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A Comparison of Lycopene and orchidectomy vs orchidectomy alone

A Comparison of Lycopene and orchidectomy vs orchidectomy alone

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05/26/2012

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2003 BJU INTERNATIONAL | 92, 375–378 | doi:10.1046/j.1464-410X.2003.04370.x
375
 LYCOPENE and ADVANCED PROSTATE CANCERM.S. ANSARI and N.P. GUPTA
A comparison of lycopene and orchidectomy vsorchidectomy alone in the management of advancedprostate cancer
M.S. ANSARI and N.P. GUPTA
Department of Urology, All India Institute of Medical Science, New Delhi, India
Accepted for publication 5 June 2003
clinical response assessed as the change inthese variables.
RESULTS
At 6 months there was a significant reductionin PSA level in both treatments, but moremarked in the OL group (mean 9.1 and26.4 ng/mL,
 
=
0.9). After 2 years thesechanges were more consistent in the OL group(mean 3.01 and 9.02 ng/mL;
< 0.001). Eleven(40%) patients in orchidectomy and 21 (78%)in the OL group had a complete PSA response(
< 0.05), with a partial response in nine(33%) and four (15%), and progression inseven (25%) and two (7%), respectively(
< 0.05). Bone scans showed that in theorchidectomy arm only four (15%) patientshad a complete response, vs eight (30%) inthe OL group (
< 0.02), with a partialresponse in 19 (70%) and 17 (63%), andprogression in four (15%) and two (7%),respectively (
< 0.02). There was a significantimprovement in peak flow rate in the OLgroup, with a mean difference of 
+
1.17 mL/s(
< 0.04). Of the 54 patients who entered thetrial, 19 (35%) died, 12 (22%) in orchidectomyand seven (13%) in OL group (
< 0.001).
CONCLUSION
Adding lycopene to orchidectomy produced amore reliable and consistent decrease inserum PSA level; it not only shrinks theprimary tumour but also diminishes thesecondary tumours, providing better relief from bone pain and lower urinary tractsymptoms, and improving survival comparedwith orchidectomy alone.
KEYWORDS
lycopene, prostate cancer, metastases,orchidectomy
OBJECTIVE
To compare the efficacy of lycopene plusorchidectomy with orchidectomy alone inthe management of advanced prostatecancer.
PATIENTS AND METHODS
Fifty-four patients with histologicallyconfirmed metastatic prostatic cancer (M1bor D2) and a performance status of 0–2(World Health Organization) were enteredinto the trial between March 2000 and June2002. The trial comprised two treatment arms,i.e. patients were randomized to orchidectomyalone or orchidectomy plus lycopene (OL),each of 27 patients. Lycopene was started onthe day of orchidectomy at 2 mg twice daily.Patients were evaluated clinically before andevery 3 months after the intervention, withmeasurements of prostate-specific antigen(PSA), a bone scan and uroflowmetry, with the
INTRODUCTION
The remarkable association between a dietrich in fruits and vegetables and the reducedrisk of several malignancies has lead to aconsideration of the role of carotenoids incancer prevention. Lycopene is one of thecarotenoids that has emerged as important inthe chemoprevention and treatment of various kinds of cancers, because of its uniqueproperties of cancer prevention andregression, besides being a potent quencherof free radicals and an immunomodulator [1–3]. There have been few interventional trials inhumans investigating the potential effect of lycopene supplementation for preventing andtreating prostate cancer. We thus conducted atrial to compare the efficacy of lycopene plusorchidectomy with orchidectomy alone in themanagement of advanced prostate cancer.
PATIENTS AND METHODS
Fifty-four patients with histologicallyconfirmed metastatic prostatic cancer (M1bor D2) and a WHO performance status of 0–2[4] were entered into a trial between March2000 and June 2002. The trial comprised twotreatment arms, with patients randomized toorchidectomy alone or orchidectomy pluslycopene (OL), each of 27 patients. Patientstreated with other methods, e.g. radiotherapy,chemotherapy or previous hormonal therapy,and with a life-expectancy of <3 months,were excluded from the study. Bonemetastasis was diagnosed by bone scan and/or X-ray. Lycopene was started on the day of orchidectomy at 2 mg twice daily. Concurrenttherapy included analgesics, antibiotics andoccasionally surgery in patients with severeobstructive features. The patients wereclinically evaluated before and every3 months after orchidectomy, by serum PSA, abone scan and uroflowmetry. Efficacy wasevaluated primarily as the changes in PSA, thefindings on bone scan and uroflowmetry. Acomplete response (CR) was defined as theserum PSA returning to normal (< 4 ng/mL)and/or a normal bone scan, and a partialresponse as a decrease in PSA level by morethan half the initial value or as a reduction inmetastatic mass by more than half of theinitial level. Progressive disease was definedas any increase over the initial PSA by 25% orthe development of any new ‘hot spot’ onbone scans. The best clinical response totreatment was assessed as changes in serumPSA level, bone scan and peak flow rate at
6 months. The changes in serum PSA levelswere assessed at 6 months initially then at2 years, while the other variables were
 
M.S. ANSARI and N.P. GUPTA
376
©
2003 BJU INTERNATIONAL
assessed at 2 years. All the patients werereviewed for a minimum follow-up of 2 years(24–28 months). The results were analysedstatistically using the Wilcoxon signed-ranktest, with overall survival calculated usingthe Kaplan-Meier method, with
< 0.05considered to indicate statistical significance.
RESULTS
The distribution of patients and diseasecharacteristics were well balanced in the twogroups; Table 1 shows the patientcharacteristics at the time of entry in to thestudy. Baseline PSA levels were comparable intwo treatment groups (Table 1). At 6 monthsthere were significant reductions in PSA levelin both arms, but it was more marked in theOL treatment, although not statisticallysignificantly (
 
=
0.9). After 2 years thechanges were more consistent in the OL group(Table 1) and were statistically significant(
< 0.001).Based on the response criteria adopted, 11patients in the orchidectomy and 21 in theOL group had a CR (
< 0.05) (Table 1); theprogression rates were significantly different(
< 0.05). The follow-up bone scans (Table 1)showed that in the orchidectomy arm onlyfour patients had a CR, compared with eightin the OL arm (
< 0.02); again theprogression rates were significantly better inthe OL group (
< 0.02). There was a linearrelationship between the response based onthe bone scan and the requirement foranalgesics. Patients with a CR in both groupsrequired no analgesics, but this was moreevident in the OL group (25% vs 15%).The baseline peak urinary flow rate wascomparable between the groups (Table 1) butdiffered after intervention. There was asignificant improvement in peak flow rate inthe OL group (
< 0.04); there was also asignificant subjective improvement in othervoiding symptoms (frequency, urgency anddysuria, 80% vs 50%) in the two groups.The mean (range) follow-up of the patientsstill alive was 25.5 (24–28) months; Fig. 1shows the duration of survival in two groups.Of the 54 patients who entered the trial, 19(35%) died, 12 (22%) in the orchidectomy andseven (13%) in the OL groups (
< 0.001). Thecauses of death were malignancy in 17 (31%)and cardiovascular in two (4%) patients (onein each arm). All the patients in the OL armtolerated the drug well and there were noadverse reactions.
DISCUSSION
About a third of patients diagnosed withprostate cancer will present with advanceddisease. Androgen ablation by castration,antiandrogens or LHRH analogues remain thestandard of care for these patients. However,responses are transient in most patients, withprogression to hormone-refractory diseasebeing inevitable over 2–3 years. Advances inmolecular and cellular biology have led to animproved understanding of prostate biologyand the characteristics of prostate cancer.Based on this improved understanding,several new approaches are being developedfor treating metastatic prostate cancer. Theserange from traditional dietary modificationsto altering the microcellular environment
TABLE 1
Patient characteristics at the time of entry, PSA changes, and the clinical response to treatment based on PSA changes and bone scans 
CharacteristicOrchidectomyOLN (%):Age group, years< 6010 (37)9 (33)> 607510 (37)11 (41)> 757 (26)7 (26)WHO performance status09 (33)10 (37)111 (41)11 (47)27 (26)6 (22)Metastatic pain at entryNone3 (11)2 (7)Mild7 (26)7 (26)Moderate6 (22)7 (26)Severe3 (11)3 (11)Intractable8 (30)8 (30) Voiding symptomsNone2 (7)2 (7)Minimal8 (30)9 (33)Moderate7 (26)7 (26)Severe10 (37)9 (33)
PSA changes at 6 and 24 months
Mean (
SD
, range), ng/mLInitial259.7 (860.5, 124500)250.7 (857.3, 154300)6 months26.4 (66.3, 0.90300)9.1 (29.7, 0.7150)24 months9.0 (7.5, 1.325)3.0 (1.9, 0.713)
Clinical response, n (%)
PSAComplete11 (40)21 (78)*Partial9 (33)4 (15)Progression7 (25)2 (7)*Bone scanComplete4 (15)8 (25)*Partial19 (70)17 (63)Progression4 (15)2 (7)*
Peak flow rate
Mean (
SD
, range), mL/sBaseline10.5 (1.29, 8.912.5)10.24 (1.55, 812.5)*After intervention11. 0 (2.6, 2. 5013.9)12.2 (2.7, 6.515. 90)
P
< 0.05; † 
P
< 0.001.
 
LYCOPENE AND ADVANCED PROSTATE CANCER
©
2003 BJU INTERNATIONAL
377
of the prostate cancer cell, and genetherapy.Among the many carotenoids lycopene hasbeen of special interest and has recentlyreceived attention because of suggestiveassociations in reducing the risk of cancer atmany sites, including breast, prostate andpancreas. Lycopene is one of the majorcarotenoids in the diet and accounts for abouthalf the carotenoids in human serum. Theanticancer action of this carotenoid canbe explained by several mechanisms; (i)inhibition of cell proliferation [2]; (ii)induction of cell differentiation andapoptosis; (iii) antioxidant, singlet-oxygenquencher and protection against oxidativeDNA damage [3–7]; (iv) potentiation of theimmune system; and (v) stimulation of gap junction communication [8]. Throughthese mechanisms lycopene controls cellproliferation and facilitates tumourregression.Epidemiological data suggest that theenvironment is responsible for most prostatecancers. One major mechanism by which theenvironment can influence carcinogenesis isoxidative damage, i.e. the generation of reactive oxygen species that act as freeradicals and damage important biomolecules,including DNA, proteins and lipids. Anantioxidant is defined as any compoundwhich breaks the free-radical reaction chain.Tomatoes are the primary dietary source of lycopene, which is one of the most potentantioxidants among the carotenoids [9–12].Many experimental studies also support theview that oxidative damage is associated withprostate cancer. There is an associationbetween prostate cancer and dietary fatconsumption (a major substrate for oxidativestress), and oxidative biomarker data suggestincreased oxidative stress among patientswith prostate cancer. There are ubiquitousdefects in the glutathione-s-transferase-
π
 pathway (a major endogenous antioxidantmechanism), and evidence that androgens (animportant promoter of prostate cancergrowth) work in part by generating reactiveoxygen species.In a recent study, Chen
et al.
[13] examinedthe effects of lycopene on oxidative DNAdamage and PSA levels in patients withlocalized prostate cancer. Thirty-two patientsconsumed tomato sauce-based pasta dishesfor the 3 weeks (30 mg of lycopene per day)before their scheduled radical prostatectomy.Serum PSA levels decreased after theintervention, from 10.9 to 8.7 ng/mL, i.e. by17.5% (
< 0.001). In a similar study, Kucuk
et al.
[14] obtained a PSA decrease of 18% afteradministering 15 mg of lycopene twice dailyfor 3 weeks, whereas it increased by 14% inthe control group (
 
=
0.25). In the presentstudy the decrease in PSA level was alsogreater in the OL group (Table 1) at 6 months.These changes were more consistent at2 years (
< 0.01). The reasons for thisconsistent and more durable decrease in PSAlevel in the OL group can be attributed tolycopene-induced protective mechanisms, e.g.possible escape from the usual hormone-independent state at 1.5–3 years,antiproliferative activity, normalization of celldifferentiation and regulation of apoptosis.Besides being an antioxidant and singletoxygen quencher, lycopene also inhibits cellproliferation, and induces cell differentiationand apoptosis [2]. Pastori
et al.
[15] reportedthat simultaneous addition of lycopene and
α
-tocopherol, at physiological concentrations(< 1 and 50
µ
mol/L, respectively) resulted instrong inhibition of prostate cancer cellproliferation of up to 90%. Kotake-Nara
et al.
 [1] assessed the effects of 15 kinds of carotenoids on the viability of three lines of human prostate cancer cells, PC-3, DU 145and LNCaP. Acyclic carotenoids such asphytofluene, zeta-carotene and lycopene, allof which are present in tomato, significantlyinhibited cell proliferation and reduced cellviability. Logically this antiproliferative andinhibitory effect should act on the primarymalignancy and metastasis, helping to reducethe gland and the secondaries. Kucuk
et al.
 [14] conducted a randomized trial of 26 menwith newly diagnosed, clinically localized(14 T1 and 12 T2) prostate cancer (15 mgof lycopene twice daily, 15 men, or nosupplementation, 11 men) for 3 weeks beforeradical prostatectomy. Eleven men in thelycopene group and two in the control grouphad no involvement of surgical margins and/or extraprostatic tissues by cancer (
 
=
0.02).Twelve men in the lycopene and five in thecontrol group had tumours of <4 mL(
 
=
0.22). This suggests that the process of malignant transformation declined and thetumour regressed. The present data also showsimilar beneficial changes on bone scans, withtwice the rate of CR (regression of bonesecondaries) in the OL than in the controlgroup. Similarly, there was greater diseaseprogression in the control group at 6 months,and a greater improvement in peak flow rateand other voiding symptoms secondary to thereduction of the malignant gland, furthersupporting the anticancer properties of lycopene. Lycopene has also shown adramatic response in hormone-resistantprostate cancer, opening a new possibletreatment for such difficult patients [16].There was a longer overall survival in the OLgroup (
< 0.01) than after orchidectomyalone, but it is too early to be sure that thesurvival benefit would be statisticallysignificant in the long-term. Appropriatelong-term randomized studies are requiredto provide further evidence to theseobservations.
REFERENCES
1
Kotake-Nara E, Kushiro M, Zhang H,Sugawara T, Miyashita K, Nagao A.
Carotenoids affect proliferation of humanprostate cancer cells.
Anticancer Res Apr 
 2002;
22
: 689–952
Djuric Z, Powell LC.
Antioxidant capacityof lycopene-containing foods.
Int J Food Sci Nutr 
2001;
52
: 143–93
Matos HR, Capelozzi VL, Gomes OF,Mascio PD, Medeiros MH.
Lycopeneinhibits DNA damage and liver necrosis in
FIG. 1.
The Kaplan-Meier curve for the duration of survival in the OL group (red line) and control (greendashed line).
369121518212427months100%90%80%70%60%50%40%30%20%10%0%
   %   p  a   t   i  e  n   t  s  a   l   i  v  e

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