Urol Clin N Am 33 (2006) 227–236
`
`Changing Perspectives of the Role of Chemotherapy
`in Advanced Prostate Cancer
`Earle F. Burgess, MD, Bruce J. Roth, MD*
`Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center,
`Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA
`
`The use of cytotoxic chemotherapy in ad-
`vanced prostate adenocarcinoma has been vali-
`dated by the recent demonstration of survival
`benefit in two large randomized phase III trials
`[1,2]. Before publication of these landmark trials,
`SWOG 9916 and TAX 327, no chemotherapeutic
`regimen had shown survival benefit in the treat-
`ment of androgen independent prostate cancer
`(AIPC). These trials provide new encouragement
`for the use of chemotherapy in all stages of dis-
`ease. Improved communication between medical
`and urologic oncologists and early patient referral
`for clinical trial participation remains essential for
`identifying new chemotherapeutic regimens with
`improved activity in AIPC and for defining the
`role of chemotherapy in earlier-stage disease.
`This article discusses the role of chemotherapy
`as the current standard of care for the treatment
`of AIPC and provides a historical perspective
`of the trials that preceded the development of
`current docetaxel-based regimens.
`
`Chemotherapy for AIPC
`
`Trials from the National Prostatic Cancer
`Project era
`
`In the 1980s, the National Prostatic Cancer
`Project (NPCP) conducted the largest series to
`date of phase II trials involving single and
`combinational cytotoxic agents in AIPC. The
`results of the NPCP and other early trials have
`
`* Corresponding author.
`E-mail address: bruce.roth@vanderbilt.edu
`(B.J. Roth).
`
`previously been reviewed and heavily criticized for
`erroneously concluding that many of the tested
`agents possessed clinically significant activity
`[3–6]. Although the trials were not designed to
`study impact on survival, patient median survival
`was generally no better than best supportive care,
`even though the response rates often exceeded
`50% with some regimens. The underlying biology
`and difficulties associated with studying advanced
`prostate cancer can explain the misleading conclu-
`sions drawn from some of the trials. The classic
`objective criteria for gauging tumor response in
`phase II trials continue to be bidimensional mea-
`surement of solid tumor lesions before and after
`therapy. Because prostate cancer often metasta-
`sizes to bone only, assessment of tumor response
`after therapy in AIPC has been difficult to achieve
`in an objective and reproducible manner. Imaging
`modalities do not provide accurate bidimensional
`measurement of skeletal lesions, and, before the
`routine use of serum prostate specific antigen
`(PSA) as a surrogate marker, the methodologic
`challenges of measuring tumor response were
`well recognized. Faced with these limitations, the
`NPCP-era trial investigators used response crite-
`ria that were often subjective and that lacked the
`specificity to provide accurate assessment of
`drug activity. For example, the presence of ‘‘sta-
`ble’’ disease, as defined by the absence of progres-
`sion on bone scan and acid phosphatase levels
`after 12 weeks of therapy, was included as one cri-
`terion for drug response in the NPCP guidelines
`[7]. The trials did show that patients who had
`‘‘stable’’ disease had longer median survival than
`those who had progressed, but they did not distin-
`guish whether disease stability was a result of
`treatment or reflected the underlying biology of
`
`0094-0143/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
`doi:10.1016/j.ucl.2005.12.006
`
`urologic.theclinics.com
`
`JANSSEN EXHIBIT 2031
`Mylan v. Janssen IPR2016-01332
`
`

`

`228
`
`BURGESS & ROTH
`
`disease in those patients [8]. In the NPCP trials,
`approximately 90% of
`the patient
`responses
`were classified as ‘‘stable disease’’
`[4]. Because
`this response criterion is hardly specific for drug
`effect, false ‘‘activity’’ was incorrectly attributed
`to drugs that ultimately were shown to lack clini-
`cal benefit.
`
`Mitoxantrone
`
`After the NPCP and other trials of the 1980s,
`much debate existed over how best to measure
`tumor response in AIPC clinical trials. At the
`time, the general attitude regarding the use of
`chemotherapy in this setting was pessimistic and
`shared by urologists and oncologists alike. How-
`ever, in the 1990s, the use of post-treatment serum
`PSA decline was validated as a surrogate marker
`for drug activity, and trialists were hopeful that
`PSA response could provide a much needed
`objective criterion that was reproducible and
`could be used in patients who had isolated skeletal
`disease [9,10]. Measurement of PSA response, as
`defined by a O50% decline from pretreatment
`baseline, solved key problems from earlier trials
`and established an end point in subsequent trials
`that more accurately reflected drug activity.
`After acknowledgment of
`limited response
`criteria before the routine use of PSA decline,
`investigators considered palliation of symptoms as
`a primary endpoint in trials of cytotoxic agents.
`The idea originated in the AIPC setting after low-
`dose prednisone was shown to improve pain
`symptoms and quality of life [11]. Although PSA
`response has limitations, its superiority over his-
`torical standards quickly established this criterion
`as a gold standard for drug activity in phase II
`trials. Mitoxantrone, a member of the anthra-
`cenedione
`class
`that
`interacts with DNA
`topoisomerase II, was selected for evaluation of
`palliative ability based on a favorable side effect
`profile in elderly patients from an earlier phase
`II study [12–14]. Based on palliative endpoints,
`two phase III trials established that the addition
`of mitoxantrone provided superior response over
`glucocorticoids alone [15–17]. Mitoxantrone sub-
`sequently became the first cytotoxic agent ap-
`proved by the FDA for use in AIPC and was
`approved for palliative treatment based on these
`trials. After FDA approval, mitoxantrone re-
`mained first-line standard of care in symptomatic
`patients before the approval of docetaxel.
`Mitoxantrone provides effective palliative ther-
`apy. Although PSA response rates ranged from
`
`33% to 48% in three phase III trials, a survival
`advantage over best supportive care has never
`been shown [16–18]. Additional phase II trials
`have explored the feasibility of mitoxantrone in
`combination with other cytotoxic agents or as se-
`quential therapy with docetaxel-based regimens
`[19–23]. However, many of these studies accrued
`taxane-naive patients and need to be re-evaluated
`because docetaxel has been approved as first-line
`therapy. Recent trials have also studied the use
`of mitoxantrone in the second-line setting after
`patients have failed initial taxane therapy, al-
`though data suggest
`limited activity [24–26].
`Based on the promise of docetaxel-based regimens
`(see below), the role of mitoxantrone will likely
`continue to diminish.
`
`Estramustine
`
`Estramustine is a synthetic conjugate of estra-
`diol and a nitrogen mustard that was rigorously
`studied in the NPCP trials and found to have
`modest activity [4,27]. Although the drug was de-
`signed to target delivery of the mustard conjugate
`to malignant cells that overexpressed sex hormone
`receptors, estramustine acts through binding mi-
`crotubule-associated proteins and inducing micro-
`tubule destabilization [27,28]. Preclinical studies
`suggest that combination of estramustine with
`other antimicrotubule agents could potentiate
`a cytotoxic effect in vivo [29,30]. These observa-
`tions provided the scientific rationale for a large
`number of clinical studies of estramustine com-
`bined with other antimicrotubule agents. Many
`of these trials consistently showed that the addi-
`tion of estramustine improved PSA response rates
`over single-agent therapy in the phase II setting
`[31–49]. Finally, the activity of an estramustine-
`containing doublet was definitively established
`by the SWOG 9916 phase III trial, which reported
`a prolongation of survival in patients who had
`AIPC treated with docetaxel and estramustine
`(D/E). SWOG 9916 was not designed to evaluate
`the contribution of each drug to the regimen. The
`TAX 327 phase III trial evaluating the docetaxel/
`prednisone (D/P) doublet showed a similar sur-
`vival benefit in the docetaxel-treated arm. The
`results from the TAX 327 trial (see below) suggest
`that
`the efficacy of estramustine in the D/E
`doublet is limited and that the survival benefit is
`primarily due to docetaxel.
`Estramustine is associated with the develop-
`ment of thromboembolic events in up to 25% of
`treated individuals [50]. Despite this risk, interest
`
`

`

`CHEMOTHERAPY IN ADVANCED PROSTATE CANCER
`
`229
`
`in combining the drug with other agents persists
`[19,51–53]. Many of these trials were written be-
`fore the results of TAX 327 and SWOG 9916
`were known. Given the risk for thromboembolism
`and limited contribution to docetaxel-based regi-
`mens, the continued use of estramustine must be
`questioned.
`
`Taxanes
`
`In the combination phase II studies involving
`estramustine, the taxanes had some of the highest
`activity among the classes tested. The early-phase
`trials involving paclitaxel and docetaxel have
`previously been reviewed in detail and are sum-
`marized here [54]. Single-agent paclitaxel has
`shown limited activity in AIPC, with PSA re-
`sponse ranging from 0% to 39% and measurable
`disease responses ranging from 4% to 50% de-
`pending on the administration schedule [55,56].
`In these studies, weekly dosing provided better re-
`sponse rates than every-3-week administration, al-
`though 33% of patients experienced grade 3
`neuropathy [55].
`Based on the synergism observed in preclinical
`models [29], multiple phase II studies evaluated re-
`sponse rates of the paclitaxel/estramustine (P/E)
`doublet [35–38]. One study combined 96-hour
`paclitaxel infusion every 3 weeks with oral estra-
`mustine and reported a 53% PSA response rate
`without any grade 3 neuropathy [35]. This study
`provided evidence that optimized paclitaxel dos-
`ing combined with estramustine could produce
`meaningful
`responses without excess
`toxicity.
`Other trials using lower doses of weekly paclitaxel
`in combination with estramustine observed PSA
`response rates ranging 42% to 60% with signifi-
`cantly less grade 3 neuropathy than the original
`single-agent study [37,38]. Higher-dose weekly
`paclitaxel in combination with estramustine failed
`to improve outcome in one trial that reported
`a 62% PSA response accompanied by grade 3
`neuropathy in 21% of patients [36].
`Docetaxel is a semisynthetic taxane that has
`been shown to have greater preclinical activity than
`paclitaxel [57]. Single-agent phase II studies have
`been conducted using weekly and every-3-week
`dosing schedules. In two studies, every-3-week dos-
`ing resulted in PSA response rates of 38% to 46%,
`and one of the studies reported a median survival
`of 27 months [58,59]. Three trials examined weekly
`administration of docetaxel and reported PSA
`response rates ranging from 41% to 48%, with me-
`dian survival ranging from 9 to 20 months [60–62].
`
`In general, single-agent docetaxel phase II
`studies showed improved activity and toxicity
`profiles over single-agent paclitaxel. Because the
`addition of estramustine to paclitaxel improved
`response rates in phase I/II trials, the combination
`of estramustine and docetaxel has also been
`examined. One small trial based on a weekly
`dosing schedule reported a 72% PSA response
`rate with median survival of 16 months, which
`suggested that,
`like paclitaxel, the addition of
`estramustine to docetaxel may provide better
`response rates than docetaxel alone [63]. Grade
`1–3 neutropenia was noted to be 17% in this study.
`Alternatively, phase I/II D/E doublets based on
`every-3-week dosing have shown PSA responses
`of 45% to 74%, measurable soft tissue response
`rates from 20% to 57%, and a median survival
`reported in two trials to be 20 to 23 months
`[32,33,64–66]. Grade 3–4 neutropenia ranged
`from 56% to 75% in these studies. Although
`greater myelosuppression was observed in studies
`based on every-3-week docetaxel administration,
`rates of neutropenic fever were low. These early
`docetaxel trials seemed to favor every-3-week ad-
`ministration, and the superiority of every-3-week
`dosing was clearly established in the two pivotal
`phase III trials discussed below.
`
`SWOG 9916
`
`In October 2004, two randomized phase III
`trials concurrently reported a modest survival
`advantage
`from docetaxel-based therapy
`in
`AIPC [1,2]. These trials ushered in a new era of ex-
`citement for the use of cytotoxic regimens because
`they marked the first time any chemotherapeutic
`agent has demonstrated a survival advantage in
`this disease setting. SWOG 9916 [2] was the first
`of these trials that compared D/E against the pre-
`vious standard of care mitoxantrone and predni-
`sone (M/P). The significant activity of D/E
`noted in combination phase I/II trials mentioned
`previously served as the basis for this trial. Overall
`survival was the primary endpoint, and the trial
`was powered to detect a 33% survival improve-
`ment in the D/E arm over the M/P arm. Progres-
`sion-free survival, PSA, and measurable response
`rates were secondary endpoints. Patients were
`randomized to receive one of the following 21-
`day regimens: (1) estramustine 280 mg three times
`a day on days 1 through 5, docetaxel 60 mg/m2 on
`day 1 and 60 mg of dexamethasone over three di-
`vided doses starting the night before docetaxel;
`or (2) mitoxantrone 12 mg/m2 on day 1 plus
`
`

`

`230
`
`BURGESS & ROTH
`
`prednisone 5 mg twice daily. Doses were increased
`to docetaxel 70 mg/m2 and mitoxantrone 14 mg/m2
`on subsequent cycles if no grade 3–4 toxicities
`were noted in the initial cycle.
`Of the 674 eligible patients in the study, 338
`received D/E, and 336 received M/P. The median
`patient age was 70 years, and approximately 90%
`of both arms were SWOG performance status
`0 or 1. The median PSA (ng/ml) was 84 and 90 in
`the D/E and M/P arms, respectively. Bone pain
`less than grade 2 was reported in 64% of both
`arms. Although the study did not achieve the
`primary endpoint of demonstrating a 33% im-
`provement in survival between the two treatment
`arms, intention-to-treat analysis revealed a median
`survival of 17.5 months among patients receiving
`D/E and 15.6 months among patients receiving
`M/P (P ¼ .02). Along with the TAX 327 trial dis-
`cussed below, the 2-month median survival ad-
`vantage noted in this study represented the first
`survival benefit from chemotherapy in patients
`with AIPC. The hazard ratio for death in this trial
`was 0.8 (95% confidence interval, 0.67–0.97), so
`during the study, the risk of death was reduced
`by 20% in the docetaxel-treated group. Analysis
`of secondary endpoints further supported the
`advantage of D/E therapy: Median time to pro-
`gression was 6.3 months in the D/E arm versus
`3.2 months in the M/P arm (P !.001). PSA
`response rates were 50% in D/E group and 27%
`in M/P group (P ! .001). Partial response of mea-
`surable disease and subjective pain relief rates
`were not statistically different between the two
`treatment groups. Withdrawal rates for adverse
`events were 16% in the D/E arm and 10% in
`the M/P arm. Eight and four treatment-related
`deaths occurred in the D/E and M/P arms, respec-
`tively. Grade 3–4 neutropenia occurred in 12.5%
`versus 16.1% of patients in the M/P and D/E
`arms, respectively, although the difference was
`not statistically significant (P ¼ .22). The rate of
`severe neutropenia in patients treated with D/E
`was markedly lower than seen in the earlier-phase
`trials, and the rate of neutropenic fever was only
`5% in this group.
`The results from SWOG 9916 showed that
`combination of docetaxel and estramustine pro-
`longs median survival by 2 months and reduces
`the risk for death relative to mitoxantrone and
`prednisone. The median survival of 15.6 months in
`the control group was approximately 3.5 months
`longer than reported in earlier phase III trials that
`studied a similar regimen of mitoxantrone and
`prednisone [16,17]. Higher tumor burden in the
`
`patients of the earlier trials may account for this
`difference because the previously studied patients
`had symptomatic disease and slightly higher me-
`dian PSA values (150–158 ng/ml). Nonetheless,
`the SWOG 9916 trial definitively established that
`docetaxel-based therapy every 3 weeks prolongs
`median survival and reduces the risk of death.
`These results were complemented by the TAX
`327 trial and immediately set a new standard of
`care for first-line therapy in patients who have
`AIPC.
`
`TAX 327
`
`The TAX 327 trial, reported concurrently with
`SWOG 9916, was a randomized phase III study
`that compared dose-equivalent docetaxel given on
`a weekly basis or every 3 weeks with prednisone
`against mitoxantrone given every 3 weeks [1].
`Notable differences of this trial compared with
`SWOG 9916 include the addition of a weekly do-
`cetaxel arm and the absence of estramustine in the
`docetaxel arms. As in the SWOG trial, the pri-
`mary endpoint of this study was to detect an over-
`all
`survival advantage in the docetaxel arm
`compared with the mitoxantrone control arm.
`Secondary endpoints in this trial differed slightly
`and included measurement of pain levels, quality
`of life (measured by the FACT-P questionnaire),
`PSA, and measurable soft tissue responses. Like
`the SWOG trial, inclusion criteria required pro-
`gressive AIPC measured radiographically and
`biochemically, ongoing androgen-ablation ther-
`apy, and prior cessation of antiandrogen ther-
`apy. Patients were randomized to receive one of
`the following treatment regimens: (1) docetaxel
`75 mg/m2 every 3 weeks (D/P), (2) docetaxel
`30 mg/m2 every week (wD/P), or (3) mitoxantrone
`12 mg/m2 every 3 weeks (M/P). All patients
`received prednisone 5 mg twice daily, and patients
`receiving docetaxel were premedicated with dexa-
`methasone. The impact of dexamethasone on
`treatment response in the docetaxel arms has
`previously been suggested not to contribute to
`the treatment response [67].
`Of the 1006 patients enrolled in the trial, 332,
`330, and 335 were treated with D/P, wD/P, and
`M/P, respectively. In each of the three arms, the
`median patient age was 68 to 69 years, and 12%
`to 14% of patients had Karnofsky performance
`status !80%. The median serum PSA value in
`the three treatment arms ranged from 108 to
`123 ng/ml, and approximately 45% of patients
`had pain. Ninety percent of patients had known
`
`

`

`CHEMOTHERAPY IN ADVANCED PROSTATE CANCER
`
`231
`
`bone metastases, and 40% had measurable soft-
`tissue lesions. Based on intention-to-treat analysis,
`the median durations of
`survival were 18.9
`months in the every-3-week docetaxel arm, 17.4
`months in the weekly docetaxel arm, and 16.5
`months in the mitoxantrone arm. Only the every-
`3-week docetaxel regimen was demonstrated to
`have a statistically significant survival benefit
`compared with mitoxantrone. The hazard ratio
`for death using this regimen was 0.76 (95%
`confidence interval, 0.62–0.94), which confirmed
`the mortality reduction seen in the SWOG trial
`with every-3-week docetaxel/estramustine. Analy-
`sis of secondary endpoints showed reduced pain in
`35% (P ¼ .01), 31% (P ¼ .08), and 22% of pa-
`tients treated with D/P, wD/P, and M/P, respec-
`tively. Quality of life improvement was noted in
`22% (P ¼ .009), 23% (P ¼ .005), and 13% of pa-
`tients treated with D/P, wD/P, and M/P, respec-
`tively. D/P provided superior palliation relative
`to the prior standard M/P, whereas, pain reduc-
`tion in patients treated with weekly D/P was not
`different from those treated with M/P. Based on
`these results, the use of weekly D/P for palliative
`intent only may be appropriate if the toxicity
`profile precludes use of every-3-week docetaxel.
`However, based on the survival advantage, every-
`3-week docetaxel is the preferred first-line standard
`regimen. The PSA response to treatment was
`45% (P ! .001) in the D/P, 48% (P ! .001) in
`the wD/P, and 32% in the M/P arms (see below).
`Grade 3–4 neutropenia was seen in 32% (P %
`.05) of patients treated with D/P, in 2% (P %
`.0015) of patients treated with wD/P, and in 35%
`of patients treated with M/P, although only 3%
`of D/P-treated patients had febrile neutropenia.
`Common adverse events with D/P that occurred
`more frequently with every-3-week administration
`included fatigue, diarrhea, alopecia, and neuropa-
`thy. Three of five treatment-related deaths occurred
`in the mitoxantrone group.
`The results of TAX 327 confirmed the findings
`of SWOG 9916 by demonstrating a 2-month
`survival advantage and a 20% mortality reduction
`over the study period in patients who had AIPC
`treated with docetaxel every 3 weeks. Weekly
`docetaxel was not associated with a statistically
`significant survival advantage, although this regi-
`men demonstrated pain reduction equivalent to
`the historical standard of mitoxantrone and pred-
`nisone. Every-3-week docetaxel was accompanied
`by a slightly worse toxicity profile than mitoxan-
`trone and prednisone, although treatment-related
`deaths were essentially the same in all arms. The
`
`survival advantage associated with every-3-week
`docetaxel reported in the TAX 327 and SWOG
`9916 trials represent independent confirmation
`from two large, randomized phase III trials that
`cytotoxic chemotherapy with an acceptable toxic-
`ity profile can prolong life in patients with AIPC.
`These two trials provide new excitement for the use
`of cytotoxic chemotherapy in patients who have
`AIPC and establish a foundation on which to
`develop improved regimens. The urologist will
`continue to play a critical role in defining better
`cytotoxic regimens by early referral to medical
`oncologists for participation in clinical
`trials.
`Although these trials report a modest survival
`improvement, they herald greater potential activ-
`ity with future regimens. Many trials have been
`designed based on the results of TAX 327 and
`SWOG 9916, and expectations for future survival
`gains in AIPC are optimistic.
`
`PSA response as surrogate marker
`for clinical benefit
`
`Post-treatment serum PSA decline of at least
`50% of pretreatment baseline has been suggested
`as a surrogate marker of survival benefit in phase
`II trials [9,10,68,69]. One interesting observation
`from the TAX 327 trial is the failure of PSA re-
`sponse to predict the proven survival advantage.
`Only 45% of patients in the every-3-week doce-
`taxel arm experienced a post-therapy PSA decline
`of at least 50% despite a 2.4-month prolongation
`of survival. Follow-up analysis by the TAX 327
`investigators further confirmed that the PSA re-
`sponse only partly explained the observed survival
`benefit [70]. Because 50% of patients treated with
`D/E in SWOG trial had at least a 50% reduction
`in post-treatment PSA, these results suggest that
`the addition of estramustine serves only to im-
`prove PSA response rates without additive sur-
`vival benefit. This suggestion is supported by
`a recent randomized phase II study comparing
`every-3-week docetaxel with docetaxel plus estra-
`mustine that showed a PSA response in 68% of
`patients treated with D/E compared with only
`29% of those treated with docetaxel alone [71].
`Based on PSA response, results from this phase
`II trial imply that every-3-week D/E should have
`far greater clinical benefit than docetaxel alone
`and that every-3-week docetaxel alone should
`not produce any survival benefit. The results of
`TAX 327 prove otherwise and highlight an impor-
`tant limitation with the use of post-treatment PSA
`decline as a surrogate marker in phase II studies.
`
`

`

`232
`
`BURGESS & ROTH
`
`The TAX 327 trial showed that PSA response
`lacks sufficient sensitivity as a marker of survival
`benefit in phase II trials to exclude drugs from ad-
`ditional phase III testing. Because a better phase
`II surrogate marker does not exist, the use of
`post-treatment PSA response should not be aban-
`doned in future trials at this time. However, this
`marker should not serve as the sole criteria for ex-
`cluding drugs from further phase III analysis.
`
`Future directions in AIPC
`
`Current and future clinical trials in AIPC are
`based on two fundamental paradigms. The search
`for novel agents with improved activity continues,
`and such agents have been recently reviewed [72].
`A larger number of trials seek to use docetaxel as
`a component of doublet therapy in combination
`with an investigational agent. An account of all
`docetaxel-based combinations under investigation
`is beyond the scope of this article; however, a few
`examples are mentioned. Bevacizumab is an anti-
`vascular endothelial growth factor monoclonal
`antibody that has shown synergistic activity in
`combination with traditional cytotoxic agents in
`other solid tumors [73,74]. Encouraging phase II
`data from patients treated with docetaxel, estra-
`mustine, and bevacizumab [75] led to the creation
`of cooperative group CALGB 90401 trial, which
`is an open phase III protocol randomizing partic-
`ipants to docetaxel/prednisone with or without
`bevacizumab. Synergy between docetaxel and
`antiangiogenic therapies has been further sug-
`gested by results from a phase II trial of docetaxel
`and thalidomide in which 51% of patients receiv-
`ing combined treatment had a PSA response ver-
`sus 37% of patients receiving docetaxel alone [76].
`The addition of high-dose calcitriol to docetaxel
`has recently garnered much interest based on fa-
`vorable preclinical studies and phase II results of
`weekly docetaxel plus high-dose pulse calcitriol
`[77,78]. These data led to the creation of the ran-
`domized, double-blind, placebo-controlled AS-
`CENT trial, which asked whether calcitriol adds
`to the effect of weekly docetaxel on serum PSA re-
`sponse [79]. Recent analysis of the trial showed
`a failure to achieve its primary goal [80]. Altho-
`ugh the data indicated a trend toward improved
`survival, the study was not powered to detect
`a survival advantage. Additional studies have
`examined the impact of calcitriol on alternate
`docetaxel-based regimens [51], although no benefit
`has been confirmed in a randomized phase III
`trial, so clinical use should be limited to the
`
`investigational setting. Given the large number
`of open trials seeking to improve docetaxel-based
`therapy with novel combinations, oncologists are
`likely to have multiple active options for the treat-
`ment of AIPC in the coming years.
`
`Chemotherapy in the nonmetastatic setting
`
`Strong interest lies in whether earlier stages of
`disease ranging from the neoadjuvant setting to
`biochemical failure can gain survival benefit from
`cytotoxic therapy. Multiple pilot studies have
`shown that docetaxel-based therapy is safe and
`active in earlier stages of disease [81–87]. These
`and other trials have served as the basis for larger
`randomized phase III trials seeking to define the
`activity of chemotherapy in earlier stages of dis-
`ease. For example, the adjuvant TAX 3501 (AT-
`LAS) trial scheduled to open this fall is a large
`international phase III trial planning to enroll
`over 2000 patients with high risk for relapse after
`radical prostatectomy. Patients with a predicted
`risk of biochemical failure within 3 years of sur-
`gery will be randomized to receive 18 months of
`leuprolide with or without docetaxel or receive de-
`ferred treatment after radical prostatectomy. The
`primary endpoint of the trial is progression-free
`survival, and secondary endpoints include overall
`survival and cancer-specific survival.
`Progress in the nonmetastatic setting has been
`hindered by poor accrual to the large, cooperative
`group studies, which has resulted in the premature
`termination of the RTOG 0014 and ECOG 1899
`trials. These two phase III trials were designed to
`examine the role of chemotherapy in the setting of
`PSA relapse after local therapy but only enrolled
`2% of target accrual. The anemic participation
`recently seen in the large cooperative group trials
`has been a subject of much debate [88]. It is unfor-
`tunate that lack of physician interest has plagued
`the nonmetastatic trials because the pilot studies
`have shown tolerable drug activity and raise critical
`clinical questions that require large phase III trials
`for proper answers. As patients become more savvy
`and seek other therapies for earlier-stage disease,
`medical and urologic oncologists have an unprece-
`dented need to communicate and to facilitate
`enrollment in clinical trials to obtain the much-
`needed answers to pressing clinical questions.
`
`Summary
`
`This article summarizes the historical perspec-
`tive of clinical trials in androgen independent
`
`

`

`CHEMOTHERAPY IN ADVANCED PROSTATE CANCER
`
`233
`
`prostate cancer. In October of 2004, the results
`from TAX 327 and SWOG 9916, two large,
`randomized, phase III trials, independently con-
`firmed that every-3-week docetaxel-based therapy
`produces a modest survival benefit and immedi-
`ately established docetaxel as first-line standard
`treatment. These trials reported the first survival
`benefit from cytotoxic therapy seen in the treat-
`ment of AIPC and led to the FDA approval of
`docetaxel in this setting. Multiple clinical trials are
`ongoing in attempts to extend the survival benefits
`gained from docetaxel in AIPC and to define the
`role of cytotoxic therapy in earlier stages of
`disease. Improved collaboration between medical
`and urologic oncologists is essential to facilitate
`clinical trial enrollment so that answers can be
`learned to important clinical questions regarding
`optimal management of all stages of disease.
`
`References
`
`[1] Tannock IF, de Wit R, Berry WR, et al. Docetaxel
`plus prednisone or mitoxantrone plus prednisone
`for advanced prostate cancer. N Engl J Med 2004;
`351:1502–12.
`[2] Petrylak DP, Tangen CM, Hussain MH, et al. Doce-
`taxel and estramustine compared with mitoxantrone
`and prednisone for advanced refractory prostate
`cancer. N Engl J Med 2004;351:1513–20.
`[3] Elder JS, Gibbons RP. Results of trials of the USA
`National Prostatic Cancer Project. Prog Clin Biol
`Res 1985;185A:221–42.
`[4] Eisenberger MA, Simon R, O’Dwyer PJ, et al. A
`reevaluation of nonhormonal cytotoxic chemother-
`apy in the treatment of prostatic carcinoma. J Clin
`Oncol 1985;3:827–41.
`[5] Tannock IF. Is there evidence that chemotherapy is
`of benefit to patients with carcinoma of the prostate?
`J Clin Oncol 1985;3:1013–21.
`[6] Yagoda A, Petrylak D. Cytotoxic chemotherapy for
`advanced hormone-resistant prostate cancer. Can-
`cer 1993;71(Suppl):1098–109.
`[7] Murphy GP, Slack NH. Response criteria for the
`prostate of the USA National Prostatic Cancer Pro-
`ject. Prostate 1980;1:375–82.
`[8] Slack NH, Brady MF, Murphy GP. A reexamina-
`tion of the stable category for evaluating response
`in patients with advanced prostate cancer. Cancer
`1984;54:564–74.
`[9] Kelly WK, Scher HI, Mazumdar M, et al. Prostate-
`specific antigen as a measure of disease outcome in
`metastatic hormone-refractory prostate
`cancer.
`J Clin Oncol 1993;11:607–15.
`[10] Bubley GJ, Carducci M, Dahut W, et al. Eligibil-
`ity and response guidelines for phase II clinical
`trials in androgen-independent prostate cancer:
`recommendations
`from the
`Prostate-Specific
`
`Antigen Working Group. J Clin Oncol 1999;17:
`3461–7.
`[11] Tannock I, Gospodarowicz M, Meakin W, et al.
`Treatment of metastatic prostatic cancer with low-
`dose prednisone: evaluation of pain and quality of
`life as pragmatic indices of response. J Clin Oncol
`1989;7:590–7.
`[12] Osborne CK, Drelichman A, Von Hoff DD, et al.
`Mitoxantrone: modest activity in a phase II trial in
`advanced prostate cancer. Cancer Treat Rep 1983;
`67:1133–5.
`[13] Koeller J, Eble M. Mitoxantrone: a novel anthracy-
`cline derivative. Clin Pharm 1988;7:574–81.
`[14] Moore MJ, Osoba D, Murphy K, et al. Use of palli-
`ative end points to evaluate the effects of mitoxan-
`trone and low-dose prednisone in patients with
`hormonally resistant prostate cancer. J Clin Oncol
`1994;12:689–94.
`[15] Osoba D, Tannock IF, Ernst DS, Neville AJ.
`Health-related quality of life in men with metastatic
`prostate cancer treated with prednisone alone or
`mitoxantrone and prednisone. J Clin Oncol 1999;
`17:1654–63.
`[16] Tannock IF, Osoba D, Stockler MR, et al. Chemo-
`therapy with mitoxantrone plus prednisone or pred-
`nisone alone for symptomatic hormone-resistant
`prostate cancer: a Canadian randomized trial with
`palliative end points. J Clin Oncol 1996;14:1756–64.
`[17] Kantoff PW, Halabi S, Conaway M, et al. Hydro-
`cortisone with or without mitoxantrone in men
`with hormone-refractory prostate cancer: results of
`the cancer and leukemia group B 9182 study.
`J Clin Oncol 1999;17:2506–13.
`[18] Berry W, Dakhil S, Modiano M, et al. Phase III
`study of mitoxantrone plus low dose prednisone ver-
`sus low dose prednisone alone in patients with
`asymptomatic hormone refractory prostate cancer.
`J Urol 2002;168:2439–43.
`[19] Samelis GF, Kalofonos H, Adamou A, et al. The
`combination of estramustine, vinorelbine, and
`mitoxantrone
`in
`hormone-refractory
`prostate
`cancer: a Phase II feasibility study conducted by
`the Hellenic Cooperative Oncology Group. Urology
`20