间歇性激素疗法治疗特定的晚期前列腺癌疗效不及持续疗法

一项长期国际多中心III期临床实验比较了两种治疗激素敏感性转移性前列腺癌的方案，发现对于本病最小范围转移的患者间歇性激素疗法不及持续疗法。接受连续疗法的患者平均生存期高出长达两年。而对于已有更广泛转移的患者，研究结果显示两种疗法效果相当。

密歇根大学综合性肿瘤中心医学和泌尿外科教授，本研究的首席研究员，Maha Hussain博士说：“一些医生推介对转移性前列腺癌患者采用间歇性激素疗法，认为这样可以在不折中治疗效果的同时也能减少副作用的发生风险。但是本研究的结果显示对某些患者这种方法是显然不利的。”“本研究发现间歇性激素疗法并不是对所有的转移性前列腺癌患者都是安全的。”“这项研究的结果将会改变许多美国及国外常规性运用间歇性疗法的医生的临床实践。”

男性激素睾酮会刺激前列腺癌的生长，激素疗法通过阻断睾酮生成从而阻止癌症生长。但是激素疗法有性冲动减少，性能力下降，潮热，体重增加等副作用，会损害患者的生存质量。基于早期的科学及临床数据，医生们一直认为间歇性疗法（周期性停用及再用）可以减少这些副作用，并可以推迟激素疗法耐药性（大多数转移性前列腺癌后来的发展结果）的发生。

间歇性激素疗法从早期的研究来看似乎是安全的，但那些研究的对象中大部分还包括前列腺癌进展依据只是PSA水平增高（相对于本研究，疾病扩散依据是X-ray证据等）或者处于广泛的不同疾病阶段（不只是转移性癌）的患者。由国立癌症研究所赞助，SWOG主导的团队协作研究旨在比较间接性激素疗法与连续疗法治疗转移性前列腺癌的生存率。试验包括1500名以上在接受了七个月连续疗法后PSA降至4ng/ml 或以下的激素敏感性转移性前列腺癌患者。这些患者之后被随机的分配去接受间歇性激素治疗（770名）和连续性激素治疗（759名）。由于治疗的周期性，间歇性激素疗法组患者的激素治疗时间平均大约是连续性疗法组的一半。

平均随访9.2年后，本病最小范围扩散（无脊柱，盆腔，淋巴以外的扩散）患者平均总生存期在连续性疗法组是7.1年，而间歇性疗法组是5.2年。对于有广泛转移的前列腺癌患者，两组的平均总生存期相似，连续性疗法组是4.4年而间歇性疗法组5年。

摘要号：4

题目：Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial.

在激素敏感转移性前列腺癌(HSM1PC)患者中比较间隙性雄激素阻断(IAD)和持续性雄激素阻断(CAD)：国际III期研究S9346 (INT-0162)结果

摘要：

Background: Castration resistance occurs in the vast majority of HSM1PC pts treated with AD, with a median survival of 2.5 years (y). It is in part an adaptive process with activation of genes resulting in the production of autocrine/paracrine growth factors that contribute to maintaining the viability of PC cells. Replacing androgens before castration resistance is hypothesized to maintain PC androgen-dependence. Preclinically IAD prolonged time to castration resistance and early clinical data indicated feasibility and potential for better quality of life.

Methods: HSM1PC pts with performance status (PS) 0-2, PSA ≥ 5 ng/ml were treated with 7 months (m) of goserelin + bicalutamide. Pts achieving PSA ≤4 ng/ml on m 6 and 7 were stratified by prior neoadjuvant AD/finasteride, PS and disease extent (minimal, extensive) and randomized to CAD or IAD. Primary objective: To assess if overall survival (OS) with IAD is noninferior to CAD using a one-sided test with an upper bound hazard ratio=1.20, adjusting for stratification factors. Sample size: 756 pts/arm, type I and II error rates of 0.05 and 0.10.

Results: 3,040 pts were accrued by SWOG, CALGB, ECOG, NCIC, and EORTC (5/95- 9/08). After 7 m of CAD, 1535 eligible pts achieved PSA ≤4.0 (median age 70 yrs, 4% PS 2, 48% extensive disease, 12% prior neoadjuvant AD) and were randomized to CAD (759 pts) or IAD (770 pts). Grade 3/4 related adverse events: IAD 30.3%, CAD 32.6%. Median follow-up was 9.2 yrs. Median and 10 yr OS: All eligible pts from study entry: 3.6 yrs, 17%; from randomization CAD: 5.8 yrs, 29%; IAD: 5.1 yrs, 23%, HR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24). No interaction with therapy was significant (p>0.25) except suggestion with disease extent (p=0.08): extensive disease HR=0.96 (95% CI 0.79, 1.15, p=0.64); minimal disease: HR=1.23 (95% CI 1.02, 1.48, p=0.035). PC was cause of death in 56% of CAD and 64% IAD pts. OSby race was not different (p=0.44).

Conclusions: In HSM1PC, IAD is not proven to be noninferior to CAD. For extensive disease pts IAD was noninferior; however, IAD was statistically inferior in minimal disease pts suggesting that CAD is the preferred treatment in this group.

编辑: xy 作者:丁香园通讯员

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