Docetaxel-based Regimens Research Articles

Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy

The intention of this study is to describe the impact and underlying potential basis of the prostate-specific antigen (PSA) flare-up phenomenon in patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel-based chemotherapy. We retrospectively identified 74 consecutive patients who received docetaxel/estramustine-based chemotherapy at our institution. Patients were evaluated based on modified criteria from the Prostate-Specific Antigen Working Group regarding survival and toxicity. Additionally, two androgen receptor mutations derived from patients with advanced disease were analyzed for promiscuous transactivation activity. The 74 patients were stratified into four groups: response, partial response, flare-up-initial PSA elevation, and progression. Median survival in the flare-up group (n=8) was 20 months and did not differ from the response group (p=0.564). The flare-up group showed a maximum PSA elevation from baseline between 3.4 and 28.3% (between three and six weeks) followed by PSA decline >or=50% from the baseline level in seven of the eight patients. The androgen receptor mutations AR(877) and AR(715) displayed a 37.5- and 5.2-fold increase in transactivation activity by progesterone and a 12.6- and 5.4-fold increase by estrogen compared to the AR(WT), respectively. A considerable portion of HRPC patients experience an initial PSA flare-up under systemic chemotherapy. In this study, occurrence of flare-up phenomenon did not impact survival. Chemotherapy should be continued a minimum of six weeks before removing patients from a docetaxel-based regimen. We showed evidence that co-medication with dexamethasone/prednisolone and/or estramustine itself can induce an initial PSA flare-up via androgen receptor mutations.

Results of a randomized phase II study of irofulven in hormone-refractory prostate cancer patients that have failed first-line docetaxel treatment

5068 Background: Currently, no available treatments demonstrate an increase in survival for patients (pts) with hormone- refractory prostate cancer (HRPC) who have failed treatment with docetaxel-based regimens. Previous monotherapy and combination Phase I/II trials with irofulven (IROF) have shown antitumor effects in pts with HRPC, including those with resistance to docetaxel. A randomized phase II study was undertaken in HRPC pts with documented resistance to docetaxel to evaluate the efficacy and safety of IROF regimens compared to mitoxantrone (MITOX). Methods: Pts with metastatic HRPC with documented progression by RECIST or PSA Working Group criteria during or within 3 months of prior docetaxel were randomized to 1 of 3 arms in a 2:2:1 ratio: Arm A: IROF (0.45 mg/kg, Day [D]1, 8 every [q] 3 weeks [w]) and prednisone (PRED; 10 mg qd); Arm B: IROF (0.4 mg/kg D1, 15), capecitabine (CAPE; 2,000 mg/m2 D1–15 q4w) and PRED; Arm C: MITOX (12 mg/m2 q3w) and PRED. Pts were stratified by baseline pain status. Efficacy endpoints included time to progression (TTP), overall survival (OS), and response. Results: Enrollment of 134 treated pts was completed as of Jan 2006 (Arm A/B/C: 53/54/27). Median age: 64/66/63 years, median KPS: 80/90/80, median baseline PSA (ng/mL): 144/136/243, disease-related pain at baseline: 65%/57%/59%, and median number of metastatic sites: 1/1/2. Median pre-study PSA doubling time (days) was 42/44/50. Efficacy: As of Jan 2007, median OS (mos) was 10.1/9.5/7.4 in Arms A/B/C (based on 73% of pt deaths). Preliminary median TTP (mos) was 2.2/3.8/1.8, based mainly on PSA progression. PSA and RECIST responses were 10%/22%/0% and 10%/10%/13%, respectively. Safety: Treatment was well tolerated in all arms. The most frequent Grade 3–4 toxicities (% pts) were asthenia (8%/15%/0%), and vomiting (4%/11%/0%). Grade 3–4 hematological events included neutropenia (22%/15%/61%) and thrombocytopenia (23%/21%/4%). Conclusions: Results to date indicate longer survival, longer TTP, and greater PSA response for IROF/PRED and IROF/CAPE/PRED compared to MITOX/PRED. Based on these data, a larger randomized trial of irofulven in docetaxel resistant HRPC patients is warranted. No significant financial relationships to disclose.

ATTAX: Randomised phase II study evaluating weekly docetaxel-based chemotherapy combinations in advanced esophago- gastric cancer, final results of an AGITG trial

4528 Background: Docetaxel (T), cisplatin (C) and 5FU(F) are active agents in esophago-gastric cancer. A recent phase III study evaluating 3-weekly TCF demonstrated a survival advantage over standard therapy, but TCF was associated with high rates of hematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-hematological side effects (Van Cutsem et al, J. Clin Oncol. 24 4991–4997 2006). Weekly docetaxel is associated with a lower incidence of hematological toxicity. This randomized phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of such regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic esophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Patients (Pts) were randomized to receive weekly (w) T 30mg/m2 d1,8 C 60 mg/m2 d1 F 200 mg/m2/d continuously q 3w or wT 30 mg/m2 d1,d8 and capecitabine (X)1,600 mg/m2/d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analyzed independently. Simon’s 2-stage design was used, with 5/21 responses required in the first stage to allow continuation to 50 pts per arm. Results: Response rates in each arm satisfied the first stage, and complete accrual of 106 pts was completed in May 2006. Demographics, toxicity and response rates are shown in the table . With a median follow-up of 14.6 months, progression free and overall survival times are 5.9 m and 12.8 m, and 4.2m and 10.1 m for wTCF and wTX, respectively. Conclusions: wTCF and wTX have encouraging activity and a far more favorable toxicity profile than TCF administered 3-weekly. Weekly docetaxel-based combination regimens should be evaluated further in this disease. [Table: see text] [Table: see text]

HER2-negative metastatic breast cancer patients receiving first-line docetaxel: Survival data and prognostic factors

1105 Background: Modern management of metastatic breast cancer (MBC) patients (pts) is currently based on molecular stratification according to HER2 status and first-line taxanes. We sought to examine outcome data and prognostic factors in a prospectively characterized cohort of HER2 negative MBC pts receiving first-line docetaxel in a routine setting. Methods: Medical records from 162 HER2-, MBC pts treated at the Institut Paoli-Calmettes with first-line docetaxel-based regimen between 1997 and 2005 were reviewed. These patients had been treated with docetaxel single-agent or in combination according to standard institutional protocols. Univariate and multivariate analysis according Cox regression model were employed to identify prognostic factors for progression-free survival (PFS) and overall survival (OS). Results: Pt characteristics were the following: median age (ys), 51 (24 -75); Histological type (ductal/lobular/other, %) 81/15/4; Grade (1/2/3, %); Hormonal Receptivity (HR) (yes/no, %) 83/17; Adjuvant chemotherapy (CT) (yes/no; %) 66/34; Disease-free interval (DFI) (<24 months/>24 months, %) 47/53; visceral disease (yes/no, %) 46/54; number of metastatic sites (<3/>3,%) 78/22; liver metastasis (yes/no, %) 31/67; bone metastasis (yes/no, %) 65/35. After a median follow-up of 33 months, median PFS and OS were 11.7 months (95%CI , 9.7 -14.8) and 35 months (95%CI, 28.1–52.1), respectively. By univariate analysis, HR- (p=7.9 e-06), visceral disease (p=0.015), shorter DFI (p=0.027) and previous adjuvant CT (p=0.0038) were negatively associated with PFS, while HR- (p=6.3e-07), visceral disease (p=0.0094) and shorter DFI (p=0.01) were also negatively associated to OS. 14. These parameters retained independent prognostic significance by multivariate analysis, the strongest being HR-(p=2.4e-5) for OS. HR- pts had a PFS of 6.87 months [95%CI, 4.27 - 11.0] Vs 14 months [95%CI, 11.84 - 18.5] in HR+ pts (log-rank test p= 3.16e-06). 2-year OS were 38% [95%CI, 21.9–65] and 76%[95%CI, 68.7–84.4] (p = 6.52e-08) in HR- and HR+ pts, respectively. Conclusions: In the taxane era, median OS of HER2- MBC pts is nearly 3 yrs. Triple negative pts (HER2-, HR-) are a very poor-risk group requiring innovative therapeutic strategies. No significant financial relationships to disclose.

Chemotherapy for hormone-resistant prostate cancer: Where are we today?

Significant progress has been achieved in chemotherapy for hormone-resistant prostate cancer (HRPC) in the last five years. Although the disease was long considered to be chemoresistant, docetaxel-based regimens in particular have been shown to both palliate symptoms and prolong survival in HRPC patients. Docetaxel is now considered the best available chemotherapy for prostate cancer progressing on first-line hormonal treatment. Other cytotoxics including mitoxantrone, anthracyclines, vinorelbin and vinblastine can alleviate symptoms and improve progression-free survival in HRPC without affecting overall survival. The survival benefit from chemotherapy seen in randomized studies has been small or nonexistent. Results of a recent trial suggest that the survival benefit may have been underestimated as a result of crossover from the less active to the active arm.

Prostate-specific antigen doubling time is associated with survival in men with hormone-refractory prostate cancer

Objectives Men with metastatic hormone-refractory prostate cancer (HRPC) form a heterogeneous population with a wide range of symptoms and variable survival. Patient selection is critical in determining which patients will receive the most benefit from aggressive chemotherapy. The prostate-specific antigen (PSA) doubling time (PSADT) has been shown to be a surrogate for survival in earlier stages of prostate cancer, but its utility as a predictor in HRPC is unknown. Methods A retrospective chart review of 224 patients with HRPC treated from 1998 to 2002 was performed. Eligible patients had HRPC and evidence of metastatic disease. The PSADT at HRPC diagnosis was calculated, and the optimal PSADT stratification was obtained using the log-rank chi-square statistic. Kaplan-Meier curves were used to estimate overall survival between the groups. Results During the follow-up period, 80% of patients died, 93% of prostate cancer. Overall, the median survival from diagnosis of HRPC was 15.1 months (range 0.5 to 90.5). The optimal PSADT stratification for survival was 70 days. Patients with a PSADT of 70 days or less survived 11 months compared with 19 months for those with a PSADT of more than 70 days [relative risk (RR) 1.79, P <0.0001]. Conclusions PSADT serves as an independent prognostic marker for survival in patients with metastatic HRPC. Men with a PSADT of 70 days or less had a significantly shorter survival time compared with men with a PSADT of more than 70 days. Inclusion of PSADT with other clinical data could help clinicians select men at high risk of early mortality who may most benefit from aggressive treatment regimens, such as docetaxel-based regimens.

Clinical significance of a prostate-specific antigen flare phenomenon in patients with hormone-refractory prostate cancer receiving docetaxel

Docetaxel has shown promise for the treatment of hormone-refractory prostate cancer and has become the standard of care. The flare phenomenon is a known entity in androgen-deprivation therapy of advanced prostate cancer and it has also been described in palliative chemotherapy of hormone-refractory prostate cancer. The aim of this study was to evaluate the clinical impact of a prostate-specific antigen flare phenomenon in docetaxel-treated hormone-refractory prostate cancer patients. From December 2002 to August 2005, we treated 44 patients with hormone-refractory prostate cancer applying docetaxel-based regimens. Prostate-specific antigen levels were determined before therapy and weekly thereafter. Patients were divided into three groups: response (group 1), progression (group 2) and flare (group 3). Flare was defined as initially rising prostate-specific antigen under therapy, dropping thereafter to values below baseline. The groups were compared for overall survival by Kaplan-Meier analysis. We observed a prostate-specific antigen flare phenomenon in eight (18%) of 44 evaluable patients; 24 (54.5%) patients were primary responders and 12 (27.3%) experienced progressive disease. In group 3, prostate-specific antigen levels rose to 107-180% from baseline and then dropped to 21-68%. Kaplan-Meier analysis showed significantly better overall median survival for groups 1 (18 months, P=0.0005) and 3 (19 months, P=0.006) than for group 2 (7 months). Survival in groups 1 and 3 was comparable. Grade 3 and 4 toxicity was below 5% and equally distributed between the 3 groups. In our limited patient cohort, prostate-specific antigen flare phenomenon does not seem to be a clinically relevant issue in terms of overall survival. Thus, an initial rise of prostate-specific antigen under docetaxel therapy in hormone-refractory prostate cancer does not indicate therapeutic failure and should not lead to early withdrawal from therapy in the absence of clinical signs of progression.

Randomized study of docetaxel (D) and dexamethasone (DX) with low or high dose estramustine (E) for patients with advanced hormone-refractory prostate cancer (HRPC)

4653 Background: D-based chemotherapy is a burgeoning option for men with advanced HRPC. Alone or in combination with E, D has been shown to improve median survival. In this study we tested the combination of D with two different doses of E in patients (pts) with HRPC to improve response rates and to lower side effects. Methods: 72 metastatic HRPC pts were randomly assigned to receive D (70 mg/m2 IV, d2, q3w) and E (3 × 280 mg/d PO starting 1 day prior to D, for 5 consecutive days) for arm A or E (3 x 140 mg/d PO starting 1 day prior to D, for 3 consecutive days) for arm B. Premedication with oral DX at a total daily dose of 16 mg, in divided doses two times a day was administered in arm A on day 1 to 5 and in arm B on day 1 to 3. Initially, 6 cycles were administered and repeated after significant PSA rise. Pts were monitored for PSA response, time to progression (TTP), survival and toxicity. Results: PSA declines of ≥75%, ≥50% and ≤50% were 36.8%, 55.3% and 44.7% in arm A and 38.2%, 67.6% and 32.4% in arm B, respectively (P = .442). TTP in Arm A and Arm B were 11 months (95% CI, 7–14) versus 14 months (95% CI, 8–19), P = .6911) and overall survival 21 months (95% CI, 6–35) versus 22 months (95% CI, 18–27), respectively, (P = .4149). The primary treatment-related side effects observed in arm A and arm B were granulocytopenia (34% and 29%, P = .663) and thrombotic complications caused by E (four pts (11%) and one pt (3%), respectively, P = .206). Associated baseline factors with overall survival in univariate analysis were ECOG performance status (P &lt; .001), hemoglobin level (P &lt; .001), bone pain (P &lt; .001), and PSA (P &lt; .097) and in multivariate analysis ECOG performance status (95% CI, 2.9–13.9) and bone pain (95% CI, 3.2–20.1), (P &lt; .001). Conclusions: In this randomized phase II study the combination of D and E had substantial activity in HRPC. We did not find a statistically significant difference of higher dose of E in combination with D compared to a lower dose of E and D regarding PSA response, TTP and survival. However, there was a tendency of higher toxicity in the high dose E group. These treatment-related toxicities were mainly hematologic and manageable. The results of this study support the assertion that estramustine is not necessary in docetaxel-based treatment regimens. No significant financial relationships to disclose.

Comparison of docetaxel and vinca alkaloid, alone or in combination with other chemotherapy agents, in the first-line treatment of advanced non-small cell lung cancer (NSCLC): A meta-analysis

7034 Background: Taxanes and vinca alkaloids are commonly used agents, in first-line therapy of advanced NSCLC. As some data in comparative studies have suggested possible differences in survival and safety, we performed a meta-analysis in order to assess the potential benefit of docetaxel-based regimens in comparison with vinca alkaloid-based regimens, in terms of overall survival (OS) and toxicity. Methods: MEDLINE, CANCERLIT and Cochrane Library searches were supplemented by information from clinical study reports and by manual searching of relevant meeting proceedings. Only randomized trials comparing docetaxel-based chemotherapy to vinorelbine- or vindesine-based chemotherapy were included. Outcomes recorded were OS and neutropenia. Fixed-effects and random-effects models were used to estimate the pooled hazard ratio (HR) of OS and the odds ratio (OR) of neutropenia. A HR or OR less than 1 indicates that docetaxel is superior to vinca alkaloids. Heterogeneity was assessed using the Cochran Q-test. Results: The seven selected trials (six using vinorelbine as vinca alkaloid) yielded a total of 2,867 patients (docetaxel regimens: 1,638; vinca alkaloid regimens: 1,229). Docetaxel was combined with a platinum compound in three trials, with gemcitabine in two trials and used as monotherapy in two trials. The vinca alkaloid was combined with a platinum compound in six trials, and used alone (vinorelbine) in one. The pooled estimate of the OS shows a significant improvement in favor of docetaxel (HR=0.89, 95%CI [0.82;0.96], p=0.03), this benefit persisting after exclusion of the vindesine study (HR=0.90 [0.83;0.98]) and also after excluding monotherapy regimens (HR=0.89 [0.82;0.97]. While neutropenia was common, it was significantly less frequent with docetaxel (OR=0.60 [0.39;0.92], p=0.019), as was febrile neutropenia (OR=0.60 [0.39;0.96], p=0.034). Conclusions: The results of this meta-analysis support the superior efficacy (OS) and safety (neutropenia and febrile neutropenia) of docetaxel in first-line therapy of advanced NSCLC as compared with vindesine or vinorelbine. Detailed results, as well as subgroup analyses, will be presented at the meeting. [Table: see text]

Hormone-Refractory Prostate Cancer: A Shifting Paradigm in Treatment

Prostate cancer, the most common male cancer, affects one in eight American men. Risk factors for the disease include increased age, race, and family history of prostate cancer. To date, surgery, radiation, and hormonal therapy have been the mainstays of treatment. In the past, chemotherapy served only a palliative role for men with prostate cancer and failed to produce a survival advantage or any significant measurable disease response. However, for the first time, docetaxel-based regimens have demonstrated improved survival in men with hormone-refractory prostate cancer in two different, large, phase III studies. Additionally, a number of novel agents are being developed with the hope that treatment for men with hormone-refractory prostate cancer will be improved. Oncology nurses provide critical symptom management strategies as well as education to men with prostate cancer and their partners. Therefore, maintaining current state of the knowledge about best practices and treatment for prostate cancer is crucial. This, in turn, directs efforts to educate patients and family members about treatments and management of side effects.

First-Line Chemotherapy for Advanced-Stage Non–Small-Cell Lung Cancer: Focus on Docetaxel

Systemic chemotherapy results in modest improvements in survival and quality of life for patients with advanced-stage non-small-cell lung cancer (NSCLC). Administration of a platinum compound in combination with a taxane (paclitaxel or docetaxel), gemcitabine, vinorelbine, or irinotecan is considered optimal first-line therapy for patients with advanced-stage NSCLC who have a good performance status. Studies that have compared various platinum agent-based doublet regimens have demonstrated comparable efficacy between these regimens. In addition, non-platinum agent-based regimens have also demonstrated response rates and survival similar to the platinum agent-based combinations. These developments have allowed for tailoring of chemotherapy to individual patients based on factors such as toxicity profile, treatment schedule, and cost. Docetaxel is approved for first-line therapy and salvage treatment of advanced-stage NSCLC. Multiple randomized clinical trials have established the efficacy of platinum-agent/docetaxel regimens for first-line treatment of advanced-stage NSCLC. Improvements in various lung cancer-related symptoms and global quality of life indices have been noted with docetaxel-based regimens. Combination chemotherapy appears to be beneficial even for elderly patients. The current generation of clinical trials is evaluating the incorporation of molecularly targeted agents into existing 2-drug chemotherapy regimens. This article will discuss the role of docetaxel as first-line chemotherapy for patients with advanced-stage NSCLC.

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.

Achieving Treatment Goals for Hormone-Refractory Prostate Cancer with Chemotherapy

The belief that hormone-refractory prostate cancer (HRPC) is a chemotherapy-resistant disease has been effectively refuted by the results of two recent randomized phase III trials. The TAX327 trial compared weekly docetaxel, every-3-weeks (Q3W) docetaxel, and Q3W mitoxantrone plus prednisone in 1,006 patients with HRPC, and results demonstrated that survival was significantly longer with a docetaxel-based regimen than with mitoxantrone. That trial demonstrated that only Q3W docetaxel was significantly superior to mitoxantrone with respect to overall survival. Quality of life was also superior in the docetaxel groups. In the Southwest Oncology Group (SWOG) 9916 trial, 674 men with progressive HRPC were randomized to 3-week cycles of docetaxel plus estramustine or mitoxantrone plus prednisone. Overall and disease-free survival times were significantly longer in the docetaxel arm. Collectively, the results of these trials demonstrate that survival can be significantly improved with chemotherapy in patients with HRPC to an extent that is comparable with the survival benefits seen in other cancers considered sensitive to chemotherapy such as breast cancer. Among various research tasks in HRPC is the definition of potential surrogate end points for survival, which will facilitate the conduct of pivotal trials. Prostate-specific antigen (PSA) response rate and changes in PSA constructs (i.e., PSA doubling time and PSA velocity) are promising potential surrogate end points for future trials and are being actively evaluated at the present time. Until there is clear demonstration of a surrogate role for these alternative end points, survival remains the appropriate end point for phase III trials in HRPC. There is a need for safe and effective second- and third-line regimens for patients progressing after docetaxel, and these patients should enter clinical trials designed for this population. Mitoxantrone, vinorelbine, the platinum analogue satraplatin, and epothilone are among compounds that require careful testing in this setting. The addition of targeted therapies, such as the endothelin receptor antagonist, atrasentan, and angiogenesis inhibitors, such as thalidomide and bevacizumab, to docetaxel-based therapy is being evaluated. High-dose calcitriol may also be an effective addition to docetaxel. The extensive effort devoted to the evaluation of chemotherapy and other systemic modalities of treatment of HRPC is likely to yield additional clinical benefit for patients, making HRPC a more manageable, less lethal, and less debilitating disease.

Docetaxel-Based Therapy for Prostate Cancer

Patients with metastatic prostate cancer can be treated with androgen deprivation strategies; however, the vast majority of patients will eventually develop androgen-independent prostate cancer. Early clinical trials with chemotherapy in advanced prostate cancer were disappointing. The last decade witnessed the approval of mitoxantrone with glucocorticoids based on palliation of symptoms without improvement in survival. Recently, two large Phase III trials demonstrated a survival advantage for docetaxel-based regimens compared with mitoxantrone with prednisone. This firmly established docetaxel-based therapies as the standard of care for patients with metastatic androgen-independent prostate cancer. In addition, this foundation provides a platform for the translation of novel agents into new combination cancer therapies. This article aims not only to review standard docetaxel-based treatment for androgen-independent prostate cancer, but also to present some of the promising new drug combinations with docetaxel currently being studied for the treatment of prostate cancer.

PSA decline does not correlate with overall survival in clinical trials with docetaxel for androgen independent prostate cancer (AIPC)

4673 Background: Since uncontrolled trials have shown an association between a decline in PSA levels of 50% or greater and survival, some investigators advocate that the rate of PSA decline in a phase II trial can guide the selection of agents for further testing and phase III trials. This approach may not be valid with docetaxel-based regimens. Methods: A computer-based search of the PubMed database was performed of all published clinical trials of docetaxel-based regimens in patients with AIPC between 1999 and November 2004. Trials were eligible for analysis if they accrued only patients with metastatic AIPC for first line chemotherapy with a docetaxel-based regimen and they reported median overall survival. We sought to define the correlation between PSA decline and median overall survival in clinical trials with docetaxel-based regimens. Analyses were done for the whole group and for two subgroups: every 3-weeks and weekly regimens. Weighted linear regression was used to assess this relationship. Results: A total of 19 published trials were retrieved, and 9 (7 phase II and 2 phase III) trials are eligible for analysis, for a total of 1330 patients and a median of 47 patients (range, 25–338) accrued for each study/arm of treatment. There are 5 regimens in the every 3-weeks group and 6 regimens in the weekly regimen group (two trials had two different treatment arms). The median > 50% PSA reduction reported was 50% (range, 37%–81%). The median median-overall survival time reported in the clinical trials was 18.9 months (range, 9.75–28.9). Correlation for the whole group, for the every 3-weeks group and the weekly regimens group were weak [respectively, R2=1.2% (p=0.746); R2=0.8 (p=0.89); R2= 5% (p=0.67)]. Conclusions: PSA decline of 50% or greater does not correlate with overall survival in clinical trials with docetaxel-based regimens in AIPC. Hence, a higher rate of PSA decline in a phase II trial should not guide the selection of a new docetaxel-based regimen as the experimental arm for future phase III trials. No significant financial relationships to disclose.

Future directions in the treatment of androgen-independent prostate cancer

The rationale for evaluating the taxanes in hormone-refractory prostate cancer (HRPC) is strong. Preclinical data demonstrate that docetaxel is a potent inhibitor of bcl-2, an antiapoptotic gene implicated in the progression of HRPC and the development of chemotherapy resistance. The results of early clinical trials with docetaxel suggested that it could improve survival; trials in which docetaxel was combined with estramustine appeared even more promising. The Southwest Oncology Group intergroup trial (SWOG 9916) phase III was developed to compare the combination of docetaxel and estramustine to mitoxantrone-prednisone in men with HRPC. A total of 684 eligible patients were enrolled. Median survival was significantly improved with docetaxel-estramustine (17.5 months vs 15.6 months with mitoxantrone-prednisone, P = .02), and the relative risk of death was reduced by 20%. Progression-free survival was improved from 3.2 months with mitoxantrone-prednisone to 6.3 months with docetaxel-estramustine ( P <.001). Significantly more patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50% compared with those treated with mitoxantrone-prednisone (50% vs 27%, P <.001). Toxicity was more common in the docetaxel-estramustine arm, likely due to estramustine. Other docetaxel-based regimens under investigation include combinations with calcitriol, thalidomide, or bevacizumab. With docetaxel/prednisone approved by the US Food and Drug Administration (FDA) as first-line treatment of HRPC, ongoing and future trials will build on its success by evaluating a number of docetaxel-based combinations in various prostate cancer settings. Other novel agents, including the oral platinum analog satraplatin, are being investigated as second-line treatment for HRPC.

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

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. 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. 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.

Docetaxel-based regimens, the standard of care for metastatic androgen-insensitive prostate cancer

Patients with recurrent prostate cancer may be treated with androgen deprivation strategies; however, most patients will develop androgen-independent prostate cancer. Strategies for treatment of this group of patients have shown significant palliation but until recently, have had no definitive increase in survival. Two large Phase III studies evaluating docetaxel-based chemotherapy were initiated to see if these could improve overall survival over mitoxantrone with prednisone. The purpose of the Tax 327 Phase III study was to determine if either weekly or every-3-week administration of docetaxel plus daily prednisone regimen could improve the overall survival for these patients as compared with mitoxantrone and prednisone, which is approved by the US Food and Drug Administration as a palliative treatment. This study is of immense importance as it represents the first time any treatment has been shown to improve overall survival in an appropriately powered study in patients with androgen-insensitive metastatic prostate cancer. Newer approaches are now looking at combinations of other drugs with docetaxel to further improve the overall survival of patients with metastatic androgen-insensitive metastatic prostate cancer.

A multicenter phase III comparison of docetaxel (D) + prednisone (P) and mitoxantrone (MTZ) + P in patients with hormone-refractory prostate cancer (HRPC)

4 Background: Docetaxel-based regimens have shown encouraging anti-tumor activity in phase II trials in HRPC. This study compared two schedules of D+P to MTZ+P, an accepted standard in HRPC. Methods: Patients (pts) with histologically-proven metastatic HRPC, testosterone <50 ng/ml, adequate hematologic and organ function, clinical and/or biochemical (PSA) progression, and no antiandrogens within 6 wk, were stratified by pain and KPS and randomized to daily prednisone (5mg po bid) plus D (ARM A-75mg/m2 q3wk x 10 cycles; ARM B-30mg/m2/wk x 5 of 6 wk x 5 cycles) or MTZ (ARM C-12mg/m2 q3wk x 10 cycles). Primary endpoint was survival; secondary endpoints included PSA response (≥50% decrease for at least 4 wk), pain response, and toxicity. A modified Bonferroni method was used to adjust for multiple comparisons. Results: 1,006 pts were randomized. Median follow up was 20.7 mo. Pts in all arms had similar baseline characteristics. Planned treatment was delivered to 98%, 96% and 99% pts in A, B, and C, respectively. Grade 3/4 toxicities (% pts A, B, C): overall (45.8%, 43.0%, 34.6%), including bone pain (7.8%, 7.3%, 9.9%), infection (5.7%, 5.5%, 4.2%), fatigue (4.5%, 5.5%, 5.1%), and diarrhea (2.1%, 4.8%, 1.2%). The most common laboratory grade 3/4 toxicity was neutropenia (32.0%, 1.5%, 21.7%). Conclusions: The D q3wk +P schedule improved overall survival and increased pain response and PSA response vs MTZ+P. It was well tolerated, but with more grade 3/4 neutropenia than MTZ+P. This is the first phase III study to show a significant survival benefit in HRPC. (Supported by Aventis) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis Research

Phase II randomized trial of docetaxel plus estramustine (DE) versus docetaxel (D) in patients (pts) with hormone-refractory prostate cancer (HRPC): a final report

4603 Background: Single-agent docetaxel has proven efficacy in pts with HRPC, but the D and E combination is synergistic in vitro. This study evaluated PSA decline (PSA↓), safety, and quality of life (QoL) for DE vs D. Methods: Major eligibility criteria were: WHO PS \(\underline{{<}}\)2, appropriate renal, hepatic, and hematologic function, no prior chemotherapy, and withdrawal of antiandrogen therapy. Pts were randomized to Arm A (D 70 mg/m2IV over 1 hour d1 q3w + E 560 mg/d PO starting 1 day prior to D, for 5 consecutive days) or Arm B (D 75 mg/m2 IV over 1 hour d1 q3w) for a maximum of 6 cycles. Prophylactic warfarin (1mg/d PO) was given continuously in Arm A. Corticosteroid was given before and after D infusion in both arms. Results: Between 02/2001 and 10/2002, 92 pts were randomized (Arm A: 48, Arm B: 44) but 1 pt did not receive treatment. Median age was 68 years (range: 46–86), PS 0/1/2 (32/50/9 pts), median PSA was 115 ng/ml (range: 0.3–1585), and 40 pts (Arm A: 22, Arm B: 18) had measurable disease (MD). With a median number of 6 treatment cycles in both arms, cycle delays >7 days were more frequent in Arm A (15% pts) vs Arm B (11% pts); dose reduction was similar, 4.3% vs 4.5% pts, respectively. Median follow-up was 12.8 months. Main grade 3–4 hematologic toxicities among pts in Arms A vs B, respectively, were: neutropenia 25.5% vs 27.3%; anemia 10.6% vs 2.3%. Main grade 3−4 treatment toxicities (pts) were: thrombophlebitis (1) and allergic reaction (1) in Arm A; febrile neutropenia (1) per arm; fatal acute pulmonary edema (1) in Arm B. Response in Arm A vs B, respectively, was: PSA↓ >50%: 68% vs 29%; PSA↓ >75%: 36% vs 16%; median PSA response duration was 6 months in both arms. Of 40 pts with MD, PR was observed in 18.2% (Arm A) vs 16.7% (Arm B). Median time to progression in Arm A was 5.7 months (range: 4.7–5.8) vs 2.8 (2–6.9) in Arm B. There was no worsening in QoL using the FACT-P instrument and the pain score was stable throughout treatment in both arms. Conclusion: Docetaxel-based regimens are active in HRPC with predictable and manageable toxicity profiles. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis