Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC. PATIENTS AND METHODS: Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE). RESULTS: Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups. CONCLUSION: Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.     

A phase II trial of docetaxel and vinorelbine in patients with hormone-refractory prostate cancer

Recent studies of docetaxel have demonstrated improved survival over mitoxantrone and prednisone in patients with hormone-refractory prostate cancer (HRPC), supporting the study of novel docetaxel-containing regimens as primary therapy or following initial docetaxel-based therapy. To evaluate the combination of docetaxel and vinorelbine in the treatment of patients with HRPC, 40 patients with proven adenocarcinoma of the prostate with progressive metastatic disease despite androgen ablation were enrolled onto this phase II trial. Patients were treated with docetaxel 60 mg/m² on day 1 and vinorelbine 15 mg/m² on days 1 and 8 of a 21-day cycle. All patients received dexamethasone 8 mg twice daily for 4 days starting 1 day prior to the docetaxel infusion. After the first three patients were enrolled, filgrastim was added on days 2–6 and 9–13. Of the 40 patients enrolled, 19 had no prior chemotherapy and 21 had received at least one prior chemotherapy regimen. Of the 19 patients without prior chemotherapy and the 21 with prior chemotherapy, 7 (37%) and 6 (29%) , respectively, demonstrated a decrease in prostate specific antigen by >50% maintained for at least 4 weeks. Out of eight patients with measurable disease, one achieved a partial response and four demonstrated stable disease. There was one patient with deep vein thrombosis, and febrile neutropenia was noted in only three patients after the protocol was modified to include filgrastim support. The combination of docetaxel and vinorelbine with filgrastim was well tolerated and active against HRPC in patients with or without prior chemotherapy.This trial was supported in part by research grants from Aventis, Amgen, and P30 CA72720-01-03.     

A phase 2 study of estramustine,docetaxel, and bevacizumab in men with castrate‐resistant prostate cancer

BACKGROUND:

The use of docetaxel prolongs survival for patients with castrate‐resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.

METHODS:

This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate‐specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression‐free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.

RESULTS:

Seventy‐nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty‐three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty‐four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.

CONCLUSIONS:

The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing. Cancer 2011. © 2010 American Cancer Society.     

Diethylstilbestrol and docetaxel: a Phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer

BACKGROUND: The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS: Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m(2) intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity. RESULTS: The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS: The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.     

Experience with docetaxel in hormone-refractory prostate cancer (HRPC) at three Australian cancer centers: A retrospective study

Background: Hormone‐refractory prostate cancer (HRPC) is associated with a poor prognosis and has historically been considered relatively chemoresistant. Emerging data demonstrate clinical benefit with the use of docetaxel in HRPC, culminating in two recent published phase III studies demonstrating survival benefit. Currently, docetaxel is registered but not reimbursed for HRPC in Australia. Aim: To retrospectively review prostate‐specific antigen (PSA) response rate, and survival following the use of docetaxel for metastatic HRPC. Methods: Retrospective audit of the use of docetaxel for HRPC from 1 January 2001 to 1 April 2004 in three medical oncology practices. Demographic data, baseline PSA, ECOG (Eastern Cooperative Oncology Group) Performance Status, sites of disease, number of cycles received and PSA response rates were collected. Results: Thirty five patients (median age, 71 years; range, 50–88) had an ECOG status of 0 (eight), 1 (20) and 2 (seven). The mean duration from initial prostate cancer diagnosis to start of docetaxel was 5.4 years (range, 0.2–13.5 years). The mean baseline PSA doubling time, available for 29/35 patients, was 1.9 months (range, 0.4–4.9). The median number of metastatic sites was 1 (range, 1–4): bone (34 patients), lymph nodes (10), liver (seven) and lung (seven). Twelve patients were chemotherapy naive; 23 had received prior chemotherapy (21/23 received mitoxantrone). Twenty patients received docetaxel three times weekly; 15 were on weekly schedules. Their mean dose density was 23 mg/m²/week. Patients received an average of 3.2 months of treatment (range, 0.2–11.8). There were 170 recorded toxicities, 13 of which were grade 3–4, and two likely treatment‐related deaths (sepsis). Twelve patients (34%) had >50% PSA response (four were chemotherapy naive); of these 12 responders, seven patients had a >75% PSA response (four chemotherapy naive). Median survival from start of docetaxel was 8 months with 37% alive at 12 months and 23% alive at 24 months. Conclusion: Docetaxel is active in HRPC (in both chemotherapy naive and exposed patients) with a predictable toxicity profile. More research is warranted to identify predictors of response and toxicity.     

Gemcitabine and docetaxel in metastatic, castrate-resistant prostate cancer: results from a phase 2 trial

BACKGROUND:

Docetaxel is the standard of care for patients with metastatic, castrate‐resistant prostate cancer (CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined docetaxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy‐naive, metastatic CRPC.

METHODS:

Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology performance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted. Patients received gemcitabine (800 mg/m²) Days 1 and 8 and docetaxel (75 mg/m²) on Day 8 every 21 days for a maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. A prostate‐specific antigen (PSA) response was defined as a decline ≥50% in baseline PSA level.

RESULTS:

Thirty‐five patients with chemotherapy‐naive, metastatic CRPC were enrolled. The median age was 67 years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among the patients who had measurable disease (n = 25), 3 patients (12%) had a confirmed, RECIST‐defined partial response (PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treatment‐related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed.

CONCLUSIONS:

The efficacy of combined gemcitabine and docetaxel in metastatic CRPC was similar to that observed with single‐agent docetaxel. In contrast to single‐agent docetaxel, the combination was moderately toxic and had an impact primarily on bone marrow reserve. Cancer 2011. © 2010 American Cancer Society.     

多西他赛联合卡铂治疗复发转移乳腺癌的效果和安全性

目的观察多西他赛联合卡铂（DC）治疗复发或转移性乳腺癌的效果和安全性。方法68例复发或转移性乳腺癌患者被随机分为DC组（33例）和对照组（35例）。DC组采用多西他赛联合卡铂治疗,对照组采用长春瑞滨（NVB）联合顺铂（DDP）组成NP方案治疗,评价两组的近远期疗效,观察不良反应。结果DC组有效率为46．9％,疾病控制率71．9％;对照组有效率为41．9％,疾病控制率68．8％。两组近期疗效差异无统计学意义（P〉0．05）。DC组患者生存率为28．1％,死亡率为71．9％;对照组生存率为22．6％,死亡率为77．4％,两组远期疗效比较差异无统计学意义（P〉0．05）。两组均出现严重的白细胞减少和脱发现象,发生率〉90％,但DC组Ⅲ-Ⅳ级毒副作用发生率显著低于对照组（P〈0．05）;DC组出现关节肌肉痛、恶心呕吐和静脉炎的发生率和Ⅲ～Ⅳ级毒副作用发生率均显著低于对照组（P〈0．05）。结论多西他赛联合卡铂治疗复发或转移性乳腺癌疗效确切,不良反应可以耐受,值得临床进一步开展研究和推广。     

A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer

A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone.     

Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study

BACKGROUND.

Cetuximab, an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, has demonstrated evidence of activity in nonsmall cell lung cancer (NSCLC). When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab has exhibited synergistic interaction in preclinical studies. Therefore, a phase 2 study was conducted to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC.

METHODS.

Chemotherapy‐naïve patients aged ≥18 years with stage IIIB (with effusion) or stage IV NSCLC received cetuximab (at a dose of 400 mg/m² on Day 1 and 250 mg/m² on Days 8 and 15) plus docetaxel (at a dose of 75 mg/m² on Day 1) and carboplatin (area under the concentration vs time curve [AUC] = 6 on Day 1) every 21 days for up to 6 cycles (graded according to the American Joint Committee on Cancer Staging System). Thereafter, patients without evidence of disease progression were continued on single‐agent cetuximab for a maximum of 1 year or until disease progression. The primary endpoint was response rate.

RESULTS.

Eighty patients were enrolled. The median number of cycles administered was 4 (range, 1‐6 cycles). The objective response rate was 15.2%, with a median progression‐free survival of 4.6 months and a median overall survival of 10.3 months. The salient grades 3 of 4 adverse events were neutropenia (30%), hypotension (3%), hypokalemia (4%), and hypomagnesemia (3%). Twenty‐five patients received single‐agent cetuximab (median duration, 12 weeks) and this was well tolerated.

CONCLUSIONS.

The results of this large, multicenter, phase 3 study indicate that the novel combination of cetuximab with docetaxel and carboplatin demonstrate modest anticancer activity for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. Cancer 2008. © 2008 American Cancer Society.     

Sequential mitoxantrone/prednisone followed by docetaxel/estramustine in patients with hormone refractory metastatic prostate cancer: results of a phase II study.

BACKGROUND: Mitoxantrone/prednisone ameliorates symptoms in hormone refractory prostate cancer (HRPC) but has no effect on survival. Docetaxel (Taxotere)/estramustine improves response but with significant toxicity. We reasoned that a sequential administration of the two regimens could be a viable alternative for delivering full doses of chemotherapy, avoiding overlapping toxicity and preserving dose intensity. PATIENTS AND METHODS: Thirty HRPC patients were treated with mitoxantrone 10 mg/m(2), day 1, every 3 weeks, plus prednisone 5 mg twice daily, for three cycles, followed by estramustine phosphate, 280 mg three times daily, days 1 to 5, plus docetaxel 75 mg/m(2), day 2, every 3 weeks for a maximum of 10 cycles. RESULTS: All patients were assessable for response and toxicity. After mitoxantrone/prednisone treatment, the prostate-specific antigen (PSA) response rate was 23%, which increased to 63% after completion of sequential mitoxantrone/prednisone and docetaxel/estramustine treatment (12 partial and 7 complete responses). With a median follow-up of 18 months, median survival for all patients was 18 months, and median progression-free survival was 10 months. The mitoxantrone/prednisone regimen was well tolerated, and the only grade 3-4 toxicity was grade 3 neutropenia in four (13%) patients. Twenty-nine patients received a total of 173 cycles of docetaxel/estramustine (median, 6 cycles/patient). Six (20%) patients had grade 3-4 neutropenia and two (6%) patients had febrile neutropenia episodes. The most frequent non-hematological toxic effects were asthenia, nausea and vomiting, edemas and onycholysis. Two (6%) patients had deep venous thrombosis. CONCLUSIONS: Mitoxantrone/prednisone followed by docetaxel/estramustine is a well-tolerated and active regimen in HRPC. Sequential therapy is feasible and can be used to integrate novel, more active regimens.     

Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer

Purpose:To evaluate the safety and efficacy of docetaxel andcarboplatin as first-line therapy for patients with advanced non-small-celllung cancer (NSCLC). Patients and methods:In this multicenter, phase II trial, 33patients with previously untreated stage IIIB (n = 8) or IV(n = 25) NSCLC received intravenous infusions of docetaxel 80mg/m² followed immediately by carboplatin dosed to AUC of 6mg/ml/min (Calvert's formula) every three weeks. Patients also receiveddexamethasone 8 mg orally twice daily for three days beginning one day beforeeach docetaxel treatment. Filgrastim was not allowed during the first cycleand was added only if a patient experienced febrile neutropenia or grade 4neutropenia lasting 7 days. Results:There were 1 complete and 11 partial responses for anobjective response rate of 43% (95% CI:24%–63%) in 28 evaluable patients and 36%(95% CI: 20%–55%) in the intent-to-treatpopulation. The median duration of response was 5.5 months (range3.0–12.5 months). The median survival was 13.9 months (range 1–35+months); one-year survival was 52%. The most common toxicity washematologic, which included grade 4 neutropenia (79% of patients and7% percent of cycles) and febrile neutropenia (15% of patients);there were no episodes of grade 3 or 4 infection. The most common severenonhematologic toxicities were asthenia (24%) and myalgia (12%);there were no grade 3 or 4 neurologic effects. Conclusions:The combination of docetaxel and carboplatin has anacceptable toxicity profile and is active in the treatment of previouslyuntreated patients with advanced NSCLC. This combination is being evaluatedin a randomized phase III trial involving patients with advanced andmetastatic NSCLC.     

Phase 2 study of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer : A Prostate Cancer Clinical Trials Consortium trial

BACKGROUND:

Treatment of high‐risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy.

METHODS:

Eligibility included any of the following: prostate‐specific antigen (PSA) >20 ng/mL or PSA velocity >2 ng/mL/y, cT3 disease, any biopsy Gleason score 8 to 10, and Gleason score 7 with T3 disease by endorectal magnetic resonance imaging (MRI) at 1.5 T. Also, those with ≥50% biopsy cores involved and either Gleason score 7, PSA >10, or cT2 disease were eligible. Patients were treated with docetaxel 70 mg/m² every 3 weeks for 6 cycles and bevacizumab 15 mg/m² every 3 weeks for 5 cycles. The primary endpoint was partial response by endorectal MRI.

RESULTS:

Forty‐one patients were treated. Median age was 55 years (range, 40‐66 years). Baseline characteristics included: median PSA, 10.1 ng/mL; cT2, 49%, cT3, 32%; and Gleason score 8 to 10, 73%. Thirty‐eight of 41 (93%) patients completed all 6 cycles. Grade ≥3 adverse events were rare, although 3 of 41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% confidence interval [CI], 16%‐45%) achieved a >50% reduction in tumor volume, and 9 patients (22%; 95% CI, 11%‐38%) achieved a >50% post‐treatment decline in PSA. Thirty‐seven of the 41 patients underwent radical prostatectomy; there were no complete pathologic responses.

CONCLUSIONS:

Neoadjuvant docetaxel and bevacizumab is safe, and results in reductions in both tumor volume and serum PSA, in men with high‐risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in general, requires further elucidation through ongoing and planned trials. Cancer 2012. © 2012 American Cancer Society.     

多西他赛联合泼尼松或米托蒽醌联合泼尼松治疗激素抵抗性前列腺癌

背景与目的：以多西他赛为核心的化疗方案已经成为激素抵抗性前列腺癌治疗的一线方案：本文初步比较多西他赛联合泼尼松或米托蒽醌联合泼尼松在雄激素抵抗性前列腺癌中的疗效差异，进一步探讨这两种方案的毒副反应。方法：入选雄激素抵抗性前列腺癌患者共83例，其中44例给予多西他赛75mg／m^2 d1静脉滴注联合泼尼松，5mg，每天2次，d1～21口服方案治疗（简称多西他赛组），39例给予米托蒽醌12mg／m^2 d1静脉滴注联合泼尼松，5mg，每天2次，d1～21口服方案治疗（简称米托蒽醌组）。两方案均以21天为1周期，平均治疗5周期：结果：多西他赛组中13．6％（6／44）完全缓解（治疗后PSA下降至4．0ng／ml以下），29．5％（13／44）部分缓解，29．5％（13／44）稳定，27．3％（12／44）进展。缓解和稳定患者的PSA进展中位时间是37．8周（12～101周）。进展的12例患者接受了后续的米托蒽醌组挽救治疗，结果部分缓解16．7％（2／12），稳定25．0％（3／12），2例患者死于疾病进展。米托蒽醌组中7．7％（3／39）完全缓解，25．6％（10／39）部分缓解，25．6％（10／39）稳定，41．0％（16／39）进展：缓解和稳定患者的PSA进展中位时间是25．3周（8～61周）。进展的14例患者接受了后续的多西他赛组方案的挽救治疗，结果完全缓解7．1％（1／14），部分缓解35．7％（5／14），稳定21．4％（3／14）．4例患者死于疾病进展：毒性评估：接受多西他赛组治疗者44例，Ⅲ～Ⅳ度骨髓抑制9例（2例因不能耐受化疗退出），Ⅱ度骨髓抑制14例；接受米托蒽醌组治疗者39例，Ⅲ～Ⅳ度骨髓抑制4例，Ⅱ度骨髓抑制12例。结论：多西他赛组或米托蒽醌组均是治疗雄激素抵抗性前列腺癌的有效化疗方案。两种方案对中国的前列腺癌患者的治疗效果比较接近，但米托蒽醌联合泼尼松的治疗方案的副作用略轻。两种方案交替使用仍可产生部分的反应率，两种方案可以互为挽救方案．且多西他赛联合泼尼松作为挽救方案疗效好于米托蒽醌联合泼尼松。     

Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel

BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level or=50% and was >or=2 ng/mL or when there was other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the 2 arms. RESULTS: A total of 250 patients were randomized 1:1. Overall, 18% of patients (20% in the high-dose calcitriol group and 16% in the placebo group) entered the intermittent chemotherapy arm. The median duration of the first chemotherapy holiday was 18 weeks (range, 4%70 weeks). On resumption of treatment after the first holiday, 45.5% of evaluable patients responded with a >or=50% reduction in serum PSA from their postholiday baseline, 45.5% met the criteria for stable PSA for at least 12 weeks, and 9.1% of patients developed disease progression. CONCLUSIONS: To the authors' knowledge, the current study is the first report of intermittent chemotherapy in patients with AIPC who were prospectively tested in a large multi-institutional trial. This strategy results in a clinically significant duration of chemotherapy holidays and can be offered to a minority of patients. At the time of retreatment, the majority of patients again respond to treatment or their PSA levels stabilized. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach.     

A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer.

BACKGROUND: The purpose was to evaluate the combined anti-microtubular regimen of vinorelbine and estramustine phosphate (EMP) in hormone refractory prostate cancer. PATIENTS AND METHODS: Weekly vinorelbine 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy) was combined with EMP at 280 mg orally tds for 3 days (the day before, the day of and the day after vinorelbine infusion). After 8 weeks of therapy the combination was given every other week. RESULTS: From February 1998 to February 1999, 23 men were enrolled with a median age of 69 years (range 50-83 years). The median prostate-specific antigen (PSA) at entry was 160 ng/ml (range 0-802 ng/ml). A median of 13 weeks of therapy was administered and the median follow-up was 14.8 months. Eleven patients (48%) had lower extremity edema requiring diuretic therapy, two (9%) had grade 2 granulocytopenia and four patients [17%; 95% confidence interval (CI) 5% to 39%] had a thromboembolic episode. There was no treatment-related mortality. Fifteen of 21 patients (71%; 95% CI 49% to 89%) had at least a 50% decrease in the PSA for at least 2 months with a median time to serologic progression of 3.5 months (range 0.75-10.5 months). One of eight patients (12.5%; 95% CI 0% to 53%) with measurable disease had a confirmed partial response. The estimated median survival was 15.1 months and the actual one year overall survival was 71% (95% CI 51% to 88%). CONCLUSIONS: Weekly vinorelbine with short course oral EMP is an active regimen as evaluated by rate of PSA response, time to progression and median survival. However, the toxicities of EMP, even when given as a short course, are still problematic.     

A phase 2 study of cetuximab in combination with docetaxel in chemotherapy‐refractory/resistant patients with advanced nonsmall cell lung cancer

BACKGROUND:

Cetuximab in combination with docetaxel was examined in chemotherapy‐refractory/resistant patients with advanced nonsmall‐cell lung cancer (NSCLC) to determine response rate, survival, safety, and pharmacokinetics (PK).

METHODS:

Patients had evidence of epidermal growth factor receptor (EGFR) expression (≥1 +) and tumor progression during or disease recurrence within 3 months after chemotherapy. Cetuximab was administered weekly (400 mg/m² initial; 250 mg/m² thereafter). Docetaxel was administered every 3 weeks (75 mg/m²). A response in 3 of the first 21 patients was required to continue accrual to the target sample size of 50 patients.

RESULTS:

Confirmed responses included 1 complete response (1.8%), 10 partial responses (18.2%), and 20 with stable disease (36.4%). The response rate was 20% (95% confidence interval [CI], 10.4% to 33.0%) and median time to disease progression was 104 days. There were no differences in PK parameters of docetaxel alone or with cetuximab. The most common grade 3 of 4 adverse events were leukopenia (27.3%) and acne (21.8%). Four patients (7.3%) discontinued due to allergic reaction. The median overall survival (OS) was 7.5 months with a 1‐year survival of 35%.

CONCLUSIONS:

Cetuximab in combination with docetaxel was well tolerated. The response rate supports more definitive evaluation of this combination in the second‐line setting. Cancer 2009. © 2009 American Cancer Society.     

Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study

BACKGROUND:

To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration‐resistant prostate cancer (PC), the authors conducted a phase 1‐2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.

METHODS:

In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m² every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m² every 21 days. Efficacy endpoints included changes in prostate‐specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied.

RESULTS:

Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3‐4 toxicity. Drug‐drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N‐telopeptide or bone‐specific alkaline phosphatase levels, respectively. Twenty‐eight patients (61%) received single‐agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months.

CONCLUSIONS:

The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration‐resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single‐agent dasatinib following docetaxel cessation warrants further study. Cancer 2012;. © 2011 American Cancer Society.     

Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients

Background:

BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.

Methods:

This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m⁻², every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.

Results:

Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.

Conclusion:

Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m⁻² of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.     

Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m(-2) of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1-3, 8-10, 15-17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1-9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44-72) and median duration of PSA response was 8.0 months (95% CI: 6.9-9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel.