Measurable Soft Tissue Disease Research Articles

Phase I/II Study of Weekly Docetaxel and Vinblastine in the Treatment of Metastatic Hormone-Refractory Prostate Carcinoma

Phase II trials have shown that taxanes have clinical activity as single agents as well as in combination with microtubule inhibitors in the treatment of hormone-refractory prostate cancer. Recent phase III trials with docetaxel have reported a survival benefit. Most trials also report significant toxicity, including thromboembolic disease. We conducted a phase I/II study to evaluate the maximum-tolerated dose, response rate, and effects on quality of life of the combination of docetaxel and vinblastine. Twenty men with hormone-refractory prostate cancer were treated after experiencing hormonal failure. Patients were enrolled in cohorts of three and treated with three weekly doses of docetaxel (20, 25, 30, 35, or 40 mg/m2) administered as 30-minute infusion and vinblastine (3 mg/m2) bolus. Treatment cycles were repeated every 28 days. Follow-up assessments included prostate-specific antigen level determinations, computed tomographic scans, bone scans, Brief Pain Inventory, and Functional Assessment of Cancer Therapy-Prostate Instrument (FACT-P). Toxicity was graded by National Cancer Institute common toxicity criteria. The maximum tolerated dose of docetaxel was 35 mg/m2. Twelve of the 19 patients (63%; 95% CI 38%-84%) evaluable patients achieved a 50% reduction in prostate-specific antigen level that persisted for 24-80 weeks. Four of eight patients with measurable soft tissue disease had a partial response. Median time to disease progression was 50 weeks. Sixteen patients completed the Brief Pain Inventory at least three times. Twelve patients reported moderate-to-severe pain scores (>or=4) at baseline. Of these 12 patients, 11 reported that their worst pain score improved by at least two levels, and five of the 12 reported decreased opioid requirements. Seventeen patients completed the FACT-P at baseline and on at least two additional visits. Nine of these 17 (53%) reported improvement in Trial Outcome Index (sum of physical, functional, prostate subscales) by >or=6 points. Anemia was common; 12/20 patients required epoetin, and two required transfusions. Venous thrombosis developed in four patients during treatment. Only two patients discontinued treatment because of toxicity. This combination of weekly docetaxel and vinblastine is effective, well tolerated, and associated with improved quality of life in most of the patients treated. Although estramustine was not given, the risk of thromboembolic disease remains significant.

A phase II study utilizing oxaliplatin and docetaxel in androgen independent prostate cancer in men treated with up to two prior chemotherapy regimens

14580 Background: Second line treatment of androgen independent prostate cancer (AIPC) is unsatisfactory. Single agent docetaxel has demonstrated survival benefit in AIPC. In a phase-I study utilizing oxaliplatin at the University of Pittsburgh (UP), two patients with AIPC experienced a substantial and durable reduction in PSA. Thus, we hypothesised that a combination of docetaxel and oxaliplatin may be synergistic in AIPC. Methods: This single arm phase II trial commenced in June 2005, with the objectives of evaluating PSA response rates, progression free survival, and the toxicity (tolerance/safety) of the regimen. Using Simon stage II design, a total of 37 patients (pts) with AIPC will be accrued. To date, 20 men have been enrolled: median age 67 yrs (56–84); 9 patients being chemo-naïve and 11 having received prior chemotherapy. Treatment consisted of docetaxel (60 mg/m2) and oxaliplatin (110 mg/m2), infused every 21 days. Follow-up assessments (every two cycles) include serum PSA and imaging studies. Results: 14 of 20 men have completed at least two cycles and are evaluable. In the chemo-naïve subset (n = 8), the average pre-treatment PSA was 312.8 ± 275.8 ng/ml, with 3 of 8 pts experiencing > 50% reduction in PSA and 2 of 8 pts with > 25% reduction. In pts with prior chemotherapy (n = 6), the average pre-treatment PSA was 1194.4 ± 1777.8 ng/ml, with 3 of 6 pts experiencing > 50% reduction in PSA and 1 of 6 pts with > 25% reduction. 4 of 8 men with measurable soft tissue disease had a partial response. There were < 7% grade 3/4 adverse events (AEs). Treatment-related AEs include: neutropenia (41%), thrombocytopenia (11.8%) and anemia (5.9%). Non-hematologic toxicity included neuropathy (53%) diarrhea (47%), nausea (41%) fatigue (76%) and anorexia (29.4%). Conclusions: The combination of oxaliplatin and doxetaxel is well tolerated in patients with AIPC, and has significant activity even in patients with prior exposure to chemotherapy. The study continues to accrue pts, and the results will be updated at presentation. [Table: see text]

The combination of estramustine, vinorelbine, and mitoxantrone in hormone-refractory prostate cancer: A Phase II feasibility study conducted by the Hellenic Cooperative Oncology Group

Objectives To evaluate the safety profile and therapeutic value of the combination of estramustine, mitoxantrone, and vinorelbine in the treatment of hormone-refractory prostate cancer. Methods Fifty-two patients with hormone-refractory prostate cancer were included in the study. Median age was 70 years (range, 49 to 100 years), World Health Organization performance status ranged from 0 to 2. The treatment schedule consisted of estramustine capsules (140 mg 3 times daily on days 1 to 3 and days 8 to 10 per os), intravenous mitoxantrone (12 mg/m 2 on day 2), and intravenous vinorelbine (25 mg/m 2 on day 2 and day 9), given in a 3-week cycle. Results Thirty-one percent of patients with measurable soft-tissue disease demonstrated an objective response, which included six complete and ten partial responses in all involved organs (bone responses not included). Twenty-nine patients (56%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 6.9 months, and the median survival for all patients was 14.5 months. Conclusions The combination of estramustine, vinorelbine, and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer.

A phase II trial of docetaxel (D), estramustine (E) and thalidomide (T) in patients with metastatic androgen-independent prostate cancer (AIPC)

4764 Background: We recently published the results of a randomized phase II trial of D+T vs. D alone. With a median potential follow-up of 46.7 mo., the median OS of D+T was 25.9 mo. and 14.7 mo. with D alone (p=0.04 for the overall difference). We subsequently conducted preclinical evaluations of this and other combinations in a PC3 xenograft prostate cancer model using SCID mice which demonstrated that the combination of D+E+T synergistically and superiorly reduced tumor volume when compared with both D alone and the combination of D+T. This may represent the synergistic effects of joining an active chemotherapy regimen with an antiangiogenic agent. To build upon these findings, we initiated a phase II trial of D+E+T in patients with AIPC. Methods: We have enrolled 12 of a planned 60 patients (pts) using standard phase II eligibility criteria. No prior chemotherapy is allowed. Baseline characteristics include a median age of 70 (55–76), Gleason 8 (6–10), PSA 54 (5–486), Alk Phos 108 (68–336), Hb 12.4 (10.5–13.2). Pts received weekly doses of D (30 mg/m2) and E (420 mg/tid on d1, 280 mg/tid on d2, 3) for 3/4 weeks as well as daily T (200 mg/day (d)). Pts also received enoxaparin (1 mg/kg/d to a max. of 80 mg/d) for thrombosis prophylaxis. Results: 12 of 12 pts (100%) have had PSA declines of > 50%. Of the 7 pts with measurable soft tissue disease, 3 had a PR (43%) and 4 had SD (57%). Toxicities likely related to treatment: 1 Gr 3 fatigue, 1Gr 3 neuropathy and 1 Gr 3 docetaxel infusion reaction. There was no Gr 3 or 4 neutropenia. 2 pts developed Gr 3 or 4 thromboses. 1 had a pulmonary embolus (but had not taken prophylactic enoxaparin consistently) and the 2nd had a DVT. T was discontinued in 5 pts after a median of 3 cycles (range 1–7 cycles) largely due to fatigue or thromboses. E was discontinued in 3 pts. 2 pts have gone off study (one due to toxicity and one due to disease progression). The median number of cycles is 5.5, 10 pts are currently receiving therapy. Conclusions: D+E+T has led to PSA decline of > 50% in all 12 pts enrolled on study. Further accrual is ongoing to better define the response rate and characterize the toxicity of this regimen. No significant financial relationships to disclose.

Clinical experience with intravenous estramustine phosphate, paclitaxel, and carboplatin in patients with castrate, metastatic prostate adenocarcinoma

The combination of paclitaxel, oral estramustine phosphate (EMP), and carboplatin (TEC) has shown antitumor activity in patients with castrate, metastatic prostate carcinoma. To improve the therapeutic efficacy and reduce the toxicity of TEC, the authors substituted intravenous (i.v.) EMP for oral EMP based on single-agent studies demonstrating an improved safety profile with i.v. EMP. Patients with progressive, castrate, metastatic prostate carcinoma were treated with up to 6 4-week cycles of i.v. EMP (500-1500 mg/m(2) per week), paclitaxel (100 mg/m(2) per week), and carboplatin (target area under the curve = 6 mg/mL every 4 weeks). Thirty patients were treated in 6 dose cohorts. Deep venous thrombosis occurred in 5 of 30 patients (17%). Other common Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria) toxicities included hepatic toxicity (23%) and leukopenia (24%). Posttherapy prostate specific antigen declines > 50% were seen in 18 of 30 patients (60%), and declines > 80% were seen in 15 of 30 patients (50%). Eleven of 17 patients (65%) with measurable soft tissue disease achieved a partial response. Four of 27 patients (15%) with osseous metastases demonstrated improvement on bone scan. Intravenous EMP was administered safely with paclitaxel and carboplatin and produced clinical outcomes similar to the outcomes achieved with the TEC regimen. Substitution of i.v. EMP for the oral formulation was found to result in a lower incidence of severe nausea but increased hepatic toxicity.

The combination of estramustine and mitoxantrone in hormone-refractory prostate cancer: a phase II feasibility study conducted by the Hellenic Cooperative Oncology Group

ObjectivesTo consider the safety profile and therapeutic value of the combination of estramustine and mitoxantrone in a bimonthly schedule to treat hormone-refractory prostate cancer. The survival of patients with prostate cancer who relapse after androgen ablation is limited and the therapeutic options are restricted. MethodsTwenty-nine patients with relapse after previous treatment were included in the study; however, 3 patients who refused to start treatment were not included in the analysis, leaving 26 eligible patients. The median age was 64 years (range 44 to 82), the World Health Organization performance status ranged from 1 to 3, and the mean prostate-specific antigen level was 103 ng/mL (range 1 to 620). The Gleason score ranged from 2 to 9. The patients received a total of 208 therapeutic cycles (mean 8, range 3 to 24). Every cycle consisted of oral estramustine 140 mg, 3 times a day continuously, and intravenous mitoxantrone 20 mg (total dose). The regimen was repeated every 2 weeks. ResultsTwenty-seven percent of patients with measurable soft-tissue disease demonstrated an objective response, which included one complete and six partial responses. Thirteen patients (50%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 9.2 months, and the median survival for all patients was 15 months. The most common side effects were neutropenia and thrombocytopenia. ConclusionsThe combination of estramustine and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer. More patients are needed to partake in Phase III studies to establish the survival benefit that this combination may offer.

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/m².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.

Oral estramustine and oral etoposide for hormone-refractory prostate cancer

Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC). Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression. Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival. We conclude that the combination of estramustine and etoposide is an active and well-tolerated oral regimen in HRPC.

A phase ii trial of oral estramustine and oral etoposide in hormone refractory prostate cancer

We previously demonstrated that the combination of oral estramustine (15 mg/kg/day) and oral etoposide (50 mg/m2/day) is effective first-line therapy for the treatment of hormone refractory prostate cancer. We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment. Estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up. Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival. We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.

Lack of correlation between prostate-specific antigen and the presence of measurable soft tissue metastases in hormone-refractory prostate cancer.

Appropriate staging procedures for patients with hormone-refractory prostate cancer are poorly defined. In particular, there are no studies correlating prostate-specific antigen (PSA) with more traditional methods of staging. We have evaluated the abdominal/pelvic CT scan, bone scan, and PSA results following initial diagnosis of hormone-refractory prostate cancer in 177 consecutive patients (median age = 63.1 years, range 45-80). Thirty-four patients (19.2%) had measurable lesions (> or = 2 cm) on CT scan compatible with metastatic disease. Of the patients with measurable lesions, 29/34 (85.3%) had retroperitoneal and/or pelvic adenopathy; 5 patients (14.7%) had measurable lesions in the liver. Other sites of metastatic disease were detected in less than 1% of the patients receiving scans. All patients had bone scan abnormalities compatible with metastatic disease. Results of these imaging studies were then compared to PSA serum concentration (Abbott IMx). The mean PSA concentration was not different in those patients with soft tissue disease as compared to those without soft tissue involvement and there was no correlation between PSA concentration and the presence or absence of measurable soft tissue disease. In contrast to previously published studies in hormone-naïve prostate cancer patients, these studies in hormone-refractory patients indicate that the detection of metastatic disease by standard radiological procedures cannot be predicted by measurement of serum PSA.

Inhibition of prostate cancer growth by estramustine and etoposide

Background. Metastatic prostate cancer that is refractory to hormone therapy remains an incurable disease without effective therapy. The authors used the nuclear matrix, the RNA-protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. In preclinical models, estramustine and etoposide appeared to interact to inhibit the growth of the hormone-refractory prostate cancer cells. Methods. These agents were tested in a Phase II clinical trial of patients with metastatic hormone-refractory prostate cancer. Estramustine,15 mg/kg/day, and etoposide, 50 mg/M 2 /day, were administered orally in divided doses for 21 days every 28 days. Therapy continued until evidence of disease progression. Results. Fifty-two patients were enrolled in this trial and had a minimum of 40 weeks follow-up. In 20 patients with measurable soft tissue disease, 3 patients demonstrated a complete response (15%) and 6 patients had a partial response (30%) for more than 2 months. Of 32 patients with disease limited to bone, 8 (25%) demonstrated improvement and 12 (38%) demonstrated stability in their bone scans. Overall, 13 men (25%) demonstrated a decrease of at least 75%, and 28 men (54%) demonstrated at least a 50% decrease in their pretreatment prostate specific antigen levels. Conclusions. The combination of estramustine and etoposide may be an active oral regimen in hormone-refractory prostate cancer. Cancer 1995 ;75 :1920-6.

Phase II Multicenter Study of Epirubicin for Hormone-resistant Prostatic Cancer with Measurable Soft Tissue Disease

Twenty-six patients with prostatic cancer were treated with courses of epirubicin at 3-week intervals, starting at an initial intravenous dose of 75 mg/m2. All patients had progressive disease after orchiectomy and/or antiandrogen therapy and had measurable soft tissue lesions. There were three partial responders (response rate: 12%; 95% confidence limits: 4-29%). Major toxicity was myelosuppression, and there were two drug-related deaths. Epirubicin in this dose and schedule cannot be recommended for treatment of prostatic cancer.

A phase II evaluation of adriamycin and cis-platinum in hormone resistant prostate cancer.

Twenty-five patients with metastatic prostate cancer were treated with a combination of Adriamycin 50 mg/m2 and cis-platinum (CDDP) 50 mg/m2 every three weeks. Response was evaluated using radioisotope bone scan, serum acid phosphatase levels, and clinical status. Response rates of 6% bone, 21% acid phosphatase, and 24% clinical status were noted. Major toxicity was gastrointestinal (due to CDDP). Treatment was well tolerated even in patients with extensive bone metastases and prior irradiation. Using the response criteria described here, patients with metastatic prostate cancer without measurable soft tissue disease are eligible for Phase II and III study.