EuropeanUrology European Urology 47 (2005) 449–455

Support Ellagic AcidTherapy in Patientswith HormoneRefractory Prostate Cancer (HRPC) on StandardChemotherapy UsingVinorelbine and EstramustinePhosphateMario Falsaperlaa, Giuseppe Morgiab, Alfredo Tartaronec,*, Raffaele Arditoc,Giampiero Romanoc

aOperative Unit of Urology, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Potenza, ItalybDepartment of Urology, University of Sassari, ItalycOperative Unit of Medical Oncology, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Potenza, Italy

Accepted 1 December 2004

Available online 18 December 2004

AbstractBackground: Recent phase III studies in hormone refractory prostate cancer (HRPC) showed an improvement interms of overall survival (OS), objective response (OR) and biochemical response (BR); however, chemotherapy isusually accompanied by negative side effects that determines poor quality of life (QoL) and only marginallyimproves individual clinical response (ICR) in terms of pain relief and performance status.

Ellagic acid is a polyphenol that is found in many species of flowering plants. It is an antioxidant that determinesapoptosis, down regulation of IGF-II, activates p21 (waf1/Cip1), mediates the cumulative effect on G1/S transitionphase and prevents destruction of p-53 gene by cancer cells.Endpoints: The aim of this study was to assess the effects of ellagic acid support therapy on toxicity, OR, ICR andBR in HRPC patients treated with estramustine phosphate and vinorelbine.Materials and Methods: Patients with HRPC were randomly distributed in two study groups: a control group (groupA) who underwent chemotherapy with vinorelbine and estramustine phosphate, and an experimental group (groupB) where chemotherapy regimen was associated with ellagic acid.Results: The mean number of chemotherapy cycles/patient was 4 (range 3–8 cycles) and 6.5 (range 5–11) in group Aand B patients, respectively. A reduction in systemic toxicity, statistically significant for neutropenia, associatedwith better results in term of OR rate, ICR, and BR were observed in group B compared with group A. On thecontrary no significant difference in OS and PFS was detected between groups.Conclusions: our study suggests that the use of ellagic acid as support therapy reduces chemotherapy inducedtoxicity, in particular neutropenia, in HRCP patients; however, further studies are required to confirm our results.# 2004 Elsevier B.V. All rights reserved.

Keywords: Ellagic acid; Hormone refractory prostate cancer (HRPC); Chemotherapy; Estramustine phosphate;Vinorelbine

* Corresponding author. Tel. +39 0972 726278; Fax: +39 0972 723509.

E-mail addresses: mayurol@yahoo.it (M. Falsaperla),

tarta1@virgilio.it (A. Tartarone).

0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved

doi:10.1016/j.eururo.2004.12.001

1. Introduction

Metastatic prostate cancer becomes hormonerefractory within a median time interval of 18–24months from diagnosis even if treated with androgen

.

M. Falsaperla et al. / European Urology 47 (2005) 449–455450

deprivation [1]. Treatment of this stage of tumor ispalliative and include symptomatic care with narcoticalanalgesics, radiotherapy and cytotoxic chemotherapy(estramustine phosphate, docetaxel, vinblastine, vinor-elbine, mitoxantrone, etoposide, etc.) [2]. Chemother-apy can reduce serum PSA levels in patients withHRPC and relieves pain in some patients, but toler-ability is of concern. Furthermore, the data reported inthe multivarious mono or associated chemotherapeuticschedules have revealed conflicting results in terms ofOR (between 19% and 71%) [3]. Other clinical find-ings on chemotherapeutic efficacy revealed medianOS between 10 and 21 months, palliative symptomresponse rate in only 43% to 53% of subjects, andreduced PSA (>50%) in 35% to 69% of treatedpatients. All these parameters were poor in terms ofoverall results [4]. Recently, two completed phase IIIstudies demonstrated a survival benefit for a fixednumber of cycles of docetaxel-containing chemother-apy of HRCP [5,6]. In the Petrylac et al. study 674HRCP patients were randomized to receive docetaxelplus estramustine vs. mitoxantrone plus prednisone;the authors reported an improvement in median survi-val of nearly two months in the first arm of patients [5].Tannock et al. have reported an improvement in termsof overall survival, pain control, quality of life andserum PSA level in HRPC patients treated with doc-etaxel plus prednisone compared to patients treatedwith mitoxantrone plus prednisone [6]. Many interest-ing clinical trials have used specific experimental noncytoxic agents aimed at essential molecular targets andpotentially possessing major biological action andminor toxicity (cell differentiation inducers, growthfactor inhibitors, antimetastatic agents, immunothera-peutic drugs, antisense oligonucleotids, gene therapy)[7,8], even if to date their therapeutic result is not clear.Scheduled cytotoxic protocols can be flanked by sup-port therapy using substances that seem to limit che-motherapy induced damage and enhance apoptoticmechanisms. Ellagic acid, a naturally occurring poly-phenol constituent possessing antioxidant properties, isone of the most interesting compounds amongst thenumerous natural substances possessing proapoptoticaction that have been experimentally investigated invitro and in vivo [9,10]. This compound is present ashydrolized tannin called ellagic tannin in at least 46different flowered plants (Fagaria xanassa Duch.,Rubus species, Rubus L. subgenus, Rubus eubatus,Punica Granatum, etc.). Ellagic tannins are glucoseesters with hexahydrolxydiphenic acid that, oncehydrolyzed, release ellagic acid as active principle.This dilactone is promptly absorbed by the humanintestinal tract and made bioavailable, but whose free

form is degraded by gastric acidity [11,12]. Ellagicacid is an effective antimutagen and anticarcinogenphytotherapeutic agent that prevents carcinogens bind-ing to DNA and strengthens connective tissue and thusmay keep cancer cells from spreading, inhibits canceronset and tumor proliferation and protects healthy cellsduring radiation therapy and chemotherapy [13–15].This mechanism is partly induced by stimulating var-ious gluthatione-S-transferase isoforms involved incytodetoxifying processes, free radical scavengeraction and inhibition of correlated lipoperoxidativedamage [16–25].

Aim of this study is to assess the cytoprotectiveeffects of ellagic acid, a powerful proapoptotic andantioxidating polyphenol, in patients with HRPC whounderwent combined chemotherapy with vinorelbine[26,27] and estramustine phosphate [28,29]. The clin-ical trial was conducted to evaluate toxicity, clinicalresponse and QoL in patients undergoing chemother-apy plus ellacic acid versus patients undergoing che-motherapy alone.

2. Material andmethods

From January 1999 until May 2002, 48 consecutive patients

(median age 66.5 years, range 58–71) with hormone refractory

prostate cancer, chemotherapy-naı̈ve, were recruited. Inclusion

criteria were: Karnofsky performance status score (KPSS) �70;

pain visual analogic-numeric scale (PVA-NS) �6; pain index (PI,

analgesics/day) �5; normal bone marrow functions (neutrophils

�1500/ml, platelets �100,000/ml, hemoglobin �10 g/dl), renal

(creatinine �1.4 mg/dl) and liver functions (bilirubin <1.1 mg/dl,

ALT and AST <34 U/L). The entire study cohort gave informed

consent and was randomly divided into two groups (A and B) of 24

patients. Group A received only chemotherapy treatment with

vinorelbine (25 mg/mq, weekly, for 6 weeks) and estramustine

(280 mg, thrice daily, for 42 days), whereas group B also received

support ellagic acid treatment. Each chemotherapy cycle was

repeated at 28 day intervals depending on patients’ blood and

functional parameters.

The instrumental examinations revealed single bone metastases

in 12 patients and multiple metastases in 16 (group A) and 20

(group B), while spread was observed in the local regional lymph

nodes and liver in 16 and 14 patients, respectively. Eighteen of the

48 patients were previously treated with external beam radio-

therapy or radiometabolic therapy with metastron, while 8 patients

were treated with biphosphonates (pamidronate or zoledronic acid)

for pain relief. The hormone refractory stage was defined by the

presence of two dimensionally detectable metastases identified by

computed tomography (CT), bone scan and chest X-ray accom-

panied by progressive increase in serum PSA concentrations (50%–

90% above baseline values) determined in three successive blood

samples taken at 30 day intervals, during ormonotherapy. Periph-

eral antiandrogenics (flutamide or cyproterone acetate) were sus-

pended in all patients who had been treated with maximal

androgenic blockade (MAB) up to development of HRPC and

bicalutamide treatment (150 mg) administered when no serum PSA

M. Falsaperla et al. / European Urology 47 (2005) 449–455 451

Table1Main patient’s characteristics

Clinical parameters Group A Group B

No. patients 24 24

Median age 66 67

Age range 63–71 58–70

Range PSA (pretreatment) 33.5–62.8 42.2–71.5

Median PSA (pretreatment) 42.7 50.1

KPSS (pretreatment) No. pts No. pts

90 4 4

80 12 10

70 8 10

PVA No. pts No. pts

3–4 8 6

4–5 10 12

5–6 6 6

Pain Index (pretreatment) No. pts No. pts

2 6 6

3 10 8

4 6 6

5 2 4

Bone metastases No. pts No. pts

Single 6 6

Multiple 16 20

Soft tissue metastases No. pts No. pts

Lymph nodes 8 10

Liver 8 4

Previous radiotherapy No. pts No. pts

External beam RT 6 4

Radiometabolic therapy 4 4

Biphosphonate therapy 4 4

response was observed. This treatment achieved a short-lived,

relatively efficacious action. LH-RH antagonist treatment was

continued in order to block proliferation of tumor hormone respon-

sive components.

Ellagic acid was HPLC extracted from Punica granatum seeds

in the laboratory and underwent spectrophotometric analysis

(254 nm) [30,31]. Each capsule contains 30 mg of active principle

in the form of ellagic tannis obtained from 75 mg concentrated

extract of standardized seeds at 40%. After reviewing the literature,

a daily dose of 180 mg (60 g/every 8 h) active principle was

selected and administered orally before meals with water (200–

250 ml) throughout the chemotherapy cycles and during the period

between cycles.

Laboratory tests were performed weekly to determine blood

count, glycemia, creatinine, nitrogen, Na+, K+, Cl�, ALT, AST,

bilirubin, gamma-GT and amylasemia values. ICR were also

determined at four weekly intervals by calculating changes in

PVA-NS, PI (Pain Index), KPSS throughout treatment and for

12 weeks after suspension of treatment in agreement with standard

criteria [32]. Complete response was achieved when physical

examination and imaging revealed disappearance of clinical signs

of the disease and/or serum PSA concentrations <4 ng/ml in two

consecutive blood tests for at least 6 weeks. Partial response was

defined as a 50% decrease in the above-mentioned values compared

with pretreatment values. Clinical responses were assessed every

month by physical examination and serum PSA concentrations, and

by CT, bone scintigraphy and chest X-ray at three monthly intervals

until 9 to 12 weeks after suspension of treatment. Median oncologic

follow up was 20 months in group A (range 14 to 24 months) and 25

months in group B (range 18 to 29 months). Main patient’s

characteristics were shown in Table 1.

A ‘‘Simon optimal two-stage design’’ has been used for both

arms (45% response target and 25% response undesiderable, with

a = 0.05 and b = 0.10; p0 = 0.20 and p1 = 0.45) [32]. PI, KPSS,

were compared by means of the Cochran-Mantel-Haenszel test.

The general x2-test was used to compare rates of response (objec-

tive and PSA) and adverse event between the two treatment groups.

The probability of OS and PFS was determined by the Kaplan–

Meier method.

Table 2Main toxicities in group A and B

Toxicities Grade 1–2 Grade 3–4

Group A Group B Group A Group B

Neutropenia 18 (74.9%) 8 (33.3%)* 0 0

Anemia 14 (58.3%) 12 (49.9%) 8 (33.3%) 0

Nausea 10 (41.6%) 8 (33.3%) 0 0

Anorexia 12 (49.9%) 4 (16.6%) 6 (24.9) 0

Constipation 8 (33.3%) 8 (33.3%) 0 0

Diarrea 6 (24.9%) 4 (16.6%) 0 0

Ipertransaminase 8 (33.3%) 0 0 0

Iperbilirubine 8 (33.3%) 2 0 0

Neuropathy 4 (16.6%) 0 0 0

* p < 0.05.

3. Results

Median number of chemotherapy cycles per patientwas 4 (range 3–8) in group A and 6.5 (range 5–11) ingroup B, showing increased tolerance in the group B onellagic support therapy. Chemotherapy was suspendedbecause of major hemopoietic and/or liver-renal defi-ciency, poor patient compliance, onset of side effectsaggravating QoL, or in cases of non-responder tumors.

There were no drop outs for immediate and/or severesystemic toxicity (Table 2). A reduction in systemictoxicity, statistically significant for neutropenia wasobserved in group B (p > 0.05). No statistically differ-ences regarding other toxicities were registered in twogroups, even if in group B a lower incidence of hema-tological and gastrointestinal toxicities was found.

In the group B an improved ICR was observed; infact, the mean PVA-NS score was lower (10–30%) than

pretreatment score in 16 patients (66.6%) and stabi-lized (mean decrease <10%) in 8 (33.3%). WhereasPVA-NS score decreased only in 10 (41.6%) group Apatients and stabilized in 14 (58.3%). Pain index didnot increase in any group B patients, stabilized (<10%reduction) in the 6 patients, reduced (10%–30%) in 18patients (74.9%). On the contrary, mean PI score ingroup A decreased progressively in 10 patients

M. Falsaperla et al. / European Urology 47 (2005) 449–455452

Table 3Clinical and biochemical response, PSA, PVA-NS, PI, KPSS pre- and post-

therapy in group A and B

Clinical parameters Group A Group B

No. (%) pts No. (%) pts

PSA reduction (>75%) 8 (33.3%) 14 (58.3%)

PSA reduction (20–75%) 4 (16.6%) 6 (24.9%)

PSA stabilized 6 (24.9%) 2 (8.3%)

PSA increased 6 (24.9%) 2 (8.3%)

Complete response 0 6 (24.9%)

Partial response 6 (24.9%) 8 (33.3%)

Stable disease 10 (41.6%) 6 (24.9)

Progressive disease 8 (33.3%) 4 (16.6%)

PVA-NS 10–30% reduction 10 (41.6%) 16 (66.6%)

PVA-NS unchanged 14 (58.3%) 8 (33.3%)

Pain Index increase 6 (24.9%) 0

Pain Index decrease 10 (41.6%) 18 (74.9%)

Pain Index no change 8 (33.3%) 6 (24.9%)

KPSS increase 10 (41.6%) 16 (66.6%)

KPSS decrease 4 (16.6%) 0

KPSS no change 10 (41.6%) 8 (33.3%)

(41.6%), stabilized in 8 (33.3%) and increased, by 10%to 30%, in the remaining 6 patients (24.9%).

KPSS followed the same pattern in the two studygroups and showed the best results in group B wherethe mean score increased (10%–20%) in 16 patients(66.6%) and stabilized in 8 (33.3%). In group A meanKPSS score improved in 10 patients (41.6%), stabi-lized in 10 (41.6%) and decreased in 4 (16.6%).However these positive results in terms of ICR notachieve statistically significant differences betweentwo groups.

A trend in favor of serum PSA reduction wasobserved in Ellagic acid support therapy group. Infact, in group A serum PSA values decreased signifi-cantly (�75%) in 8 patients (33.3%), were slightlyreduced (�20%) in 4 (16.6%), stabilized (increase/decrease �10%) in 6 patients (24.9%), while itincreased (�20%) in 6 patients (24.9%). In group B,serum PSA concentrations markedly declined (�75%)in 14 patients (58.3%), reduced slightly (�20%)in 6 (24.9%), stabilized (increase/decrease �10%)in 2 (8.3%) (increase/decrease �10%) and rapidlyincreased (�20%) in 2. Median duration of humoralresponse in terms of reduced serum PSA concentra-tions was 20 weeks (range 9–26 weeks) in group A and27 weeks in group B (18–39 weeks).

Complete response was achieved in 6 group Bpatients (24.9%) but not in any group A ones; PRwas observed in 6 (24.9%) and 8 (33.3%) group A andB patients, respectively, spread stabilized in 10(41.6%) group A and 6 (24.9%) group B patients,and cancer progressed in 8 (33.3%) group A and 4(16.6%) group B patient (Table 3). According toKaplan-Meier analysis, the median progression-freesurvival in group A was 4.55 months, while in thegroup B was 5.85 months (Fig. 1). At median followup of 24 months (range 18–29 months), 14 pts (58.3%)were alive in group A and 18 pts (74.9) in group B.These differences not achieved statistical significance,probably due to the limited number of patientsenrolled in two arms.

Fig. 1. A Kaplan–Meier graph showing progression-free survival in group

A (median 4.55 months) and group B (median 5.85 months); (p = 0.2).

4. Discussion

Ellagic acid is one of the most interesting substanceswith proapoptotic and antioxidant action that deter-mines apoptosis, down regulation of IGF-II, activatesp21 (waf1/Cip1) a cyclin-dependent kinase inhibitorable to arrest the cell cycle at the G1, and preventsdestruction of p-53 gene by cancer cells [13–25]. TheFlorida State University confirmed the above men-tioned data and revealed additional information on

ellagic acid’s mechanism of action, specifying that itacts as a scavenger and binds or chemically engagescancer-causing chemicals or cytotoxic substances,making them inactive. Moreover, it has been reportedthat ellagic acid inhibits cancerogenes interacting withDNA, thus reducing the incidence of carcinoma inhuman cells exposed to mutagenic substances[19,20]. The Evaluation of Ellagic Acid Content ofOhio Berries Final Report published by Ohio StateUniversity confirmed ellagic acid’s anticancerogenic,antimutagenic and cytoprotective activities in humans:they observed that this acid formed adducts with DNAand so masked the binding site to be occupied by themutagen or carcinogen. However, ellagic acid may notonly protect healthy cells and reduce cancer and cyto-toxic induced chromosome damage, but it may also

M. Falsaperla et al. / European Urology 47 (2005) 449–455 453

enhance the apoptotic mechanism normally inhibitedin cancer cells [21]. Activation of cancer apoptosis hasbeen widely demonstrated by in vivo and in vitrobiochemical tests using ellagic acid carried out bythe Hollings Cancer Institute (Medical University ofSouth Carolina). A multistep process inducing pro-grammed death in cancer cells has been observedand this process inhibits the mitotic phase and blocksthe cells in G1/S transition phase, prevents genep53 destruction by cancer cells, determins IGF-IIdown-regulation, activats gene p21 (wafl/Cip1) andenhances NK cell mediated antitumoral immuneresponse [22–25].

Our study results revealed that ellagic acid supporttherapy in association with vinorelbine and estramus-tine phosphate in patients with HRPC reduces che-motherapy toxicity, in particular neutropenia, and thusimproves treatment tolerance. These results agree withexperimental data sreported in the literature showingthe detoxifying cytoprotective and antiproliferative

proapopotic action of ellagic acid. Moreover, the lowerintra treatment and post treatment PVA-NS and PIscores observed in patients on ellagic support therapycompared with the control group, even if not statisti-cally significant, seemed to indicate cancer pain relief.These positive results were flanked by an improvedKPSS.

Ellagic acid support therapy may possess cytopro-tective, anticytotoxic and pain relief actions, and itsantioxidant action may lead to anticancerogenic action,as shown by the decreased serum PSA concentrationsin group B compared with controls.

Finally, the group with ellagic support therapy pre-sents a positive trend in terms of OR and OS.

In conclusion, our study suggests that the use ofnatural polyfenol as support therapy reduces che-motherapy induced toxicity, in particular neutropenia,in HRCP patients; however, further studies are requiredto confirm the positive trends observed in terms ofimprovement in ICR, OR and OS.

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Editorial CommentA. Heidenreich, Cologne, Germanyaxel.heidenreich@uk-koeln.de

The authors touch a clinically very importantissue in the management of patients with metastatichormone refractory prostate cancer (HRPC) under-going systemic chemotherapy: prevention of sideeffects reducing therapeutic efficacy of the cytotoxicregime by significantly interfering with quality oflife. Since the treatment of HRPC is only palliativewithout curative intention, the therapeutic resultsof any cytotoxic regime have to be weighed againstits treatment-associated side effects as already hasbeen described by Loeb in the early 19th century.Treatment and prevention of chemotherapy-inducedside effects are especially important in HRPCpatients presenting with bone metastases in anadvanced age associated with an impaired bone mar-row reserve. In the past, several trials have addressedthe issue to reduce chemotherapy-induced sideeffects in the management of metastatic breast cancerby the use of natural substances [1,2]. The applica-tion of standardized mistletoe extracts resulted ina significant reduction of chemotherapy-inducedside effects associated with a significant improve-ment in quality of life and a significantly longeroverall survival. Based on these data, prospectivestudies in HRPC patients undergoing palliative sys-temic chemotherapy associated with a significantfrequency of grade III/IV side effects are urgentlyneeded.

In their prospective study, Tartarone et al. evaluatedthe effect of the antioxidant ellagic acid with regard tothe prevention of side effects associated with theadministration of vinorelbine in a small cohort ofpatients. The authors observed a significant reductionof neutropenia consecutively resulting in a bettertolerability of the cytotoxic regime associated withan improved response rate in terms of PSA reduc-tion >50%.

However, despite the promising data achieved, thereare several drawbacks of the study which have to beadressed:

(1) V

inorelbine is a generally well tolerated cytotoxicregime with a low frequency of grade III/IVtoxicities [3,4]. Therefore, the authors onlyobserved a significant reduction of grade I/IIneutropenia. Grade I/II neutropenia is definedby 3.0–3.9 � 109/l and by 2.0–2.9/109/l leuko-cytes. Putting this into the correct clinical context,ellagic acid was able to reduce the frequency ofclinically irrelevant side effects. It would be ofvalue to test the therapeutic efficacy in docetaxel-based therapy which appears to be the standardtreatment.

(2) T

he study cohort including 24 patients is just toosmall to draw any clinically significant conclu-sions.

(3) T

he study medication was prepared by the authors;the production process of ellagic acid is unclear.There needs to be a standardized protocoll prior toits routine clinical use.

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