Management strategies for locally advanced prostate cancer

Locally advanced prostate cancer represents a subpopulation of prostate cancer diagnosed in patients who are either untouched by screening efforts or whose disease has an unusually rapidly progressive natural history. The diagnostic work-up for the locally advanced patient is distinct from that of early stage disease in several respects in that it is related principally to ruling out metastases. The typical metastatic work-up consists of a serum alkaline phosphatase, bone scan, CT of the abdomen/pelvis, and chest x-ray. Once metastatic disease has been ruled out, individual components of the management of locally advanced prostate cancer patients may include surgery (palliative or curative), external beam radiation therapy (with photons or particles) or brachytherapy (with low-dose rate/permanent or high-dose rate/temporary radiation sources), and hormone therapy. Unlike in early stage disease, observation/watchful waiting is typically not a treatment option in locally advanced prostate cancer. Of the curative local control modalities, the one most commonly used, and the one which has emerged as the clinical standard, is photon external beam radiotherapy (EBRT). Numerous randomised studies have shown that androgen ablation has an established role in conjunction with radiotherapy for locally advanced disease--the current standard of care is thus photon EBRT plus neoadjuvant and adjuvant androgen ablation. Long-term androgen ablation appears to be better than short-term ablation, even when hormone complications are considered. EBRT is typically delivered to the prostate, seminal vesicles and pelvic lymph nodes, although in some circumstances local fields to the prostate and seminal vesicles may be adequate. New treatment planning and delivery techniques, such as intensity-modulated radiotherapy and organ motion tracking, are being developed to reduce the morbidity of radiotherapy while permitting a higher delivered dose. Further work is necessary to determine the precise sequencing and duration of hormone therapy in conjunction with radiotherapy and the optimum radiotherapy treatment volume. Additional work is also needed to determine the precise groups benefiting from other local control modalities such as surgery and brachytherapy. Finally, novel investigational strategies such as chemotherapy and gene therapy are being applied in an attempt to improve outcomes of locally advanced prostate cancer patients.     

Preferences of hxealthy men for two different endocrine treatment options offered for locally advanced prostate cancer

ABSTRACT

Objective: The aim of this study was to determine whether healthy men would prefer either luteinizing hormone releasing hormone analogues (LHRHa) or non-steroidal anti-androgen therapy (NSAA) should they hypothetically develop locally advanced prostate cancer.

Participants and methods: A representative sample of 180 men without prostate cancer (68% over 65 years of age, range 50–90 years), read two scenarios describing LHRHa or NSAA treatments for locally advanced prostate cancer. Participants chose which drug treatment they hypothetically would prefer, gave a reason for their choice and indicated the degree to which they wanted to avoid side effects specific to each drug.

Results: Eighty-six per cent (156/180) of the men chose NSAA therapy, 7% (12/180) chose LHRHa therapy and 7% (12/180) could not decide. The main reason men chose LHRHa therapy was because of the method of administration (9/12) whereas those who chose NSAA therapy cited avoidance of the side effects associated with LHRHa treatment (115/156). The side effects, ranked in order of importance, that men who chose NSAA therapy most wanted to avoid included risk of potential fractures (85%), reduced physical strength (76%), decreased sexual interest (56%), impotence (51%), hot flushes (49%), breast enlargement (17%) and breast tenderness (13%).

Conclusion: Although this project was a hypothetical study, several important issues emerged from the data that are relevant to patient choice. Men should be fully informed about the side-effect profiles of different endocrine treatments, involved in decision making and allowed to choose therapies less likely to cause side effects they would prefer to avoid.     

Preferences of healthy men for two different endocrine treatment options offered for locally advanced prostate cancer

OBJECTIVE: The aim of this study was to determine whether healthy men would prefer either luteinizing hormone releasing hormone analogues (LHRHa) or non-steroidal anti-androgen therapy (NSAA) should they hypothetically develop locally advanced prostate cancer. PARTICIPANTS AND METHODS: A representative sample of 180 men without prostate cancer (68% over 65 years of age, range 50-90 years), read two scenarios describing LHRHa or NSAA treatments for locally advanced prostate cancer. Participants chose which drug treatment they hypothetically would prefer, gave a reason for their choice and indicated the degree to which they wanted to avoid side effects specific to each drug. RESULTS: Eighty-six per cent (156/180) of the men chose NSAA therapy, 7% (12/180) chose LHRHa therapy and 7% (12/180) could not decide. The main reason men chose LHRHa therapy was because of the method of administration (9/12) whereas those who chose NSAA therapy cited avoidance of the side effects associated with LHRHa treatment (115/156). The side effects, ranked in order of importance, that men who chose NSAA therapy most wanted to avoid included risk of potential fractures (85%), reduced physical strength (76%), decreased sexual interest (56%), impotence (51%), hot flushes (49%), breast enlargement (17%) and breast tenderness (13%). CONCLUSION: Although this project was a hypothetical study, several important issues emerged from the data that are relevant to patient choice. Men should be fully informed about the side-effect profiles of different endocrine treatments, involved in decision making and allowed to choose therapies less likely to cause side effects they would prefer to avoid.     

内分泌联合唑来膦酸治疗晚期前列腺癌临床对照研究

目的：评价内分泌联合唑来膦酸治疗晚期前列腺癌的疗效及安全性。方法：回顾分析40例晚期前列腺癌患者,给予内分泌治疗并检测血清ALP值的临床资料。结果：与基础值相比,治疗组第3、6、9、12个月血清ALP值分别减少79.3%（P=0.017）、84.7%（P=0.015）、82.9%（P=0.017）、82.5%（P=0.020）;对照组分别减少45.9%（P=0.13）、35.2%（P=0.21）、30.3%（P=0.26）、20.2%（P=0.45）。治疗组血清ALP水平显著低于对照组（P〈0.01）。结论：唑来膦酸可降低合并骨转移前列腺癌患者的骨代谢水平,防治肿瘤细胞及内分泌治疗引起的骨质疏松。     

Pharmacotherapeutic management of locally advanced prostate cancer: current status

Locally advanced prostate cancer (LAPC) is a heterogeneous entity usually embracing T3-4 and/or pelvic lymph-node-positive disease in the absence of established metastases. Outcomes for LAPC with single therapies have traditionally been poor, leading to the investigation of adjuvant therapies. Prostate cancer is a hormonally sensitive tumour, which usually responds to pharmacological manipulation of the androgen receptor or its testosterone-related ligands. As such, androgen deprivation therapy (ADT) has become an important adjuvant strategy for the treatment of LAPC, particularly for patients managed primarily with radiotherapy. Such results have generally not been replicated in surgical patients. With increased use of ADT has come improved awareness of the numerous toxicities associated with long-term use of these agents, as well as the development of strategies for minimizing ADT exposure and actively managing adverse effects. Several trials are exploring agents to enhance radiation cell sensitivity as well as the application of adjuvant docetaxel, an agent with proven efficacy in the metastatic, castrate-resistant setting. The recent work showing activity of cabazitaxel, sipuleucel-T and abiraterone for castrate-resistant disease in the post-docetaxel setting will see these agents investigated in conjunction with definitive surgery and radiotherapy.     

Extended adjuvant endocrine therapy of early breast cancer

ABSTRACT

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen.

This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.     

Extended adjuvant endocrine therapy of early breast cancer

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen. This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.     

Managing locally advanced prostate cancer: a urologist's and a patient's perspective

A 60-year-old man presented to his general practitioner with prostatic symptoms and high blood pressure. Based upon a prostate-specific antigen level of 44 ng/ml and further investigations (digital rectal examination, transrectal ultrasound-guided needle biopsy, and magnetic resonance imaging, ultrasound and bone scans), the patient was diagnosed with locally advanced (cT3, N0, M0) prostate cancer. Here, the urologist and the patient describe treatment from their respective viewpoints. Following discussion of the advantages and disadvantages of the various therapeutic options, radiotherapy plus hormonal therapy (bicalutamide 150 mg) was chosen as the approach that best suited the patient's lifestyle. In this review, the patient and the urologist consider the impact of the chosen treatment in terms of efficacy, tolerability and quality of life.     

前列腺癌内分泌治疗现状与研究进展

前列腺癌是欧美国家男性最常见的恶性肿瘤,其在我国发病率呈逐年上升趋势.内源性糖皮质激素水平在前列腺癌的发生发展中发挥重要作用,内分泌疗法一直是临床治疗前列腺癌的研究重点,其可能诱发的激素抵抗型前列腺癌也是临床面临的一大屏障.本文就前列腺癌内分泌治疗的分类、作用机制、临床效果及用药策略等作一综述.     

Recent advances in combined modality therapy for locally advanced head and neck cancer

Half of all patients with squamous cell carcinoma of the head and neck (SCCHN) present with locally advanced disease. Despite the development of new treatment strategies, mortality rates have only improved over the last decade by 2.6% per year, and prognosis remains poor. Combined modality therapy offers the potential for organ preservation, particularly for tumors arising in the larynx, hypopharynx and oropharynx. Organ preservation with concurrent chemoradiotherapy (CRT) was first established in laryngeal carcinoma. Recent results of the laryngeal study, RTOG 9111, indicate that even though larynx preservation is improved with CRT compared to induction chemotherapy followed by radiotherapy alone, laryngectomy-free survival is the same. Future attentions should be focused not only on improving treatment efficacy, but also on efforts to minimize the long term toxicities of therapy for SCCHN, particularly because long term toxicities not only diminish quality of life, but seem to impact on survival. In the future, targeted therapies may be incorporated into combined modality therapy for SCCHN, offering the chance to enhance the anticancer effects of treatment without increasing toxicity. Improvements in radiotherapy techniques may also move the field forward. Finally, there is renewed interest in the role of induction chemotherapy as part of a sequential treatment approach for advanced SCCHN. If the current generation of studies evaluating sequential therapy is favorable, future studies incorporating targeted therapies into this platform will offer further potential for advancing the treatment of SCCHN.     

Goserelin and locally advanced prostate cancer: new indication. Pros and cons

(1) Goserelin, a GnRH agonist, has a new licensed indication in France, as an adjuvant to external radiotherapy for locally advanced prosate cancer. (2) The clinical file in this indication includes two trials of satisfactory methodological quality comparing radiotherapy + goserelin with radiotherapy alone. (3) In these trials the radiotherapy + goserelin combination increased the specific-symptom-free survival time. (4) In one trial goserelin caused endocrine disorders in 19% of patients. There were also more cases of urinary incontinence (13% in absolute values) among patients receiving the radiotherapy + goserelin combination. Furthermore, goserelin almost always causes impotence and reduced libido.     

Spotlight on bicalutamide 150mg in the treatment of locally advanced prostate cancer

Bicalutamide (Casodex) is a competitive androgen receptor antagonist that inactivates androgen-regulated prostate cell growth and function, leading to cell apoptosis and inhibition of prostate cancer growth. It is administered orally as a once-daily dose. In the EU and a number of other countries, bicalutamide 150 mg/day is approved in men with locally advanced nonmetastatic prostate cancer as immediate therapy either as an adjuvant to active treatment or as monotherapy as an alternative to surgical or medical castration.Combined analysis of the three trials that comprise the bicalutamide Early Prostate Cancer programme showed that bicalutamide administered in conjunction with standard care in men with locally advanced prostate cancer offers disease-free survival benefits over standard care alone and is generally well tolerated. Overall survival was improved to a greater extent in the subgroup of patients who received bicalutamide plus radiation therapy compared with radiation therapy alone. Men with localised prostate cancer do not benefit from the addition of bicalutamide to standard care. Combined analysis of two other studies in men with locally advanced prostate cancer show that bicalutamide monotherapy offers better tolerability and higher health-related quality-of-life scores for sexual interest and physical capacity compared with surgical or medical castration, while achieving disease-free and overall survival durations that were not significantly different. Thus, when treatment options are being evaluated, bicalutamide as adjuvant therapy or monotherapy should be considered as an alternative to other available hormonal therapies in men with locally advanced prostate cancer, especially in those who wish to maintain an active lifestyle.     

Androgen deprivation therapy with Leuprolide acetate for treatment of advanced prostate cancer

Introduction: Hormone sensitive advanced prostate cancer (PCa) is an incurable disease that is treated with a variety of hormonal therapies targeting the androgen/androgen receptor signaling axis. For decades androgen deprivation therapy (ADT) by surgical or chemical castration is the gold standard for the treatment of advanced PCa.

Areas covered: This review discusses the pharmacological features of Leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonists/analog and the most commonly used drug in ADT.

Expert opinion: Although Leuprolide has been on the market for more than 30 years it is still the leading option for ADT and serves as a basis for most multimodal therapy concepts. The fact that with the onset of castration-resistance in late stage metastatic disease, a prolongation of ADT in combination with a second line hormonal manipulation is recommended supports the importance of the compound for daily clinical practice.     

中低位局部晚期直肠癌术前放化疗的临床治疗分析

目的探讨卡培他滨联合放疗同步治疗中低位局部晚期直肠癌的有效性。方法回顾分析我院2009年1月至2012年12月收治的36例行术前放化疗的Ⅱ～Ⅲ期直肠癌（T3～4／N＋）病人。术前放疗量1．8-2．0Gy／（25f·5w）,总量45—50Gy。放疗期间同时服用卡培他滨1650mg／（m^2·d）。放化疗结束后5—8周行全直肠系膜切除术。结果治疗前临床分期：ⅡB期5例,ⅢB期22例,ⅢC期9例。经放化疗后,pCR4例,PR21例,SD11例。PR＋CR共25例,占69．4％。手术后病理分期：0期4例,Ⅰ期5例,ⅡA期5例,ⅡB期8例,ⅢA期1例,ⅢB期6例,ⅢC期7例。23例行保肛手术,其中11例行末段回肠预防造口。出现吻合口瘘4例,吻合口瘘率17．4％。结论卡培他滨联合放疗同步治疗中低位局部晚期直肠癌可达到术前肿瘤降期,提高根治性切除率,降低肿瘤局部复发。对保肛手术,建议行末段回肠预防造口。     

Neo-adjuvant therapy with dose-dense docetaxel plus short-term filgrastim rescue for locally advanced breast cancer

Neo-adjuvant, dose-dense docetaxel, 100 mg/m(2) every 2 weeks x 4 cycles, was administered to 12 patients with locally advance breast cancer (LABC) (10 stage IIIa and three stage IIIb). Eligibility requirements included a PS 0-2, normal hepatic and renal function, and radiologic absence of metastatic disease. Filgrastim [granulocyte colony stimulating factor (G-CSF)] was started 1 day after chemotherapy and was given for 6 days. Complete blood counts were determined weekly. Surgery was planned upon recovery from the last dose of docetaxel and followed by 4 cycles of adjuvant doxorubicin plus cyclophosphamide (AC) and radiotherapy. Patients with ER status received tamoxifen. The median age was 45 (range 34-73) and pre-treatment pathology revealed poorly differentiated infiltrating duct carcinoma in 11 and infiltrating lobular cancer in one, with positive ER/PR status in five. Twelve patients were treated, and all are evaluable for response and toxicity. Nine patients had a major clinical tumor response with five PR and four pathologic complete responses (pCR rate of 33%). Three patients (of whom two with stage IIIb) had progressive disease and went on to receive neo-adjuvant therapy with AC. There was one instance of grade 3 hematologic toxicity (neutropenic fever in one G-CSF non-compliant patient). There were two instances of grade 3 extra-hematologic toxicity: one patient had severe pain and one had treatment-related fatigue. After a median follow-up of 20 months (range 7-49 months) all patients are alive and eight of nine responders remain progression-free. Despite the small size of our study, we believe that dose-dense neo-adjuvant docetaxel is well tolerated and its activity warrants confirmation in a larger number of patients.     

紫杉醇联合卡铂同步放化疗治疗局部晚期非小细胞肺癌的临床观察

目的观察常规剂量及方法下紫杉醇联合卡铂同步放化疗治疗局部晚期非小细胞肺癌的疗效。方法对24例Ⅲa和Ⅲb期的非小细胞肺癌患者，采用肺内病灶及纵隔淋巴结引流区放射治疗，肿瘤量为60～65Gy／30f。在放疗第1周和第4周同时给予紫杉醇（135mg／m^2），和卡铂（Auc=6mg·ml^-1·min^-1）方案化疗2疗程。结果完全缓解（CR）3例，部分缓解（PR）10例，稳定（sD）5例，进展（PD）6例。总有效率为59．6％，中位生存期（MST）18月，1、2、3年生存率分别为64．3％、30．2％、12％。主要剂量限制性毒性为骨髓抑制，其中主要是Ⅱ～Ⅲ级粒细胞减少，放射治疗的主要副作用为放射性食管炎、放射性肺炎。结论常规剂量、方法下紫杉醇联合卡铂同步放化疗治疗局部晚期非小细胞肺癌放疗化疗毒副作用可以耐受，有望提高局部晚期非小细胞肺癌的疗效。     

曲普瑞林治疗中国局部晚期或转移性前列腺癌的药物经济学评价

目的：对曲普瑞林治疗局部晚期或转移性前列腺癌（PCa）进行药物经济学评价。方法：从卫生体系角度出发,采用Markov模型,对比曲普瑞林相较于其他促性腺激素释放激素激动剂（luteinizing hormone releasing hormone agonists,LHRHa）的经济性。结果：曲普瑞林3M剂型相较戈舍瑞林和亮丙瑞林3M剂型的增量成本效果比（ICER）分别为41 950元/QALY和6 515元/QALY,均远低于2020年中国的1倍人均GDP。相较于戈舍瑞林和亮丙瑞林3M剂型,曲普瑞林6M剂型为患者增加的QALYs分别为0.14和0.11,同时总成本均降低。结论：与目前已上市的LHRHa相比,曲普瑞林治疗局部晚期或转移性PCa具有成本效果优势。