Docetaxel in the Integrated Management of Prostate Cancer

June 1, 2002
Christopher J. Logothetis, MD

Oncology, ONCOLOGY Vol 16 No 6, Volume 16, Issue 6

Docetaxel (Taxotere)-based regimens can be included among the most effective treatment options for the management of patients with advanced, androgen-independent prostate cancer. Results with docetaxel as a single agent and in combination regimens with estramustine (Emcyt) have consistently achieved a palliative response, reduced serum PSA levels by 50% or more, and produced objective responses in patients with measurable disease. In addition, encouraging survival data have been demonstrated in several phase II trials.

ABSTRACT: Docetaxel (Taxotere)-based regimens can be included among the most effective treatment options for the management of patients with advanced, androgen-independent prostate cancer. Results with docetaxel as a single agent and in combination regimens with estramustine (Emcyt) have consistently achieved a palliative response, reduced serum PSA levels by 50% or more, and produced objective responses in patients with measurable disease. In addition, encouraging survival data have been demonstrated in several phase II trials. The ability to administer docetaxel on a weekly basis has substantially enhanced research efforts for treatment in prostate cancer patients. The results of ongoing phase III randomized trials evaluating docetaxel regimens in androgen-independent prostate cancer are eagerly awaited for their potential to definitively demonstrate a beneficial impact on overall patient survival. Docetaxel-containing regimens are likely to demonstrate a substantial role in the management of early-stage prostate cancer patients in the adjuvant and neoadjuvant settings, where clinical investigations are under way. In addition, study results from ongoing trials that integrate docetaxel with hormonal therapies for patients with biochemical recurrence following definitive local treatments will be important in refining the future role of chemotherapy for prostate cancer in general. The preliminary findings from studies conducted with docetaxel are encouraging and await final analysis. Finally, preliminary results from studies exploring combination regimens of docetaxel and novel agents that possess completely different mechanisms of action (eg, proapoptotic agents, angiogenesis inhibitors, and vitamin D analogs) have demonstrated the regimens to be feasible and safe, with promising early response data. These types of investigational studies will likely occupy a dominant position in future research initiatives for patients with advanced prostate cancer. [ONCOLOGY 16(Suppl 6):63-72, 2002]

The clinical approach to patients with advancedprostate cancer has evolved rapidly with the confirmation that cytotoxicchemotherapy can improve patient outcomes. The documentation that chemotherapycan improve quality of life altered the long-held belief that cytotoxic therapyhad no role for hormone-refractory disease. In fact, chemotherapy is used on aroutine basis because of such convincing data.[1] The scope of clinical researchfor chemotherapy in prostate cancer has broadened from initial trials inpretreated patients with advanced disease to neoadjuvant trials in patients withearly-stage disease. The current goals of chemotherapeutic research strategiesare

  • improving the efficacy of existing therapies by optimizing dose andschedule,

  • integrating cytotoxic therapy earlier into the treatment of prostatecancer patients in conjunction with surgery, androgen ablation, and/or radiationtherapy,

  • and combining cytotoxic therapy with agents that possess novel mechanismof action (eg, tyrosine kinase inhibitors, angiogenesis inhibitors, proapoptotictherapies, bone targeting therapies, and proteosome inhibitors).

Summarized in this article is the historical evidence to support the efficacyof chemotherapy in androgen-independent prostate cancer in general. Therationale and specific data to support the clinical efficacy of docetaxel (Taxotere)are presented, and strategies to integrate docetaxel earlier into the managementof prostate cancer patients are discussed. Finally, novel investigationalcombinations with docetaxel under exploration are reviewed.

Historical Development of Chemotherapy in Prostate Cancer

Major changes in the clinical management of patients with advanced,androgen-independent (hormone-refractory) prostate cancer resulted from thedemonstration that patient outcome could improve significantly fromchemotherapy. A beneficial palliative effect and improved quality of life wasdemonstrated in symptomatic, androgen-independent prostate cancer patientstreated with cytotoxic therapies that utilized mitoxantrone (Novantrone) ordoxorubicin in combination regimens. Palliation of disease and/or improvedquality of life were demonstrated with mitoxantrone/prednisone andmitoxantrone/hydrocortisone in two phase III randomized trials that compared thechemotherapy-hormone combination vs hormonal therapy alone.[2,3] The findingscontrasted with historical data on single-agent cytotoxic therapy, which did notdemonstrate a significant evidence of benefit.

The investigation of chemotherapy for prostate cancer has also beensubstantially influenced by the ability to use serum prostate-specific antigen(PSA) as a surrogate end point for assessment of therapeutic effectiveness.[4,5]As a result of the efficacy of chemotherapy and the ability to use serum PSA tomonitor therapeutic outcome, the clinical management of patients with prostatecancer has changed substantially.[6] The medical oncology community has acceptedchemotherapy as an effective treatment modality for routine use, and clinicaland laboratory investigators are enthusiastically pursuing methods to improveupon the benefits of chemotherapy in prostate cancer.

Molecularly-Based Therapeutic Targets for Prostate Cancer

The further clinical development of chemotherapy for prostate cancer has beenthe result of a better understanding of the biology of hormone-refractoryprostate cancer and the thoughtful investigation of molecular-based therapeutictargets for drugs directed against the disease. One such molecular target is thecytoplasmic microtubule. In fact, the antimicrotubule activity of the taxanesled to their investigation in prostate cancer. The cytotoxic effect of docetaxelis mediated by disruption of the microtubular network essential for mitotic andinterphase cellular functions. Docetaxel binds to tubulin, promotes the assemblyof tubulin into stable microtubules, and inhibits microtubuledepolymerization.[7] A greater and more slowly reversible degree ofpolymerization has been demonstrated for docetaxel than for paclitaxel.[8] Inaddition, docetaxel appears to have a higher affinity for tubulin than forpaclitaxel and is a more potent inducer of microtubule assembly.[9]

Preclinical Investigations of Docetaxel

Several preclinical studies have demonstrated the potential activity ofdocetaxel in prostate cancer. In tissue culture, docetaxel is more active thanpaclitaxel against established prostate cell lines. Recently, the combination ofdocetaxel and estramustine (Emcyt) was shown to exert significant cytotoxiceffects in PC-3 and MatLyLu prostatic cell lines.[10]

The topoisomerase II enzyme, nuclear matrix proteins, and modulators ofapoptosis (or programmed cell death) are additional molecular targets upon whichdocetaxel has shown to have an effect. Several pro- and antiapoptotic pathwayshave been identified in androgen-independent prostate cancer cell lines andtissues. The antiapoptotic protein bcl-2 is expressed in approximately 65% ofandrogen-independent human prostate cancer specimens.[11] In vitro analysessuggest that docetaxel’s mechanism of action may involve inactivation of bcl-2by phosphorylation.[12] Results demonstrate 100-fold greater potency ofdocetaxel over paclitaxel in the induction of bcl-2 phosphorylation, whichcauses apoptotic cell death.

Of interest was the recent demonstration of different pathways fordocetaxel-induced apoptosis between the androgen-responsive (LNCaP) andandrogen-independent (PC-3) prostate cancer cell lines.[13] These findings willassist researchers in choosing distinct therapies with activity againstlocalized vs advanced prostate cancer.

Clinical Trials of Docetaxel in Prostate Cancer

Docetaxel has demonstrated beneficial activity in hormone-refractory prostatecancer as a single agent and in combination regimens. Traditionally, therecommended administration schedule of docetaxel has been once every 3 weeks.[7]Data on the weekly administration schedule of docetaxel, compared with theevery-3-week schedule, suggest it to be equally efficacious with potentiallyfewer toxicities.[14] These findings have substantially enhanced investigationalstrategies for docetaxel in hormone-refractory prostate cancer, a disease inwhich a number of patients are elderly and unable to tolerate the every-3-weekschedule. The results of clinical trials evaluating every-3-week and weeklydocetaxel are presented here (Table 1).[15-18]

Single-Agent Docetaxel in Hormone-Refractory Disease

Every-3-Week Regimens

To gain information on the single-agent activityof docetaxel in hormone-refractory prostate cancer, Picus and Schultzinvestigated every-3-week docetaxel at 75 mg/m² in 35 chemotherapy-naivepatients.[15] A > 50% PSA decline was demonstrated in 46% of patients. A full24% of patients met the National Cancer Institute (NCI) criteria for partialresponse, defined as a 80% pr more PSA decline in conjunction with a 50% reduction inmeasurable soft-tissue disease, if present. An additional 46% of patientsdemonstrated stabilization of their disease. Therapy was generally welltolerated, with primarily hematologic toxicity, including grade 3/4 neutropenia,in 43% of patients.

Friedland and colleagues conducted a similar phase II study of single-agentdocetaxel at 75 mg/m² every 3 weeks.[16] A total of 21 hormone-refractoryprostate cancer patients with a median age of 69 (range: 55-79 years) wereentered into the study. Prior chemotherapy had been administered to 48% ofpatients. In 16 patients evaluable for response, a 38% overall response rate wasobserved, with a 50% response rate in chemotherapy-naive patients and a 25%response rate in patients who had received prior chemotherapy. Six of 10patients with measurable disease had a reduction in disease, and 8 of 11patients experienced a reduction in bone pain. Hematologic toxicities werepredominant, with grade 3/4 neutropenia in 71% of patients.

Weekly Docetaxel

The use of weekly docetaxel in elderly patients withvarious tumor types has demonstrated a more favorable toxicity profile thanevery-3-week regimens, while maintaining comparable levels of antitumoractivity.[14] Since many men with prostate cancer are elderly and toleratechemotherapy poorly, investigators have evaluated weekly regimens of docetaxelfor hormone-refractory prostate cancer with the aim of reducing side effects.

Berry and colleagues conducted a multi-institution phase II study of weeklydocetaxel in 60 heavily pretreated hormone-refractory prostate cancer patients.Patients were scheduled to receive three cycles of therapy with docetaxel at 36mg/m² per week for 6 weeks, followed by 2 weeks of rest (one cycle).[17] Allpatients received premedication with oral dexamethasone (three 8-mg doses at12-hour intervals starting 12 hours before each infusion of docetaxel). In the60 patients enrolled, median patient age was 72 years (range: 41-86 years),and 83% of patients had an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0 to 1. Prior mitoxantrone treatment had been administered in 27% ofpatients, orchiectomy had been performed in 43%, secondary hormonal therapy hadbeen given to 97%, and palliative radiotherapy had been delivered to 70% ofpatients. On an intent-to-treat basis, an objective tumor response (50% or more decrease in serum PSA from baseline lasting 4 weeks or longer with a stable orimproved performance status) was reported in 24 patients (41%). A total of 16patients (27%) had a PSA decrease of  80% or more for 2 months or longer. Theestimated median time to progression (TTP) from the start of treatment was 5.1months. The estimated median TTP for patients with a > 50% PSA reduction was6.6 months vs 4.4 months for patients who did not achieve a > 50% PSAreduction (P < .01). The median overall survival was 9.4 months. Of sixpatients with measurable soft-tissue disease, two had an objective tumorresponse, one of which was a CR. Therapy was well tolerated and the dosereduction allowance resulted in grade 3/4 neutropenia in just 3% of patients.Grade 3/4 asthenia and diarrhea were each reported in 10% of patients.

A nearly identical study was conducted by Beer and colleagues; however,eligible patients were not allowed to have received prior chemotherapy for theirdisease.[18] A total of 25 men with a median age of 72 years (range: 55-81years) and a median baseline PSA of 201 ng/mL (range: 0.6-1,432 ng/mL) wereenrolled in the study. Patients received treatment with single-agent docetaxelat 36 mg/m² weekly for 6 consecutive weeks of an 8-week cycle. The primary endpoint was palliative response, defined as a pain reduction using the PresentPain Intensity (PPI) scale, or a 50% decrease in analgesic consumption.Secondary end points included PSA response and global quality-of-lifeassessment. The primary end point of palliative response was demonstrated in 12of 25 patients (48%). PSA response, defined as > 50% decrease in PSAmaintained for two consecutive evaluations at least 4 weeks apart, was achievedin 11 of 24 (46%) evaluable patients. Of the 11 PSA responders, 6 patientsachieved a 75% reduction or more in PSA, and 4 of these patients achieved a 90%or more reduction in PSA. No difference in overall quality of life or anyquality-of-life domain was detected between patients who responded to treatmentand those who did not. Two of five patients with measurable disease demonstrateda partial response to therapy. The median survival for the entire patient cohortwas 39 weeks (range: 18-89+ weeks).

Therapy was well tolerated, with 25% of patients experiencing grade 3/4hematologic toxicity, and 36% of patients experiencing grade 3 nonhematologictoxicity. Grade 3/4 neutropenia was reported in 16% of patients; however, nocases of neutropenic fever were reported. The authors concluded thatsingle-agent weekly docetaxel was efficacious, with activity seen by allrelevant measures, including palliation of symptoms, PSA, and measurable diseaseresponse.

A retrospective comparison of two studies utilizing weekly or every-3-weekdocetaxel-containing regimens in hormone-refractory prostate cancer concludedthat the PSA response rate was similar with the two regimens and that the weeklyregimen represented a practical treatment alternative for elderly men withprostate cancer.[19] The dose consistently tolerated on the weekly schedulerepresents an increase in dose intensity compared with every-3-weekadministration.

The question of whether the higher cumulative dose delivered or the uniqueweekly administration schedule accounts for the potential benefit of weeklyschedules remains unclear and is the subject of ongoing investigation.Therefore, while the current overall impression is that weekly regimens possessa higher therapeutic index than every-3-week regimens, this fact must beconfirmed in a randomized trial. A prospective randomized phase III studycomparing weekly to every-3-week administration of docetaxel is under way (Figure1). In this comparative study, patients are randomized into one of threearms:

  • the control arm of mitoxantrone plus prednisone,

  • every-3-week docetaxel plus prednisone,

  • or weekly docetaxel plus prednisone.

The primary end point of this trial is survival.

Docetaxel and Estramustine-Based Combinations

As a result of the remarkable activity demonstrated by docetaxel as a singleagent in androgen-independent prostate cancer, investigations of combinationregimens building upon the docetaxel base have been pursued (Table2).[20-24]The most widely investigated combination has been docetaxel plus estramustine.The rationale behind the combination is to achieve greater inhibition ofmicrotubule function and cytotoxicity by using drugs that bind to different, butcomplementary, protein targets in the microtubular system.

Petrylak conducted a phase I dose escalation trial of docetaxel plusestramustine in patients stratified as minimally pretreated (MPT) or extensivelypretreated (EPT).[20] A fixed dose of oral estramustine at 280 mg tid on days 1to 5 was given in combination with intravenous docetaxel at 40 to 80 mg/m² givenon day 2 of an every 21-day cycle. A total of 34 patients were evaluable fortoxicity, and 33 patients were evaluable for response. Median patient age was 68years (range: 55-80 years) and the median ECOG performance status was 1.Median baseline PSA was 62.7 ng/mL and 193.5 ng/mL in MPT and EPT patients,respectively. Decline in PSA by > 50% was documented in 20 patients for anoverall response rate of 63% (70% in MPT and 50% in ETP patients). Of the 18patients with bidimensionally measurable disease, 28% achieved a partialresponse. Following treatment with the docetaxel/estramustine combination, 53%(8/15) were able to eliminate narcotic analgesics for bone pain for a medianduration of 6 weeks. Of the 29 patients with disease present in bone, 7% haddisappearance of one or more metastatic foci on bone scan. The overall survivalat 1 year was 68%. The docetaxel plus estramustine regimen proved feasible.

Grade 3/4 neutropenia was observed in 62% and 38% of MPT and EPT patients,respectively, but resulted in febrile neutropenia in one patient only. Threepatients (two patients with a history of deep venous thrombosis) developedthromboembolic events, including two deep venous thromboses and one cerebralvascular accident, for an overall incidence of 8.8%. The investigatorsrecommended a phase II dose of docetaxel at 70 mg/m² in MPT and 60 mg/m² in EPTpatients when combined with estramustine at 280 mg tid for 5 days.

Another phase I trial of the docetaxel and estramustine combination wasundertaken by Kreis.[21] Patients were treated with escalating doses ofdocetaxel (40-80 mg/m²) every 21 days and estramustine (14 mg/kg) daily. Atotal of 17 patients with hormone-refractory prostate cancer, not previouslytreated with a taxane or with estramustine, were entered into the study. Themean patient age was 66 years (range: 52-81 years), and most patients had anECOG performance status of 0 to 1, with ECOG performance status of 2 attributedto one patient. The median baseline PSA was 72 ng/mL (range: 2.1-965 ng/mL).Decreases of > 50% in PSA levels were reported in 14 of 17 (82%) patients atall dose levels. Four of the 17 (23.5%) patients demonstrated a completebiochemical response (PSA of 4 ng/mL or less). One patient with measurable diseasedemonstrated a partial response in lung and liver lesions.

Dose-limiting toxicities included neutropenia and fatigue at the 80 mg/m²-dose level. Two thromboembolic events (one arterial embolus and one deepvenous thrombosis) occurred at the 70-mg/m²-dose level in patients without aprior history of vascular disease. The recommended dose for furtherinvestigation was docetaxel at 70 mg/m² every 21 days in combination withestramustine at 12 mg/kg per day.

Petrylak and colleagues continued their investigation of docetaxel andestramustine with a phase II study in chemotherapy-naive patients with risingserum PSA levels after antiandrogen withdrawal.[22] Patients were treated withdocetaxel at 70 mg/m² every 21 days and estramustine at 280 mg tid on days 1 to5 of an every-21-day cycle. A total of 37 minimally pretreated patients wereevaluable for response. The median age was 69 years (range: 47-85 years) andthe median baseline PSA was 89.6 ng/mL (range: 11-1,607 ng/dL). Of 37 patientsevaluable for response, 25 (68%) patients experienced a > 50% decline in PSAlevel; 38% of patients experienced a > 80% decline in PSA. Assessment oftumor response in 11 patients with measurable disease demonstrated a partialresponse rate of 55%. The median 1-year survival rate is 77%.

The most notable toxicities included grade 3/4 neutropenia in 62% of patientsand grade 3/4 hyperglycemia in 19%. In addition, four vascular events wereobserved, including deep venous thromboses in two patients and cerebrovascularaccidents in two patients. The addition of prophylactic warfarin (Coumadin) andaspirin in the last 15 patients treated prevented further thromboembolic eventsfrom occurring.

Another phase II study of the docetaxel and estramustine combination wasreported by Sinibaldi.[23] A total of 42 patients with androgen-independentprostate cancer were enrolled in the study. Treatment consisted of docetaxel at70 mg/m² plus short-course estramustine at 280 mg every 6 hours for five dosesevery 21 days for a maximum of six cycles. Median patient age was 68 years(range: 47-80 years), median ECOG performance status was 1, and medianbaseline PSA was 110.5 ng/mL (range: 5-2,804 ng/mL). Ten patients (25%) hadreceived prior chemotherapy and 14 (33%) had prior palliative radiation therapy.In 40 patients evaluable for response, 18 (45%) had a > 50% decline in PSAfor 4 weeks or longer with a median time to PSA progression and a medianduration of PSA response of approximately 4.0 months. In 20 patients withmeasurable disease, four (20%) achieved a partial response. In 17 patients withsymptomatic disease, 10 (59%) reported an improvement in pain. The mediansurvival for all patients was 13.5 months. The most prominent toxicities weregrade 3/4 neutropenia and grade 3 fatigue. No thromboembolic events werereported in this study, which utilized daily warfarin prophylaxis.

On behalf of Cancer and Leukemia Group B (CALGB), Savarese and colleaguesreported the findings of a multicenter phase II study of intravenous docetaxel,oral estramustine, and low-dose daily hydrocortisone in men withhormone-refractory prostate cancer who demonstrated progression after initialhormone therapy.[24] A total of 47 chemotherapy naive patients were entered intothe trial with a median age of 73 years (range: 67-77 years) and a medianbaseline PSA of 166 ng/mL (range: 45-419 ng/mL). Treatment consisted of oralestramustine 10 mg/kg/d administered on days 1 to 5, intravenous docetaxel 70mg/m² administered on day 2, and oral hydrocortisone 40 mg daily, with thetreatment cycle repeated every 21 days. Patients received prophylacticdexamethasone 8 mg bid on days 1 to 3, beginning the day prior to docetaxeladministration. Among 44 patients evaluable for PSA response, 30 (68%) achieveda 50% or more reduction in PSA, and 25 (57%) achieved a 75% orgreater PSA reduction. Among24 patients with measurable disease, a 50% response rate was observed, with 3complete and 9 partial responses. The combined measurable disease andbiochemical response rate in all 46 assessable patients was 54%, with 3 completeresponses and 22 partial responses. With a median follow-up of 17 months, themedian overall survival for all patients was 20 months.

Therapy was moderately well tolerated, with the nature of grade 3/4 toxicitybeing predominately hematologic. Grade 3/4 neutropenia was reported in 56% ofpatients; however, no cases of febrile neutropenia were reported. Grade 3/4nonhematologic toxicities included malaise and/or fatigue (24%), edema (22%),and dyspnea (22%). The incidence of thromboembolic events during therapy was 9%and included one arterial thrombus, one deep venous thrombus, and twosuperficial venous thromboses.

These compelling study results form the basis for the launch of a randomized,phase III, comparative study in advanced, hormone-refractory prostate cancer bythe cooperative research groups CALGB, North Central Cancer Treatment Group (NCCTG),and Southwest Oncology Group (SWOG) (Figure 2).[27] The comparative study ofintermittent, every-3-week docetaxel plus estramustine vs mitoxantrone plusprednisone is rapidly accruing patients on a protocol that is powered to detecta 33% difference in median survival.

In summary, these study results support the enhanced role of systemicchemotherapy with docetaxel-based regimens in the management ofhormone-refractory prostate cancer. The improvement in overall survivalsreported by several of the studies is of importance. The prolonged survivalobserved may be due not only to the effectiveness of chemotherapy, but may alsobe the result of stage migration and patient selection. Therefore, the survivalfindings must be confirmed in ongoing phase III randomized trials—the resultsof which will properly define the full potential of docetaxel-based therapy inhormone-refractory prostate cancer.

Integration of Docetaxel in Adjuvant and Neoadjuvant Treatment

An extension of the beneficial antitumor activity achieved inandrogen-independent prostate cancer with docetaxel-based therapies is the goalof investigational strategies that are evaluating docetaxel therapy in theearlier stages of the disease. Investigators have adopted a research approachfor the integration of chemotherapy in the neoadjuvant and adjuvant settings.One important aim of this approach is to obtain biological insight into theeffectiveness of therapy in the preoperative or immediate postoperative periods.Docetaxel is also being evaluated in prostate cancer patients with biochemicalrecurrence, since the optimal treatment has not yet been established.

Oh and colleagues recently reported results from a study utilizing weeklysingle-agent docetaxel as neoadjuvant chemotherapy in patients with high-risklocalized prostate cancer.[25] Patients were treated with weekly docetaxel at 36mg/m² plus premedication with dexamethasone at 8 mg for three doses for a totalof 24 weeks, followed by radical prostatectomy. A total of 15 high-risk patientsreceived 280 doses of docetaxel. Median patient age was 54 years (range: 43-63years), and median baseline PSA was 15.6 ng/mL (range: 3.2-1.3 ng/mL).Overall, treatment was very well tolerated, with only two grade 3 toxicities(fever/infection and vasovagal in one patient each). Grade 1/2 toxicitiesincluded fatigue (n = 14), anorexia (n = 9), diarrhea (n = 9), nausea (n = 8),nail changes (n = 6), weight loss (n = 3), edema (n = 3), and fever/infection (n= 8).

At 2 months, 14 of 15 endorectal magnetic resonance images demonstratedevidence of decreased tumor burden compared with baseline, with only one patientdemonstrating progressive disease. Ten of 15 (67%) patients had a > 50%decline in PSA. Pathologic data from 11 patients who underwent a radicalprostatectomy revealed stage T2 disease in four patients, T3a in two patients,T3b in four patients, and stage T4 in one patient. At the time of surgery, all11 patients demonstrated node-negative disease, and 5 of 11 patients had marginsclear of disease. The authors concluded that weekly docetaxel was feasible andwell tolerated. The decrease in PSA levels seen in the majority of patients ispromising and is independent of a testosterone-lowering effect. Continuedanalysis of the results for the effect upon pathologic end points is beingconducted.

A similar phase II neoadjuvant study has been undertaken by Dreicer andcolleagues.[26] Patients with locally advanced prostate cancer are treated withweekly docetaxel at 40 mg/m² every 7 days for a maximum of 6 weeks, followed byradical prostatectomy. At the time of this report, 10 patients had completedneoadjuvant therapy with docetaxel. Preliminary data suggested the regimen iswell tolerated, with a delay in docetaxel administration in only three patientsto allow for recovery from grade 3 neutropenia. Nonhematologic toxicitiesconsisted of grade 3 fatigue (n = 3), grade 2 nail bed changes (n = 3), andgrade 2 edema (n = 2). Preliminary PSA response demonstrated improvement inseven of 10 patients at the completion of neoadjuvant docetaxel treatment, withPSA reductions ranging from 4% to 63%. The full benefit of weekly docetaxel asneoadjuvant chemotherapy for locally advanced prostate cancer awaits forthcomingpathologic response data.

Biochemical Recurrence

An increasingly important area in the management of prostate cancer patientsis the clinical scenario referred to as biochemical recurrence. Biochemicalrecurrence is characterized by increasing serum PSA levels in patients withlocalized prostate cancer who initially underwent definitive treatments(prostatectomy and/or radiation therapy) with curative intent. Two groups ofinvestigators have reported preliminary results from studies incorporatingsingle-agent docetaxel in the treatment scheme for patients with biochemicalrecurrence.[27,28]

Hussain et al undertook a pilot investigation in prostate cancer patientswith rising PSA (> 4 ng/mL) following definitive local therapy includingprostatectomy, external-beam radiotherapy, or brachytherapy.[27] Patientsreceived treatment with docetaxel at 70 mg/m² every 21 days for a maximum of sixcycles. This was followed in 3 weeks by total androgen suppression (TAS),administered in 4-month blocks until PSA decreased to < 4 ng/mL, at whichpoint peripheral androgen blockade was instituted for 8 months. A total of 27men have entered the trial. The median patient age was 67 years (range: 46-76years), and ECOG performance status was 0 or 1 in all 27 patients. The medianbaseline PSA was 13.0 ng/mL (range: 7.7-99 ng/mL). To date, 21 of 27 patientscompleted six cycles of docetaxel treatment before proceeding to TAS, and twopatients completed four cycles of docetaxel treatment (with PSA decreasing >90%) before proceeding to TAS. The remaining four patients discontinuedchemotherapy after one cycle because of unanticipated, and possibly unrelated,toxicities, including a syncopal episode, pancreatitis, grade 2 fatigue, andgastrointestinal bleeding.

In patients treated with four or six cycles of docetaxel chemotherapy, themost prominent toxicity was hematologic in nature, including grade 3/4neutropenia in 21 patients and one episode of neutropenic fever. Nonhematologictoxicities were limited to isolated cases of grade 3 toxicities, with nopatients experiencing grade 3/4 fatigue or other grade 4 toxicities. Preliminaryefficacy findings revealed that 12 of the 23 patients (52%) who completed eitherfour or six cycles of docetaxel had a > 50% decrease in PSA before proceedingto TAS therapy. To date, 18 patients have completed 4 months of TAS therapy, and16 of 18 patients (89%) achieved PSA values of < 0.1 ng/mL. These preliminarydata indicate that patients retain hormone sensitivity despite initial treatmentwith chemotherapy. Further analyses of these results are awaited.

Talpin and colleagues investigated the combination of docetaxel andestramustine followed by bicalutamide (Casodex) and goserelin acetate (Zoladex)in patients with biochemical recurrence after either prostatectomy and/orradiation therapy.[28] Patients are treated with estramustine at 10 mg/kg/d ondays 1 to 5 and docetaxel at 70 mg/kg on day 2 every 21 days for four treatmentcycles. This is followed by bicalutaminde at 50 mg/d and goserelin acetate at10.8 mg subcutaneously every 12 weeks for a total of 15 months. Preliminaryresults are available for 15 patients. The median patient age is 64.1 years, andmedian ECOG performance status is 0. The mean baseline PSA was 5.83 ng/mL forpatients pretreated with prostatectomy and 13.7 ng/mL for patients pretreatedwith radiotherapy. Eleven of 15 patients have completed protocol chemotherapy.

Following cytotoxic chemotherapy with docetaxel/estramustine, 12 of 15patients (80%) achieved a complete response. Of the remaining three patients,two achieved a complete response following therapy with bicalutamide andgoserelin acetate, and one continues to have measurable PSA (0.17 ng/mL). Grade3/4 toxicities secondary to docetaxel/estramustine included 3/4 neutropenia(53%) with one episode of fever and neutropenia. Isolated cases ofnonhematologic toxicities were reported, including myalgia (n = 1) and palmardesquamation (n = 1), which required dose reduction. Two cases of thrombosisrequiring discontinuation of treatment were reported. It is anticipated that thefinal results of these trials will assist investigators in the design andconduct of randomized trials for prostate cancer patients with biochemicalrecurrence.

Novel Docetaxel-Containing Combination Regimens

Docetaxel/Calcitriol

Beer and colleagues reported the results of a phase II trial investigatingweekly docetaxel and calcitriol, the active form of vitamin D, in 37 patientswith metastatic androgen-independent prostate cancer with no priorchemotherapy.[29] Patients were treated with calcitriol, 0.5 mg/kg orally on day1, and docetaxel, 36 mg/m² on day 2, weekly for 6 of every 8 weeks, withstandard dexamethasone. The median patient age was 73 years (range: 46-83years), and the median baseline PSA was 99 ng/mL (range: 6-921 ng/mL). Theyreported 92% of patients had bone metastases, 41% had soft-tissue metastases,and 81% reported pain. A > 50% reduction in PSA was confirmed in 81% ofpatients, with a > 75% reduction in PSA achieved in 59%. Among 15 patientswith measurable disease, 53% achieved a confirmed response, and 33% maintainedstable disease. Survival results by Kaplan-Meier estimate demonstrated medianprogression-free survival of 11.4 months and median overall survival of 19.5months. Treatment was generally well tolerated, with the most prevalent grade3 or more  toxicities consisting of leukopenia (41%), neutropenia (24%), hyperglycemia(24%), and peptic ulcer (11%). These highly promising findings of the weeklydocetaxel/calcitriol combination will be tested in a phase III trial.

Docetaxel/Exisulind

Ryan et al reported findings from a phase I/II dose escalation study inpatients with hormone-refractory prostate cancer who are being treated with thecombination of docetaxel with exisulind (Aptosyn), an agent with proapoptoticproperties.[30] Under investigation are doses of docetaxel, 35 to 75 mg/m² onceevery 3 weeks, with daily oral exisulind, 100 to 250 mg bid. To date, 15patients have been enrolled in the study and have received treatment with eitherdocetaxel at 75 mg/m² once every 3 weeks with daily exisulind at 250 mg bid, ordocetaxel at 75 mg/m² once every 3 weeks, with daily exisulind at 150 mg/m² bid.Among 12 patients evaluable for PSA response, seven (58%) have demonstrated adecline in PSA by > 50%. To date, therapy has been well tolerated, withtoxicities being similar to those expected for docetaxel alone.

Docetaxel/Thalidomide

Figg and colleagues are conducting a phase II study in patients withandrogen-independent prostate cancer who are randomized to receive docetaxelalone, or docetaxel plus thalidomide (Thalomid), an agent with antiangiogenicproperties.[31] Fifty-nine patients had been enrolled in the study at the timeof this report. Seventeen patients received docetaxel at 30 mg/m² per week for 3weeks followed by a week of rest, and 36 patients received docetaxel at 30 mg/m²weekly plus oral thalidomide at 200 mg daily for 3 weeks followed by a week ofrest. Six of 17 (35%) patients who received docetaxel alone had decreases in PSAlevels of > 50%, and 19 of 36 (53%) patients in the combination arm had adecline in PSA levels of > 50%. Thus far, hematologic toxicities have beenminimal in both arms, however eight (20.5%) of 39 patients in the combinationarm have experienced a venous thromboembolism. Strategies to decrease theincidence of thrombotic events are being pursed in this study for which thepreliminary efficacy data are encouraging.

Docetaxel/Trastuzumab

The combination of docetaxel, estramustine, and trastuzumab (Herceptin), amonoclonal antibody which binds to the HER2/neu receptor, is being investigatedby Small and colleagues in patients with androgen-independent prostatecancer.[32] Patients receive treatment with estramusine at 280 mg orally tid ondays 1 to 5, docetaxel at 70 mg/m² on day 2, and trastuzumab 2 mg/kg weekly for3 consecutive weeks on days 2, 9, and 16 (following a one-time loading dose of 4mg/kg on day 1 of cycle 1). The regimen is administered every 21 days untilprogressive disease or unacceptable toxicity. At the time of this report, 13patients had been enrolled and treated with a median of six cycles. Nine of 13patients (69%) evaluable by PSA response achieved the targeted PSA responsecriteria. Two of six patients (33%) demonstrated an objective partial responsein measurable disease, and one patient had a complete response on bone scan.

Toxicities included grade 4 neutropenia reported in 10% of administeredcycles, with two episodes of neutropenic fever. Pulmonary embolism and deepvenous thrombosis were reported in one patient each. Of note, no episodes ofcardiac toxicity were reported. The preliminary data suggest the regimen ofdocetaxel/estramustine/trastuzumab to be feasible for administration; however,the exact contribution of trastuzumab to the active docetaxel/estramustinecombination must await completion of the trial and correlation with HER2/neuoverexpression rate data in prostate cancer patients.

The integration of bone-targeted therapy in conjunction with chemotherapy isone that has been extensively studied at The University of Texas M. D. Anderson Cancer Center. Theapproach developed at our institution utilizes bone-targeted consolidationtherapy with stronium-89 (Metastron) and doxorubicin following a course ofinduction chemotherapy with ketoconazole and doxorubicin alternating withestramustine and vinblastine. This regimen has been serially developed over timeand has shown to possess substantial antitumor activity.[33,34]

Future Study Designs

An obvious design for future studies at The University of Texas M. D. Anderson Cancer Center would bethe incorporation of docetaxel into the chemotherapy component. Considerationwill also be given for the integration of novel agents that have completelydifferent mechanisms of actions. These novel agents include proteosomeinhibitors, candidate bcl-2 antisense (Genasense) and other proapoptotictherapies, angiogenesis inhibitors, and tyrosine kinase inhibitors (Table3).

Thus, future investigative studies may incorporate both docetaxel and novelagents in combination with bone-targeted therapy for an overall strategy for themanagement of disease. Such an approach may be effective given the evidence thatbone-targeted therapy may favorably alter the course of prostate cancer whenused in conjunction with chemotherapy. The ultimate aim of this research is thesuccessful integration of chemotherapy into the complex treatment strategy toimprove the overall long-term outcome of patients with prostate cancer.

Conclusions

Docetaxel-based regimens can be included among the most effective treatmentoptions to effectively palliate patients with advanced prostate cancer. Resultswith docetaxel-based regimens have consistently demonstrated an ability toachieve a palliative response, reduced serum PSA levels by > 50%, producedobjective responses in patients with measurable disease, and demonstratedimproved survival findings in phase II trials. Further improvement in theoutcome of androgen-independent prostate cancer patients will come withoptimization of both dose and schedule of docetaxel-based regimens to maximizethe therapeutic index. The results of ongoing phase III randomized trials inandrogen-independent prostate cancer are eagerly awaited for their potential todefinitively demonstrate a beneficial impact on overall patient survival.

Results from ongoing investigations that integrate docetaxel with hormonaltherapies in the early stages of prostate cancer progression will be importantin refining the future role of chemotherapy for prostate cancer in general. Itis likely that docetaxel-containing regimens will also have a substantial rolein the adjuvant and neoadjuvant settings, where several trials are under way.Finally, studies exploring combination regimens of docetaxel and novel agentswith completely different mechanisms of action will likely occupy a dominantposition in future research initiatives for men with prostate cancer.

References:

1. Oh WK, Kantoff PW: Management of hormone refractory prostate cancer:Current standards and future prospects. J Urol 160:1220-1229, 1998.

2. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantroneplus prednisone or prednisone alone for symptomatic hormone-resistant prostatecancer: A Canadian randomized trial with palliative end points. J Clin Oncol14:1756-1764, 1996.

3. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or withoutmitoxantrone in men with hormone-refractory prostate cancer: Results of theCancer and Leukemia Group B 9182 Study. J Clin Oncol 17:2506-2513, 1999.

4. Kelly WK, Scher HI, Mazumadar M, et al: Prostate-specific antigen as ameasure of disease outcome in metastatic hormone-refractory prostate cancer. JClin Oncol 11:607-615, 1993.

5. Smith DC, Dunn RL, Strawderman MS, et al: Change in serumprostate-specific antigen as a marker of response to cytotoxic therapy forhormone-refractory prostate cancer. J Clin Oncol 16:1835-1843, 1998.

6. Kim J, Logothetis CJ: Serologic tumor markers, clinical biology, andtherapy of prostatic carcinoma. Urol Clin North Am: 26:281-290, 1999.

7. Taxotere Product Package Insert. Aventis Pharmaceuticals, Parsippany, NewJersey, 1/2000.

8. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisyntheticanalogue of Taxol. J Natl Cancer Inst 83:288-291, 1991.

9. Diaz JF, Andreu JM: Assembly of purified DP-tubulin into microtubulesinduced by Taxol and Taxotere: Reversibility, ligand stoichiometry, andcompetition. Biochemistry 32:2747-2755, 1993.

10. Williams JF, Muenchen HJ, Kamradt JM, et al. Treatment ofandrogen-independent prostate cancer using antimirotubule agents docetaxel andestramustine in combination. An experimental study. Prostate 44:275-278, 2000.

11. McDonnell TJ, Navone NM, Troncoso P, et al: Expression of bcl-2oncoprotein and p53 protein accumulation in bone marrow metastasis ofandrogen-independent prostate cancer. J Urol 157:569-574, 1997.

12. Haldar S, Basu A, Croce C, et al: Bcl-2 is the guardian of microtubuleintegrity. Cancer Res 57:229-233, 1997.

13. Muechen HJ, Poncza PG, Pienta KH: Different docetaxel-induced apoptoticpathways are present in prostate cancer cell lines LNCaP and PC-3. Urology57:366-370, 2001.

14. Hainsworth JD, Burris HA, Erland JB, et al: Phase I trial of docetaxeladministered by weekly infusion in patients with advanced refractory cancer. JClin Oncol 16:2164-2168, 1998.

15. Picus J, Shultz M: Docetaxel (Taxotere) as monotherapy in the treatmentof hormone-refractory prostate cancer: Preliminary results. Semin Oncol 29(suppl17):14-18, 1999.

16. Friedland D, Cohen J, Miller R, et al: A phase II trial of docetaxel (Taxotere)in hormone-refractory prostate cancer: Correlation of antitumor effect tophosphorylation of bcl-2. Semin Oncol 26(5 suppl 7):19-23, 1999.

17. Berry W, Dakhil S, Regich M, et al: Phase II trial of single-agent weeklydocetaxel in hormone-refractory, symptomatic, metastatic carcinoma of theprostate. Semin Oncol 28(suppl 15):8-15, 2001.

18. Beer T, Pierce WC, Lowe BA, et al: Phase II study of weekly docetaxel insymptomatic androgen-independent prostate cancer. Ann Oncol 12:1273-1279, 2001.

19. Scholz MC, Guess B, Barrious F, et al: Low-dose, single-agent weeklydocetaxel is effective and well tolerated in elderly men with prostate cancer(abstract 2441). Proc Am Soc Clin Oncol 20:173b, 2001.

20. Petrylak DP, Macarthur RB, O’Connor J, et al: Phase I trial ofdocetaxel with estramustine in androgen-independent prostate cancer. J ClinOncol 17:958-967, 1999.

21. Kreis W, Budman DR, Fetten J, et al: Phase I trial of the combination ofdaily estramustine phosphate and intermittent docetaxel in patients withmetastatic hormone refractory prostate carcinoma. Ann Oncol 10:33-38, 1999.

22. Petrylak D, Shelton G, England-Owen C, et al: Response and preliminarysurvival results of a phase II study of docetaxel and estramustine in patientswith androgen-independent prostate cancer (abstract 1312). Proc Am Soc ClinOncol 19: 344a, 2000.

23. Sinibaldi V, Carducci M, Moore-Cooper S, et al: Phase II evaluation ofdocetaxel plus 1-day oral estramustine phosphate in the treatment of patientswith androgen-independent prostate carcinoma. Cancer 94:1457-1465, 2002.

24. Savarese DM, Halabi S, Hars V, et al: Phase II study of docetaxel,estramustine, and low-dose hydrocortisone in men with hormone-refractoryprostate cancer: A final report of CALGB 9780. J Clin Oncol 19:2509-2515, 2001.

25. Oh WK, George DJ, Kaufman DS, et al: Neoadjuvant docetaxel followed byradical prostatectomy in patients with high-risk localized prostate cancer: Apreliminary report. Semin Oncol 28(suppl 15):40-44, 2001.

26. Dreicer R, Klein EA: Preliminary observations of single-agent docetaxelas neoadjuvant therapy for locally advanced prostate cancer. Semin Oncol 28 (suppl15):45-48, 2001.

27. Hussain A, Dawson N, Amin P, et al: Docetaxel followed by hormone therapyafter failure of definitive treatments for clinically localized/locally advancedprostate cancer: Preliminary results. Semin Oncol 28(suppl 15):22-31, 2001.

28. Taplin ME, Bubley G, Rajeshkumar B, et al: Docetaxel, estramustine, andshort-term androgen withdrawal for patients with biochemical failure afterdefinitive local therapy for prostate cancer. Semin Oncol 28(suppl 15):32-39,2001.

29. Beer TM, Eilers KM, Garzotto M, et al: Androgen-independent prostatecancer (AIPC) treatment with weekly high-dose calcitriol and docetaxel (abstract707). Proc Am Soc Clin Oncol 21:177a, 2002.

30. Ryan C, Stadler W, Vogelzang N: Docetaxel and exisulind inhormone-refractory prostate cancer. Semin Oncol 28(suppl 15):56-61, 2001.

31. Figg W, Arlen P, Gulley J, et al: A randomized phase II trial ofdocetaxel (Taxotere) plus thalidomide in androgen-independent prostate cancer.Semin Oncol 28(suppl 15):62-66, 2001.

32. Small E, Bok R, Reese D, et al: Docetaxel, estramustine, plus trastuzumabin patients with metastatic androgen-independent prostate cancer. Semin Oncol28(suppl 15):71-76, 2001.

33. Tu SM, Millikan RE, Mengistu B, et al: Bone-targeted therapy for advancedandrogen-independent carcinoma of the prostate: A randomized phase II trial.Lancet 357:336-341, 2001.

34. Ellerhorst JA, Tu SM, Amato RJ, et al: Phase II trial of alternatingweekly chemohormonal therapy for patients with androgen-independent prostatecancer. Clin Cancer Res 3:2371-2376, 1997.