Chemotherapy for hormone-refractory prostate cancer

 

Abstract

Background

Prostate cancer mainly affects elderly men, and its incidence has steadily increased over the last decade. The management of this disease is replete with controversy. In men with advanced, metastatic prostate cancer, hormone therapy is almost universally accepted as the initial treatment of choice and produces good responses in most patients. However, many patients will relapse and become resistant to further hormone manipulation; the outlook for these patients is poor. Many have disease extending to the skeleton, which is associated with severe pain. Therapies for these men include chemotherapy, bisphosphonates, palliative radiotherapy, and radioisotopes. Systemic chemotherapy has been evaluated in men with hormone-refractory prostate cancer (HRPC) for many years, with disappointing results. However, more recent studies with newer agents have shown encouraging results. There is therefore a need to explore the value of chemotherapy in this disease.

Objectives

The present review aims to assess the role of chemotherapy in men with metastatic HRPC. The major outcome was overall survival. Secondary objectives include the effect of chemotherapy on pain relief, prostate-specific antigen (PSA) response, quality of life, and treatment-related toxicity.

Search methods

Trials were identified by searching electronic databases, such as MEDLINE, and handsearching of relevant journals and conference proceedings. There was no restriction of language or location.

Selection criteria

Only published randomised trials of chemotherapy in HRPC patients were eligible for inclusion in this review. Randomised comparisons of different chemotherapeutic regimens, chemotherapy versus best standard of care or placebo, were relevant to this review. Randomised, dose-escalation studies were not included in this review.

Data collection and analysis

Data extraction tables were designed specifically for this review to aid data collection. Data from relevant studies were extracted and included information on trial design, participants, and outcomes. Trial quality was also assessed using a scoring system for randomisation, blinding, and description of patient withdrawal.

Main results

Out of 107 randomised trials of chemotherapy in advanced prostate cancer identified by the search strategy, 47 were included in this review and represented 6929 patients with HRPC.
Only two trials compared the same chemotherapeutic interventions and therefore a meta-analysis was considered inappropriate. The quality of some trials was poor because of poor reporting, low-patient recruitment, or poor trial design. For clarity, trials were categorised according to the major drug used, but this was not a definitive grouping, since many trials used several agents and would be eligible for inclusion in a number of categories. Drug categories included estramustine, 5-fluorouracil, cyclophosphamide, doxorubicin, mitoxantrone, and docetaxel. Only studies using docetaxel reported a significant improvement in overall survival compared to best standard of care, although the increase was small (< 2.5 months). The mean percentage of patients achieving at least a 50% reduction in PSA compared to baseline was as follows: estramustine 48%; 5-fluorouracil 20%; doxorubicin 50% (one study only); mitoxantrone 33%; and docetaxel 52%. Pain relief was reported in 35% to 76% of patients receiving either single agents or combination regimens. A three weekly regime of docetaxel significantly improved pain relief compared to mitoxantrone plus prednisone (the latter regimen approved as standard therapy for HRPC in the USA). All chemotherapeutics, either as single agents or in combination, were associated with toxicity; the major ones being myelosuppression, gastrointestinal toxicity, cardiac toxicity, neuropathy, and alopecia. Quality of life was significantly improved with docetaxel compared to mitoxantrone plus prednisone.

Authors' conclusions

Patients with HRPC have not traditionally been offered chemotherapy as a routine treatment because of treatment-related toxicity and poor responses. Recent data from randomised studies, in particular those using docetaxel, have provided encouraging improvements in overall survival, palliation of symptoms, and improvements in quality of life. Chemotherapy should be considered as a treatment option for patients with HRPC. However, patients should make an informed decision based on the risks and benefits of chemotherapy.

 

Plain language summary

Chemotherapy for men with prostate cancer who have not responded to hormone therapy

Men with advanced prostate cancer and painful bone metastases are a difficult group of patients to treat. Data from recent randomised trials of chemotherapy suggest an improvement in overall survival, pain relief, and quality of life with this form of therapy. Side effects are common and can be severe. Chemotherapy offers a treatment option for men with hormone-refractory prostate cancer (HRPC), but the decision to treat should be carefully considered by the patient and clinician. More studies are needed to find new and better agents.

 

摘要

背景

荷爾蒙失效型前列腺癌之化學治療

前列腺癌主要好發於老年男性，而其發生率在過去十年中一直持續地增加。針對這個疾病的治療總是充滿著爭議。對於末期轉移性前列腺癌的病患，荷爾蒙治療一直被公認是初步最好的治療，並且在大部分病人皆有很好的反應。然而，大多數病人最終會復發，並且對持續的荷爾蒙治療產生抗藥性，這些病人的預後通常很差。大部分的疾病會有骨骼的轉移，且伴隨著嚴重的疼痛。針對這些病人的治療，包括了化學治療、雙磷酸鹽 (bisphosphonates) 藥物、緩解性放射治療及放射線同位素治療。全身性化學治療被評估用來治療荷爾蒙失效型前列腺癌已行之有年，但是結果總是令人失望。然而愈來愈多的新藥劑開發帶來令人振奮的結果，因此對於荷爾蒙失效型前列腺癌之化學治療，還是有值得開發的必要。

目標

此篇回顧分析的目的主要是評估化學治療在治療轉移性荷爾蒙失效型前列腺癌之角色。主要評估結果為總存活率 (overall survival)，而次要目標包括了化學治療對疼痛緩解之效果、前列腺特異抗原對治療之反應、生活品質及治療相關之毒性。

搜尋策略

我們搜尋了電子資料庫如MEDLINE中發表的臨床試驗，並且以人工搜尋相關的期刊及研討會手冊。搜尋條件中並沒有語言或地區的限制。

選擇標準

本文只選擇已發表的荷爾蒙失效型前列腺癌化學治療之隨機臨床試驗。本文中只比較化學治療處方之隨機比較、化學治療與最佳標準療法或安慰劑之比較。隨機劑量增減研究並不包括在本文文獻回顧中。

資料收集與分析

我們特別為本研究設計了一資料摘錄表來幫助資料的收集。並擷取相關研究的資料，其中包含了試驗設計、受試者及結果的資訊。試驗的品質則是利用一評分系統來評估試驗之隨機分佈、盲性設計及病人退出試驗之描述。

主要結論

搜尋策略共找出了107個針對末期前列腺癌化學治療的隨機試驗中，其中本回顧包含了47個隨機試驗及6,929位荷爾蒙失效型前列腺癌患者。其中只有2個試驗使用相同的化學治療藥物處方，因此統合分析 (metaanalysis) 是不適用的。有些試驗的品質不佳，如報導不完整、病患人數不足或試驗設計不佳。試驗根據主要的使用藥物來分類，但是此種分類並不是絕對的，因為有許多的試驗使用了多種的藥物，所以可能被歸類在不同的組別。藥物分類包括了estramustine、5fluorouracil、cyclophosphamide、doxorubicin、mitoxantrone及docetaxel。與原有之最佳標準療法相比，只有docetaxel在整體存活率有顯著的改善(小於2.5個月)。前列腺特異抗原與治療前比較下降至少50%之平均百分比為estramustine 48%；5fluorouracil 20%；doxorubicin 50% (只有一個研究)；HRPC的mitoxantrone 33%及docetaxel 52%。在接受單一或合併治療的病患中，有35%至76%報告了疼痛的緩解。與美國核准的標準治療mitoxantrone加上prednisone相比較，3週一次的docetaxel治療有效地降低了癌症所帶來的疼痛，並且也有效地改善了病人的生活品質。所有的化學治療藥物不論是單一或是合併使用都會有毒性，而最主要的包含骨髓抑制、胃腸道毒性、心臟毒性、神經病變及落髮。

作者結論

因為化學治療相關的毒性及治療反應不佳，傳統上我們並不提供化學治療作為荷爾蒙失效型前列腺癌之常規治療。但是最近的隨機臨床試驗已證明使用docetaxel可改善病患之整體存活率、繯解症狀及改善生活品質。因此化學治療應該被視為荷爾蒙失效型前列腺癌治療的一種選擇。然而，在決定治療計畫之前，必需要讓病患充分了解接受化學治療的風險及益處。

翻譯人

本摘要由臺灣大學附設醫院戴槐青翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

末期前列腺癌合併骨骼轉移的病患在臨床上是屬於較不容易治療的一群。最近的隨機對照試驗證明了化學治療可提昇病患之整體存活率、疼痛緩解及生活品質，但化學治療所帶來的副作用也是很常見的，而且有時會很嚴重。化學治療對於荷爾蒙失效型前列腺癌之病患提供了一個治療的選擇，但是在做決定前，病患與醫師本身需仔細地討論。我們尚需要更多的研究來開發更多更新的治療藥物。