Drug insight: Use of docetaxel in prostate and urothelial cancers

Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies, with two taxanes now in clinical use. Their mechanism of action against tumor cells is by alteration of microtubule dynamics, which causes cell-cycle arrest during mitosis. Docetaxel binds to the microtubules with a higher affinity than paclitaxel, and over a broader range of cell-cycle activities. It has also been shown to promote apoptosis via BCL2 phosphorylation. In hormone-refractory prostate cancer, docetaxel has been studied as both a single agent and in combination with estramustine, and in different treatment schedules, with demonstrated efficacy. Two phase III trials have confirmed a survival benefit, making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer. In urothelial cancer, docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens. A phase III trial comparing docetaxel and cisplatin to methotrexate, vinblastine, doxorubicin, and cisplatin was inferior when evaluating response rates and overall survival. More recent phase II trials combining docetaxel with two additional agents have shown promise, but confirmatory trials are needed.     

Combination chemotherapy following adrenal suppression in androgen- independent prostate cancer

OBJECTIVES: Recent trials with modern chemotherapy have demonstrated activity in androgen-independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen-independent, hormone-refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen-independent prostate cancer. METHODS: From January 1995 until April 1999, 19 patients with hormone-refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m(2). RESULTS: A decrease in prostate-specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3-83.7%). The median decrease in prostate-specific antigen was 71.2% (range 50.5-85.2%). None of the 7 patients with measurable soft-tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4-27.7) months and from initiation of adrenal suppression 16.9 (range 3.8-40. 5) months. CONCLUSIONS: The combination of estramustine and vinblastine is capable of inducing activity in androgen-independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft-tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen-independent prostate cancer.     

Single-agent chemotherapy with docetaxel significantly reduces PSA levels in patients with high-grade localized prostate cancers

OBJECTIVE: Chemotherapy has been shown to be effective in the management of prostate cancer in patients with androgen-independent metastatic disease, however, a survival benefit has not been demonstrated yet. Docetaxel alone or in combination with estramustine has been shown to exhibit a high level of activity in the treatment of hormone-refractory prostate cancer. To date there are only few reports on chemotherapy for localized prostate cancer. METHODS: The efficacy and safety of neoadjuvant chemotherapy with docetaxel as a single agent given prior to radical retropubic prostatectomy (RRP) has been evaluated in 5 patients presenting with Gleason score 8 prostate cancers at biopsy. RESULTS: The mean reduction in prostate-specific antigen levels in the 5 patients was 66.5% (range 47.6-94.0%). Histology after RRP yielded pT2N0MxR0 prostate cancers in all subjects. Testosterone and secretoneurin levels were not significantly affected by docetaxel monotherapy. CONCLUSIONS: Although the use of neoadjuvant chemotherapy prior to RRP is still experimental, the dramatic prostate-specific antigen decrease during chemotherapy and the pathologic findings after radical prostatectomy are encouraging. Studies including larger number of patients will have to confirm the present results.     

Recent advances in chemotherapy for advanced prostate cancer

Recently, several important studies have validated prostatespecific antigen (PSA) as a reliable measure of response to chemotherapeutic treatment in advanced hormonerefractory prostate cancer. Furthermore, although chemotherapy in this setting has always been considered palliative, several analyses of recent clinical trials have demonstrated a significant association between declines in PSA values of 50% or more and prolonged survival. Mitoxantrone, in combination with prednisone, has been shown to provide significant palliation and improved quality of life. The use of combinations of chemotheraputic agents also seems to provide significantly superior objective and subjective responses compared with single-agent regimens. In particular, estramustine has been shown to synergize many of the agents used in prostate cancer treatment and has been demonstrated to provide significant palliation and decline in PSA levels in combination with vinblastine, vinorelbine, etoposide, paclitaxel, and docetaxel. The results of several important trials of the taxanes both as single agents and in combination with estramustine have been completed in the past year and have demonstrated that these agents are very effective in the treatment of hormone-refractory prostate cancer.     

Current indications for chemotherapy in prostate cancer patients

Recently, data from two randomized studies, TAX327 and SWOG 9916, which compared docetaxel-based chemotherapy to mitoxantrone-based therapy, have demonstrated that treatment with docetaxel can prolong life in a statistically significant way in patients with hormone refractory prostate cancer (HRPC). In the TAX237 trial the median overall survival rates for patients treated with docetaxel every 3 wk was 18.9 mo, compared with 16.4 mo for the patients in the control arm (p=0.009). Patients treated with the combination of docetaxel and estramustine in the SWOG trial had a significant improvement in median survival (18 mo vs 16 mo, p=0.01), longer progression-free survival (6 mo compared with 3 mo, p<0.0001), and a 20% reduction in the risk of death. The optimal timing of docetaxel-based chemotherapy is still unknown because there are no prospective clinical trials indicating whether earlier treatment is more effective than delayed treatment. There are now increasing options also for second-line therapies in the palliative treatment of HRPC, and ongoing studies on new drugs such as satraplatin and ixabepilone will define the role of these agents in this setting. Preliminary neoadjuvant and adjuvant chemotherapy studies in high-risk prostate cancer patients have demonstrated that these approaches are feasible and do not add morbidity to surgery or radiotherapy, but their impact on survival still needs to be proven in randomized studies.     

Chemotherapy for androgen-independent prostate cancer

The evolution of taxanes as treatment for androgen-independent prostate cancer hes emerged from both the laboratory and clinic. Docetaxel is a potent in vitro inhibitor of Bcl-2, an antiapoptotic gene. Phase I and II studies with docetaxel alone or in combination with estramustine demonstrated promissing median survivals of 14--23 months, higher than what would have been expected for historic controls. Two randomized trials have proven the superiority of docetaxel based treatment in improving survival in men with androgen-independent prostate cancer. SWOG 99-16 and TAX 327 found that docetaxel-based therapy reduced the risk of death by 20--24% when compared to mitoxantrone-based therapy. Future trials will build on docetaxel-based combinations with novel targeted agents.     

Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study

BACKGROUND: Estramustine in combination with other chemotherapeutic agents has demonstrated synergy in hormone-refractory prostate cancer. Docetaxel has demonstrated antineoplastic activity in a variety of chemotherapeutic-unresponsive tumors. We evaluated the effects of estramustine and docetaxel in preclinical models of prostate cancer. METHODS: Cell viability of PC-3 and MAT-LyLu (MLL) cells were assessed 48 hr after drug treatment. For in vivo studies, each flank of five animals in six groups was injected with 1 x 10(6) MLL cells: control, estramustine, docetaxel (low- and high-dose), and low- and high-dose docetaxel with estramustine. Animals were treated on days 4 and 11, and sacrificed on day 14. RESULTS: The IC(50) value for docetaxel was 2 nM in the PC-3 cells and 40 nM in the MLL cells. The addition of 100 nM of estramustine did not alter the IC(50) value for PC-3 cells. In the MLL cells, however, the IC(50) value was lowered to 15 nM. In vivo, low-dose docetaxel with estramustine demonstrated antineoplastic activity similar to that of high-dose docetaxel alone, suggesting additive activity between the drugs. CONCLUSIONS: These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone.     

Therapeutic options in androgen-independent prostate cancer: building on docetaxel

Of men with metastatic prostate cancer who undergo androgen ablation, 70-80% respond rapidly to therapy, as manifested by a reduction in prostate cancer-related symptoms and declines in serum prostate-specific antigen (PSA) level. Unfortunately, after a median of 18-24 months, nearly all patients with metastatic prostate cancer will progress to androgen independence. Until recently the standard of care for treating hormone-refractory prostate cancer (HRPCa) was the combination of mitoxantrone and prednisone, which palliated bone pain but did not extend survival. Two randomized trials with > 1700 patients showed for the first time a survival benefit for patients with HRPC treated with chemotherapy; when compared with mitoxantrone-based therapy, docetaxel based-therapy reduced the risk of death by 20-24%. Future trials in HRPC are attempting to improve the efficacy of docetaxel by incorporating new agents targeting angiogenesis, apoptosis, and signal transduction pathways; there is promising activity for these novel combinations in phase I and II studies. Concepts are also being refined about definitions of response and progressive disease, patient eligibility criteria, and the validity of surrogate markers of efficacy and survival, as shown by changes in PSA level.     

A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer

OBJECTIVE: To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival. PATIENTS AND METHODS: In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m(2) intravenously, on day 2 every 21 days) and estramustine (3 x 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 x 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1-5 and in arm B on day 1-3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity. RESULTS: Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation. CONCLUSIONS: In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.     

Therapieoptionen des hormonrefraktären Prostatakarzinoms

Surgical or medical androgen deprivation therapy in its multiple variants represents the standard therapeutic approach in the management of metastatic prostate cancer resulting in a primary response rate of about 90%. However, about 90% of the men treated will develop PSA progression within 3–4 years resulting in androgen-independent and later on hormone-refractory prostate cancer. Management of AIPCA and HRPCA still represents a therapeutic challenge despite the development of new and effective treatment options. PSA progression following primary ADT defines an androgen-refractory but still hormone-sensitive PCA which might respond to secondary hormonal manipulations such as antiandrogen withdrawal, addition of nonsteroidal antiandrogens, and administration of estrogens, ketoconazole and hydrocortisone, and somatostatin analogues. Secondary hormonal manipulations will result in a PSA decline >50% in about 60–80% of the patients with a mean duration of 7–17 months depending on the type of treatment. PSA progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of two prospective, randomized clinical phase III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA and pain response, and represents the treatment of choice in the management of HRPCA. Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal-related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain as has been demonstrated for ibandronate and zoledronate. The current article critically reflects on the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer. The development, rationale, and results of systemic chemotherapy are discussed critically and a therapeutic algorithm is demonstrated.     

Treatment options for hormone-refractory prostate cancer

Surgical or medical androgen deprivation therapy in its multiple variants represents the standard therapeutic approach in the management of metastatic prostate cancer resulting in a primary response rate of about 90%. However, about 90% of the men treated will develop PSA progression within 3-4 years resulting in androgen-independent and later on hormone-refractory prostate cancer. Management of AIPCA and HRPCA still represents a therapeutic challenge despite the development of new and effective treatment options. PSA progression following primary ADT defines an androgen-refractory but still hormone-sensitive PCA which might respond to secondary hormonal manipulations such as antiandrogen withdrawal, addition of nonsteroidal antiandrogens, and administration of estrogens, ketoconazole and hydrocortisone, and somatostatin analogues. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of two prospective, randomized clinical phase III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA and pain response, and represents the treatment of choice in the management of HRPCA.Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal-related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain as has been demonstrated for ibandronate and zoledronate. The current article critically reflects on the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer. The development, rationale, and results of systemic chemotherapy are discussed critically and a therapeutic algorithm is demonstrated.     

Update in the management of patients with hormone-refractory prostate cancer

PURPOSE OF REVIEW: 2004 was a critical year for advances in prostate cancer treatment. The results from two pivotal multicenter phase III randomized studies are the first to demonstrate a survival benefit associated with chemotherapeutic treatment interventions in patients with hormone-refractory prostate cancer. This review will focus on an interpretation of the data from these two studies, the emerging role for chemotherapy in 2005 and beyond, and ongoing areas of clinical research. RECENT FINDINGS: Phase I and II studies have demonstrated biochemical and objective responses achieved with docetaxel-based chemotherapy in men with hormone-refractory prostate cancer. Two pivotal phase III clinical trials, TAX 327 and SWOG 9916 have demonstrated a survival advantage of docetaxel-based chemotherapy over mitoxantrone. Novel targeted therapies under investigation include calcitriol, growth factor-targeted agents, epothilones and others. SUMMARY: We now have a new standard of care for men with metastatic hormone-refractory prostate cancer. Further investigation of docetaxel-based regimens in earlier clinical states of disease is warranted and may demonstrate greater clinical benefit. Additional chemotherapy agents are being studied, and may also add to the future armamentarium available for prostate cancer. The enrolment of patients into these studies is critical to the ongoing evolution of prostate cancer management.     

Therapy of hormone-refractory prostate cancer

PSA-progression following primary ADT defines an androgen-refractory but still hormone sensitive PCA which might respond to secondary hormonal manipulations. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA-progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of 2 prospective, randomized clinical phase-III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA- and pain response and represents the treatment of choice in the management of HRPCA. Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain. The current article critically reflects the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer.     

The evolving role of docetaxel in the management of androgen independent prostate cancer

PURPOSE: Androgen independent prostate cancer is an advanced disease with an extremely poor outcome. In view of this fact, a great deal of interest has recently been generated in the potential use of chemotherapeutic agents, particularly docetaxel. We reviewed the evolving role of docetaxel as a chemotherapeutic agent for the management of this disease. MATERIALS AND METHODS: The main emphasis of this review is discussion of the various clinical trials that have investigated the use of docetaxel alone or combined with other agents for androgen independent prostate cancer. RESULTS: Docetaxel, which acts primarily by inhibiting microtubular depolymerization, in combination with other agents has consistently demonstrated a palliative response, a decrease in serum prostate specific antigen levels by 50% or greater in more than 60% of patients, a decrease in measurable disease and the suggestion of improved survival. CONCLUSIONS: Docetaxel based regimens are moderately well tolerated and they have shown promising results in various phase 2 trials. The completion of ongoing phase III randomized trials are eagerly awaited since they may determine whether a definite beneficial impact on overall survival can be achieved.     

Current and emerging treatment modalities for metastatic castration-resistant prostate cancer

Docetaxel-based therapy is established as the standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from two landmark Phase III studies. However, prognosis remains poor, with a median survival of less than 2 years. There is no standard of care for patients who progress during or after docetaxel treatment, which represents a real unmet medical need. Several small retrospective studies suggest that patients with mCRPC who responded to first-line docetaxel-based therapy are sensitive to re-treatment, but a survival benefit in prospective randomized trials has not been demonstrated. Epithelial-stromal interactions in the tumour microenvironment appear to play a central role in prostate cancer progression and response to therapy. Recent insights into the molecular mechanisms that underpin prostate cancer progression have allowed the identification of potential therapeutic targets. New agents, including angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines and immunotherapies are currently undergoing clinical development in advanced prostate cancer using docetaxel as a backbone. Several Phase III studies have now been completed. Sipuleucel-T prolonged survival compared with placebo in asymptomatic or minimally symptomatic patients with mCRPC. Cabazitaxel plus prednisone prolonged survival in patients with mCRPC who progressed during or after docetaxel-based therapy compared with the active agent mitoxantrone, plus prednisone. Multidisciplinary management and optimization of the role and timing of new agents in this evolving treatment continuum will be critical to maximizing patient outcomes. Identification of predictive markers and better gene expression profiling will be critical to tailoring therapies to individual patients and disease states, whereas validated surrogate markers of overall survival will help accelerate drug approval.     

Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells

Dendritic cells from patients with cancer are deficient in number and functional activity, leading to inadequate tumor immunosurveillance as a result of poor induction of T-cell antitumor responses. Loaded dendritic cell therapy is a vaccination strategy aimed at eliciting tumor antigen-specific, T-cell immune responses. Loaded dendritic cell therapy using prostatic acid phosphatase (APC8015; Provenge, Dendreon Corp., Seattle, WA) as an immunogen has shown a survival benefit in patients with metastatic hormone-refractory prostate cancer in a randomized phase III trial. This review will summarize the prostate cancer clinical trials using APC8015 and discuss the potential future role of APC8015 in prostate cancer treatment.     

Chemotherapy for the Treatment of Hormone-Refractory Prostate Cancer

Men with metastatic prostate cancer treated with androgen ablation therapy respond rapidly and often dramatically, with improvement in bone pain, regression of soft tissue metastases, and decreases in serum prostate-specific antigen (PSA) levels. Unfortunately, few treatment options are available to men with advanced prostate cancer in whom disease progresses after hormonal therapy. The combination of mitoxantrone with a corticosteroid is effective palliative therapy for bone pain; however, it is not associated with an improvement in overall survival. Recent studies have focused on the proteins that regulate apoptosis as a target for the treatment of hormone-refractory prostate cancer (HRPC). Agents that inhibit microtubule-associated proteins, such as estramustine, and agents known to phosphorylate Bcl-2, such as the taxanes, demonstrate high activity in HRPC. Estramustine-based regimens are commonly used for the treatment of men with HRPC. Results of phases I and II clinical trials evaluating the taxanes as single agents and combined with estramustine have demonstrated significant activity in terms of response rate, decrease in PSA level, and improvement of bone pain. Moreover, although completion of phase III trials is awaited, survival data with estramustine-taxane combinations appear promising in phase II trials.     

Pre-clinical and clinical evaluation of estramustine, docetaxel and thalidomide combination in androgen-independent prostate cancer

OBJECTIVE: To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC. PATIENTS, MATERIALS AND METHODS: In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days. RESULTS: In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013). CONCLUSION: Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.     

Effects of docetaxel on pain due to metastatic androgen-independent prostate cancer

Bone pain commonly plagues patients with metastatic androgen-independent prostate cancer. Studies of mitoxantrone demonstrated that chemotherapy can substantially reduce this debilitating symptom. Two of the available studies examining the use of docetaxel with and without estramustine for treatment of androgenindependent prostate cancer include a detailed prospective analysis of pain and quality of life. One study required patients to have pain at entry and demonstrated significant improvement in pain. The second study enrolled patients with low prevalence and intensity of pain and did not demonstrate pain relief. The available results, although preliminary, suggest that patients with significant bone pain due to androgen-independent prostate cancer can experience substantial pain relief with docetaxel-based therapy. Larger randomized studies targeting patients with sufficient prevalence and intensity of pain are needed to refine our understanding of the contribution of docetaxel to pain control in this patient population.     

Clinical evaluation of estramustine phosphate and vinblastine in patients with hormone-refractory prostate cancer

We evaluated the efficacy of the combination of estramustine phosphate and vinblastine in 13 patients with hormone-refractory prostate cancer. Of 12 patients with an elevated prostate specific antigen (PSA) level at the start of treatment, 5 (42%) had a greater than 50% decrease in PSA level. In a patient with cervical and mediastinal lymph node metastases, about a 57% decrease was observed in bidimensional measurement. Side effects were mild and manageable. The survival rate was not significantly different between patients who showed a greater than 50% decrease in PSA levels or regression of lymph node metastases versus the other patients.