KIT (Keep in Touch) Mail from OLLI

Management of Advanced Prostate Cancer
Gerard Auclerc, Eric C. Antoine, Francis Cajfinger, Arlette Brunet-Pommeyrol, Chahrok
Agazia and David Khayat
The Oncologist 2000, 5:36-44.
doi: 10.1634/theoncologist.5-1-36
Downloaded from by guest on June 9, 2014
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
Management of Advanced Prostate Cancer
SOMPS, Salpêtrière Hospital, Department of Medical Oncology, Paris, France;
Centre Charlebourg, la Garenne-Colombes, France
Key Words. Advanced prostate cancer · Hormonal therapy · Hormone resistance · Irradiation · Chemotherapy · Quality-of-life evaluation
aromatase inhibitors, and hormone-refractory prostate
cancer multiple cytotoxic agents. For painful bone
lesions, external beam radiotherapy, biphosphonates,
and strontium 89 or samarium 153 provide pain relief.
The use of new methods for the evaluation of response
and quality of life will allow the rapid identification of
effective treatments and permit powered phase III trials.
The Oncologist 2000;5:36-44
Prostate cancer is the cause of more than 1% of all deaths
in men. Its incidence is increasing by 2%-3% per year. There
are two main reasons for this increase. The first is increased
life expectancy, and the second is that prostate-specific antigen (PSA) testing has enabled earlier and more accurate
diagnosis of the disease. The general prognosis for diagnosed
prostate cancer remains poor, with 70% survival at 10 years
compared to the general population. About 50% of cases are
diagnosed at a locally advanced stage, and about 30% have
bone metastases at the time of diagnosis [1].
In 1996 in the United States, 317,000 new cases were
diagnosed and 41,000 deaths reported. This latter figure represents 13% of all U.S. cancer deaths. In lay terms, this means
that one death from prostate cancer occurred every 13 minutes
[2]. In 1990, similar figures were recorded in France, with
17,600 new cases and 9,200 deaths reported (11% of all cancer deaths) [3]. However, in 1999 the 33rd annual compilation
of cancer statistics [4] showed that the incidence of prostate
cancer had decreased significantly with a decline in death rate
of 11% since 1991. These statistics also reported an increase
of 20% in 10-year survival between 1988 and 1995.
Systemic treatments for prostate cancer include various
types of hormone therapy. Biphosphonates or radionuclides
such as strontium 89 or other isotopes may be used in cases
where bone lesions are identified. Other treatments include
external radiotherapy and surgery. Chemotherapy has become
an additional option when hormone treatment fails [5, 6].
Around 75% of metastatic prostate cancers are hormone sensitive. The average time for response to androgen
deprivation is about 18 months; survival after second-line
treatment varies from 6 to 10 months [7].
Early Treatment
For symptomatic patients or for those with progressive
disease, hormonal treatment is considered compulsory.
However, for nonsymptomatic hormone-sensitive patients
this may not necessarily be the case. Hormonal treatment has
unwanted side effects, particularly of a sexual nature. The
costs of such treatment may also be considerable. It is also
important to remember that hormone treatment continues to
remain effective in nonsymptomatic patients. However,
delaying treatment by just nine months introduces the risk of
spinal cord compression. In their study, Crawford and coworkers [8] have shown that 45% of prostate cancer patients
regarded quality of life as more important as opposed to 29%
who stated a preference for prolonged survival. A trial carried
Correspondence: Gerald Auclerc, M.D., Salpêtrière Hospital, Department of Medical Oncology, 47 Boulevard de l’Hôpital,
75013 Paris, France. Telephone: 33-1-4216-0474; Fax: 33-1-4336-4841. Accepted for publication January 20, 2000.
©AlphaMed Press 1083-7159/2000/$5.00/0
The Oncologist 2000;5:36-44
Downloaded from by guest on June 9, 2014
Most cases of advanced carcinoma of the prostate
are hormonosensitive. The use of combined androgen
blockade (CAB) seems to improve survival and quality
of life, but only when combined with chemical castration by luteinizing-hormone-releasing hormone analog
and without the use of steroidal antiandrogens. After
CAB, further hormonal treatments remain efficacious,
such as antiandrogen withdrawal followed by estrogens,
Auclerc, Antoine, Cajfinger et al.
advantage of having both a hormonal steroidal component
and a nitrogen mustard alkylating agent. The best known
action of estramustine is the depolymerization of microtubules by interaction with tubulin. However, estramustine
has also been demonstrated to have a cytotoxic action by
binding to the nuclear matrix [13, 14].
Androgen Deprivation
Since the publication of the early works of Huggins in
1941 [10], the primary treatment for prostate cancer has been
to stop testicular androgen production. This can be achieved
by castration using estrogens such as diethylstilbestrol (DES)
or more recently using antiandrogens (AAs) and luteinizinghormone-releasing hormone (LHRH) agonists (monthly or
every three months). This treatment decreases the plasma
level of testosterone by 95%. Androgen deprivation, however, is associated with numerous possible side effects. These
include decreased libido, impotence, hot flushes, anemia,
hair loss, osteoporosis, fatigue, and psychological factors.
The appearance of these effects markedly alters the patient’s
quality of life.
Total Androgen Blockade
This concept, developed by Huggins in 1945, is based on
the fact that the prostatic cells are androgen dependent and
this is particularly so for dihydrotestosterone (DHT), a very
active metabolite of testosterone. The production of this
metabolite in the prostatic gland means that levels of androgen following castration vary between 20% and 40% of normal levels [15]. In fact, there are two pathways to bring about
the transformation of testosterone into DHT. One route
depends on the action of the enzyme 5-alpha-reductase that
transforms testosterone into DHT. The other route involves
production of dehydroepiandrosterone by the adrenal
glands. This is converted to testosterone and then to DHT
in the prostatic gland. The discovery that most metastatic
prostate cancers are stimulated by androgens led to the
search for and development of different means for their
suppression. As a result of Huggins’ work [10], bilateral
orchiectomy was long considered to be the standard treatment. More recently, estrogens, LHRH agonists, and AAs
have emerged as newer treatment options.
Castration is either carried out surgically by bilateral
orchiectomy or medically by LHRH agonists such as triptoreline, leuproreline, busereline, and gosereline. These
treatments may sometimes induce a paradoxical effect usually described as a “flare-up.” This effect is more frequent
in cases involving bone lesions and is due to initial, temporary increases in levels of LH and testosterone. These may
lead to bone pains that last for about a week. This phenomenon explains the need for an AA that must be taken for two
weeks before and after medical castration in order to avoid
this flare-up effect.
For many years these agents have been regarded as the
gold standards in androgen blockade. They influence the
pituitary axis, adrenal secretion, and 5-alpha-reductase activity. They have played a very important role in hormonal therapy. However, DES does have its drawbacks due to its
cardiovascular toxicity. As has been demonstrated in a study
of veterans [11], the benefits obtained from 5 mg/d of DES
appear to be countered by the reported side effects. These
results have led to the use of lower doses of DES, even as low
as 1 mg/d. These low doses have resulted in therapeutic benefits and reduced risk of cardiotoxicity in certain patients,
even though it appears that the threshold dose of 3 mg/d is
necessary to obtain total androgen blockade. In France, fosfestrol is widely used, mostly by i.v. administration [12].
Another estrogen is estramustine phosphate, which has the
The mode of action of the AAs results in the blockade
of the androgen receptors of the prostate cells. There are
two types of AAs: steroidal AAs and nonsteroidal AAs
(NSAAs). Steroidal AAs induce a decrease in plasma levels of testosterone by slowing the release of pituitary LH
and by partial inhibition of 5-alpha-reductase. Steroidal
AAs include cyproterone acetate and megestrol acetate,
which also block the cellular androgen receptors.
The NSAAs are more interesting from a clinical point of
view because they are purely AAs acting mainly by inhibiting competition with the fixation of DHT on the androgen
receptors. They do not reduce, and may even increase, the
plasma levels of testosterone and this may have an impact on
the libido of the patients. The NSAAs include flutamide,
nilutamide, and bicalutamide.
Total Androgen Blockade
The association of AAs with an LHRH agonist such as
leuprolide allows total androgen blockade (TAB) at both
testicular and adrenal levels. Results of the first randomized
National Cancer Institute study that took place in 1989 [16]
were very encouraging. In this study, 603 stage 2 patients
Downloaded from by guest on June 9, 2014
out by Medical Research Council Prostate Cancer Working
Party Investigator Group comparing early versus delayed
treatment has recently been published [9]. For the first time
the benefits of early treatment have been clearly demonstrated in terms of metastatic progression, complications,
and deaths related to cancer.
Intermittent Androgen Blockade
Several investigators [24] have suggested that hormone
therapy be stopped when normalization of PSA level is
achieved and that hormone therapy should be started again
in case of relapse. The aims are to increase the quality of
life of these patients and to delay the appearance of hormonal resistance. To justify this strategy, these investigators consider that apoptosis is hormone dependent and the
tumor can grow even in the absence of testosterone.
Certainly, this is linked to the selection of hormone-resistant clones, but genetic alterations may appear in this cellular-resistant population [25, 26]. Androgen (testosterone)
production would allow a tumoral redifferentiation and
reinduce the capacity of prostate cancer cells for apoptosis
and so would retain hormonal dependence [27] and again
effectiveness of androgen blockade. This approach would
permit a better quality of life along with associated obvious
economic benefits. As has already been mentioned, the
Crawford study [8] has shown that patients prefer preservation of quality of life rather than prolonged survival (43%
for preservation of quality of life, 29% for the prolongation
of survival, and 13% for survival without progression).
Conversely, physicians seem to focus on efficacy of treatment. M. Zerbib, in a personal communication, has reported
that 25 out of 31 patients treated with intermittent androgen
blockade, who were sexually active before the beginning of
the treatment, rediscovered their sexual activity when hormonal therapy was stopped once the desired response had
been achieved.
AA Withdrawal
The need for second-line treatment, or the need to interrupt AA therapy [28] may follow failure of TAB. This may
take place after an 18-month response to androgen deprivation. Three studies reported by Small [7] involving 139
patients on flutamide with progressive disease have indeed
shown that simple withdrawal of flutamide brought a PSA
decrease in about 21% of the cases, with a median response
of 3.5 to 5 months. Patients who have a more extended
response to flutamide are often those who respond to its withdrawal [29]. In cases of combination of flutamide with
another hormonal treatment, the response seems more marked
when this latter treatment was given at the start of flutamide
rather than later (i.e., when flutamide seems less active). Thus,
it seems logical to suggest the withdrawal of flutamide as a
treatment when it has been used alone or in earlier association
and especially when it has been used for a long period (more
than 18 months). This phenomenon has a relationship with a
possible amplification of the gene of androgen receptors
Downloaded from by guest on June 9, 2014
were randomized between chemical castration with leuprolide
and placebo or AA with flutamide. The results showed an
improvement in the rate of progression (13.6 versus 16.5
months) and a marked improvement in global survival (28.3
versus 35.6 months), a gain of 7.3 months (p = 0.035) in the
TAB group. These results, reported by Crawford and colleagues were later confirmed in 1993 by a European
Organisation for Research and Treatment of Cancer (EORTC)
study. At the same time, Denis and co-workers [17] reported a
similar improvement in survival time of 7.3 months (p = 0.02),
in favor of a combination of flutamide with LHRH agonist
compared to orchiectomy alone.
In 1995, Crawford [18], in a second study with 1,387 D2
patients treated with orchiectomy and flutamide or placebo,
did not find such a clear-cut difference in the decrease of
PSA or in progression-free survival (33 versus 30 months).
In the same year, a meta-analysis of 25 trials comparing castration alone to TAB [19] found no significant difference
between the two treatments (five-year survival: 22.8% versus
26.2%; p = 0.0512).
The different means of achieving TAB do not appear to
be equivalent. The long-term effects of using estrogens and
LHRH agonists compared to bilateral orchiectomy do not
seem to be the same [20]. The trials that show a significant
benefit with TAB in terms of survival are those where castration is medical and nonsurgical. It has been shown that
estrogens and the LHRH agonists have a direct cytotoxic
effect on prostate cancer cells [21]. Moreover, the association between LHRH agonists and AAs seems to have an
additive if not synergistic effect. Indeed, investigations of
receptors to LHRH [20] on immortal lines of prostate cancer cells (LNCaP and ALVA-31) have taken place. Results
revealed that the combination of LHRH agonists with AAs
has greater powers of inhibition than each one of them
alone acting on androgen sensitive (LNCaP) or resistant
lines (ALVA-31).
Caubet and colleagues [22] in a recent meta-analysis
used rigid inclusion criteria that excluded nonrandomized
studies and those studies where there is no NSAA. This
meta-analysis included nine studies and established the
benefits of TAB in terms of objective response as well as
progression-free survival and overall survival (but without
significant statistical difference). In the context of TAB,
the use of LHRH agonists with NSAAs appears to be the
better option.
Flutamide is the reference AA. A recent randomized
study of 813 patients [15] compared flutamide with bicalutamide associated with an LHRH agonist. The results show
progression-free survival and an identical survival at 95
weeks but with a better tolerance to bicalutamide, especially
gastrointestinal (lower incidence of diarrhea) [23].
Management of Advanced Prostate Cancer
Auclerc, Antoine, Cajfinger et al.
Table 1. Criteria of evaluation of response to second-line treatment
Level and minimal lengh of decrease of PSA levels (>50%,
>80%, and for a defined period of time, i.e., eight weeks).
Return of PSA to a level considered satisfactory (<4, <10 µg/ml).
Minimum length of decrease of PSA levels to consider the
presence of response (>8 weeks).
Post-therapy changes in bone scan (intensity and number of foci).
Isolated changes of measurable lesions or associated with other
elements (PSA levels, bone scan).
Scale of quality of life (pain relief, decrease in use of analgesics,
performance status, weight).
Survival without progression (with what criteria of relapse?).
Global survival.
Androgen Deprivation
Surgical or chemical adrenalectomy with aminogluthetimide and hydrocortisone gives a less than 10% objective response. Similar response figures are obtained with
ketoconazole, which needs high doses that are poorly tolerated [35]. Suramin may be more active (from 35% to 54%
of objective response) but exhibits some renal and neurological toxicity. The duration of response is usually short
and in general lasts about five months [36].
The estrogens could be more interesting, especially fosfestrol, which is less cardiotoxic than DES [37]. Fosfestrol has the
advantage of being administered via an i.v. line and has a more
rapid uptake. Because fosfestrol is a prodrug that is metabolized
to DES in the cancer cells, it exhibits very low plasma levels
and has low cardiotoxicity. Standard treatment with fosfestrol
is 10 days’ perfusion at incremental doses (from 1,200 mg on
day 1 to 3,000 mg on day 5) followed by oral administration.
Grise [12] reports a level of response of 40% (on the PSA level
as well as on the quality of life), which may be a very
important prognostic factor since the median survival of the
responders is 19.6 months versus 4.2 months among the
nonresponders. Similar results have been reported by other
investigators with a median survival of around five months.
Sometimes, after progression under AA therapy followed
by failure of estrogen, a new benefit related to AA therapy can
be obtained. This is due to a redifferentiation of cancer cells by
mutation of the androgen receptors [7]. Also, sensitivity to
androgens can be noted [24]. The activity of antiestrogen therapy (tamoxifen) has also been noted. This may be explained by
the possibility of the presence of estrogen receptors.
The inhibition of aromatase blocks the conversion of
cholesterol in pregnenolone. Aminoglutethimide inhibits the
biosynthesis of adrenal steroids as does ketoconazole at high
doses. More recently, similar effects have been noted for lioprozole and liarozole [7]. Other aromatase inhibitors already
used in advanced breast cancer such as letrozole or anastrozole are under study. At a similar level, low doses of steroids
may be active by slowing the activity of the adrenals [7, 30].
If the treatments already described have failed, this is
indicative of hormone refractory prostate cancer. This leads
to the use of chemotherapy, but strict precautions must be
observed with elderly patients. The first publications on
chemotherapy go back some 20 years [32, 33], and success
was evaluated in these studies using different criteria. This
may help explain the discrepancies in the reported results [6].
Hormone refractory prostate cancer has long been considered to be a chemotherapy-resistant disease [38]. Indeed,
no randomized study has been able to demonstrate the benefit of chemotherapy on survival rate [5, 6, 32]. Over the last
10 years, several nonhormonal agents have been shown to
exhibit a certain efficacy when evaluated according to
decrease of PSA. However, none of these studies had patient
populations greater than 100 [6]. Consideration of the quality-of-life evaluation criteria has somewhat modified this
situation. Thus, the results obtained by Tannock [39] confirm
Downloaded from by guest on June 9, 2014
(ARs) [26] or with mutations in hormonal relationships
between the ARs [25] and the cancer cells that can be activated by the AAs or other steroid hormone as adrenal
androgens [24].
Unfortunately, the benefit of withdrawal of AAs like
flutamide, when seen, lasts only for a few months. This
leads to the need for a new second- or third-line treatment.
The choice of a new second- or third-line treatment is rather
difficult since the criteria of evaluation and activity are difficult to standardize. This is due to the fact that 80%-90% of
the patients do not have a measurable lesion. The major difficulties in considering the value of treatment are the large
number of parameters to be taken into consideration
(Table 1), the knowledge that evaluation criteria have
changed over the years [30], and that they sometimes appear
to be in conflict [31]. This was somewhat discouraging during the 1980s and could explain a renewed interest in the
use of chemotherapy [32, 33].
Before deciding on the second- or third-line treatment,
previous exposure to hormones must be considered as this
can have an influence on the response to subsequent therapy. The difficulty in comparing prospective studies where
evaluation criteria were often very different may help
explain the wide range of different choices for second-line
treatments: aromatase inhibitors, estrogens, chemotherapy
alone, and hormone chemotherapy [34].
Management of Advanced Prostate Cancer
used as an antiemetic with chemotherapy, gives alone
about a 20%-40% response rate [39], and the interval of
time since the end of the previous hormonal therapy must
be considered for the withdrawal effect. The response to
withdrawal usually happens within a month. Exceptions
are nilutamide and bicalutamide, which have longer halflives (response in eight weeks) [7]. Thus, in cases of response
to hormonal therapy, we have to wait for the objective
signs of relapse before starting with chemotherapy. Finally,
it is important to be sure that the plasma levels of testosterone obtained are consistent with the levels associated
with castration [6].
Hudes [41], in a randomized study of 192 patients on
second-line treatment, has compared vinblastine alone versus
vinblastine and estramustine. He has obtained measurable
responses of 6% and 18%, respectively, a progression-free
median survival of 1.9 and 3.7 months (p = 0.001) and a
global survival of 9.2 and 11.9 months (p = 0.18). Although
nonsignificant, this figure corresponds to an increase of 25%
in global survival.
Even if chemotherapy has no impact on survival, it
demonstrates benefits in terms of quality-of-life parameters
[6, 42]. Tannock, in 1989, investigated steroid therapy [39] as
Table 2. Second-line treatment with medical therapy
Response Rate (%)
PSA > 50%
Doxorubicin (20 mg/m2/week )
Doxorubicin + cyclophosphamide
Mitoxantrone + prednisone
Response Rate (%)
Response Rate (%)
PSA > 50%
Cyclophosphamide + prednisone + diethylstilbestrol (DES)
Doxorubicin + ketoconazole
+ VLB/doxorubicin + ketoconazole
+ Etoposide
+ Paclitaxel
+ Paclitaxel + etoposide
+ Docetaxel
+ Vinblastine (VLB)
Downloaded from by guest on June 9, 2014
the interest of chemotherapy with respect to certain criteria
(visual scale of evaluation of pain, performance status, and
modification of weight).
A better evaluation of the classical drugs (vinblastine,
cyclophosphamide, doxorubicin, mitoxantrone), the newer
ones (cisplatinum, taxanes), or simultaneous combination
with hormonal therapy (estramustine) or in sequential
administrations [40] should be possible through phase III
trials. This evaluation could consider quality-of-life criteria
to be of the same level of importance as decrease in PSA,
the prolongation of survival, and global survival.
Of the most widely studied drugs, the best results have
been obtained with cyclophosphamide, doxorubicin, and
mitoxantrone. Unfortunately, few studies exist and the new
molecules are still being evaluated. However, it is already
well recognized that the combination of antihormonal therapy, particularly with estramustine, increases the level of
response (Table 2).
We must be very careful about the evaluation of
responses to these drugs [31] and, as has already been mentioned, we must take into account previous treatments. For
example, bicalutamide is more active following flutamide
than following castration [7]. Steroid therapy, which is
Auclerc, Antoine, Cajfinger et al.
Although external radiotherapy is the best treatment for
pain related to localized bone metastases, i.v. biphosphonates
exhibit considerable activity against pain in diffuse bone
lesions. These compounds act rapidly [46] and are nontoxic.
Biphosphonates do not themselves have any antitumor
activity and only have a secondary role to play in the treatment of prostatic cancer. They act on the osteoclastic hyperresorption linked to the coupling of activity of bone cells
(osteoblasts and osteoclasts). Clodronate and pamidronate
have shown some analgesic activity and are of interest only
in cases when usual treatments have failed [46].
External Beam Radiation
Radiotherapy is the mainstay of treatment for the nondiffuse painful metastases. These occur in about 85% of progressive, hormone-resistant cancers. Short, localized external
beam irradiations (20 Gy in five fractions over one week or,
more often, 30 Gy in 10 fractions over two weeks) bring partial or total pain relief in 80% of patients with negligible morbidity. Complete responses were most often found in patients
with prostate cancer in comparison to other tumors [47].
Irradiations by large hemibody fields (6 Gy for the upper half
of the body and 8 Gy for the lower half) are also efficient in
relieving pain in about 75% of cases, with relief lasting several months. About 40% of patients responded within 48
hours [48].
Strontium 89
The preferential fixation of certain radiopharmaceutical
isotopes on the bones, especially at points of growth, led initially to the use of phosphorus 32 in multifocal bone lesions.
Because of its severe myelotoxicity, this agent has been
largely replaced by strontium 89 or by other radioisotopes
such as samarium 153 and rhenium 186 [49]. Strontium 89 is
a pure β-emitting radionuclide that follows the same pathways as calcium and induces an almost total disappearance of
bone pain between 10% and 50% of patients and partial disappearance in approximately 50% of the patients. It is associated with moderate blood toxicity (thrombocytopenia from
four to eight weeks after the injection), but a possible benefit
in terms of global survival has not been proven yet.
Nevertheless, its combination with other products or techniques may be promising. In fact, strontium 89 combined with
localized external irradiation, although not modifying survival, is associated with a decrease in the biological markers
throughout the half-life of strontium. The use of cisplatinum
(CDDP) in association with strontium 89 is especially interesting since CDDP reduces the possibility of repair of the
radio-induced sublethal lesions. It has been seen that low
doses of CDDP after low doses of strontium 89 have an obvious effect in terms of pain relief and in the decrease of disease
markers without toxic effects [50].
Strontium 89, at the usual dose of 30 to 60 MCi/kg, after
failure of medical treatment induces an improvement in
Downloaded from by guest on June 9, 2014
second-line treatment. In a randomized study [42] of 161
patients he compared prednisone alone (10 mg/d) versus the
combination of prednisone and mitoxantrone (12 mg/m2/3
weeks). This followed the results of a phase II study [43]
showing activity and good tolerance. A significant benefit of
the chemotherapy was demonstrated in terms of objective
response (29% versus 12%), median responses (43 weeks versus 18 weeks), and global palliative benefit (38% versus
21%). Among patients in failure with prednisone alone, the
association with mitoxantrone gave a 22% response rate (with
a median of 18 weeks). Global survivals were identical, with
a median of 11 months, but 50 out of 80 patients treated with
prednisone alone relapsed and then received mitoxantrone.
This treatment was associated with improvement in pain relief
and global quality of life. The global quality of life was very
significantly improved by mitoxantrone and lasted longer
according to two different methods of evaluation (EORTC
QLQ-30 and QOLM-P14, a trial-specific module) [44].
Moreover, tolerance was very good with only two cardiac
failures recorded among the 130 patients (average age 68
years) taking mitoxantrone.
Ellerhorst [40] has described another approach that has
shown very interesting results. In his study of 46 patients resistant to flutamide, he employed a regimen of alternated hormonochemotherapy (one week with doxorubicin and ketoconazole,
and the other with vinblastine and estramustine) combined with
daily hydrocortisone. On measurable lesions (soft tissues), he
has obtained 75% response (12 out of 16), a decrease of the levels of PSA of more than 50% among 67% of the patients (38 out
of 46) and a decrease of more than 80% among 52%, and an
improvement in the quality of life among 76%. The median
response has been 8.4 months with an interesting global survival
of 19 months. He has confirmed the prognostic value of the
response (at 18 months, 64% of the responders are alive versus
35% of the nonresponders). Because of these promising results
and the good tolerance, a phase III study has been started for
hormone-sensitive forms. The association of two inhibitors of
microtubules such as vinblastine and estramustine have already
proved their activity [41].
A Japanese study has obtained similar results (8 objective responses out of 14, and a median survival of 18
months) with an association of interferon-α-2a at low doses
and 5-fluorouracil with good tolerance. Unfortunately, the
study involved insufficient numbers of patients to provide
conclusive evidence [45].
terms of pain relief that lasts several months in more than
50% of cases. Some investigators [49] have noted a benefit
in survival. However, strontium 89 may induce transient
increases in bone pain or flare-up within the first few days of
administration. There is also the possibility of thrombocytopenia grade III to IV in more than 20% of cases. It is highly
advisable to employ steroids during at least the first month of
treatment. Samarium 153, a new radionuclide at a dose of 1
mCi/kg, induces pain relief in 62%-72% of patients with no
instances of grade 4 and, rarely, grade 3 myelosuppressive
toxicity [51].
More recently, the combination of ketoconazole with hydrocortisone has been proven to be very active following the
withdrawal of AAs [7]. This provides a dramatic improvement of the quality of life and, when associated with mitoxantrone, a positive effect has also been obtained [42]. Low
doses of steroid therapy alone are active as well [39].
Estrogens like i.v. fosfestrol have the advantage of rapid
activity especially as pain killers [12]. Estramustine is also
active and is often associated with chemotherapy [41]. Its
mechanism of action provides inhibition of microtubules (vinblastine, paclitaxel, etoposide), but the side effects in elderly
patients are worse than those seen with mitoxantrone [31, 40].
In Tannock’s randomized study, this drug provided a very significant improvement to steroid therapy in terms of response
and in terms of quality-of-life criteria, particularly because of
its very good tolerance [42]. The use of chemotherapy at low
doses alternated or associated with various hormonal agents is
another possibility. Ellerhorst [40] has reported on some very
interesting results in terms of duration of response (8.4
months) as well as on global survival (19 months), but also an
incidence of 49% of peripheral edema and 18% incidence of
venous thrombosis linked to estramustine. Consideration
could be given to a therapeutic protocol based on the same
concept but of reduced toxicity by including in Tannock’s protocol vinblastine alternated with mitoxantrone combined with
i.v. fosfestrol.
In cases of multiple painful bone lesions, the therapeutic approach is rather different. Strontium 89, apart from its
myelosuppressive effect (essentially thrombocytopenia), is
well tolerated (steroid therapy is mandatory) with an obvious benefit in terms of quality of life [49]. It also has the
advantage that it may be repeated after three to four
months. Samarium 153 could be more active on painful
lesions and less toxic than strontium 89 [51]. In cases of a
single painful bone lesion, localized external beam radiotherapy is highly effective, with pain relief occurring in
80% of patients [48].
The choice of second-, third-, or even fourth-line treatment is difficult and must be based on the clinical response
of the patient and the precise evolution of the disease. It is
important to realize that clinical reports concerning the
response rates to different treatment regimens vary widely
since evaluation criteria differ considerably from one study
to another [29]. The usual criteria to be considered are PSA
levels (decline in PSA of 50%), measurable lesions (sum of
the products of diameters of all measured lesions), activity
against pain (measured by a visual-analog scale or analgesic consumption), change in weight, quality of life, and
global survival. Among young patients or patients whose
hormone refractory disease developed quickly, there is a
tendency to start chemohormone therapy as a second-line
Downloaded from by guest on June 9, 2014
Metastatic prostate cancer must be treated as quickly as
possible. This is because of the risk of complications, particularly spinal cord compression, increases with time.
Another factor is the recognition that patients in general
appear to favor quality of life rather than length of survival.
A recent randomized study shows a significant benefit of
early treatment compared to delayed treatment based on the
evolution of the disease, its complications, and the survival
related to prostate cancer [9].
Androgen blockade is the treatment of choice, but should
it be total (TAB) or selective? For TAB, which AA should be
used? Castration may be surgical (bilateral orchiectomy) or
medical with LHRH agonists (all the different agonists have
the same activity). The first option has the advantage of its
simplicity, its moderate cost, and its permanence. The second
approach provides the psychological comfort of temporary
castration. Several studies have shown the superiority of TAB
[16, 20, 22, 52] over medical castration alone. The nonsteroidal AA cyproterone acetate has never shown any benefits in survival when associated with medical castration [53].
Surgical castration seems to diminish the benefit of TAB [18].
Intermittent treatment is still under investigation. The first
clinical results indicate that it may delay the occurrence of hormone resistance [24] and that it is not a harmful method
(M. Zerbib, personal communication). In cases of progression
under AA treatment, its withdrawal may bring about a 20%
response (decrease of the values of PSA >50%). This effect
has been observed with various AAs including not only flutamide but also bicalutamide and megestrol acetate [7].
However, the possible benefit lasts only a few months, raising
the question of a second-line treatment: new AA, aromatase
inhibitors, estrogens, or chemotherapy.
Bicalutamide, as a single agent (>150 mg/d), is active
after the failure of flutamide but the contrary has not been
proven [23]. The activity of megestrol acetate is very weak
[7] and less interesting than the aromatase inhibitors. The
association of aminoglutethimide with hydrocortisone is well
tolerated and gives an approximate 50% response rate [54].
Management of Advanced Prostate Cancer
Auclerc, Antoine, Cajfinger et al.
treatment (estramustine). For the other patients, aromatase
inhibitors or estrogens (fosfetrol) are commonly employed,
but single steroid therapy can still be an alternative. In case
of failure or in the presence of painful bone lesions these
treatments may be exchanged, replaced, or combined with
external beam radiotherapy or strontium 89 or samarium
153. In all the cases the balance between tolerance and
effectiveness must be maintained.
The criteria for evaluation of the responses in case of
hormone resistance are at last becoming better understood.
This will allow objective and trustworthy comparisons
between different treatments.
It is clear that the nature and the duration of first-line
treatments such as the use and then withdrawal of AAs may
interfere with second-line hormonal therapy. The use of
chemotherapy alone or combined with hormonal therapy has
provoked renewed interest thanks to revised criteria for treatment evaluation. At the present time, there are not enough
data to choose one second- or even one third-line treatment
over another one. Comparative multicenter studies are currently under way to investigate all the elements of treatment
of prostate cancer. The aim of these large-scale trials is to
provide the best possible care for patients who are often
elderly and debilitated and for whom quality of life, as
defined by the patients themselves, is the principal concern.
1 Petrovich Z, Baert L, Bagshaw MA et al. Adenocarcinoma of
the prostate: innovations in management. Am J Clin Oncol
12 Grise P, Mnif A, Navarra S et al. Traitement par ST52 du cancer de la prostate au stade d’échappement hormonal. Ann Urol
2 Parker SL, Tong T, Bolden S et al. Cancer statistics, 1996.
CA Cancer J Clin 1996;65:5-27.
13 Dahllof B, Billstrom A, Cabral F et al. Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res
3 Richard F. Epidémiologie du cancer de la prostate et ses
implications en santé publique. Rev Prat 1994;44:575-579.
4 Landis SH, Murray T, Bolden S et al. Cancer statistics, 1999.
CA Cancer J Clin 1999;49:8-31.
14 Tew KD, Stearns ME. Hormone independent nonalkylating
mechanism of cytotoxicity for estramustine. Urol Res
5 Dawson NA. Treatment of progressive metastatic prostate
cancer. Oncology 1993;7:17-24.
15 Blackledge G, Kolvenbag G, Nash A. Bicalutamide: a new
antiandrogen for use in combination with castration for patients
with advanced prostate cancer. Anticancer Drugs 1996;7:27-34.
6 Scher HI. Cytotoxic chemotherapy for advanced prostate cancer:
does it work, and if no, how do we prove it? In: Perry MC, ed.
Educational Book, 34th Annual Meeting ASCO; May 16-19,
1998. Los Angeles, CA, 1998:356-367.
16 Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of leuprolide with and without flutamide in prostatic
carcinoma. N Engl J Med 1989;321:419-424.
7 Small EJ, Vogelzang NJ. Second-line hormonal therapy for
advanced prostate cancer: a shifting paradigm. J Clin Oncol
8 Crawford ED, Bennett CL, Stone NN et al. Comparison of perspectives on prostate cancer: analysis of survey data. Urology
9 The Medical Research Council Prostate Cancer Working Party
Investigators Group: immediate versus deferred treatment for
advanced prostatic cancer: initial results of the Medical
Research Council Trial. Br J Urol 1997;79:235-246.
10 Huggins C, Hodges CV. Studies on prostatic cancer. I. The
effects of castration, of œstrogen and of androgen injection
on serum phosphates in metastatic carcinoma of the prostate.
Cancer Res 1941;1:293-297.
11 Byar DP, Corle DK. Hormone therapy for prostate cancer: results
of the Veteran’s Administration Cooperative Urological Research
Group Studies. Natl Cancer Inst Monogr 1988;7:165-170.
17 Denis LJ, Whelan P, Carnerio De Moura JLC et al. Goserelin
acetate and flutamide versus bilateral orchidectomy: a phase
III EORTC Trial (30853). Urology 1993;42:119-130.
18 Crawford ED, Eisenberger MA, McLeod DG et al.
Comparison of bilateral orchidectomy with or without flutamide for the treatment of patients with stage D2 adenocarcinoma of the prostate: results of NCI intergroup study 0105
(SWOG and ECOG). J Urol 1997;157:336a.
19 Prostate Cancer Trialists’ Collaborative Group. Maximum
androgen blockade in advanced prostate cancer: an overview
of 22 randomised trials with 3283 deaths in 5710 patients.
Lancet 1995;346:265-269.
20 Crawford ED, Stenner J, Rosenblum M. Changing concepts
in hormonal therapy. Cancer Invest 1998;16(suppl 1):60-62.
21 Limonta P, Dondi D, Moretti RM et al. Antiproliferative
effects of luteinizing hormone-releasing hormone agonist on
the human prostatic cancer cell line LNCaP. J Clin Endocrinol
Metab 1992;75:207-212.
Downloaded from by guest on June 9, 2014
Over the last few years, important changes have taken
place in the management of metastatic prostate cancer. TAB
seems to bring benefits if castration is medical and the androgen is nonsteroidal, but must TAB be permanent or intermittent in order to improve quality of life without modifying the
vital prognosis? There is an ongoing clinical trial that will try
to answer this question.
22 Caubet JF, Tosteson TD, Dong EW et al. Maximum androgen blockade in advanced prostate cancer: a meta-analysis of
published randomized controlled trials using non steroidal
antiandrogens. Urology 1997;49:71-78.
23 Schellhammer P, Sharifi R, Block N et al. Clinical benefits of
bicalutamide compared with flutamide in combined androgen
blockade for patients with advanced prostatic carcinoma:
final report of a double-blind randomized multicenter trial.
Urology 1997;50:330-336.
24 Akakura K, Bruchovsky N, Goldenberg SL et al. Effects of
intermittent androgen suppression on androgen dependant
tumors. Cancer 1993;71:2782-2790.
25 Taplin ME, Bubley GJ, Shuster TD et al. Mutation of the
androgen receptor gene in metastatic androgen independant
prostate cancer. N Engl J Med 1995;332:1393-1398.
27 Bruchovsky N, Rennie PS, Coldman AJ et al. Effects of
androgen withdrawal on the stem cell composition of the
shionogi carcinoma. Cancer Res 1990;50:2275-2282.
28 Kelly WK, Scher HJ. Prostate specific antigen decline after
antiandrogen withdrawal. The flutamide withdrawal syndrome.
J Urol 1993;149:607-609.
40 Ellerhorst JA, Tu S, Amato RJ et al. Phase II trial of alternating
weekly chemohormone therapy for patients with androgen independant prostate cancer. Clin Cancer Res 1997;3:2371-2376.
41 Hudes G, Roth B, Loehrer P et al. Phase III trial of vinblastine versus vinblastine plus estramustine phosphate for
metastatic hormone refractory prostate cancer (HRPC). Proc
Am Soc Clin Oncol 1997;16:316a.
42 Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with
mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized
trial with palliative end points. J Clin Oncol 1996;14:1756-1764.
43 Moore MJ, Osaba D, Murphy D et al. Use of palliative end
points to evaluate the effects of mitoxantrone and low dose prednisone in patients with hormonally resistant prostate cancer.
J Clin Oncol 1994;12:689-694.
44 Osoba D, Tannock IF, Ernst AS et al. Health-related quality
of life in men with metastatic prostate cancer treated with
prednisone alone or mitoxantrone and prednisone. J Clin
Oncol 1999;17:1654-1663.
45 Shinohara N, Demura T, Matsumura K et al. 5-Fluorouracil
and low dose recombinant interferon alpha-2a in patients with
hormone refractory adenocarcinoma of the prostate. Prostate
46 Diener KM. Biphosphonates for controlling pain from metastatic bone disease. Am J Health Syst Pharm 1996;53:1917-1927.
29 Scher HI, Kelly WK. Flutamide withdrawal syndrome: its
impact on clinical trials in hormone-refractory prostate cancer.
J Clin Oncol 1993;11:1566-1572.
47 Dearnaley DP, Bayly RJ, A’Hern RP et al. Palliation of bone
metastases in prostate cancer: hemibody irradiation or strontium
89? Clin Oncol 1992;4:101-107.
30 Berry WR, Laszlo J, Cox E et al. Prognostic factors in
metastatic and hormonally unresponsive carcinoma of the
prostate. Cancer 1979;44:763-775.
48 Tong D, Gullick L, Hendrickson FR. The palliation of symptomatic osseous metastases: final results of the radiation therapy
oncology group. Cancer 1982;50:893.
31 Scher HI, Steineck G, Kelly WK. Hormone-refractory (D3)
prostate cancer: refining the concept. Urology 1995;46:142-148.
49 Porter AT. Strontium 89 (Metastron) in the treatment of prostate
cancer metastatic to bone. In: Murphy G, Khoury S, Chatelain A
et al., eds. 4th International Symposium on Recent Advances in
Urological Cancer Diagnosis and Treatment. Paris, June 22-24,
32 Eisenberger MA, Abrams JS. Chemotherapy for prostatic
cancer. Semin Urol 1988;6:303-310.
33 Yagoda A. Cytotoxic agents in prostate cancer: an enigma.
Semin Urol 1983;1:311-321.
34 Collste LG. Second line treatment of hormone refractory prostatic cancer patients. EORTC Genito-urinary Groupe
Monograph 1990;7:29-39.
35 Daneshgari F, Crawford ED. Endocrine therapy of advanced
carcinoma of the prostate. Cancer 1993;71:1089-1093.
36 Matzkin H, Soloway MS. Response to second-line hormonal
manipulation monitored by serum PSA in stage D2 prostate
carcinoma. Urology 1992;40:78-80.
37 Kristiansen P, Bergquist D, Janzon L et al. Thromboembolic
side effects of diethyl stilbestrol diphosphate in patients with
prostatic carcinoma. Urol Int 1988;43:44-46.
50 Mertens W, Porter AT, Reid RH et al. Strontium 89 and low dose
infusion cisplatinum for patients with hormone refractory prostate
cancer metastatic to bone. J Nucl Med 1992;33:1437-1443.
51 Serarini AN, Houston J, Resche I et al. Palliation of pain
associated with metastatic bone cancer using samarium-153
lexidronam: a double-blind placebo-controlled clinical trial.
J Clin Oncol 1998;16:1574-1581.
52 Didkman GA, Jauknegt RA, De Reijke TM et al. Long-term
efficacy and safety of Nilutamide plus castration in advanced
prostate cancer and significance of early PSA normalisation.
International Anandron Study Group. J Urol 1997;158:160-163.
38 Catalona WJ. Management of cancer of the prostate. N Engl
J Med 1994;15:996-1004.
53 Thorpe SC, Azmatullah S, Fellow GJ et al. A prospective randomized study to compare gosereline acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus a combination of
the two in the treatment of metastate prostatic carcinome. Eur
Urol 1996;29:47-54.
39 Tannock IF, Gospodarowicz M, Meakin W et al. Treatment of
metastatic prostate cancer patients with low dose prednisone:
evaluation of pain and quality of life as pragmatic indices of
response. J Clin Oncol 1989;7:590-597.
54 Sartor O, Cooper M, Weinberger M et al. Surprising activity of
flutamide withdrawal, when combined with aminoglutethimide
in treatment of “hormone refractory” prostate cancer. J Natl
Cancer Inst 1994;86:222-227.
Downloaded from by guest on June 9, 2014
26 Visakorpi T, Hyytinen E, Koivisto P et al. In vivo amplication of the androgen receptor gene and progression of human
prostate cancer. Nat Genet 1995;9:401-405.
Management of Advanced Prostate Cancer
This article has been cited by 5 HighWire-hosted articles:
Downloaded from by guest on June 9, 2014