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Journal of Cancer Therapy, 2011, 2, 548-556
doi:10.4236/jct.2011.24075 Published Online October 2011 (http://www.SciRP.org/journal/jct)
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of
Prostate Cancer
András Kovács1, Imre Guller1, Krisztina Krempels2, Ildikó Somlyai2, István Jánosi3, Zoltán Gyöngyi4,
István Szabó4, István Ember4, Gábor Somlyai2*
1Saint John’s Hospital, Budapest, Hungary; 2HYD LLC. for Cancer Research and Drug Development, Budapest, Hungary; 3Planimeter
Ltd., Budapest, Hungary; 4University of Pécs, Medical School, Institute of Public Health, Pécs, Hungary.
Email: ad.kovacs@mail.janoskorhaz.hu, gullerimre@yahoo.com, {krempels, isomlyai, *gsomlyai}@hyd.hu, janosi@planimeter.hu,
{zoltan.gyongyi, istvan.ember}@aok.pte.hu, bokor28@yahoo.co.uk
Received July 7th, 2011; revised August 10th, 2011; accepted August 19th, 2011.
ABSTRACT
Deuterium-depleted water (DDW) is a new promising agent in cancer therapy. The efficiency of the method is based on
the discovery, that cancer cells are extremely sensitive to depletion of deuterium (D) and might cause necrosis of the
tumour. The purpose of this study was to show the efficacy of D-depletion in prostate cancer (PC) patients. In the dou-
ble blind, four-month-long, randomized Phase II clinical trial the daily water intake was replaced with DDW in 22 PC
patients. Other 22 PC patients took normal water while both groups received the same forms of conventional treatment.
In the retrospective study, 91 DDW-treated PC patients were evaluated and median survival time (MST) in the sub-
groups was calculated. The time course of changes in DDW dose and PSA is presented in two cases. In the prospective
trial seven patients in the treated group and one patient in the placebo group achieved partial response (p = 0.046). In
the treated group, the net decrease in the prostate volume was three times higher (160.3 cm3 vs. 54.0 cm3; p = 0.0019),
urination complaints ceased at a higher rate (8 vs. 0 patients, p = 0.0041), and the one-year survival rate was also
higher (2 vs. 9 deaths; p = 0.034). The 91 retrospectively evaluated patients achieved an MST of 11.02 years, despite
the fact that 46 of them suffered from distant metastasis. In the two monitored patients, drop of PSA level correlated
with the DDW intake. In summary, D-depletion prolonged MST in patients with PC. The method proved to be safe thus
its integration in the PC cure as an adjuvant or complementary therapy would be considered.
Keywords: DeuteriumDepletion, DDW, Prostate Cancer, Phase II Clinical Trial, Retrospective Evaluation, Median
Survival
1. Introduction
Hydrogen has a naturally occurring stable isotope, deute-
rium (D), with a mass number of 2. It is present in sur-
face waters mainly in the form of HDO at a concentra-
tion of appr. 16.8 mmol/L. The two isotopes, hydrogen
(1H) and deuterium (2D) have the largest mass difference
among stable isotopes of the same element, resulting in
significantly different chemical and physical properties
[1-3].
Although the effect of D at an elevated concentration
in biological systems has been investigated in several
experiments [4-5], these studies ignored the significance
of natural D-concentration. The first paper, suggesting
that reduced D-concentration has an impact on living
organisms, was published in 1993 [6]. Since then, nu-
merous studies have been conducted on different cell
lines using culture media prepared with deuterium-de-
pleted water (DDW) [6-7]. The growth rate of different
cancer cell lines significantly decreased in DDW-con-
taining media in vitro. In mice xenotransplanted with
MDA-MB-231, MCF-7 human breast adenocarcinomas
or PC-3 human prostate tumors, DDW resulted in com-
plete or partial tumour regression [7-8]. The apoptosis-
triggering effect of DDW was observed both in vitro [7]
and in vivo [8]. D-depletion exerts an influence on proto-
oncogenes and tumor suppressor genes, such as c-myc,
Ha-ras and p53. Expression of these genes, induced by
carcinogen exposure, was significantly lower when the
animals received DDW as drinking water [9]. The most
striking discovery was that cancer cells proved to be ex-
tremely sensitive to D-depletion which might even cause
the necrosis of tumours, while non-cancer cells are able
to tolerate the decreasing D-concentration. This finding
Deuterium Depletion May Delay the Progression of Prostate Cancer 549
raised the possibility that DDW might be one of the
agents which can reduce the risk of cancer and acts as an
effective modality in cancer therapy [10].
Prostate cancer (PC) is placed third in cancer mortality
among men in Europe. The estimated mortality rate in
2011 is between 12.6 and 8.1/100,000 men [11]. In the
years 2001-2005 the mean deaths of prostate cancer was
1265 in Hungary [12]. PC is the most frequently screened
out malignant transformation; the incidence is 214 out of
1000 men. PC often lies behind the cases that are catego-
rized as “died from other tumour” [13,14].
Decline in PC mortality is expected through Europe
likely due to the attributable improvement in screening,
diagnosis and predominantly treatment of the disease
[11]. Treatment options for PC may have severe side
effects, therefore an optimal choice attains a balance be-
tween deteriorations in quality of life and therapeutic
benefit [15-17].
Hormonal therapy is a mainstay of treatment for pa-
tients with advanced PC [18]. The recently published
clinical trials indicate a median survival time (MST) of
15 to 21 months in patients suffering from advanced
hormone refractory PC [19-22].
In order to investigate whether DDW might exert an
anticancer effect in humans and improve the results of
conventional treatments, a four-month-long double-blind
phase II placebo controlled clinical trial was conducted
on PC patients. The primary outcome was the best re-
sponse, and the agent’s safety was also assessed. In addi-
tion, the course of the disease was retrospectively evalu-
ated in 91 DDW-treated patients.
2. Patients and Methods
DDW was produced from normal tap water using frac-
tional distillation [23] as described earlier [24].
2.1. Prospective Study
The four-month-long phase II clinical trial was con-
ducted (under the permission of the Hungarian Institute
of Pharmacology: No. 5621/40/95) in four Hungarian
trial sites in a double blind, randomized, placebo con-
trolled setting according to GCP principles. The daily
water intake of PC patients was replaced with DDW of
85 ppm D concentration (treated group), or remained
normal with 150 ppm D (placebo group). The protocol
contained no restrictive requirements with respect to the
conventional treatments. The endpoints were the best
overall response and the change in prostate size. Urina-
tion complaints, PSA value and safety were also evalu-
ated. All patients were followed after closing their files
for years, and the impact of DDW on survival was de-
termined as well. Eligible patients had histologically
confirmed primary or relapsed PC and their life expec-
tancy was longer than six months. Forty-four patients
were evaluated in the Intention-to-Treat analysis (ITT
Population), 22 patients were involved in the treated and
22 patients in the placebo group. Thirty-three patients
completed the trial in full accordance with the protocol
requirements (PP Population), 17 of them (51.5%) were
treated with the agent and 16 patients (48.5%) were tak-
ing the placebo. Here we present the evaluation of the
ITT population alone, since the analysis of the ITT and
PP population showed no substantive difference in the
outcome. There was no statistical difference between the
test groups in staging, histological diagnosis and the
conventional treatments applied, so these factors were
irrelevant in the statistical analysis.
The volume of the prostate gland was calculated with
the formula
3
π
62
ab
V
where a and b were the two diameters (cm) determined
by transrectal ultrasonography. The prostate volume at
the first visit (baseline) and the value calculated at the
last (6th) visit were compared in both groups. Urination
problems were also categorized. The PSA value at the
last visit was compared to the baseline PSA level. During
the extended follow-up, the mortality rates were com-
pared in the test groups with Fisher’s Exact test.
Adverse events were to be also reported and charac-
terized. At the time of involvement and the last visit he-
matologic values and serum chemical parameters were
measured for screening liver- and renal function accord-
ing to GLP requirements.
2.2. Retrospective Study
Ninety-one PC patients were evaluated retrospectively.
Eligible patient was who: 1) was histologically diagnosed
with PC; 2) started consuming DDW at the time of the
diagnosis or after that; 3) was taking DDW for at least 90
days in addition to the conventional forms of treatment.
Patients were provided with all the available information
regarding DDW-treatment. In this study a) D concentra-
tion of DDW was gradually decreased from 105 to 25
ppm; b) duration was longer than a year in most cases; c)
the cure was interrupted and then continued several times.
In order to gain comparable data a new rate, deuterium
depletion unit (DdU), was introduced:
150 ppm D concentration of DDW ppm
Dose DdU body weight kg
daily volume of DDW L
The time pattern of PSA changes and DDW dose was
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer
550
evaluated in detail in two patients.
The statistical analysis were performed using the SAS
statistical package. The result was considered statistically
significant at p < 0.05. The graphs were generated in R.
Survival curves were created using the method of Kaplan
and Meier.
Based on the presence or absence of distant metastasis,
homogenous groups were made up. Forty-five patients
had no metastasis. Among patients with metastasis (46
subjects) there were 32 patients who had exclusively
bone metastasis and made up two homogenous sub-
groups; 20 of them developed bone metastasis within a
year and 12 other patients later than one year after the
diagnosis of PC. Fourteen patients were not involved in
the evaluation due to the heterogeneity of metastases.
3. Results
3.1. Prospective Study
Seven patients in the treated group, and one patient in the
placebo group achieved partial response (PR) (significant
difference, p = 0.046). No change (NC) was verified in
11 patients in the treated, and in 13 patients in the pla-
cebo group (non-significant difference). Progression of
disease (PD) was diagnosed in 4 cases in the treated
group and in 8 patients of the control group. Because of
the duration of the clinical trial (only 4 months), com-
plete response (CR) was not verified in any of the pa-
tients during the study.
Prostate volume decreased in 18 out of 22 patients in
the treated arm. No change was detected in one patient
while the prostate volume increased in two subjects.
There was no available data on the prostate size in one
patient. In the placebo group, prostate size decreased in
11 patients, no change was recorded in 5 patients, and
increased prostate size was found in another 5. One pa-
tient was excluded because the decrease in prostate size
was not in connection with the improvement of the dis-
ease (the patient died after the 2nd visit). In the treated
group, the cumulated decrease of prostate size was 171.6
cm3 and the increase was 11.3 cm3, while in the placebo
group 108.1 cm3 decrease and 54.1 cm3 increase were
found. The net decrease was 160.3 cm3 in the treated, and
54 cm3 in the control group (p = 0.0019). Furthermore, in
those 7 patients who achieved PR, the prostate volume
became smaller by 125.2 cm3 in total. One patient in the
control group showing PR achieved 13.4 cm3 decrease in
prostate volume.
Urination complaints ceased in 8 patients of the treated
group, but in the placebo group none of the patients ex-
perienced changes in their complaints (p = 0.0041).
Changes in the PSA values are summarized in Table 1.
It became evident that the PSA and prostate size were
changing concomitantly in numerous cases. Cumulative
PSA showed decrease in the test groups in the four-
month-long study. The baseline value was 406.4 ng/mL
and 521 ng/mL in the treated and placebo group, respec-
tively. By the end of the trial the cumulative PSA value
decreased to 80.3 ng/mL in the treated and 277.4 ng/mL
in the placebo group.
Survival data were obtained during the three-year-long
extended follow-up: in the first year 2 patients (9.1%)
died in the treated group and 9 patients (40.9%) in the
placebo group (p = 0.034, Fisher’s exact test). After two-
year follow-up, 7 patients died in the treated, and 12 in
the placebo group, by the end of the third year the ratio
was 8:12.
3.2. Retrospective Study
The cumulative time period that elapsed from the diag-
nosis of PC till the start of DDW treatment was 142.5
years (52,003 days) in the 91 DDW-treated PC patients.
The cumulative duration of DDW treatment was 139.2
years (50,808 days), and the follow-up period from the
initial diagnosis was 350.1 years (127,800 days).
The MST was 11.02 years (4022 days), and 19 deaths
(21 %) were detected (Figure 1(a)).
The Kaplan Meier curve of the 45 patients having no
metastasis (Figure 1(b)) showed that only 4 patients (9%)
died.
Due to the extremely long survival, the data were not
suitable for calculating MST. Out of the 46 patients hav-
ing distant metastasis, the subgroup of 20 patients whose
bone metastasis was verified within one year from the
diagnosis of PC was separated. On this subgroup, we
addressed the question whether DDW extended MST;
considering the poor prognosis at this stage. During the
Table 1. Distribution of changes in PSA values during the
four-month-long clinical trial in the DDW treated and pla-
cebo group.
TEST GROUP
CHANGES IN PSA Treated
group Placebo
group Total
Marked improvement
(decrease > 50%) 15 9 24
(p = 0.089)
Mild improvement
(decrease of 10% - 50%) 1 1 2
Unchanged
(decrease or increase < 10%) 0 4 4
Mild deterioration
(increase of 10% - 50%) 0 2 2
Marked deterioration
(increase > 50%) 6 6
12
Total 22 22 44
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer
Copyright © 2011 SciRes. JCT
551
(a)
(b)
Deuterium Depletion May Delay the Progression of Prostate Cancer
552
(c)
(d)
Figure 1. (a) Kaplan Meier survival curves in the retrospectively evaluated 91 DDW-treated PC patients. Days from the di-
agnosis of prostate cancer to the end of the follow-up. MST was 11.02 years (4022 days). (b) Survival curve of the 45 DDW-
treated PC patients with no metastasis during the follow-up. Days from the diagnosis of prostate cancer to the end of the fol-
low-up. MST cannot be calculated due to the long survival. (c) Survival curve of 20 DDW-treated PC patients, who developed
bone metastasis within one year from the diagnosis of PC. Days from the diagnosis of prostate cancer to the end of the follow-
up. MST was 65.27 months (1958 days). (d) Survival curve of 12 DDW-treated patients, who developed bone metastasis later
than one year from the diagnosis. Days from the diagnosis of prostate cancer to the end of the follow-up. MST could not be
alculated because of the low number of incidences (2 deaths). c
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer
Copyright © 2011 SciRes. JCT
553
follow-up, 8 patients (40%) died. MST from the diagno-
sis of PC was 1958 days (65.27 months), with individual
values varying between 989 days (32.97 months) and
3396 days (113.2 months) (Figure 1(c)). In another sub-
group, consisting of 12 patients who developed bone
metastasis later than one year after the diagnosis of PC,
MST could not be calculated because of the low inci-
dence rate (2 deaths) and the small number of subjects
(Figure 1(d)). The remaining 14 patients were not evalu-
ated as a subgroup because of the heterogeneity, metas-
tases in different organs or other type of cancer diag-
nosed beside PC.
The time pattern of PSA changes in relation to DDW
dose is exemplified on the data of two patients. Patient 1.
started DDW at a relatively low PSA level following
prostatectomy. Patient 2. started the cure with bone me-
tastasis and highly elevated PSA level (over 1.000 ng/mL).
Patient 1. (53 years old; Figure 2(a)): Elevated PSA
(11.9 ng/mL) and no bone metastasis were present at the
time of diagnosis. The patient underwent prostatectomy
followed by antiandrogen therapy, PSA still remained
elevated (6 ng/mL). DDW treatment resulted in a de-
crease in PSA level. The patient repeated 12 - 16 weeks
long DDW cures with interruptions of 8 weeks, whereby
DDW dose was increased gradually during each cure but
the DdU value was kept steady close to 1.0 which was
sufficient to keep PSA close to 0.0 ng/mL. Four years
later progression was detected therefore the DDW dose
was increased up to 1.45 DdU that resulted in regression
again. Five years after the initial diagnosis, PSA level is
still steady below 1.0 ng/mL.
Patient 2. (61 years old; Figure 2(b)): Bone metastasis
was confirmed at the diagnosis of PC; PSA level was
over 1.000 ng/mL at that time. The conventional treat-
ment plus DDW―the latter was initiated 21 months after
the diagnosis―resulted in a striking decrease in PSA.
The patient interrupted DDW consumption for six months
that resulted in a slight increase of PSA. Then, the re-
peated cures with DDW resulted in a decrease of PSA
again and the low level remained steady for years. De-
spite the potentially poor initial prognosis, the patient
remained in regression for 7.5 years.
3.3. Safety of DDW Treatment
During the prospective trial, 16 adverse events were re-
ported in 9 patients: three of them received the agent and
six patients belonged to the placebo group. In a single
case the detected symptoms (i.e. nausea, fatigue and
weakness) were classified as treatment-related, in the
other patients no causality was provable. In the treated
group there was no significant change in the examined
laboratory parameters.
During the 17-year-long history of the DDW treated
PC patients, there were absolutely no adverse events re-
lated to DDW, apart from the concomitant phenomena of
the healing process such as general weakness, despon-
dency, drowsiness, flush, occasional high temperature,
temporary increase of pain, alleviation and cessation of
pain, and warming of the affected area. Those patients
who started to use DDW in remission did not experience
the above symptoms. There was no significant change in
blood count even if the patient had taken high dose of
DDW during the years.
4. Discussion
Application of DDW is a new opportunity in cancer
therapy. Growing evidence suggests that D-depletion
might play a role both in treatment and prevention of
cancer. In vitro and in vivo experiments confirmed the
inhibition of proliferation of cancer cells [25] and the
possible cancer preventive effect [26]. Numerous other
experiments, including the study had been conducted on
mice xenotransplanted with PC-3 cells, proved the anti-
cancer effect of D-depletion induced by the application
of DDW [8]. Because of the novelty of this research area
there are still a limited number of publications concern-
ing D-depletion and first of all the human clinical appli-
cation of DDW. In 2008 a case series of four lung cancer
patients have been published [24]. The present study is
the first evaluation of the effects of D-depletion in hu-
mans that was conducted on a substantially higher popu-
lation of cancer patients. A human phase II clinical trial
was launched to evaluate the possible anticancer effect of
DDW in humans. Forty-four patients—a homogenous
groups with respect to staging and the applied conven-
tional forms of treatment—were evaluated in the treated
and the placebo group. The only (non-significant) dif-
ference was that anaplastic adenocarcinoma was diag-
nosed in a single patient in the treated, and in four pa-
tients in the placebo group and therefore the final out-
come of the trial could have been slightly altered. While
the four patients in the control group, expectedly, did not
show any improvement, the patient in the treated group
with anaplastic adenocarcinoma achieved PR. These data
suggest that D-depletion might be effective even in those
cases where histological diagnosis predicts poor progno-
sis. The distribution of the best response (PR) to treat-
ments differed significantly after four-month-long DDW
or placebo treatment in the test groups (7 subjects vs. 1
subject).
The three times higher net decrease in prostate volume
in the DDW treated group explains why the urination
complaints ceased at a significantly higher rate (8 pa-
tients vs. 0 patients, p = 0.0041) in the treated group.
urthermore, this was in line with the fact that 15 out of F
Deuterium Depletion May Delay the Progression of Prostate Cancer
554
(a)
(b)
Figure 2. a-b The time course of DDW dose (DdU) and PSA levels (ng/mL) in two patients. The Y axis shows the DDW dose
(right side) and the PSA value (left side). The pecked line depicts the timeline of PSA values, while the solid line represents
the DDW dose. Notes: DdU = deuterium depletion unit, that was calculated considering the difference in D-concentration
between plain tap water and the DDW used, the daily volume of the DDW, and body weight. (a) Patient 1: Five-years follow
up of a 53 years old PC patient, who underwent prostatectomy followed by antiandrogen therapy. Further decrease in PSA
was achieved, when DDW treatment was introduced. Repeated, 12 - 16 weeks long DDW cures kept PSA close to 0.0 ng/mL,
and after the detection of an increase in PSA value the higher DDW dose ensured further reduction of PSA again. (b) Patient
2: Follow-up of a 61 years old PC patient with bone metastasis and highly elevated PSA (1000 ng/mL). DDW treatment was
introduced in addition to the conventional forms of treatment. Despite the potentially poor prognosis the patient remained in
regression for 7.5 years.
22 patients showed over 50% decrease in PSA level in
the treated group while in the placebo group only 9 pa-
tients showed such result. All these results clarify the
impressive difference in the death rate in the two groups
(2:9, treated vs. placebo group) within the first year.
In addition to the prospective study, we had the possi-
Copyright © 2011 SciRes. JCT
Deuterium Depletion May Delay the Progression of Prostate Cancer 555
bility to follow 91 PC patients after the diagnosis for a
cumulative time of 350 years. Patients without distant
metastasis showed extremely low death rate during the
cumulative follow-up period of 157 years (Figure 1(b)).
In patients who suffered from early developing distant
metastasis, D-depletion was able to extend MST to 64.8
months (Figure 1(c)), while other studies indicated a 15 -
20 month-long MST for progressive metastatic PC [22].
Considering also the MST in all prostate cancer patients
that was published in the Hungarian National Cancer
Registry [27] we suggest that D-depletion contributed to
the long overall MST of 11 years calculated in the pre-
sent study (Figure 1(a)).
Examining the PSA values in certain patients’ causal-
ity was observed between DDW cures and the time pat-
tern of PSA-changes (Figures 2(a) and (b)). DDW-con-
sumption could also prolong the progression-free interval
in the early stages of PC.
Based upon the preclinical toxicological investigations
[28], the prospective and retrospective clinical studies,
the application of DDW at a concentration of 25 to 105
ppm D seems to be completely innocuous, and can act as
a highly effective tool in cancer therapy which can be
easily integrated in the treatment regimens. Consequently,
the application of DDW in the most affected population
might reduce the mortality of PC, since it is able to delay
progression as well as to prolong MST in patients with
histologically confirmed PC.
5. Acknowledgements
The authors wish to acknowledge the valuable contribu-
tion of the following clinicians: Gábor Árpási, Béla Böc-
skei, Gábor Csúsz, Tibor Kázmér, Jorgosz Szapanidisz
(St. Johns Hospital, Budapest, Hungary); Dénes Répássy
(St. István Hospital, Budapest, Hungary); Barnabás Rusz-
inkó, György Sára (Uzsoki Hospital, Budapest, Hungary).
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