Chemotherapy For Hormone-refractory Prostate Cancer Research Articles

Phase II trial of non-pegylated liposomal doxorubicin and low-dose prednisone in second-line chemotherapy for hormone-refractory prostate cancer.

Non-pegylated liposomal doxorubicin (NPLD) (Myocet) has shown marked in vitro activity in castration-resistant prostate cancer (CRPC) and also in docetaxel-resistant cells, higher than that shown by pegylated liposomal doxorubicin. Its activity would seem to be due to a high intracellular drug concentration and induction of Golgi-dependent apoptosis. On the basis of these results, a clinical study was designed to assess the activity of NPLD and low-dose prednisone in second-line therapy. Fifty-four patients were enrolled and evaluated. Eligibility criteria were histologically confirmed CRPC, PSA >20 ng/mL or measurable lesions according to the RECIST criteria, previous docetaxel-based chemotherapy, and adequate cardiac function. Patients were treated with weekly intravenous NPLD 25 mg/m2 and daily prednisone 10 mg until progression. Median patient age was 69 years (range, 52-83) and median baseline PSA concentration was 120 ng/mL (range, 5.35-4350). Sixteen (29.6%) patients had measurable lesions. Objective or PSA responses (>50% reduction) were observed in 8 (14.8%) patients. The median time to progression was 2.8 months and the median overall survival was 11.3 months. Toxicity was generally mild (grade 1-2) and infrequent, with grade 3-4 neutropenia in 12.9% of cases. Grade 3 nonhematological toxicities included nausea in 2 patients (3.7%) and fatigue and stomatitis in 1 case (1.9%). No drug-related serious adverse events were reported. Weekly administration of NPLD is a well tolerated treatment with proven albeit limited activity.

Chemotherapy in hormone-refractory prostate cancer: Docetaxel with and without VT122.

e16062 Background: Randomized study in metastatic castration resistant prostate cancer treated with docetaxel and the benefit of adding VT122. Methods: Castration resistant prostate cancer with bone metastasis, symptomatic were treated with docetaxel 75 mg/m2 every 3 week and prednisolone with continued androgen suppression, LHRH analogue and zoledronic acid, every 28 days with or without VT122. VT122 is a drug combination of etodolac, a COX-2 inhibitor and propranolol, a beta blocker with anti angiogenic properties; this combination has previously been shown to be anti cachectic, anti neoplastic.The dose of etodolac was titrated by C-reactive protein levels to a maximum of 800 mg/day. The dose of propranolol was titrated to keep heart rate at around 60 b/min to 70 b/min. GCSF was allowed, all patients were given Calcium and VitaminD. The primary end point was time to progression, a composite end point of objective progression by RECIST criteria, PSA progression or pain progression, whichever occurred first was applied.The McGill questionnaire was applied to patients. Number of patients 69; 34 in docetaxel arm; 35 in VT122 arm. Age between 50-65 years. Taken from 3 centers with PS ECOG <2 controlled comorbidity with stable analgesic regime. All patients were planned for 6 cycles of docetaxel. Follow-up was for a period of two years. Results: Median age of 62 years with ECOG status 1 was seen in 88%. The median PSA value was seen as 138 ng/ml (10 - 600). 66% in both arms had measurable disease. Conclusions: Addition of VT122 improves response rates, duration of response and symptom scales along with 1-year survival which are statistically significant; toxicities are also significantly decreased and indicating increased efficacy and safety profile of docetaxel. The efficacy and control of toxicity and easy to administer makes this an attractive combination. [Table: see text]

Phase II trial of non-pegylated liposomal doxorubicin and low-dose prednisone in second-line chemotherapy for hormone-refractory prostate cancer

Non-pegylated liposomal doxorubicin (NPLD) (Myocet) has shown marked in vitro activity in castration-resistant prostate cancer (CRPC) and also in docetaxel-resistant cells, higher than that shown by pegylated liposomal doxorubicin. Its activity would seem to be due to a high intracellular drug concentration and induction of Golgi-dependent apoptosis. On the basis of these results, a clinical study was designed to assess the activity of NPLD and low-dose prednisone in second-line therapy. Fifty-four patients were enrolled and evaluated. Eligibility criteria were histologically confirmed CRPC, PSA >20 ng/mL or measurable lesions according to the RECIST criteria, previous docetaxel-based chemotherapy, and adequate cardiac function. Patients were treated with weekly intravenous NPLD 25 mg/m2 and daily prednisone 10 mg until progression. Median patient age was 69 years (range, 52-83) and median baseline PSA concentration was 120 ng/mL (range, 5.35-4350). Sixteen (29.6%) patients had measurable lesions. Objective or PSA responses (>50% reduction) were observed in 8 (14.8%) patients. The median time to progression was 2.8 months and the median overall survival was 11.3 months. Toxicity was generally mild (grade 1-2) and infrequent, with grade 3-4 neutropenia in 12.9% of cases. Grade 3 nonhematological toxicities included nausea in 2 patients (3.7%) and fatigue and stomatitis in 1 case (1.9%). No drug-related serious adverse events were reported. Weekly administration of NPLD is a well tolerated treatment with proven albeit limited activity.

Docetaxel plus prednisone versus mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer: long-term effects and safety

To compare docetaxel plus prednisone with mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer (mHRPC). From January 2007 through August 2010, 62 patients with mHRPC received 5 mg of prednisone twice daily were randomly assigned to receive mitoxantrone 12 mg/m² every three weeks (group A) or 75 mg/m² every three weeks (group B). The cycles of each regimen were less than 10 times. The primary end point was overall survival. The secondary end points were the prostate-specific antigen (PSA) response rate, the duration of PSA response and the objective tumor response rate (ORR). All the t test, χ² test and Fisher's exact test were performed between 2 groups. Thirty-one patients enrolled in group A received a median 4 cycles of regimen (range 1 - 10), whereas 30 patients enrolled in group B received a median of 7 cycles of regimen (range 2 - 10). There were 45.2% patients in group A and 70.0% in group B had PSA response (χ² = 3.85, P < 0.05). The duration time of PSA response was 121 days (range 20-323 days) in group A and 168 days (range 42 - 447 days) in group B, respectively. The ORR was 15.0(3/20) in group A and 10.3% (3/29) in group B, respectively. The median survival was 511 days (95%CI: 357 - 665 days) in group A and 833 days (95%CI: 634 - 1032 days) in group B, respectively (χ² = 4.20, P = 0.040). The incidence of thrombocytopenia in group A was higher than group B (χ² = 5.60, P = 0.018); the incidences of nausea and vomiting (χ² = 4.32, P = 0.038), diarrhea (P = 0.024), fatigue (χ² = 5.90, P = 0.015), and alopecia (χ² = 5.42, P = 0.020) in group B were higher than group A. Docetaxel plus prednisone can lead to superior overall survival and PSA response rate in patients with mHRPC.

A phase II trial of chemotherapy plus hormone therapy as initial treatment of unresectable/metastatic adenocarcinoma of the prostate.

247 Background: Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone is present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy could be effective initial treatment for locally advanced or metastatic prostate cancer. This study examined the efficacy and safety of chemohormal therapy approach. Methods: Patients received medical castration plus an anti-androgen and chemotherapy (nab-paclitaxel, leuprolide, bicalutamide). Patients were followed with PSA levels and radiographic assessments. Results: Forty-six men (median age) 64.7 years were treated. Fifty-eight percent underwent prior local therapy including prostatectomy (30%), prior radiation (15%), or both (13%). Median baseline PSA was 8.9 ng/ml, and 96% of patients had a Gleason score of ≥7%. At 2 years, 78% of patients experienced tumor regression with a median reduction in PSA level of &gt;90%. Median time to progression was 28.43 months measured by PSA and 34.52 months measured radiographically. Median OS was 62.4 months. The most frequent significant adverse events included grade 3 hypokalemia (17%) and lymphopenia (59%). Conclusions: Combination chemohormonal therapy for locally advanced and metastatic prostate cancer delayed disease progression and enhanced OS. Information presented will include curves and correlation detailing efficacy and adverse events of various sub-populations.

Biochemical pathways in cancer.

The revolutionary advances in cellular and molecular biochemistry in the last quarter century have provided an unprecedented opportunity for systematic approaches to understand the cancer process. With these new advances and the knowledge acquired as a direct result, an enormous impact has positively affected the clinical areas of cancer prevention, disease management, and treatment of malignancy. Despite these scientific achievements, we are still faced with the challenge of fully understanding the complex nature of cancer, including issues of disease recurrence and drug resistance. Therefore, dissecting biochemical pathways that underlie the development of cancer should be given high priority to improve knowledge of human health. In this special issue, we will explore the various aspects of cancer-related biochemical pathways. The papers in this issue discuss multiple signaling pathways involved in the regulation of proliferation, senescence, and death of cancer cells. M. K. Altman et al. demonstrated that the regulator of G-protein signaling 5 (RGS5) is able to reduce the proliferation of ovarian cancer cells and extend the survival of mice. The tumor suppressor p53 plays an essential role in cell proliferation, cell cycle progression, cell death, and senescence [1, 2]. Reisman et al. reviewed the evidence that DNA-binding factors RBP-Jκ and C/EBPβ-2 transcriptionally activate p53 to ensure a rapid cellular response to DNA damage. p53 is also involved in complex networks of mitotic kinase signaling in response to mitotic spindle damage to ensure the proper cell cycle progression. G. H. Ha and E. K. Breuer discussed a mutual regulation network between mitotic kinase and p53 signaling. The tumor suppressor p16INK4A has shown to be implicated in replicative senescence. Here, the role of p16INK4A in replicative senescence and DNA damage-induced premature senescence in the absence of p53 was reviewed by R. Mirzayans et al. The authors also discussed a possible existence of a negative regulatory relationship between p53 and p16INK4A. R. Jager and H. O. Fearnhead reviewed cancer cell proliferation and death in a different point of view. These authors suggested that cancer cell proliferation might be a consequence of inappropriate or corrupted tissue-repair programs, initiated by a signal from dying cells. Mounting evidence suggested that dissecting the biochemical process of genetic alterations will help us understand mechanisms underlying the genesis and spread of cancer and develop novel strategies for targeted therapy and tailored cancer management [3, 4]. J. L. Johnson et al. discussed the genetic and biochemical alternations in heterogeneous cell signaling pathways in non-small-cell lung cancer and its implications in targeted cancer therapy. The papers also provide new insights into the pathogenesis of cancer and therapeutic intervention strategies. As a new therapeutic target, S. Mohanan et al. suggested that peptidylarginine deiminases (PADs) play an important role in cancer pathogenesis and its inhibition may have a profound impact on the regulation of the inflammatory tumor microenvironment and tumor growth. To improve the efficacy of chemotherapy in hormone-refractory prostate cancer, E. Tsakalozou et al. investigated the combination effects of docetaxel and doxorubicin and proposed the synergistic ratios of drug combinations. We believe that a better understanding of cellular biochemical pathways and activities will ultimately have important implications in the management of cancer patients. Previous work in this area has demonstrated the power of translating molecular and biochemical findings to therapeutics and the clinic. It is our hope that the papers in this issue will be of great help in understanding the complex nature of cancer and in designing and conducting preventive and therapeutic interventions in the near future. Eun-Kyoung Yim Breuer Mandi M. Murph Rolf J. Craven

Phase II trial of nonpegylated liposomal doxorubicin and low-dose prednisone in second-line chemotherapy for hormone-refractory prostate cancer: A translational study.

4683 Background: Nonpegylated liposomal doxorubicin(NPLD) (Myocet) has shown an important in vitro activity in hormone-refractory prostate cancer(HRPC) and also in docetaxel-resistant cells, higher...

Salvage chemotherapy for hormone-refractory prostate cancer: Association of Adriamycin and ifosfamide

Prostate carcinoma is the most common cancer in men. Hormone-resistance is the natural history of this metastatic disease and requires the use of docetaxel as the standard chemotherapy. At present, there is no approved second-line treatment. Here, we report a combination of treatment with Adriamycin and ifosfamide in a series of 7 relatively young patients with an average age of 57 years at the time of diagnosis. Chemotherapy was administered over 3 days with the following schedule: 20 mg/m(2) Adriamycin per day and 1-1.5 mg/m(2) ifosfamide per day, in association with Uromitexan. Treatment was repeated every 3 weeks. Three biological responses, one CT scan response, one bone scan response and two CT scan stabilizations, were obtained. Mean survival following this combination was 6.6 months, and over 26 months after first-line chemotherapy. Tolerance was good with the use of granulocyte-colony stimulating factors. Our observations clearly show that the use of this type of salvage therapy for relatively young patients in good physical condition should be further assessed in a clinical trial, particularly when different lines of chemotherapy are required.

Vinflunine (VFL) as salvage chemotherapy in hormone-refractory prostate cancer (HRPC)

16059 Background: Two randomized, phase III trials have demonstrated survival benefits for docetaxel-based chemotherapy in patients (pts) with HRPC. Though some pts retain sensitivity to this agent after completion of therapy, progression of their disease eventually occurs. To date, there is no second-line therapy with proven survival benefits. VFL is a novel vinca alkaloid with demonstrated preclinical antitumor activity in prostate cancer models, and clinical activity in several solid tumors including breast and bladder cancer. In this multicenter phase II trial, we evaluated VFL as salvage chemotherapy in HRPC. Methods: Eligibility criteria: progressive hormone-refractory metastatic or incurable localized prostate carcinoma; ECOG PS 0–2; prior docetaxel; ≤ 2 prior chemotherapy regimens; no prior anthracycline; adequate bone marrow, kidney and liver function; informed consent. All pts received: VFL 320 mg/m2 IV every 3 weeks (280 mg/m2 for pts ECOG PS 2, GFR < 60 cc/min, or prior pelvic RT). Pts were reevaluated after 2 cycles (6 weeks); responding/stable pts received 6 cycles. This study was designed to detect a response rate > 15%; 4 responses in the first 26 evaluable pts were necessary to proceed to the second stage. Results: Between May 2007 and November 2007, 35 pts were enrolled: median age, 75 years (range 52–86); ECOG 0/1/2, 6/26/3 pts; bone metastases, 33 pts (94%); measurable disease, 14 pts (40%); > 1 prior chemotherapy regimen, 23 pts (66%). Pts received VFL for a mean of 2.6 cycles (range 1–6). 27 pts were evaluable for PSA response: 1 pt had a partial response (4%), 9 pts (33%) had stable disease, and 17 pts (63%) had progression. The single PSA responder also had an objective PR. Eight pts were inevaluable (too early, 6; withdrew from study for personal reasons, 2). Most patients progressed rapidly; only 32% were progression-free at 3 months. Grade 3/4 toxicities included neutropenia (40%), fatigue (14%), dehydration (11%), anemia (9%), and abdominal pain/cramping (6%). No treatment-related deaths occurred. Conclusions: VFL has minimal activity in heavily pretreated pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Genentech Bristol-Myers Squibb Bristol-Myers Squibb, Eli Lilly and Company, Genentech, GlaxoSmithKline, GPC Biotech, sanofi-aventis, SCRI

Outcome of second-line chemotherapy with a combination of docetaxel and carboplatin (DC) in docetaxel-resistant (DR) hormone refractory prostate cancer (HRPC) patients

16090 Background: Docetaxel is the standard chemotherapy for HRPC. However, a standard protocol has not yet been defined for patients with DR disease. Initial reports support the use of carboplatin (C) in combination with docetaxel (D) in these patients (pts). Methods: Metastatic HRPC pts that were resistant to treatment with D were included in our retrospective analysis. Between February 2005 and December 2007, 17 pts received treatment with C AUC 5 q3wks in combination with D 75 mg/m2 q3wks or D 35 mg/m2 d1, d8, d15 q4wks. 3 pts additionally received estramustine 140 mg on 3 consecutive days in parallel to weekly applications of D. All pts were assessed for PSA response and clinical outcome. Results: Seventeen pts were identified at our institution for analysis. The median follow-up was 13 months (range: 0–31) with a median number of 4 cycles administered (range: 1–16). PSA reduction >50% was achieved in 9 pts (53%) and PSA stabilization in 5 pts (29%). 4 pts (24%) progressed without PSA response. The median duration of PSA response was 19 wks. Pts with PSA normalization or >90% reduction tended to achieve a longer PSA response (median 79 wks, range: 18–80) compared to pts with PSA stabilization or reduction by 50–90% (20 wks, range: 4–57). The most common grade 3/4 toxicities were neutropenia in 29% and thrombocytopenia in 11% of pts. Conclusions: This retrospective analysis supports the usefulness of second-line chemotherapy in HRPC. DC shows promising activity in DR pts with clinically meaningful responses. Patient Characteristics ECOG 0, No. of patients (%) 13 (76%) ECOG 1, No. of patients (%) 3 (18%) ECOG 2, No. of patients (%) 1 (6%) Liver metastases, No. of patients (%) 4 (24%) Visceral or lymphatic metastases, No. of patients (%) 6 (35%) Pain, No. of patients (%) 12 (71%) ≥2 metastatic sites, No. of patients (%) 7 (41%) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis

A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate

Objective Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results. Materials and methods Chemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m 2 and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m 2 and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy. Results Data for 31 men (median age, 63 years [range, 41–74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%–99.9%) from a baseline value of 14.3 ng/ml (range, 1.9–497.9 ng/mL). Median time to progression was 34+ months (range, 14–68+ months). Median OS was 56+ months (range, 17–73+ months). Conclusions Combination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial.

A long and winding road: the role of chemotherapy for hormone-refractory prostate cancer

A long and winding road: the role of chemotherapy for hormone-refractory prostate cancer

Chemotherapy for the treatment of hormone-refractory prostate cancer

This review aims at analysing the published literature on chemotherapy for hormone-refractory prostate cancer (HRPC) to provide recommendations for the treatment of this important patient group. The information for this review was compiled using the PubMed and Medline databases and the Proceedings of the American Society of Clinical Oncology annual meetings to search for articles, abstracts and presentations up to 1 March 2007. Electronic early-release publications were also included. Only articles published in English were considered. The search terms included hormone-refractory prostate cancer, docetaxel, mitoxantrone, satraplatin, ixabepilone, cyclophosphamide, vinorelbine, atrasentan, calcitriol, bevacizumab and targeted therapies. Priority was given to studies in high impact factor journals when available. Two recent trials (TAX 327 and SWOG 9916) have shown that docetaxel chemotherapy can significantly improve survival for HRPC. Docetaxel has become the standard of care for first-line chemotherapy for HRPC and has been approved for use in the United States and Europe. Many patients with HRPC will require second- and even third-line treatment upon progression and more data are required in this setting. It is likely that the future management of patients with HRPC will build on the success of docetaxel using a sequence of chemotherapy and targeted therapies to reduce the risk of death, prevent or improve disease-related symptoms and improve quality of life for this important condition.

Estramustine Phosphate Based Chemotherapy for Hormone Refractory Prostate Cancer

Purpose: We wanted to evaluate the efficacy and side effects of estramustine monotherapy and estramustine plus etoposide or dexamethasone combined therapies for patients with hormone refractory prostate cancer (HRPC). Materials and Methods: Between 2000 and 2004, 33 patients who were diagnosed with HRPC and treated with estramustine-based chemotherapy were evaluated. Eleven patients had oral estramustine monotherapy (group 1), 12 patients had oral estramustine plus oral etoposide (group 2), and finally 10 patients had oral estramustine plus oral dexamethasone (group 3). The prostate-specific antigen (PSA) response, progression-free survival and disease-specific survival were evaluated. Results: The median patient age was 71 years and the median PSA was 97.3ng/ml. The median follow-up period was 17 months (range: 5-47). The overall response rate was 45.5%, and the response rate for each group was 36.4% for group 1, 41.7% for group 2 and 70.0% for group 3, respectively. The median time to progression (TTP) was 5 months (range: 1-16) overall and it was 5 months, 5.5 months and 5 months in groups 1, 2 and 3, respectively. Regarding the response rate, progression-free survival and disease specific survival, there were no statistically significant differences between the three groups (p>0.05). The most common hematologic complication was anemia that occurred in 28 patients and deep vein thrombosis occurred in 2. Severe toxicities (≥grade 3) occurred in only 2 patients. Conclusions: Estramustine phosphate showed over a 45% response rates with less morbidities. Estramustine-based chemotherapy can be considered as an option for the treatment of HRPC. However, larger randomized controlled trials for regimens combined with other efficacious agents are necessary to elucidate the efficacy of chemotherapy for HRPC. (Korean J Urol 2007;48:684-690) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Phase II Trial of Weekly Paclitaxel, Cisplatin Plus Infusional High Dose 5-Fluorouracil and Leucovorin for Metastatic Urothelial Carcinoma

Conventional chemotherapy for urothelial carcinoma, such as methotrexate, vinblastine, doxorubicin and cisplatin, is associated with significant toxicity. We have previously reported a low toxicity and yet moderately active regimen containing weekly infusional cisplatin and high dose 5-fluorouracil/leucovorin for advanced urothelial carcinoma. We tested the efficacy and toxicity of adding paclitaxel to that regimen. Between April 2000 and December 2004, 44 patients with a median age of 66 years with metastatic urothelial carcinoma were enrolled. The paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin regimen consisted of 70 mg/m2 paclitaxel daily as a 1-hour infusion on days 1 and 8, 35 mg/m2 cisplatin daily as a 24-hour infusion on days 2 and 9, 2,000 mg/m2 5-fluorouracil daily and 300 mg/m2 leucovorin daily as a 24-hour infusion on days 2 and 9. The cycles repeated every 21 days. A total of 25 patients (64%) had a creatinine clearance of 35 to 60 ml per minute. A total of 210 cycles (mean 4.8 per patient) were administered. Of the 40 patients eligible for response evaluation 11 (28%) and 19 (48%) were complete and partial responders with an overall response rate of 75% (95% CI 61 to 89). Median overall and progression-free survival in the whole group was 17.0 (95% CI 13.7 to 20.3) and 8.3 months (95% CI 6.4 to 10.2), respectively. Two-year disease-free survival was 15%. Grade 3 or 4 anemia, leukopenia and thrombocytopenia occurred at 23, 30 and 12 cycles, respectively. Nonhematological toxicity included infection, vomiting and diarrhea, etc. There were 2 treatment related deaths. Paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin is an active regimen against metastatic urothelial carcinoma which has an acceptable toxicity profile.

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.

Phase II trial of weekly docetaxel and oral capecitabine in metastatic hormone-refractory prostate cancer

4634 Background: Docetaxel based chemotherapy for hormone-refractory prostate cancer (HRPC) has demonstrated survival benefit. The combination of docetaxel-capecitabine has demonstrated synergistic anti-tumor effect, which is attributable to docetaxel-mediated up-regulation of thymidine phosphorylase (TP). Hence, a phase II trial is being conducted to assess efficacy and tolerability of weekly docetaxel and capecitabine in metastatic HRPC. Methods: Patients with metastatic HRPC, who have not received prior chemotherapy for metastatic disease were eligible to receive docetaxel 36 mg/m2/week IV on days 1,8, and 15 and Capecitabine 1250 mg/m2 /day in two divided doses on days 5–18. Cycles were repeated every 28 days and response was assessed every 2 cycles. The primary end point was response rate. A two stage Simon study design required 15 patients to be accrued in first stage and additional 13 patients in second stage. Results: First stage was completed and response was adequate to proceed to second stage. 21 patients have been registered to this ongoing trial. Baseline characteristics included median age of 71 (range 47–80 years); median performance status of 1; median PSA at study entry of 60.6 ng/ml (range 1.2–3716.9); Of the 21 patients, 16 had bone pain pretherapy, Gleason score ≥ 8 in 14; 8 had measurable disease; 8 had new bone metastases and 14 had PSA progression. 83 cycles have been administered (median 4, range 1–10 cycles). To date 18 patients were assessable for toxicity and response. Grade 3 and 4 neutropenia was noted in 3 patients and Grade 3 hand-foot syndrome in 2 patients. There were no treatment related deaths. A PSA partial response (PR) defined as ≥ 50% decline sustained for ≥ 4 weeks was observed in 14/18 (77%) with ≥90% PSA decline in 7/18 (39%) patients. PR noted in 5/8 measurable disease patients. Stable disease by bone metastases in 15/18. Median time to PSA progression was 5 months (95% CI of 3.5–7.2+ month). Conclusions: The combination of capecitabine and weekly docetaxel demonstrated encouraging activity and acceptable toxicity profile. [Table: see text]

PSA flare-up in patients with hormone-refractory prostate cancer (HRPCA) receiving docetaxel-based chemotherapy: Incidence and differentiation from progressive disease

14523 Background: Docetaxel-based chemotherapy displays the standard therapy for patients with hormone-refractory prostate cancer. A subset of patients will experience an initial PSA increase after initiation of therapy followed by a subsequent PSA decrease. The aim of our study was to investigate the incidence of this phenomenon and to identify factors that differentiate the flare-up from progressive disease. Methods: We retrospectively analyzed the patient records of 46 patients who received docetaxel as monotherapy or in combination with either mitoxantron or estramustine for hormone-refractory prostate cancer. PSA flare-up was defined as an initial PSA increase of more than 25% after initiation of therapy over baseline followed by a PSA decrease of at least 75% compared to the maximum increase over baseline. Progressive disease was defined as a PSA increase of at least 25% over baseline in patients with no PSA response which had to be confirmed four weeks later. Results: Of 46 patients who received docetaxel-based chemotherapy 16 (34.8%) showed a PSA decrease of at least 50%, 6 (13.0%) between 30–50%, 17 (37.0%) had stable disease and 7 (15.2%) patients experienced progressive disease. An initial PSA increase followed by a subsequent PSA decrease was seen in 6 (13.0%) of the patients. Median PSA increase compared to baseline was 81.0% (25–239). The median following PSA decrease was 110.5% (77–160) compared to the initial increase. Median PSA doubling times of patients with PSA flare up or progressive disease were 113.3 and 100.7 days (p = 0.7941), respectively. Conclusions: PSA flare-up seems to be a common phenomenon in patients being treated with docetaxel-based chemotherapy for hormone-refractory prostate cancer. In order not to prevent those patients from a subsequent PSA decrease by early cessation of therapy it would be useful to discriminate them from patients with progressive disease. According to the results of our study PSADT does not differ between patients with flare-up or progressive disease and can therefore not be used to distinguish between the two. No significant financial relationships to disclose.

Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles

Caspase-cleaved proteins are released from disintegrated apoptotic cells and can be detected in the circulation. We here addressed whether caspase-cleaved cytokeratin 18 (CK18-Asp396) can be used as a serum biomarker for assessment of the clinical efficiency of chemotherapy in hormone-refractory prostate cancer (HRPC). A total of 82 patients with HRPC were evaluated during 751 treatment cycles, either with estramustine (EMP)/vinorelbine or with EMP/docetaxel. The levels of CK18-Asp396 and of total CK18 were measured in patient serum before and during therapy by ELISA. Docetaxel induced significant increases in serum CK18-Asp396 (P<0.0001) and total CK18 (P<0.0002), suggesting induction of apoptosis. Similarly, vinorelbine induced increases in both CK18-Asp396 and CK18 (P<0.001 and 0.011). In contrast, EMP induced increases in total serum CK18 (P<0.0001), but not in CK18-Asp396 (P=0.13). The amplitudes of docetaxel-induced increases were associated with baseline prostate-specific antigen (PSA) and CK18 serum levels in these patients, consistent with tumoral origin of caspase-cleaved fragments. Docetaxel induced significant increases in CK18-Asp396 during second-, third- and fourth-line therapy and induced increased levels of CK18-Asp396 during treatment cycles 1–8. In contrast, vinorelbine induced significant increases only during cycles 1–3. In a subgroup of 32 patients that received EMP/vinorelbine in second line followed by EMP/docetaxel in third line, docetaxel induced stronger increases than vinorelbine (P=0.008). These results show that the CK18-Asp396 serum marker can be used to assess tumour apoptosis in vivo and suggest that the clinical efficiency of docetaxel in HRPC is due to induction of apoptosis during multiple treatment cycles.

Studienlandschaft Prostatakarzinom

Current prostate cancer studies in Germany encompass the indications "adjuvant therapy", "rising PSA following radical prostatectomy", "metastasized, hormone sensitive prostate cancer", and "hormone refractory prostate cancer". In the adjuvant field, the potential of zoledronic acid for the prevention of bone metastases is being investigated in a large phase III trial. The activity of imatinib in low volume prostate cancer is being tested in patients with rising PSA following radical prostatectomy (phase II). The randomized phase III trial intermittent versus continuous hormone therapy in D1 and D2 patients has finished accrual and follow-up will be extended until the end of 2006. In hormone refractory prostate cancer(HRPC), the results of a recent phase II study (Association of Urological Oncology; AOU AP 33/02) were promising. This led to a currently activate phase III trial comparing intermittent with continuous chemotherapy in HRPC. The interdisciplinary study group of the AUO (Urology) and the ARO (Radio-oncology) has developed several new protocols which are currently under review by the German Cancer Aid (Deutsche Krebshilfe).