Screening and treatment of localized prostate cancer

The Aging Male 2999;2:33-43

Screening and treatment of localized prostate cancer decreases mortality: first analysis of the first prospective and randomized study on prostate cancer screening Aging Male Downloaded from informahealthcare.com by University of Laval For personal use only.

F. Labrie, L. Cusan, J. Gomez, J. Levesque and B. Candas Oncology and Molecular Endocrinology Research Center, Department ofllledicine, Lava1 University and CHUL Research Center, Centre Hospitalier Universitaire de Quebec ( C H U Q ) , Quebec, Canada Key words: PROSTATE CANCER, SCREENING, LOCALIZED DISEASE, COMBINED A N D R O G E N BLOCKADE, EARLY DIAGNOSIS, EARLY TREATMENT, QUALITY O F LIFE, CANCER-SPECIFIC SURVIVAL

ABSTRACT It is believed that the only possibility o f an important decrease in deathfrom prostate cancer is the diagnosis and treatment ofthe disease at a localized stage. A s a response to this need, thepresent study was started in apopulation of 46 193 men aged 45-80 years registered in the electoral roll ofQuebec C i t y and its metropolitan area. These men were randomized between screening and no screening in a study aimed at assessing the impact ofprostate cancer screening on cancer-spec@ death. AtJirst visit, screening included measurement o f serum prostatic spec@ antigen (PSA)using 3.0 ng/ml as the upper limit of normal, and digital rectal examination. Transrectal ultrasonography o f the prostate was performed only fi PSA and/or digital rectal examination were abnormal. At follow-up visits, only PSA measured annually was used as a screening test during the recent years. T h e prostate cancer death rates

during the 8-year period o f this study were 48.7/ 100 000 and 15/ 100 000 man-years in the unscreened and screened groups, respectively, for a 3.25 odds ratio in favor ofscreening and early treatment (p < 0.01), or a 69% decrease in the incidence ofprostate cancer death. T h e present data show that screening is an eficient, reliable and acceptable technique for detecting localized prostate cancer in the general population. Coupled with treatment o f localized disease, the present approach demonstrates, for the j r s t time, that early diagnosis and treatment result in a dramatic decrease in death jiom prostate cancer. I f the current trend continues, the data suggest that, among the male population in the United States, the present approach could save 2.0 million lives o f the 3.0 million men expected to die from prostate cancer.

INTRODUCTION it is predicted that 37 800 men will die from pros-

Prostate cancer is the second cause of cancer death in men in the Western world due, largely, to late diagnosis and, consequently, late treatment. In fact,

tate cancer in the United States in 1999 while only 15.6% more deaths, i.e. 43 700, are predicted for

Correspondence: Professor F. Labrie, Oncology and Molecular Endocrinology Research Center, Department of Medicine, C H U L Research Center, 2705 Laurier Boulevard, Quebec, G1V 4G2, Canada ORIGINAL ARTICLE

Received 30-3-99 Accepted 20-4-99 33

Aging Male Downloaded from informahealthcare.com by University of Laval For personal use only.

Screening and treatment of localized prostate cancer save lives

Lubrie et al.

breast cancer during the same time period’. It is estimated that 179 300 new prostate cancers will be diagnosed in the USA in 1999, thus corresponding to 29% of all new cases of cancer in men. Despite progress in the treatment of advanced o r metastatic prostate cancer2-’, it is well recognized that the only possibility of an important reduction in prostate cancer death is treatment of localized disease. Prostate cancer grows slowly but steadily until it reaches the bones. At such an advanced stage, even the best treatment, namely combined androgen blockade or the association of surgcal or medical (luteinizing hormone releasing hormone (LHRH) agonist or antagonist) castration with a pure antiandrogen at the appropriate doseR,9 can only prolong life with no or minimal possibility of a cure. The situation, however, is very different in localized prostate cancer where the possibility of a cure is high*-I0. It is reasonable to assume that the recently observed decrease in deaths from prostate cancer1’Il2 is due to earlier diagnosis with serum prostatic specific antigen (PSA)l3-I5and transrectal ultrasonography of the prostateI6, coupled with improved treatment of localized disease by surgery, radiotherapy, brachytherapy and endocrine therapy10.17-23, Despite the widespread belief in the.benefits of early diagnosis and treatment of prostate cancer, proof of such advantages of screening and treatment oflocalized disease can only be obtained from prospective and randomized studies comparing the incidence of death from prostate cancer in a group of men screened and treated early with a parallel group of men receiving standard medical care. Accordingly, the Laval University Prostate Cancer Screening Program (LUPCSP) was started in November 1988 and the first analysis was recently published24. This is a somewhat summarized review of these data.

group invited by letter for annual screening or to the control unscreened group at a ratio of 2 : 1 in favor of screening. The unequal group size was intended to compensate for the expected lower attendance rate, mainly related t o the lack of awareness regarding prostate cancer in the target population. The age and the constituency ( i e . the location) were used for stratification to balance possible differences in the sociodemographic factors between groups. Men in the control unscreened group were followed according to current medical practice. To minimize bias, no public announcement was made through the media. Men with a diagnosis of prostate cancer before November 15, 1988 were not eligible. Men who had previous screening and were referred to our clinic for consultation were not eligble. A total of 46 193 were thus finally included in the study after all the exclusion criteria were applied. Death from prostate cancer was the primary end-point. T h e study was approved by the Institutional Review Board of Laval University. At the first visit, serum PSA was measured and the participants underwent digital rectal examination. These two tests were performed independently. Transrectal ultrasonography of the prostate was performed only in cases with positive PSA (> 3.0 ng/nil) and/or abnormal digtal rectal examination, except for the first 1002 men who all had the three procedures, as previously des~ribed’~-l~. At follow-up visits, transrectal ultrasonography of the prostate was carried out if serum PSA had increased above 3.0 ng/ml for the first time. In cases where PSA was already above 3.0 ng/ml at the previous visit, transrectal ultrasonography was performed only if PSA had increased by more than 20% compared with the value measured 1 year earlier (the interassay coefficient of variation being 9.696, 10% was accepted as a possible increase attributable to the interassay) or if the measured PSA had increased by 10% or more over the predicted PSA calculated at a previous visit (prostate Serum samples were taken volume x 0.12)25.26. before digital rectal examination and transrectal ultrasonography ofthe prostate for measurement of PSA by immunoradiometric assay (Tandem-R PSA, Hybritech, Inc. or its equivalent). Transrectal ultrasound-guided biopsies were performed with the automatic Biopty system (Bard Urologcal, Covington, Georga, USA) and an

PATIENTS AND METHODS The prospective randomized and controlled prostate cancer detection study included all the men aged from 45 to 80 years regstered in the 1985 electoral rolls ofthe nine constituencies ofthe metropolitan area ofQuitbec City who were traceable in the Qutbec provincial health registries in November 1988, the time ofstart ofthe study. The 46 732 men were randomly allocated either to the

34

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Labrie et al.

18-gauge needle as previously d e s ~ r i b e d ' ~ ~prostate ~ ~ ~ ~ cancer ~. while 15 237 were allocated to the Transrectal ultrasound-guided biopsy was percontrol unscreened group. Figure 1 shows the formed if a hypoechoic image was seen, if the breakdown of these numbers according to origmal measured PSA was above the predicted PSA or if randomization and participation to screening. In digital rectal examination was abnormal. In cases of the invited group, 7155 (23.1%) eligible men were negative biopsies at previous visits with measured screened at our prostate clinic from November 15, 1988 up to December 31, 1996. O n the other PSA above predicted PSA, the frequency of follow-up biopsies was at the judgement of the hand, 982 men or 6.5% of the initial control group radiologst and clinician. Six-sextant biopsies were of 15 237 men presented themselves at the clinic for screening, despite not being invited by letter, performed in only 149 men with normal transand had to be withdrawn from the original control rectal ultrasonography evaluation because of either group. The age distributions of the men in the four abnormal digital rectal examination or a measured PSA greater than the predicted PSA. subgroups were the same. The mean age ranged Evaluation of the impact of screening is based from 59 to 61 years and the standard deviation from upon comparison of the incidence rate of death 7 to 9 years. Four out of the 7 155 men who responded to the from prostate cancer between the two groups. The information on cause-specific death was obtained invitation for screening (Group A) died from from the Death Regstry ofthe Health Department prostate cancer while 44 men died among the of the Province of Quebec. This analysis covers the 14 255 unscreened men ofthe initial control group period from January 1, 1989 to December 31, (Group C). The exposures in the screened and 1996. The annual incidence rate of cause-specific unscreened control groups were 29 097 and mortality is reported as the number of deaths per 105 852 man-years, respectively. Thus, over the 100 000 person-years. Details of the statistical 8-year period, the annual cause-specific death analysis can be found in reference 24. rate incidences were 13.7 and 41.6 per 100 000 man-years in the screened and control unscreened groups, respectively (p = 0.02). The prostate RESULTS cancer death rate incidence was thus 67.1o/o lower O f the 46 193 eligible men aged between 45 and in men of the screened group (Figure 2). 80 years included in the study started in 1988, Several other tests were performed on the basis 30 956 were invited by letter to be screened for of the eligible cases in order to assess any possible

(Screening effect analysis dataset)

Invited 30 956 men

Not invited 15 237 men -I

(A) 7155 screened men Average age, 60 ? 7 years 4 deaths/29 097 man-years

(B) 23 801 unscreened men Average age, 60 f 9 years 93 deaths/l75 600 man-years

(C) 14 255 unscreened men Average age, 59 2 9 years 44 deathdl05 852 man-years 41.6 deathdl00 000 man-years

(D) 982 screened men Average age, 61 f 7 years 1 death/4215 man-years

Figure 1 Trial profile of the Lava1 University Prostate Cancer Screening Program (November 15, 1988-December 31, 1996). Ages are given as average

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f standard deviation

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Labrie et al.



lack of homogeneity that might be related to the lack of compliance to initial randomization. The men who were invited but did not come to our clinic for screening were first compared to the unscreened controls (Figure 1, Group B vs. Group C). Ninety-three prostate cancer deaths were recorded in the 23 801 men (Group B) who did not respond to the invitation for a total number of 175 600 man-years. This translates into an annual death rate of 53.0/ 100 000 man-years compared to 41.6/100 000 man-years in the unscreened men who were not invited (Group B) (p = 0.22). Thus, among men who were not screened, no difference in prostate cancer death can be detected between the group ofmen who were not invited for screening (original control group, Group C) and were not screened and the group of men who were invited for screening but were not screened (Group B). O n the other hand, among the origmally invited men, comparison of the incidence rates of death between the screened (Figure 1, Group A) and the unscreened (Figure 1, Group B) men reveals a highly significant effect of screening (odds ratio, 3.85; p < 0.01). Finally, the odds ratio of the two 2 x 2 tables of men who complied with initial randomization (Figure 1, Groups A and C) and those who did not (Figure 1, Groups B and D) are not statistically different (p = 0.57). It can thus be concluded that there is no significant relationship between the randomly assigned invitation and the observed incidence rates of death from prostate cancer, screening being the only significant determinant factor of the outcome. According to the results of the above-described analyses, the subpopulations of screened (Figure 1, Groups A and D) and unscreened (Figure 1, Groups B and C) men can be pooled, regardless of the initial treatment allocation (Figure 3). Among the 38056 men who were not screened, 137 deaths from prostate cancer occurred for an annual death rate of 4 8 . 7 ~ 0 0000 man-years while only five deaths were found in the 8137 men enrolled in the screening program for an annual incidence rate of 15.0/100 000 man-years. The death rate was thus 3.25-fold lower in the screened men (p < 0.01). In the total population, screening led to a 69% decrease in prostate cancer death. Since a limitation ofscreening studies is the high percentage of men who do not respond to the invitation to be screened, it was also of interest to

36

Invited screened (Group A) (7155 men) 4 deaths 29 097 man-years

Not innvited not screened (Group C) (14 255 men) 44 deaths 105 852 man-years

100 000 man-years

100 000 man-years

i 3 . 0 3 (p = 0.02) 67% decrease in prostate cancer death

Figure 2 Effect of screening o n the incidence of death. Comparison is made between 71 55 men invited for screeningand screened (Group A) and 1 4 255 men not invited for screening and not screened (controls, Group C)

Screened invited (7155 men) not invited (982 men) total = (8137 men) 5 deaths 33 3 12 man-years

Not screened not invited (14 255 men) invited (23 801 men) total = (38 056 men) 137 deaths 281 452 man-years

100 000 man-years

100 000 man-years

1 L 3.25 (p < 0.01) 69% decrease in prostate cancer death Figure 3 Effect of screening in the total population of screened (8137) and not screened (38 056) men following demonstration of lack of influence of compliance to the original invitation

analyze the data on an intent-to-screen basis24.The intent-to-screen analysis with 23.1% of men actually screened shows a 6% decrease of the prostate cancer death rate in favor of the group of men who were initially invited to be screened. This 6% difference is obtained despite a non-compliance of 76.9% and a contamination ofthe non-invited men of 6.6%. When the difference observed between the randomization groups is adjusted for such non-compliance and contamination, the effect of screening is estimated to reduce death from prostate cancer by 54 and loo%, respectively. The analysis, presented above, of a 69% benefit associated with screening is thus well supported by the results of the intent-to-screen analysis. The prevalence of prostate cancer at first visit was 3.00% and the average annual incidence was 0.52% over the 8 years of follow-up (Table 1). As can also be seen in Table 1,8.4% of cancers were

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at the metastatic stage at first visit. Most interestingly, none of the 123 prostate cancers diagnosed during the 23 423 follow-up visits was clinically metastatic, thus confirming that the diagnostic procedures used practically eliminate the diagnosis of metastatic prostate cancer15. Four out ofthe five deaths in the screened group were in men diagnosed at their first visit. The fifth man who died from prostate cancer was not seen at our clinic after his first follow-up visit and was diagnosed in another institution. O f these five deaths from prostate cancer in the screened group, one was diagnosed at clinical stage D2, one at stage C2 who was later identified as a D1 after radical prostatectomy, while a third one was diagnosed at Table 1 Prostate cancer diagnosis in the screened cohort between November 15, 1988 and December 31, 1996

First visit CIinical stage

n

%

FoIIow-up visits n

%

A1 A2

1 2

0.4 0.8

BO B1 B2

15 86 69

6.4 36.4 29.2

21 17.9 63 53.9 22 18.8

c1 c2

28 20

11.9 8.5

10 1

D1 D2

3 12

1.3 5.1

N/A Total Number of visits Ratio o f diagnosis/visit

8

-

6

244

123

8137

23 423

3.00%

8.5 0.8

-

0.52%

Lubrie et al.

stage C2 and failed radiation therapy, with a nadir PSA at 29 ng/ml. The two other patients were staged elsewhere. Among the 367 patients diagnosed with prostate cancer, 339 (92%) were followed at our clinic, at least for their initial treatment (Table 2). Radical prostatectomy or radiation therapy was performed in 155 (46%) and 109 (32%) men, respectively, either alone or in association with combined androgen blockade. Hormonal therapy alone was received by 50 (15%)patients. Altogether, 70.5% of all patients received combined androgen blockade during their initial treatment.

DISCUSSION This first randomized and prospective study on prostate cancer screening shows a 69% decrease in the incidence of deaths due to prostate cancer in the screened compared to the unscreened populations. Ten years after the start of this screening study, the present data clearly demonstrate the efficacy, reliability, feasibility and acceptability of diagnosis and treatment oflocalized prostate cancer in the general population. The data obtained in this study permit, for the first time, information to be given to men of the estimated risk of death from prostate cancer if not screened and not treated early. Knowing the medical benefits of a screening program, it is now a matter of medical policy and ethics to create the appropriate conditions which will allow the general population of men to benefit from this new information. It thus seems appropriate to briefly comment on the algorithm ofprostate cancer screening recommended for the general population. We would like to insist that the upper limit of normal of serum PSA should be 3.0 ng/ml and not 4.0 ng/ml (as measured by the Hybritech assay

Table 2 Treatment received by 339 patients (92%) out of the 367 men diagnosed with prostate cancer between November 15, 1988 and December 31, 1996 (others were treated elsewhere)

Total Radical prostatectorny 49

Radiotherapy

No combined androgen blockade Hormonal monotherapy

-

Combined androgen blockade

106

25 1 83

Total

155

109

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Hormonal treatment

n

%

25 (delayed) 50

99 1 239

29.2 0.3 70.5

75

339

-

37


Screening and treatment

of localized prostate cancer save lives

or its equivalent). It should be remembered that the cut-off value of 3.0 ng/ml is the only value scientifically demonstrated to provide optimal sensitivity and specificity to the PSA (Figure 4). In fact, the still commonly used value of 4.0 ng/ml suggested by the manufacturer is empirical and not scientifically based. It should be remembered that 11%and 18%of the smaller and potentially most curable prostate cancers are missed when a cut-offvalue of4.0 n g / d is used instead of 3.0 ng/ml at first and follow-up visits, respectively15. It should be mentioned that the same cut-off value of 3.0 n g / d has been adopted in the European screening study29. Another observation of practical importance is the relative value of digtal rectal examination and PSA measurement for the diagnosis of prostate cancer. At first visit, where both PSA and digtal rectal examination were used, 14%ofcancers were found by digtal rectal examination in men having normal PSA, thus indicating that men at first visit should have both serum PSA measurement and digital rectal e ~ a r n i n a t i o n ' ~in~ 'order ~ to avoid missing 14% of detectable cancers. It should be mentioned, however, that the European screening study has removed digital rectal examination when At follow-up serum PSA is below 3.0 r~g/ml*~. visits, however, only 3% of cancers were found by digtal rectal examination in men having normal

20% have detectable cancer W5)

of normal

c"1

1% have detectable cancer (1/loo)

Figure 4 Schematic representation of the cut-off value of serum prostatic specific antigen (PSA) determined at 3.0 n g / d (Hybritech test or e q ~ i v a l e n t ) ' ~At . first visit, 20% of m e n having a PSA higher than 3.0 n g / d have detectable prostate cancer while only 1 out of 100 ofthose having a PSA at 3.0 ng/ml o r below can be found to have prostate cancer

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Labrie et al.

PSAl5. Accordingly, approximately 5000 digtal rectal examinations were required to diagnose one case of prostate cancer, thus strongly arguing against the routine use of digital rectal examination at follow-up visits. It thus seems reasonable to suggest that PSA measurement alone, performed once a year or once every 2nd year should be used at follow-up visits in the general population. Screening once every 2nd year or biannually should be for men having serum PSA I2.0 ng/ml, a recommendation which applies to 70% of the population of men aged 50 years or morel5, while men having a serum PSA of 2.0 ng/ml or above should have their serum PSA measured annually (Figure 5). The approach used in the present study, while being highly efficient in detecting prostate cancer at the clinically localized stage in practically 100% of cases15 (Table l), does minimize the number of transrectal ultrasonographies of the prostate and biopsies. In fact, 34.3 and 25.5% of biopsies at first and follow-up visits, respectively, were positive for cancer15.The overall sensitivity and specificity of the proposed strategy compare favorably with screening for breast, colon, uterine and lung cancer30. Progtate cancer can be diagnosed by the present approach at an estimated cost of $2665 per cancer at first visit31, a value well below the costs estimated at $10 000 and $30 000 per case of cervical and breast cancer diagnosed by screening, respectively. In agreement with the recommendations of the American Cancer Society, the present data indicate that screening should be started at the age of 50 years except in men OfAfrican-American descent and those having a history of prostate where screening could be started at the age of 40 years. A major source of controversy concerning early diagnosis and treatment of prostate cancer is that, until recently, no prospective and randomized trial had shown statistically significant benefits of treatment oflocalized prostate cancer on survival34.The absence of data from well-designed clinical trials was erroneously interpreted as negative data. Most fortunately, two prospective randomized trials have recently demonstrated €or the first time that not only quality of life but, most importantly, prolongation of life could be achieved in localized prostate cancer patients treated with androgen blockade. In the European Organization for Research and Treatment ofCancer (EORTC) trial

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Labrie et


Follow-up visit

First visit

PSA

DRE + I

I

f

I I


I

Treatment

I I I I I

-

I - _ _ _ _ _ - - - - - - - _ _ - -

I

:I

I

.I

PSA25%

PSA0-25%

abovePrPSA

above PrPSA

: sextant biopsies

I

I I

: Treatment

I I

IA

PSA and DRE every 3 months

1 year every 3 months ..........................................

: :

PSA every 3 months

PSA in 2 years PSA in 1 year

Site of abnormality + sextant biopsies Treatment

I I I I

3.1 or more 2.1-3.0

PSA follow-up

I

I

PSA in 2 years

I

I

TRUS +

1 I I-

-

I

3.1 or more 2.1-3.0

a1

\

I

A

Previous T R U S (5 years or less before)

I

B Biopsy according to judgment for mPSA > PrPSA

I

PSA in 1 year

:......................................... B

I

No previous TRUS (or T R U S more than 5 years earlier)

25% above .I :I 8 1

I_______________________________________--_--~

Figure 5 Proposed algorithm of prostate cancer screening. PSA, prostatic specific antigen; DRE, digital rectal examination; TRUS, transrectal ultrasonography of the prostate; Pr, predicted; m, measured

performed in stage T3 patients, survival at 5 years was increased from 62% in the group of patients w h o received radiation therapy alone to 79% (45% difference) in those who received androgen blockade using an LHRH agonist for 3 years and an antiandrogen for 1 month in association with radiotherapyz2. A similar observation has been made in the Radiation Therapy Oncology Group ( R T O G ) trial 85-31 in the subgroup of high Gleason score patients35. Many studies have suggested that time to progression is prolonged by early hormonal treatment in surgically proven stage N + MO (Dl) Following a long controversy, a large prospective and randomized clinical trial performed by the Medical Research Council Prostate Cancer Working Party Investigators' Group4" has shown the benefits of early androgen blockade in a study of 938 patients with locally advanced or asymptomatic metastatic disease. The patients were randomized to immediate androgen blockade (orchiectomy or L H R H agonist) versus treatment deferred until symptoms developed. Significant benefits of early treatment were observed o n time to progression and development of pain.

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Complications from metastatic disease were twice as frequent in the deferred group and, most impor-

tantly, longer overall survival was seen in the early treatment group, especially in patients with MO disease. Consequently, n o valid reason remains to doubt that treatment of clinically localized prostate cancer can prolong survival. In fact, the major benefits observed in the present study in the screened group, namely a 69% decrease in the incidence of death from prostate cancer, can only be due to the treatments used and their timing. The patients diagnosed with localized prostate cancer in the present study were usually enrolled in our randomized trials associating neoadjuvant and/or adjuvant combined androgen blockade with surgery", radiotherapy2" or endocrine therapy alone"). T w o other randomized screening trials for prostate cancer are ongoing, namely the prostate, lung, colon and ovarian (PLCO) trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). The objective is to recruit 70 000 and 50 000 men, respectively, in those trials. Results from those trials are not expected before the year 2005. Moreover, their

39



relatively late start carries the high risk that the popular knowledge about PSA has already led to screening of a significant proportion of men, thus increasing contamination by screening in the control group to an unacceptable level. In the United States, it has been estimated that the health-care costs for the treatment of prostate cancer are $4.5 billion annually4'. These costs, in fact, are largely related to the treatment of advanced disease. In addition to the major impact on prostate cancer deaths, the economic savings on health-care costs have been discussed previously31,42-44. The calculationsperformed leave little doubt that the present strategy based upon efficient screening and treatment, namely androgen blockade, surgery, radiotherapy or brachytherapy alone or in combination with androgen blockade should play a key role in the successful fight against prostate cancer while decreasing the costs for the health-care system and s o ~ i e t y ~ ~ . ~ ~ , ~ ~ . Although PSA shows unique usefulness as an early sign of recurrence of prostate cancer after any form of therapy, its high sensitivity to androgen deprivation needs great caution. Especially in localized disease, serum PSA decreases to undetectable levels under androgen blockade much before complete cancer cell death is achieved. In other words, an undetectable serum PSA is not equivalent to disappearance of cancer. It should also be remembered that the only form of endocrine therapy demonstrated to prolong life is the one where androgen blockade was administered continuously for years without interruption. Cancer cell genetic deterioration occurs through mutation, translocation or amplification which all require cell division. Inhibition of cell division by adequate androgen blockade thus prevents further genetic alteration and increased malignancy. Before being recommended, intermittent therapy needs to be proven in large randomized trials as being equivalent to the effect of continuous treatment on survival, the prime and essential objective of prostate cancer therapy. The degree of androgen dependency of prostate cancer when growing in the prostatic area is dramatically different from the cancer growing in the bones. Prostate cancer does in fact spread selectively to the cancellous bones of the axial skeleton where it produces osteoblastic lesions4'. Such bone-specific facilitated growth of prostate cancer could be related to the paracrine secretion

40

Labrie et al.

by bone cells of growth factors which stimulate prostate ~ a n c e F 3These ~ ~ . authors found that bone fibroblasts were the most potent stimulators of human prostate cancer LNCaP cell growth. The much more important benefits of androgen blockade observed in localized compared to advanced prostate cancer are in agreement with the well-known observation that, in patients with metastatic disease treated with combined androgen blockade, progression occurs almost always in the bones and rarely in the prostate, thus clearly indicating that prostate cancer localized in the prostatic area is particularly sensitive to androgen deprivation. All available means should thus be taken to prevent prostate cancer from migrating to the bones where treatment becomes extremely difficult and cure or even long-term control of the disease is an exception. The only available means for preventing prostate cancer from migrating to the bones and becoming incurable is treatment of localized disease. It is also clear from the data summarized above that combined androgen blockade could well be the most efficient therapy for localized disease while it has been recognized for almost 60 years as the best therapy for metastatic disease. O f the male population living in the USA, 3.0 million are expected to die from prostate cancer if no drastic change occurs in the diagnosis and treatment of this disease. A 69% decrease in prostate catxer death suggested in this study corresponds to 2 million lives saved. One must remember, however, that the usefulness of early diagnosis is entirely dependent upon the timing and efficacy of the treatment used. It is noteworthy to remember that 70.4% of the patients diagnosed at our clinic received combined androgen blockade alone or in association with surgery or radiotherapy. W e feel that androgen blockade is a major element in the success of prostate cancer therapy, localized disease being extremely sensitive and responsive to such treatmentlo. With today's knowledge, almost 100% of the cases of prostate cancer can be diagnosed at a localized stage, thus practically eliminating the diagnosis of metastatic non-curable prostate cancer. It should be remembered that the efficacy of androgen deprivation is at least an order of magnitude greater for localized than for metastatic disease, thus indicating the critical importance of early diagnosis and treatment before cancer reaches the bones where therapeutic success is limited2j.

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Labrie et al.

Simple measurement of PSA every year starting at the age of 50 years as recommended by the American Cancer Society in 1992 can, as demon-

strated for the first time in t h e present study, lead t o a dramatic decrease in prostate cancer death.



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