Background. Cryosurgical ablation of prostate (CSAP) has gained
popularity as alternative treatment for localized prostate cancer
with excellent local tumor control, being performed at more than
100 centers in USA (1). But there are only isolated reports with
CSAP with CSPA using for palliation of stage D prostate cancer,
includingsolely to eliminate or ease local symptoms and make the
patients more comfortable (2,3).
Remarkable recent advances in our understanding of the immune system
and the advent of new immunostimulants, especially recombinant cytokines,
now permit direct activation and regulation (direction) of immune
responses as well as ways of obtaining more long-lasting immunity
As it is known, IL-1 is as main cytokine vital to the proliferation
and maturation of whole immune cascade (5).
Aims and Objectives. The purpose of this study is to use the combination
of CSAP with cytokinotherapy by IL-1 as more guided and accordingly
more effective approach to treat patients with advanced (stage D)
prostate cancer. There will be attempt to eradicate the prostate
cancer or treat any metastases or other symptoms arising from this
Rationale and Methods. Many investigators (6,7) on the basis of
the wide range of tissue effects that can be attained by cryonecrosis,
expressed great expectations for the cryoimmunologic (both a specific
humoral and a cellular immune response) augmentation of tumor destruction.
Moreover, in advanced-stage disease- where tumor heterogeneity confounds
treatment by conventional therapy and patients succumb to the direct
effects of metastasis and complications associated with treatment-
cryoimmune response may additionally be tumoricidal to metastases
Cryoimmunisation may result in a response that may be tumoricidal
as well as tumor enhancing - bidirectional (Figure 1). Primary tumor-antigen
liberation lies not merely in augmentating an antitumor response
but in directing (modulating) the response toward that will be tumoricidal.
However further antigenic stimulation actually attenuates the immune
response by an intrictic biochemical feedback mechanism. This one
decreases the T cell activity, thereby self-regulating the production
of interleukin- 1 and other cytokines. This idea further explains
a prolongation of immune response. This a "booster" response
was successfully achieved by multiple freezing of the prostate at
intervals of 30 days or more (8).
But these considerations may be prevented by precryosurgical using
of rec. IL-1 with pleiotropic action. Our preliminary results of
immunotherapy have shown the efficacy of this modality in advanced
prostate cancer (9). We have noted the preventive action of IL-1
to the whole cascade of humoral and cellular immunity to possible
side-effects of basic palliative therapy- chemotherapy, radiotherapy
and cryodestruction ( ).
The regime of proposed immunotherapy may be as follow: IL-1b (betaleukin),
which has already got an approval from Russian National Pharmacological
Comittie and now is produced by St.Petersburg State Research Institute
of Highly Pure Biopreparations , - in dose 5ng/kg subcutaneously
daily during 3-5 days with 1-2 days interval of resting before cryoablation
. Then cryoablation of the prostate will be performed utilising
the Spembly Cryosurgical Systems with a standard five probe double
freeze technique. Respectively we suspect to treat patients with
advanced prostate cancer- T3-4,N1-2,MX/0-1. Based upon the data
of immunity disturbances changing, may be repeating of systemic
IL-1b course at 1 month (minimum) after cryoablation.
Moreover, in an inflammatory response, such as that initiated by
cryonecrosis, the target tissue will be subjected to the action
of not just only IL-1 but several cytokines as a result of chain-reaction,
that may act synergistically to promote one arm of the immune response
while inhibiting the other. Cytokines are pleiotropic and may function
in autocrine, paracrine and endocrine manner. Developing data suggest
that locally produced cytokines may arouse immunogenicity and facilitate
cell-to-cell interactions and antigen presentation by inducing or
enhancing expression of select membrane proteins.
According to this hypothesa, we are proposing to inject IL-1b (up
to 10 ng) into tumor also followed 24 hours later by cryosurgery
The initial immunological status and its consequent alterations
will be evaluated by studies of systemic and local immunity .
A n evaluation of this new therapeutic approach against advanced
prostate carcinoma will be conducted with routine clinical evaluation
(physical examination, sexual story, laboratory findings, Internationalo
Prostate Symptom Score:IPSS, urodynamic pressure-flow studies) as
well as stated markers of tumor progression- bone scan, prostate-specific
antigen (PSA), acid phosphatase, lymph node status by CT and MRI.
In addition, the newer diagnostic immunocytochemical and molecular-biological
methods especially for chemo-and hormonal relapsed prostate cancer-
multidrug resistance (P-glycoprotein expression by Western blotting
cell lysates using specific antibodies) with determination the sensivity
to Estracyt, level of androgen receptors ( exon 2-8 amplification
of androgen receptors gene by polymerase-chain reaction) and apoptosis
index (tumor supressor gene p53 from paraffin-embedded prostate
specimens using monoclonal antibody do7- Dako UK Ltd.) (10 ).
Expected results. One important clinical consideration is the fact
that nearly all prostate cancers are at least initially sensitive
to a variety of anti-neoplastic drugs. Treatment regimemens incorporating
combinations of these drugs currently are the mainstay of theraoy,
and can often achieve substantial reductions in tumor burden and
prolongation of survival. One of the more attractive this drug is
estracyt, consisting of cytotoxic as well as antiandrogen agent.
Unfortunately, for many of the tumor cases, recurrence with drug-resistant
tumors often follows chemo-and hormonal therapy-induced remissions.
It seems likely that our new approach that attempt to generate T-cell
mediated anti-tumor immunity will need to occur in the context of
existing remission including systemic chemo- and hormonotherapies.
Many of these agents are themself highly immunosuppressive. Nevertheless,
our preliminary results have demonstrated that in the setting of
cryoimmunmotherapy with basic adjuvant therapy by estracyt resulting
in a combined efficiacy that exceeds either modality ( 9 ). Additionally,
human recombinant IL-1b has prevented significantly myelosuppression
and other adverse effects of estracyt, allowing to increase its
doses up to maximum efficacy. Finally, from the bidirectional nature
of the cryoimmune response exhibited, evaluation and elucidation
of the role of local and systemic cytokinotherapy before and after
cryosurgery and their possible regulation should prove most enlightening.
We hope this approach allows us to improve the CSAP efficacy and
inhibit the metastases growth in the combinative treatment of advanced
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