Bi-weekly epirubicin, etoposide and low-dose dexamethasone for hormone-refractory prostate cancer

BACKGROUND: Recent studies have demonstrated the efficacy and favorable toxicity profile of chemotherapy regimens given at lower doses and frequent intervals. The aim of our study was to evaluate the efficacy and toxicity of a bi-weekly chemohormonal regimen consisting of epirubicin, etoposide, and low-dose dexamethasone (EED) in patients with hormone-refractory prostate cancer (HRPC). METHODS: We treated a total of 32 patients who had failed hormonal therapy and antiandrogen withdrawal. Chemotherapy was given every 2 weeks and consisted of epirubicin (30 mg/m2 intravenously, day 1) and etoposide (50 mg/m2 orally, days 1-7). Dexamethasone (1.5 mg orally, every other day) was given continuously until disease progression. Twenty patients (63%) had received prior treatment with estramustine phosphate. Each patient's pain response was evaluated according to analgesic use. Toxicity was graded using the Common Toxicity Criteria (version 2.0). RESULTS: Prostate-specific antigen (PSA) levels showed a decline of 50% or greater in 16 of 32 patients (50%, 95% confidence interval [CI], 32-68%) with a median time to biochemical progression of 5 months (range, 4-9 months). The median survival for all patients was 10.5 months (range, 3-35 months). Four of 10 patients (40%) with measurable soft tissue lesions achieved partial response according to standard criteria. Eleven of 23 symptomatic patients (48%, 95% CI, 27-69%) experienced an improvement in pain with a median duration of 6 months. The regimen was tolerated well by the patients, with only four patients (12%) having grade 3 leukopenia. CONCLUSION: Chemohormonal EED regimen proved to be active and well-tolerated in patients with HRPC.     

Sequentially alternating hormone chemotherapy with high-dose medroxy-progesterone acetate and low-dose epirubicin for the treatment of hormone-resistant metastatic prostatic cancer

Thirty patients with hormone-resistant metastatic progressive prostatic carcinoma were treated with sequentially alternating hormone chemotherapy. They were given 1,000 mg medroxyprogesterone acetate (MPA) orally for 26 days followed by intravenous doses of 25 mg/m2 epirubicin weekly for 4 weeks. The median duration of the treatment was 29 weeks (range 8-84). In 2 patients a more than 50% reduction in the size of measurable lymph node metastases was observed and in 2 others skeletal metastases decreased. Serum acid phosphatase normalized in 6 patients. Twenty-five patients achieved a subjective response (median duration 24 weeks; range 4-76 weeks). Median survival from the start of treatment (30 +/- 16 weeks) was unrelated to the achievement of subjective response. Normalization of serum acid phosphatase and a more than 50% reduction in serum alkaline phosphatase correlated with the achievement of a subjective response. Toxicity was generally mild, but in 1 case therapy was discontinued because of suspected cardiotoxicity. Sequentially alternating high-dose MPA low-dose epirubicin hormone chemotherapy has a marginal objective effect but a good subjective effect on progressing hormone-resistant prostatic cancer.     

晚期前列腺癌联合雄激素阻断治疗的长期随访

目的:了解晚期前列腺癌联合雄激素阻断治疗的长期生存率。方法:选取1993年1月~2000年1月初采用联合雄激素阻断治疗的59例前列腺腺癌患者,其中28.81%和45.76%为临床局部晚期(T3-4 N0M0期)和转移(TxNxM+期)病例,全部随访5年以上。结果:全组病例3、5、7年的总体生存率分别是79.36%、61.46%、49.15%,其中,临床局部晚期和转移者的5年生存率分别为80.77%和32.65%,而高分化腺癌和低分化腺癌的5年生存率分别为86.21%和30%(P<0.01)。另外,PSA>30μg/L时其长期生存率有明显下降趋势。结论:采用内分泌治疗的晚期前列腺癌,病理低分化、临床分期达T3 c-4NxMx或TxNxM+期及PSA>30μg/L均提示预后较差,晚期前列腺癌病例的治疗应综合多因素,选择个体化方案。     

Etoposide,epirubicin and carboplatin in hormone-refractory prostate cancer

Twelve patients with hormone-refractory prostate cancer were treated with combination chemotherapy of etoposide, epirubicin and carboplatin (EEC). At relapse, all patients had metastases to the bone and/or soft tissues. The median number of courses was 3 (range 1–10). Epirubicin was not administered in 6 patients because cause of heart disease. Three patients (25%) had a partial response and 8 (67%) showed no change. The overall response rate was 92%. Pain relief was observed in 4 patients (44%). Four patients were still alive after a mean observation period of 18 months (range 4–36 months), while 8 died with a mean survival period of 11 months (range 7–15 months). Nausea, appetite loss, and alopecia were observed in some patients. All except one patient experienced bone marrow suppression, 5 of whom were treated with granulocyte-colony stimulating factor. EEC chemotherapy in hormone-refractory prostate cancer is considered to be more effective than other kinds of chemotherapy, whereas it frequently induces bone marrow suppression.     

Combination chemotherapy following adrenal suppression in androgen- independent prostate cancer

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

Hormone-resistant metastatic prostate cancer. Comparisons between estramustine phosphate and low-dose epirubicin treatments.

We compared the effect and toxicity of estramustine phosphate and weekly low-dose epirubicin in a prospective randomized trial in 41 patients with metastatic prostate cancer refractory to hormonal manipulation. No significant difference between treatment modalities was seen. Palliation was reached in over 60% of patients. The median survival was 15 months in both groups. Toxicity was mild. Further, we investigated the effect of epirubicin after the failure of preceding estramustine phosphate therapy in additional 20 patients. Pain relief was achieved in 50% of these patients. The median survival was 10 months. Toxicity was acceptable.     

A retrospective study of the time to clinical endpoints for advanced prostate cancer

OBJECTIVE: To determine the natural history of patients with prostate cancer who start initial androgen-deprivation therapy (ADT) for biochemical failure with no radiographic evidence of disease (D0) or with radiographic metastatic disease (D2), as the history is either not well-defined or is changing, and such data are critical for guiding therapy after prostate cancer recurrence. PATIENTS AND METHODS: We retrospectively assessed the time to androgen-independence (AI), defined as the first sustained rise in prostate-specific antigen (PSA) level on ADT, time to metastatic disease and overall survival for 80 patients with metastatic prostate cancer in clinical trials at the National Cancer Institute. RESULTS: ADT was initiated after metastatic disease in 37 patients and before metastatic disease in 43 patients; in these 43 patients, the median time to developing metastatic disease on ADT was 37.8 months. The median time to AI from the initiation of ADT was 19.3 and 13.1 months in D0 and D2 patients, respectively. The median overall survival from the start of ADT was 89.0 and 63.0 months, and the median overall survival from the time of AI was 63.1 and 44.2 months in D0 and D2 patients, respectively. These 80 patients, which included 43 who had no metastatic disease when starting ADT, had a median survival of 54.8 months after AI prostate cancer. CONCLUSIONS: We describe the natural history of AI prostate cancer in D0 patients who eventually developed metastasis, and in D2 patients. The results suggest a longer than expected survival with AI prostate cancer, and to our knowledge this is the first study to report the time to metastatic disease for D0 patients from ADT and from AI. These results can be used to help design clinical trials in patients with D0 prostate cancer.     

Gemcitabine and epirubicin in patients with metastatic breast cancer: a phase I/II study

Gemcitabine and epirubicin were evaluated in metastatic breast cancer (MBC) patients to determine the maximum tolerated dose (MTD), efficacy, and toxicity of the combination. Patients initially received 800 mg/m(2) of gemcitabine (days 1 and 8) and 50 mg/m(2) of epirubicin (day 1) every 21 days. Each dose level had three to eight patients. Phase II used the dose level preceding the MTD. Forty-eight patients enrolled without reaching MTD; therefore, phase II used the highest dose level (1500 mg/m(2) of gemcitabine, 90 mg/m(2) of epirubicin). After 23 patients (group A) experienced hematologic toxicities and frequent dose reductions, 15 received 1250 mg/m(2) gemcitabine (days 1 and 4) and 90 mg/m(2) epirubicin (day 1) every 21 days (group B). Out of 38 patients, 46% responded (group A 32%, group B 67%). Median response duration was 8.5 months; median time to progression 8.4 months; and median time to treatment failure 4.8 months. Gemcitabine and epirubicin are well tolerated and active in MBC patients, and the group B regimen warrants further investigation.     

Association of body mass index with response and survival in men with metastatic prostate cancer: Southwest Oncology Group trials 8894 and 9916

PURPOSE: We evaluated the effect of body mass index on prostate specific antigen response, and progression-free and overall survival in men with androgen dependent or androgen independent metastatic prostate cancer. MATERIALS AND METHODS: We examined the prognostic impact of body mass index in patient cohorts from phase III randomized studies coordinated by the Southwest Oncology Group. The first study included 1,006 men treated with androgen deprivation for metastatic prostate cancer. The second study included 671 patients treated with chemotherapy for metastatic, androgen independent prostate cancer. RESULTS: Among men with androgen dependent disease, higher body mass index was associated with longer overall (p <0.001) and progression-free (p = 0.009) survival, as well as with an increased likelihood of achieving a prostate specific antigen nadir less than 4 ng/ml (p = 0.008). In multivariate analysis adjusting for risk factors, increasing body mass index was positively correlated with overall survival (p <0.01) and overweight but not obese patients (body mass index 27 to 29.9) had a significantly improved outcome compared to normal weight patients, with hazard ratios for risk of progression and death of 0.82 (95% CI 0.69, 0.98) and 0.75 (95% CI 0.63, 0.89), respectively. Among men with androgen independent prostate cancer, no clear association could be detected between body mass index and progression-free survival, overall survival or prostate specific antigen response. CONCLUSIONS: This study revealed higher body mass index to be associated with better overall and progression-free survival in patients with androgen dependent metastatic prostate cancer. Among men who had androgen independent disease, no significant association was found between body mass index and survival.     

寡转移CRPC原发灶与转移灶全覆盖放疗的疗效和毒性反应分析

目的:探讨原发灶和所有转移灶同时全覆盖放疗治疗寡转移性去势抵抗性前列腺癌(CRPC)的疗效和毒性反应。方法:回顾性分析北京大学第一医院2011年10月至2017年6月收治的44例寡转移(≤4处转移灶)CRPC患者的临床资料。平均年龄72(57~86)岁,初诊时PSA中位值38.545(6.640~1 066.000)n...     

A phase II study of oral etoposide in elderly patients with small cell lung cancer.

Thirty five previously untreated patients with small cell lung cancer older than 70 years were treated with oral etoposide (800 mg/m2 over five consecutive days) every four weeks. Twenty two patients had extensive disease and 13 limited disease. The overall response rate was 71%. The median survival for patients with limited diseases was 16 (range 6-32) months and for patients with extensive disease nine (range 4-17) months. There was mild haematological toxicity and alopecia but no major toxicity. It is concluded that etoposide in this dose regimen is an effective and well tolerated treatment for elderly patients with small cell lung cancer.     

Quantitative evaluation of bone metastases in patients with advanced prostate cancer during systemic treatment

OBJECTIVE: To assess the clinical usefulness of quantifying the extent of disease on bone scans in monitoring treatment response in patients with advanced prostate cancer, using computer-assisted image analysis. PATIENTS AND METHODS: The percentage of the positive area on the bone scan (%PABS) was quantified automatically using a personal computer with an image-analysis program. Serial measurements of %PABS in 42 patients with bone metastasis from prostate cancer followed for a mean (range) of 33 (4-72) months with hormonal therapy were compared with those of the extent of disease (EOD) grades in bone lesions and serum prostate specific antigen (PSA) levels according to treatment response. RESULTS: Serial values of EOD grades and %PABS decreased during treatment in 11 patients with a partial response and in 12 with progressive disease who had no bone metastasis progression. However, EOD grades and %PABS increased in the remaining 19 patients with progressive disease who had bone metastatic progression. Estimated survival curves showed that %PABS was a useful prognostic indicator, in that patients with a > 25% decline in %PABS survived longer than those with a < 25% decline after treatment (P = 0.0207). CONCLUSIONS: The %PABS is a simple and reproducible estimate of the proportion of the skeleton involving tumours in patients with advanced prostate cancer, and serial measurements of %PABS can assist in monitoring the treatment response in patients with bone metastatic prostate cancer.     

Our experience with 23 consecutive patients on gemcitabine/carboplatin chemotherapy for treatment of metastasized transitional cell carcinoma of the urothelium

AIM: To evaluate the activity and toxicity of gemcitabine plus carboplatin in patients with metastatic transitional cell carcinoma (TCC) of the urothelium. METHODS: Twenty-three consecutive patients (from February 1999 to January 2002) with metastatic TCC and no prior chemotherapy were referred to our institution. Each patient was treated with gemcitabine (1000 mg/m2) on Days 1 and 8 and carboplatin (area under curve, 4.5) on Day 1. Cycles were repeated every 21 days until tumor progression or severe toxicity was seen, or for a maximum of six cycles. Median age of the patients was 68 years (range 47-82). The median Eastern Cooperative Oncology Group (ECOG) performance score was one and the median creatinine clearance rate was 56 mL/min (range 31-94). RESULTS: The overall response rate was 60.8%, with five of the 23 patients achieving a complete response, and nine showing a partial response. Median time to tumor progression (TTP) was 7.8 months, with a median survival of 15.4 months and a 1-year survival probability of 56%. Most of the complications from toxicity were hematological. CONCLUSIONS: Gemcitabine plus carboplatin is active in the treatment of metastatic urothelial cancer in those patients new to chemotherapy and has an acceptable safety profile. The potential clinical benefit of this novel combination in the treatment of transitional cell carcinoma warrants further testing in Phase III studies.     

9-Nitrocamptothecin as second line chemotherapy for men with progressive, metastatic, hormone refractory prostate cancer: Results of the CALGB 99901

BACKGROUND: Institution of early hormone therapy in the PSA era coupled with demonstration of clinical benefit with chemotherapy in hormone refractory prostate cancer (HRPC) and acceptance of PSA decline as a surrogate for response has resulted in introduction of chemotherapy earlier in the natural history of disease. There now exists a need to identify, effective agents for second line chemotherapy. 9-nitrocamptothecin (9-NC) a novel, oral camptothecin analogue was tested as second line chemotherapy for patients with progressive hormone refractory prostate cancer. PATIENTS AND METHODS: Eligible patients had metastatic hormone refractory prostate cancer with performance status (0-1) following progression on at least 1 prior cytotoxic chemotherapy. 9-NC was administered orally at the dose of 1.5 mg/m2/d for 5 days each week for 3 weeks, followed by rest for 1 week. Response was evaluated after 2 cycles according to the guidelines set forth for Phase II trials in HRPC by the PSA working group. RESULTS: Thirty-five patients were recruited to the study within a period of 6 months; 33 were evaluable for analysis. No patients had a >50% decline in PSA levels. Two out of 8 (25%) patients with measurable disease and 5/25 (20%) patients with nonmeasurable disease showed stable disease. The median time to disease and PSA progression was 2 months [95% confidence interval (CI), 0.9-2.8]. The median overall survival was 10 months (95% CI = 5-12). Seven patients are alive after a median follow-up of 23 months. CONCLUSIONS: 9-nitrocamptothecin failed to elicit clinical or PSA responses. Further study in pretreated HRPC patients is not warranted.     

Adjuvant mitozantrone chemotherapy in advanced prostate cancer

OBJECTIVE: To assess the role of mitozantrone, active in relapsed prostate cancer, as an adjuvant to hormonal treatment in patients with advanced prostate cancer. PATIENTS AND METHODS: Between October 1990 and May 1995, 96 patients were entered into a stratified, randomized, single-institution study of hormonal therapy with a luteinizing hormone-releasing hormone agonist and flutamide, with or without four cycles of adjuvant mitozantrone. Of these, 93 patients were evaluable and the results were analysed in June 1999. RESULTS: Patients with localized prostate cancer receiving adjuvant chemotherapy had a higher initial objective response rate (95% vs 53%, P = 0.008) and median survival (80 vs 36 months, P = 0.04) than patients who were treated with hormonal therapy alone. There was no advantage to adjuvant chemotherapy in patients with metastatic prostate cancer. There were insignificant advantages to chemotherapy in overall response rates (55% vs 39%, P = 0.3) and PSA responses (82% vs 64%, P = 0.11). There was no difference between the patient groups in time to treatment failure. CONCLUSION: There was a survival advantage in using adjuvant mitozantrone in patients with locally advanced prostate cancer. Although the study comprised relative few patients, the follow-up period was long and the advantage significant. We recommend that the study be extended to include more patients.     

Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer.

An open randomised Phase III trial was conducted of the depot GnRH analogue goserelin (Zoladex) versus stilboestrol (3 mg/day) in patients with advanced or metastatic prostate cancer. The study included 250 patients and the median follow-up was 43 months. In the Zoladex arm the time to first response was achieved earlier and more patients reported an improvement in symptoms. There was no statistically significant difference between the Zoladex and the stilboestrol arms with regard to survival and time to treatment failure. A major reason for treatment failure was the preponderance of adverse events in patients receiving stilboestrol. It is suggested that stilboestrol should no longer be used for prostate cancer when equally effective alternative treatments are available.     

Gleason score and pretreatment prostate-specific antigen in survival among patients with stage D2 prostate cancer

Although multiple studies have addressed the prognostic importance of tumor differentiation in patients with clinically localized prostate cancer, few data are available in patients with metastatic disease. We evaluated and compared survival data in two groups of men with Whitmore stage D2 metastatic prostate cancer initially treated with hormonal therapy. A series of 76 patients with D2 metastatic disease were evaluated and treated at the National Cancer Institute (NCI) in conjunction with an additional cohort of 141 patients from the Louisiana State University School of Medicine (LSU). Pathological specimens were classified according to the Gleason score. Fifty-two (25%) of the combined NCI/LSU specimens had a Gleason score of 6 or less, 71 (34%) had a value of 7, and remaining 87 (41%) had scores between 8 and 10. The median PSA at the time of diagnosis for the NCI patients was 294.2 ng/ml. Time to treatment failure was defined as the time that a greater than 50% increase above nadir PSA was noted. In neither group was Gleason score correlated with overall survival. There was no association between the time to progression following hormone therapy and primary tumor Gleason score. The PSA concentration at the time of diagnosis was not correlated with the Gleason score for the NCI patients; however, there was an inverse correlation between pretreatment PSA level and time to progression following hormonal ablation. Gleason score does not appear to impact survival in metastatic prostate cancer. PSA as a marker of the biological behavior in metastatic disease may also be limited. These findings should be reevaluated in larger, better matched cohorts. Novel techniques such as serum proteomics, microarrays, and metastatic cell isolation methods may better predict outcome in advanced prostate cancer.     

Chemohormonal therapy as primary treatment for metastatic prostate cancer: A randomized study of estramustine phosphate plus luteinizing hormone-releasing hormone agonist versus flutamide plus luteinizing hormone-releasing hormone agonist

BACKGROUND: The present study was undertaken mainly to investigate whether chemohormonal therapy with estramustine phosphate plus luteinizing hormone-releasing hormone (LHRH) agonist has a more beneficial effect than the hormonal therapy with flutamide plus LHRH agonist for newly diagnosed patients with metastatic prostate cancer. METHODS: A total of 57 patients with metastatic prostate cancer aged 59-80 years (median 74 years) were entered in the study and were randomized to the treatment of estramustine phosphate (560 mg/day) plus LHRH agonist (estramustine group) or flutamide (375 mg/day) plus LHRH agonist (flutamide group) with stratification for the degree of performance status, histological differentiation and bone metastasis. RESULTS: Both of the treatment regimens were well tolerated with similar incidences of adverse drug reactions. The overall response rates (complete response plus partial response) at 12 weeks after treatment in the estramustine and flutamide groups were 76 and 55%, respectively. The median time to objective progression for the estramustine group (25.4 months) was longer than that of the flutamide group (14.6 months). The serum levels of follicle stimulating hormone and testosterone were significantly lower in the estramustine group. CONCLUSIONS: Chemohormonal therapy with estramustine phosphate plus LHRH agonist showed longer clinical progression-free survival than the hormonal therapy with flutamide plus LHRH agonist (P = 0.03), although there was no significant difference in the overall survival. A larger-scaled trial with more statistical power is required to clarify that the former regimen is more beneficial than the latter for newly diagnosed patients with advanced prostate cancer.     

Combination therapy consisting of gemcitabine, docetaxel and carboplatin as a second-line chemotherapy for patients with MVAC-treated metastatic urothelial carcinoma

From 2001 to 2006, 11 patients with MVAC-treated metastatic urothelial carcinoma received as a second-line therapy GDC therapy consisting of gemcitabine (1,000 mg/m2) on day land 8, docetaxel (80 mg/m2) on day 1 and carboplatin (AUC 5) on day 1 in each 21-day cycle. The 11 patients received a total of 42 cycles. The median progression-free survival and the median overall survival were 3 months (range 0-51) and 10 months (range 2-51), respectively. The median overall survival from diagnosis of the metastasis was 13.0 months (range 7-55). Complete response and partial response rates were 1/11 (9%) and 5/11 (45%), respectively. One- and two-year survival rates were 36 and 9%, respectively. Grade 3 or 4 hematologic toxicity included neutropenia (69.0%), thrombocytopenia (47.6%) and anemia (45.2%). Non-hematologic toxicity of grade 3 or 4 consisted mainly of diarrhea (23.8%) and anorexia (21.4%). GDC regimen as a second-line chemotherapy was effective in 54% of patients with MVAC-treated metastatic urothelial carcinoma, although the high incidence of hematologic toxicities and short period of progression-free survival remain to be major problems.     

胃癌术后辅助化疗两药和三药方案的选择

目的观察性研究胃癌术后辅助化疗中的两药方案（氟尿嘧啶联合铂类）与三药方案（在两药基础上联合蒽环类）对患者预后的影响。方法回顾性分析2004-2008年在上海复旦大学附属中山医院接受上述两药或三药方案进行术后辅助化疗的胃癌患者的临床资料和随访资料．随访终点为死亡或最终随访日（2010年4月30日）。结果共计316例接受过胃癌根治性手术且无远处转移的患者术后4-6周开始接受辅助化疗．化疗方案的选择根据主治医师和患者双方的讨论后决定。两药组210例,三药组106例。其中三药组较两药组年龄略轻（51岁比57岁．P〈0．01）,余基线情况两组间差异无统计学意义（P〉0．05）。中位随访时间47个月．两药组中位无进展生存期16个月,3年总体生存率59．6％：三药组则分别为23个月和64．8％,两组差异无统计学意义（P=0．656和P=0．293）。严重不良反应发生率两药组21．9％（46／210）。三药组30．2％（32／106）。两组差异无统计学意义（P=0．107）。结论胃癌术后辅助化疗中的三药联合方案未显示优于两药方案。