1. BACKGROUND AND RATIONALE
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. But there are only isolated reports with CSAP using for palliation
of stage D prostate cancer. 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. Many investigators 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. 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 (IL-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.
Therefore, 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.
A novel "biochemotherapy" approach includes a combination
of standard chemotherapy regimens and biological agents appear to
work well together when given simultaneously to patients with several
different types of cancer. As it is known, IL-1 is as main cytokine
vital to the proliferation and maturation of whole immune cascade,
with a wide range of biological activities related to host response
to infectious, immunological, antinflamatori stimuli. Previously
it has been reported that recombinant human interleukin 1 (rHu IL-1)
shows antitumor activity against syngenic tumors in mice.
Antitumor drugs are considered to be cytotoxic and probably inhibit
tumor growth through their direct activation against the tumor cells.
On the other hand, IL-1 is a cytokine with multiple antitumor mechanisms,
i.e. the enhancement of cytotoxic activity of monocytes, of natural
killer cells, and of cytotoxic T-lymphocytes, the production of
lymphokines such as interleukin 2 and gamma-interferon, which have
been demonstrated to have antitumor activity, and the direct cytotoxic
action against some tumor cells. It is uncertain which mechanisms
are important for the antitumor action of IL-1, although there is
some evidence showing that the action of IL-1 appears through the
induction of cytotoxic T-lymphocytes and its adjuvant activity potentiating
antitumor immunity. But Nakamura S. et al. (1991) demonstrated that
rHu Il-1 alone are not sufficient for curing of tumors even at high
doses but optimal combinations of the frequently bring about complete
cure of tumors.
Moreover, in an inflammatory response, such as that initiated by
cryonecrosis, the target tissue will be subjected to the action
of not just only rHu 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.
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 regimens incorporating combinations
of these drugs currently are the mainstay of therapy, and can often
achieve substantial reductions in tumor burden and prolongation
Most notable are the estramustine phosphate (EMP or "Estracyt"
by Pharmacia&Upjohn) combinations, which combine microtubule
inhibitors with different mechanisms to achieve superadditive or
synergistic effects. EMPis estradiol attached to nitrogen mustard
via a carbamate ester linkage. This linkage is a very stable, and
its antineoplastic activity is predominantly attributable to its
two main metabolites, estramustine and estromustine. Their cytotoxic
effects are exerted through binding to microtubule-associated proteins,
and this produces microtubule disruption and prevents microtubule
assembly during metaphase. Recently phase II trials yielded an average
overall response rate of EMP-monotherapy up to 37% in over 600 men
with hormon-unresponsive prostate cancer (Benson R. et al., 1990).
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 hormonal therapy.
Many of these agents are themself highly immunosuppressive.
With recognition that EMP was a microtubule inhibitor, it was theorized
that its combination with matural IL-1with different sites of action
might result in an additive or synergistic antitumor effect. Our
pilot-study results have demonstrated that in the setting of cryoimmunnotherapy
by rHu IL-1b with basic adjuvant therapy by estracyt resulting in
a combined efficacy that exceeds either modality. Additionally,
we have noted the protective action of rHu IL-1b to the whole cascade
of humoral and cellular immunity to possible side-effects of basic
palliative therapy- significantly myelosuppression and other adverse
effects of estracyt, allowing to increase its doses up to maximum
During last year we have been treating six prostate cancer patients
with stage D2 under this protocol of cryoimmunotherapy. In 3 cases
we have investigated the clinical remission of metastatic lesions,
biochemical significant failure of PSA (from 83 to 125 ng/ml initially
to 15 - 45 consequently), improvement of quality of life, indirect
features of increasing of tumor-specific immunity (increasing of
quantitative parameters of antigen activation- CD25, HLA-2, total
lymphocytes, cytotoxic lymphocytes and natural killers; enhancing
of functional activity of lymphocytes, stimulation of IL-2, IL-8
etc.). It was a very important event to support this specific immune
response not by means of consequential cryotherapy, but the repeated
immunotherapy by rHuIL-1-b. In 1 case we have reached the partial
immune response with regression of some metastases from inner organs
(not osteolytic origin).
In 1 case with terminal stage of D2 patient was died due to the
polyorgan failure as the result of the toxic complications of the
intensive scheme of chemotherapy.
The purpose of this study is to use the combination of CSAP with
cytokinotherapy by IL-1b as more guided and accordingly more effective
approach to treat patients with metastatic (stage D2) prostate cancer.
There will be attempt to eradicate the prostate cancer or treat
any metastases or other symptoms arising from this disease.
These objectives of the trial are to determinate the safety and
efficacy of cryoimmunotherapy in patients as measured by:
2.1. Time to treatment failure
2.2. Time to progression
2.3. Time to survival
2.4. Quality of life
3. STUDY DESIGN
The study is designed to treat 24 patients with D2 prostate cancer..
In other randomized group including 16 similar patients we plan
to use the conventional cytoreductive CSAP without immunotherapy
as palliative treatment, solely as attempt to eliminate or cease
the local symptoms (persistent bleeding from prostatic urethra or
locally referrable pain notcontrolled by analgetics) and make the
patient more comfortable.
4. SUBJECT POPULATION
Patients will be included in this study if they meet the following
4.1.Biopsy proven prostate cancer
4.2.Positive bone scan, chest x-ray, abdominal/pelvic CT or MRI
4.3.Local voiding problems, bleeding, rectal obstructive problems
or perineal/pelvic pain
4.4. Ability to grant informed consent
Patients will be excluded from this study if they have any inherent
non- correctable bleeding problems.
The treatment design may be started using EMP 600mg/m2 intravenously
daily weeks 1-4 and 6-10 with consequent changing to enteral treatment
(orally) of similar dose day 1-42, cycles repeated every 56 days.
The regime of proposed immunotherapy may be as follow: rHu 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
Then CSAP will be performed utilising the Spembly Cryosurgical Systems
(LCS 3000, manufactured by Candela ,Inc.) with a standard five probe
of single freeze technique.
This procedure is carried out as a minimal invasive cytoreductive
surgery without cystostomy, using the 'home-made' urethral warmer
similar to that described by Cohen and Miller, consisting of a double
lumen urethral catheter attached to a pump that recirculates warmed
saline (approximately 43C). Then we are leaving a Foley catheter
in the urethra for 3 weeks after cryosurgery.
Based on the changes of local and systemic
immunity rates, repeated systemic IL- 1b courses may be needed of
every 1--3 months after cryoablation. Additionally for enhancement
of tumor destruction, we have proposed to inject IL-1b (up to 10
ng) into tumor just at the end of CSAP, i.e. after complete thawing
of prostate tissue. An evaluation of this new therapeutic approach
against advanced prostate carcinoma will be conducted with routine
clinical evaluation (physical examination, sexual story, laboratory
findings, urodynamic pressure-flow studies) as well as stated markers
of tumor progression- bone scan, chest X-ray, lymphscintigraphy,
prostate-specific antigen (PSA), acid and alkaline phosphatase,
CT or MRI, prostate biopsy. Also 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.).
5. ASSESSMENT OF TUMOR RESPONSE
5.1. Specific tests for assessing response will be the digital rectal
examination, serum PSA, TRUS, repeat bone scan, acid phosphatase
and prostate biopsy.
5.2. Complete objective response: remission of metastatic lesions
and no new lesions, no progression of residual cancer (controlled
local tumor) as demonstrated by reduction of serum PSA more than
50% , constant local tumor as assessed by digital rectal examination.
Persistent tumor may be observed on biopsy, but often with the evidance
of "downstaging" and "downgrading".
5.3. Partial objective response: reduction of serum PSA by at least
75% without trend to local control but with partial regression of
inner organs metastases and and stable systemic disease.
5.4. Treatment failure: less than 50% reduction in serum PSA, uncontrolled
local tumor growh and instable systemic disease.
5.5. Disease progression: rise in serum PSA by more than 25%, systemic
progression of tumor with new distant metastatic lesions. These
patients are taken off study and may be offered alternative palliative
6. ANALYSIS OF RESULTS
PSA values will be analyzed by using a repeated measures analysis
of variance with Greenhouse-Geisser corrections and post-hoc comparisons.
The patients' survival data will be expressed as a percentage of
patients surviving from one month to two years.
In addition, survival curves will be generated using the Kaplan-Meier
Patients will also be divided into groups based on the above assessment
of tumor categories. Analyses between groups will use the generalized
Wilcoxon test of Gehan and log-rank test. Survival and success rates
from this study will be compared with historical populations consisting
of patients who have undergone more traditional treatments (maximal
hormonal blocade, different design of chemotherapy etc.).
7. TESTING SCHEDULE