Angiogenesis is essential to progression of prostate cancer. In
1993, Weidner and colleagues demonstrated a correlation between microvascular
density and stage of prostate cancer. A number of studies over the next several
years showed a correlation between microvessel count and disease stage or risk
of disease recurrence after local therapy.[2-6]
A program for antiangiogenesis trials was started at M. D.
Anderson Cancer Center on the basis of these data. One of the major questions at
this time is how best to measure the activity of putative antiangiogenesis drugs
in prostate cancer in light of the fact that the target is the host (endothelial
cell) rather than the epithelial malignant compartment per se (prostate cancer
cell), and that markers of biologic activity of angiogenesis inhibitors might be
different than tumor markers (ie, prostate-specific antigen [PSA]). The
availability of soluble, surrogate markers of antiangiogenic activity would
accelerate assessment of drug activity and development of novel therapies;
however, it remains unknown which soluble markers might be relevant to
prediction of clinical effect. Further, methods such as positron-emission
tomography (PET) scanning or new technologies for measuring tumor blood flow
have not been clinically validated in this setting. We therefore hypothesized
that assessment of the in vivo effect of the antiangiogenesis treatment on
endothelial cells/vessels and malignant compartment (comparison of tissue
samples prior to and after treatment with putative angiogenesis inhibitors)
would constitute the optimal approach to assessment of drug effect.
Initial studies have included patients with locally advanced
prostate cancer defined as clinical stage T1c/T2 (Gleason score of ³
7 and PSA level > 10 ng/dL) or stage T3; such patients are categorized as ‘potentially
resectable’ but not ‘highly curable’ with local therapies alone.
Studies have shown that 50% to 97% of patients with stage T1c/T2
disease and a Gleason grade ³ 8, and 73% of those with T2 disease and Gleason
grade ³ 7 and PSA level > 10 ng/dL, have
extracapsular extension of disease at surgery. Positive surgical margins
range between 22% and 33% for patients with high-grade T1/T2 disease and 50% for
those with T3 disease. Ten-year and 15-year survival rates varying from 12%
to 60% and 20% to 28% for patients with stage T3 disease were observed. The
addition of androgen ablation to radiation therapy shows improvement in
disease-free survival, but no clear improvement in overall survival for patients
with locally advanced prostate cancer. The European Organization for Research
and Treatment of Cancer (EORTC) trial indicated improved disease-free and
overall survival while the Radiation Therapy Oncology Group (RTOG) trial
showed improvement only in disease-free survival.
We have offered patients with locally advanced prostate cancer,
good performance status, and extended life expectancy participation in clinical
studies of preoperative investigational treatments, including antiangiogenesis
therapy. The safety of preoperative treatment with another angiogenesis
inhibitor (fumagillin analog) has been established in a previous trial,
although the results may not be comparable because of the different mechanism of
action and much longer half-life of thalidomide (Thalomid). As with other
studies, it was observed that microvascular density correlated with the Gleason
score. We observed marked intertumoral and intratumoral changes in microvascular
density, which mandates careful assessment of consecutive, matched, pre- and
posttreatment biopsies and correlation with putative serum/urine markers.
Thalidomide is a promising candidate for antiangiogenic
treatment in prostate cancer. It inhibits vascular endothelial growth factor
(VEGF)-induced angiogenesis and basic fibroblast growth factor (bFGF)-induced
angiogenesis, both of which are implicated in prostate cancer
progression[12-14]; it also down-regulates interleukin-6, an autocrine and
paracrine growth factor in prostate carcinoma,[11,16,17] and suppresses
production of tumor necrosis factor-alpha, a cachexia factor that is elevated
in advanced prostate cancer. Thalidomide has shown some evidence of
"clinical benefit" in patients with androgen-independent prostate
cancer enrolled in National Cancer Institute (NCI) phase II trials.
Angiogenesis is tumor site-specific; it remains uncertain
whether beneficial effects of antiangiogenic treatment would be observed at both
primary and metastatic tumor sites. This question will be addressed in an
ongoing neoadjuvant trial of thalidomide. The rationale for the trial is based
on the hypothesis that thalidomide may reduce postoperative disease recurrence
and that neoadjuvant angiogenesis inhibition, assessed by consecutive prostate
biopsies, may constitute a useful strategy for identifying intermediate markers
of antiangiogenic and antitumor activity.
Objectives of the trial are (1) to assess safety of treatment,
(2) to determine efficacy of preoperative thalidomide treatment through
assessment of tumor size and PSA levels, and (3) to obtain qualitative
measurements of the in vivo effects of thalidomide on endothelial cellsconsisting
of measurement of microvascular density, bFGF, VEGF, E-selectin, thrombomodulin,
and tumor blood flowand on the epithelial compartment, including assessment
of apoptosis and proliferation of prostatic carcinoma cells. The study design is
shown in Figure 1.
Patients and Methods
Patients are to undergo transrectal ultrasound and needle biopsy
prior to initiating thalidomide treatment at 200 mg/d; the thalidomide dose is
to be increased to 600 mg/d over the initial 6 weeks of administration, during
which urine and serum markers are to be assessed. After ultrasound and biopsy
are repeated, patients with stable disease are to receive 6 additional weeks of
thalidomide (600 mg/d) before undergoing prostatectomy, with urine and serum
markers being assessed at the start of the second phase and prior to and after
prostatectomy. It is hoped that the findings of this trial and other neoadjuvant
studies will help in the development of optimal combination therapy strategies.
Chemotherapy is active in metastatic androgen-independent
prostate cancer. Synergistic effects of antiangiogenic agents and chemotherapy
have been observed in preclinical investigations. Thalidomide has been
associated with "clinical improvement" in some patients with
metastatic androgen-independent prostate cancer. We have anecdotal experience
with thalidomide in some patients with metastatic androgen-independent prostate
cancer refractory to chemotherapy. We observed clinical improvement (pain
relief) as well as PSA reduction using thalidomide combined with the previous
chemotherapy that had resulted in progression of disease for these patients
(personal communication, C. Logothetis, 2000).
Based on such clinical experience, we have initiated a phase
I/II trial of thalidomide, paclitaxel (Taxol), and estramustine (Emcyt) in
patients with metastatic androgen-independent prostate cancer progressing after
prior chemotherapy. In addition to determining the maximum tolerated dose of
thalidomide in this setting, the study will evaluate the safety of the regimen
and assess effects on analgesic consumption, nausea, mental status, time to
disease progression, and overall survival.
Angiogenesis is important for prostate cancer progression. The
development of the clinical methodology to assess the in vivo effect of
angiogenesis inhibitors will expedite the assessment of their efficacy and their
clincal applications. The clinical trials described here will provide insight
into the clinical activity of thalidomide, a potent angiogenesis inhibitor, in
early as well as advanced prostate cancer.
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19. Figg WD: in press.
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