gleave
et al, 1992; Nakamoto et al, 1992; Warren, 2001) transforming growth factor
(TGF) a and -b, (Ikeda et al, 1987; Hofer et al,
1991; Harper et al, 1993; Truong et al, 1993; Cohen et al, 1994; Eastham et al,
1995; Steiner et al, 1994) epidermal growth factor (Ching et al, 1993; Ware,
1993) and platelet derived growth factor (Fudge et al, 1994; Sitaras et al,
1988). Elevated
serum levels of TNF-a and basic FGF can be seen in patients with prostate
cancer (Meyer et al, 1995; Nakashima et al, 1995).
B. Clinical
trials
With the emergence of evidence implicating the
involvement of angiogenesis in prostate cancer, the use of thalidomide as a
potential therapeutic agent has been investigated. Figg et al, (2001b) have
compared low-dose (200mg/day) and high dose (up to 1200 mg/day) thalidomide in
patients with AIPC. The high dose regime commenced at 200mg/day with
incremental rises of 200mg /day every two weeks up to a maximum of 1200mg where
tolerated. Fifty patients were randomised to the low dose arm. In the high dose
arm, thirty percent of patients were unable to tolerate doses of above
200mg/day due to the side effect profile. As a result of the high incidence of
adverse effects, and since no patient showed a substantial decline in PSA, the
high dose arm was discontinued after 13 patients were enrolled. The median time
on study was 2.1 months for the low dose arm and 2.0 months for the high dose
arm (range 35-247 days). Response to treatment was evaluated in terms of PSA
reduction, changes in metastatic lesions on bone scan and measured tumour load
as detected on serial CT scans. The assessment of circulating growth factors
(basic FGF, VEGF, TNF-a and TGF-b) was also carried out.
Reductions in PSA were observed in 58% of patients in the low dose arm and 68%
of the high dose arm. Nine out of the 63 patients (14%) showed declines in PSA
of ³50%, all of whom were in the low dose arm of the study. The failure of PSA
response in the high dose arm may result from the up-regulation of PSA
secretion which is seen in prostate cancer cell lines exposed to thalidomide
(Dixon et al, 1999). Of the patients who had measurable disease on CT scanning,
14% had some reduction in tumour load. Two patients had radiographic
improvement of bone scan lesions and both had sustained reductions in serum
PSA. Declines in serum TGF-b
were seen in the eight patients with PSA reductions at four months. There were
also reductions in basic FGF in six of these patients. Figg and colleagues
concluded from this trial that thalidomide may have modest anti-tumour activity
through its anti-angiogenic properties in patients with hormone refractory
prostate cancer.
Drake et al, (2003)
examined the benefits of low dose thalidomide in patients with rising PSA
after initial response to hormone manipulation therapy. Response to treatment
was evaluated in terms of serum PSA reduction and growth factor levels. Twenty
patients were enrolled in this study and given 100mg thalidomide once daily at
bedtime. The mean time on study was 109 days (range 4–184 days) with 16
patients continuing thalidomide treatment for more than two months. Three men
had PSA falls of ³50% with five other patients showing some decline. Of the 16
men who tolerated treatment for more than two months, six showed a fall in
their serum PSA by a mean of 48%.
In this study serum growth factors were analysed in 11
patients at three months. There was an overall mean rise in both basic FGF and
VEGF. However, when analysed according to PSA response, five out of the six men
who manifested a decline in PSA showed a decline in mean values of both basic
FGF and VEGF; at the time of loss of PSA response, there was a coincident rise
in growth factor levels. Patients who demonstrated increasing PSA levels had
associated rises in growth factors. Three patients discontinued low dose
thalidomide due to adverse effects. The most commonly reported adverse reaction
was constipation (n=9) followed by sedation hangover (n=3) and dizziness (n=2).
Clinical trials of single agent docetaxel in AIPC have
demonstrated response rates of 20-60% (Logothetis, 2002). Accordingly,
thalidomide has also been studied in combination with docetaxal in a phase II
trial enrolling 75 patients with AIPC (Figg et al, 2001a; Dahut et al, 2004).
Patients were treated with intravenous docetaxel, with or without a single
night-time dose of thalidomide 200mg. 35% of those receiving docetaxel alone
showed decrease in PSA of at least 50%, while 53% of patients in the
combination arm demonstrated an equivalent response. At 18 months, overall
survival in the docetaxel group was 42.9%. Compared with 68.2% in the combined
arm. Of the first 43 patients treated with docetaxel and thalidomide, nine
patients developed deep venous thrombosis and a further three suffered a
cerebrovascular incident. There were no thromboembolic complications in the
docetaxel group. Subsequent patients enrolled into the combined group were
given low molecular weight heparin, preventing further thrombotic events.
Thalidomide combination therapy with the cytotoxic
agents paclitaxel and estramustine has been evaluated (Daliani, 2003). Thirty
patients with AIPC were given weekly paclitaxel for 2 of 3 weeks together with
oral estramustine and escalating doses of thalidomide, titrating from 200 mg a
day to 600 mg a day. Seventy-two percent of the 25 evaluable patients achieved
a sustained decline in PSA levels of 50% or more. Twelve percent showed a drop
of 80% or more. The men who experienced a drop in PSA also reported less bone
pain. Four of the 29 men evaluable for toxicity developed Grade 3-4 deep venous
thrombosis, despite warfarin prophylaxis, requiring treatment discontinuation
in two patients. There were no cases of grade 2-4 neuropathy. The U.S. National
Cancer Institute is undertaking a phase II trial of Estramustine,
Docetaxel and Thalidomide in AIPC.
A phase II trial using a
combination of thalidomide (100-200mg) with granulocyte macrophage colony
stimulating factor in 17 AIPC patients with soft tissue or bone disease has
been carried out (Dreicer et al, 2002). Partial response was seen in five of 13
evaluable patients. Treatment was generally well tolerated
VI. Renal cell carcinoma
Renal cell carcinoma (RCC) accounts for 3% of all
adult malignancies. Incidence of RCC has risen over the last 30 years, with
greater use of ultrasonography and CT scanning increasingly detecting
incidental tumours. The identification of early tumours has seemingly led to
improved survival. However, the overall mortality rates for RCC have increased
over this time, suggesting a possible change in tumour biology, perhaps due to
environmental factors (Chow et al, 1999). One third of patients with RCC
present with metastatic disease and 40% of the rest eventually develop distant
metastases. The prognosis for these patients is poor, as RCC is resistant to
most chemotherapeutic agents. Patients who have non-bulky metastatic disease
and who are of good performance status may be suitable for immunotherapy.
Nonetheless, only 10-15% of patients experience an objective response to
immunotherapy with either interleukin-2 (IL-2) or a-interferon (α-IFN)(Negrier et al, 1998).
A. Tumour biology
and angiogenesis
RCC is one of the few tumours in which spontaneous
regression is recognised, with an estimated incidence of 0.3% (Vogelzang et al,
1992). Most cases have been in patients with pulmonary metastases and have
occurred after nephrectomy, but regression of primary RCC has also been
documented even in the absence of any treatment (Vogelzang et al, 1992).
RCCÕs are highly vascular tumours, as demonstrated by
the distinctive neovascular pattern on renal angiography. The up-regulation of
a variety of angiogenic factors and the renin angiotensin system has been
reported (Nicol et al, 1997; Hii et al, 1998; Horie et al, 1999). Increased levels of mRNA for VEGF have been found in the majority
of hypervascular renal cell carcinomas, while hypovascular tumours have
exhibited low levels of this transcript (Brown et al, 1993; Takahashi et al,
1994). Increased levels of VEGF have also been found in the serum of
patients with RCC and a correlation with stage and grade has been noted (Kato
et al, 2000). Elevated serum levels of basic FGF have also been demonstrated in
RCC and other possible angiogenic growth factors contributing include placental
growth factor, TGF-b1, angiogenin,
interleukin-8 and hepatocyte growth factor (Campbell, 1997). Sporadic and familial
RCCÕs commonly demonstrate mutations or deletions in the Von Hippel Lindau
gene, and this genetic change may lead to increased expression of VEGF
(Stebbins et al, 1999). The angiogenic dependence of RCCÕs and the involvement
of such genes and growth factors have led to the investigation of a variety of
antiangiogenic treatments including thalidomide, endostatin, interleukin-2,
squalamine and neutralising antibodies to VEGF.
B.
Clinical trials
Numerous trials employing thalidomide in RCC have been
undertaken. These are summarised in Table
1. Eisen et al, (2000) carried out a study to assess the efficacy and
toxicity of thalidomide in the treatment of patients with metastatic melanoma,
renal cell carcinoma and ovarian and breast cancer. Three of 18 patients with
RCC showed a partial response to treatment (100mg daily). A further three
patients had stable disease for at least three months. A further phase II trial
by the same group evaluated the use of high dose oral thalidomide (600mg daily)
(Stebbing et al, 2001). 25 patients were enrolled in this study with advanced
metastatic RCC. Nearly all had undergone prior surgery and systemic
immunotherapy or immuno-chemotherapy. Progressive disease was identified in all
patients prior to study entry. Three patients were removed from the trial at an
early stage due to toxicity
and
five other patients required dose reduction due to peripheral neuropathy. Of
the 22 assessable patients, two (9%) achieved a partial response and 12 had
stable disease for 12 months, with dose reduction due to toxicity. In many of
these patients there was a significant reduction in serum TNF-a.
Minor et al, (2002) investigated the activity of
thalidomide in patients with advanced RCC in a phase two study involving 29
patients. All patients had advanced progressive metastatic RCC disease and many
were poor performance status. 72% had received prior therapy in the form of
interleukin-2, a-interferon
and cytotoxic chemotherapy. Patients were started on a daily dose of
thalidomide of 400mg rising in increments of 200 mg to a maximum dose of 1200
mg. Tumour responses were evaluated using South Western Oncology Group criteria
and in some patients serum levels of VEGF 165 was monitored. Of the 24 patients
assessable for response, only one demonstrated a partial response. Three
patients had stable disease for over six months. The median time to progression
for all 29 patients was 2.3 months and median survival was 3.5 months. VEGF 165
was measured in 8 patients and no obvious change in plasma levels was demonstrated.
The largest trial to date involved 40 patients treated
with thalidomide doses starting at 400mg daily rising to 800mg and then 1200mg
(Escudier et al, 2002). At 12, 18 and 24 weeks 31, 25 and 17 patients remained
on treatment respectively. At nine months, only eight patients were still on
study therapy, with all patients stopping treatment after one year due to
severe neuropathy. After 6 months, two patients (5%) achieved partial response,
with 9 patients (22%) having stable disease. The one year survival was 38%. In
this study, neuropathy and thromboembolism were significant side effects.
A further trial examining the use of escalating doses
of thalidomide was carried out by Daliani et al, (2002). Twenty patients with
metastatic RCC were enrolled and treated with doses starting at 200mg,
increasing in weekly increments up to a target maximum dose of 1200mg per day.
Nineteen patients were evaluable for response, of whom two patients (10.5%) had
a partial response and nine patients had stable disease. Median time to
progression was 4.7 months (range 0.7-31.3 months). Thirteen patients remained
on the study at three months and 12 of these tolerated a maximum dose of
1200mg. Delayed dose reductions were required for three patients because of
peripheral sensory neuropathy. A further three patients developed thomboembolic
events believed to be related to thalidomide.
Motzer used doses of thalidomide up to 800mg in
advanced RCC (Motzer et al, 2002). Twenty five patients were assessable for
response. No patient achieved a partial or complete response; stable disease
was observed in 16 patients (64%), which was maintained for a mean duration of
6 months. The median time to disease progression was 4 months. The one-year
survival was 57%. A further small study recruited 14 patients (Srinivas and
Guardino, 2002) comparing low dose thalidomide (200mg/day) to higher escalating
doses (800–1200mg/day). Six patients (46%) achieved stable disease,
mainly in the low dose arm, with no objective responses. Stable disease was the
best response obtained by Novik et al, (2001) in a phase II trial involving 27
patients with metastatic RCC, including lung, brain and liver metastases. Li et
al, (2001) treated 36 patients with thalidomide (200-1200mg) All of these
patients had failed to respond to prior interleukin-2 therapy. Seventeen of the
patients managed to tolerate the maximum dose. Partial responses were seen in 2
of the 29 evaluable patients with stable disease in 9 further patients.
Thalidomide has also been investigated in combination
with immunotherapeutic agents for the treatment of RCC. In a phase II trial to
examine the efficacy of interferon a-2a (IFNa-2a) with thalidomide (Nathan et al, 2002), no
responses to treatment were seen. Five patients experienced serious adverse
side effects, which were attributed to the membrane destabilising effects of
both of these agents. The authors concluded that caution is needed in combining
these two therapies. A further phase II trial (Clarke et al, 2004) looking at
thalidomide in combination with IFN-a in 30 patients reported an objective response rate of
7% with no complete responses, 2 partial responses and 8 patients achieving
stable disease. One third of patients experienced toxicity that required
discontinuation of thalidomide.
In a phase III study of the Eastern Co-operative
Oncology Group (Gordon et al, 2004), interferon–a2b (IFN-a2b) in combination with
thalidomide (200-1000mg daily) was compared with IFN–a2b alone. There was no
difference in objective response, but there was a higher percentage of patients
with stable disease in the combination therapy arm (31.3% vs 18.5%). This is
consistent with thalidomideÕs known cytostatic activity, but there was no
discernable difference in the progression free survival curves. Furthermore, no
clinically significant difference in quality of life was achieved between the
arms at baseline or through treatment.
As single therapy for metastatic RCC, IL-2 can elicit
clinical responses, but only in a minority of patients. A phase I trial of
combination IL-2 and oral thalidomide involving 31 patients (Olencki et al,
2003) demonstrated moderate to severe toxicity with one complete response and
one partial response. More promising responses have been reported by (Amato et
al, 2002), administering combination therapy for 9 months, followed by 6 months
of thalidomide monotherapy. An initial phase I trial, involving only a small
number of patients (n=15), showed 5 partial responses and 1 complete response.
Later data from the same trial reported further responses, which were sustained
for at least 12-18 months. A phase II trial recruited 37 patients, of whom 33
were assessable for response. This produced an objective response rate of 39%
with 2 complete responses, 11 partial responses and 10 patients with stable
disease.
VII. Conclusions
Thalidomide has numerous biological actions;
suppression of growth factor levels gives rise to anti-angiogenic and tumour
cytostatic effects, but also substantial adverse drug reactions. The biological
actions have led to the application of thalidomide in various clinical
scenarios on an empirical basis, particularly where current management options
are limited. The current treatment options for AIPC and advanced RCC are
primarily palliative. The events leading to progression in prostate cancer
include angiogenesis. Clinical trials of thalidomide in AIPC indicate a
response in a subgroup of patients, which correlates with alterations in growth
factor levels. This has not been translated into a clinical management option
as yet, but does provide some insight into the biology of androgen-independence
and the potential for pharmacological manipulation of this complex process. The
use of thalidomide in combination with other chemotherapeutic drugs appears
more promising. RCCs are chemotherapy-resistant; objective responses to
thalidomide also appear to be infrequent (Table
1). The greater clinical benefit with low dose thalidomide in certain
clinical trials in AIPC and RCC indicates that the immunomodulatory effects of
thalidomide can outweigh the cytokine responses.
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