Aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy

Purpose High-risk prostate cancer (PC) has poor outcomes due to therapeutic resistance to conventional treatments, which include prostatectomy, radiation, and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in PC patients. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC.Materials and Methods Analysis was performed on 74 high-risk PC patients who were treated with radiotherapy from 2005 to 2008 at UT Southwestern. Of these patients, 43 were on AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were analyzed.Results Median follow-up was 56.6 mo for all patients. For patients taking any AC compared with no AC, there was improved FFBF at 5 years of 80% vs. 62% (P = 0.003), and for aspirin the FFBF was 84% vs. 65% (P = 0.008). Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7%, P = 0.039). On subset analysis of patients with Gleason score (GS) 9–10 histology, aspirin resulted in improved 5-year OS (88% vs. 37%, P = 0.032), which remained significant on multivariable analysis (P < 0.05).Conclusions AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with GS 9–10, who are most likely to experience mortality from PC. This hypothesis-generating result suggests AC use may represent an opportunity to augment current therapy.     

Health-related quality of life after intensity modulated radiation therapy for localized prostate cancer: comparison with conventional and conformal radiotherapy

OBJECTIVE: No previous studies have reported the longitudinal health-related quality of life (HRQOL) for intensity modulated radiation therapy (IMRT). We compared HRQOL after IMRT with that after conventional and after conformal radiation therapy (XRT). METHODS: A total of 110 patients underwent XRT (34 patients underwent conventional radiation therapy and 76 underwent conformal radiation therapy) and 30 underwent IMRT for clinically localized prostate cancer between 2000 and 2002. We measured the general and disease-specific HRQOL using the Medical Outcomes Study 36-Item Health Survey and University of California, Los Angeles, Prostate Cancer Index, respectively. RESULTS: There were no significant differences in the preoperative characteristics and HRQOL scores of the two groups. Repeated measure analyses of variance revealed significantly different patterns of alteration in several general HRQOL domains between XRT and the IMRT groups. In the urinary domain, there was no difference in the alteration patterns between the two groups. The XRT group suffered worse bowel function at 3 and 6 months than the IMRT group (P < 0.05). In the XRT group, sexual function decreased at 3 months and remained substantially lower than the baseline level. However, the IMRT group showed no significant difference from the baseline level at any of the observation periods. At 18 months the XRT group showed worse sexual function than the IMRT group. CONCLUSION: The two approaches showed different longitudinal profiles regarding general and disease-specific HRQOL during the first 2 years after treatment. The IMRT approach produced little impairment in bowel and sexual function.     

Long-term outcomes of 60 Gy conventional radiotherapy combined with androgen deprivation for localized or locally advanced prostate cancer

BACKGROUND: Until 1998 in Japan, very few institutions were treating prostate cancer solely with radiotherapy (RT) >70 Gy and most were using < or =65 Gy in combination with hormone therapy. The present study reports the long-term results of RT combined with hormone therapy for localized and locally advanced prostate cancer. METHODS: We investigated 57 patients who were treated by external beam RT plus hormone therapy (median age 79 years, median prostate-specific antigen concentration 15.0 ng/ml) between 1992 and 1998. Patients received 40 Gy of radiation to the pelvis and an additional 20 Gy as a prostatic boost. Hormone therapy was begun on the first day of irradiation and continued thereafter. RESULTS: The median follow-up was 93.3 months and the 5 and 10 year actual overall survival rates were 67.8 and 32.6%, respectively, with 5 and 10 year cause-specific survival rates of 97.9 and 95.0%, respectively. The expected survival rate was 66.2% at 5 years, and overall survival was above expected survival. Only one patient developed severe proctitis (Grade 3). The 5 year occurrence of Grade 1/2 genitourinary toxicity was 23.2%. CONCLUSIONS: Combined RT and hormone therapy has a good long-term outcome without severe adverse events. The overall survival rate compares well with the expected survival rate.     

The use of hormonal therapy with radiotherapy for prostate cancer: analysis of prospective randomised trials

In 1901, Wilhelm Conrad R?ntgen won the Nobel prize in Physics for his discovery of the R?ntgen rays or, as he himself called them, X-rays. In 1966, Dr Charles Brenton Higgins won the Nobel Prize in Medicine for his breakthroughs concerning hormonal treatment of prostatic cancer. After 31 years, in 1997, the first prospective randomised trials of the combination of hormonal therapy and radiation therapy were published, showing increased survival when compared to radiation therapy alone for patients with prostate cancer. Since 1997, many investigators have published trials combining hormonal and radiation therapy for prostate cancer. This minireview will address the largest and most influential of these trials, and attempt to guide physicians in selecting the appropriate patients for this combined approach.     

Monotherapy with carbon ion radiation for localized prostate cancer

BACKGROUND: Radiation treatment for localized prostate cancer has become a prominent choice of monotherapy, and carbon ion beam is a powerful means for this purpose. METHODS: In total, 37 patients with localized prostate cancer were treated by monotherapy with carbon ion radiation and the outcome, more than 4 years later, was followed. RESULTS: PSA relapse-free survival was overall 85%, 5 years after radiation, and 96% in low-risk patients. Local control was mostly achieved, and no cancer-specific death was obtained. Except in cases of relapse, 1.0 ng/ml or less of PSA was shown in 78%, 3 years after radiation. Half of biopsy specimens out of 12 cases revealed non-viable or no cancer cells after a rather short time from treatment. CONCLUSION: Monotherapy with carbon ion radiation may be an excellent treatment for localized prostate cancer with low risk.     

Chronic oral anticoagluation and risk of prostate cancer: Evidence of detection bias

Warfarin treatment has been associated with lower risks of prostate cancer, without a specified biological mechanism. Our study tested the hypothesis that reluctance to perform prostate biopsies in men who are anticoagulated results in lower rates of diagnosed prostate cancer, leading to an apparent protective effect. Rates of prostate biopsies have decreased from 2000 to 2015, allowing calendar time to be used as the intervention. In a national population-based sample of elderly men, our study compared trends in prostate cancer incidence between 17,815 men treated with chronic oral anticoagulation for prosthetic heart valve thromboprophylaxis and a general population comparison group of 356,300 men. Cancer events were based on administrative claims. Among men enrolled in 2000–2001 and followed through 2015, prostate cancer incidence was substantially lower in the anticoagulation group (adjusted incidence rate ratio [IRR] 0.70; 95% confidence interval [CI] 0.62–0.80). Incidence decreased over time in the general population group to approach that of the anticoagulation group among men enrolled in 2008–2010 (IRR 0.86; 95% CI 0.71–1.04). Rates of prostate biopsies also decreased over time in the general population group to match the rate in the anticoagulation group. These results indicate that the apparent protective effect of warfarin treatment on the risk of prostate cancer is likely the result of detection bias from lower rates of biopsies among men who are anticoagulated.     

Palliative radiation therapy for localized prostate symptoms in hormone refractory prostate cancer

Hormone refractory prostate cancer (HRPCa) can cause debilitating local pelvic symptoms including urinary obstruction, pelvic pain, haematuria and obstructive rectal symptoms. High‐dose palliative radiation therapy (RT) is used in many centres to relieve these symptoms despite limited published evidence for its efficacy. This study aimed to assess if RT provides effective and durable palliation for local prostate symptoms in HRPCa. Thirty‐five HRPCa patients received RT to the prostate for local symptoms between November 2002 and March 2006. The median dose was 60 Gy in 30 fractions (range 30–70 Gy). Response around a 6‐month time point was scored as complete resolution, partial resolution, no change or local progression. Time to progression (defined as new or recurrent symptoms) or persistence of symptoms was recorded. Factors influencing outcome, such as dose, type and number of symptoms and previous transurethral resection, were examined. Twenty‐one (60%) patients had a complete (n = 3) or partial improvement (n = 18) in symptoms. All three complete responders had haematuria as their only symptom. In the eight (23%) patients with local progression, half progressed during treatment and all had done so within 3 months. This series represents a bigger cohort than any reported in published works examining this issue. It suggests that radiation is effective in palliating the local pelvic symptoms in HRPCa.     

前列腺癌伴贫血与外照射合并内分泌治疗疗效的关系

背景与目的：贫血是恶性肿瘤诊断及治疗过程中常见的并发症。我们主要观察联合雄激素阻断治疗（androgen-deprivation therapy,ADT）对前列腺癌患者血色素的影响及血色素与疗效的关系。方法：分析自2000年5月至2002年4月间有血色素记录的46名前列腺癌患者的资料,所有患者均接受了根治性放射治疗及联合雄激素阻断治疗（双侧睾丸去势术及氟他胺250 mg,每日三次,口服）,观察去势手术前、放射治疗前、放射治疗过程中及放射治疗结束时患者Hb的变化。根据放疗前血色素的水平将患者分为贫血组（Hb〈12 g/dl）和正常血色素组（Hb≥12 g/dl）,采用Paired-T检验来检验放射治疗前、后及新辅助雄激素阻断治疗前至放射治疗前血色素的变化;用Cox回归模型进行无疾病进展生存率的多因素分析来了解放疗前Hb,放疗过程中最低Hb、Gleason score、T分期和治疗前PSA是否为影响无疾病进展生存率的预后因素。结果：46名患者中,新辅助雄激素阻断治疗开始至放疗前,28%的患者Hb下降≤1 g/dl,33%的患者Hb下降介于1-2 g/dl,30%的患者Hb下降超过2 g/dl;放疗期间,37%的患者Hb下降≤1 g/dl,30%的患者Hb下降介于1-2 g/dl;放射治疗前Hb〈12 g/dl和Hb≥12 g/dl患者的3年无疾病进展生存率分别为65%和69%,Log-rank检验显示两者统计学差异无显著性（P=0.567）;多因素分析显示治疗前PSA值,T分期和肿瘤Gleason分级是影响前列腺癌无疾病进展生存率的预后因素,放疗前Hb水平和放疗过程中的最低Hb水平与无疾病进展生存率无显著相关性。结论：联合雄激素阻断治疗导致患者血色素下降,放射治疗前及放射治疗过程中贫血对前列腺癌患者的无疾病进展生存率无显著影响。     

Contemporary treatment of high-risk localized prostate cancer

High-risk prostate cancer poses a significant challenge to the treating physician and much debate exists regarding the ideal treatment approach. The purpose of this article is to enable physicians to identify patients with high-risk localized prostate cancer and evaluate whether monotherapy is sufficient for these patients. We review the current data on use of surgery, radiation therapy and hormonal therapy independently and in combination. We also discuss emerging therapeutics for high-risk disease including neoadjuvant chemotherapy and protocols under current and future investigation.     

Mortality in men with localized prostate cancer treated with brachytherapy with or without neoadjuvant hormone therapy

BACKGROUND:

Discrepancies exist regarding the impact of neoadjuvant hormone therapy (NHT) on the risk of all‐cause mortality (ACM) in men who receive brachytherapy for localized prostate cancer. Therefore, the objective of the current study was to examine the effect of NHT on the risk of ACM in men with prostate cancer who receive with brachytherapy.

METHODS:

The study cohort included 2474 men with localized prostate cancer who either received NHT (N = 1083) or did not receive NHT (N = 1391) and brachytherapy without supplemental external beam radiation between 1991 and 2005 at centers within the 21st Century Oncology Consortium. All men had at least 2 years of follow‐up. Low‐risk, intermediate‐risk, and high‐risk disease was present in 65%, 23%, and 12% of men, respectively. A Cox regression multivariate analysis was used to evaluate the risk of ACM in men who received NHT compared with all others adjusting for age, prostate‐specific antigen level, Gleason score, and tumor classification.

RESULTS:

After a median follow‐up of 4.8 years (interquartile range, 3.3‐7.5 years) and adjusting for known prostate cancer prognostic factors and age, treatment with NHT was associated significantly with an increased risk of ACM (adjusted hazard ratio, 1.24; 95% confidence interval, 1.01‐1.53; P = .04) in men aged ≥73 years. In men who were younger than the median age of 73 years, hormone therapy use was not significant (P = .34).

CONCLUSIONS:

Compared with men who were younger than the median age of 73 years, men aged ≥73 years with localized prostate cancer who received brachytherapy and NHT had an increased risk of ACM compared with men who did not receive NHT. Cancer 2010. © 2010 American Cancer Society.     

Radiation dose escalation for localized prostate cancer

BACKGROUND:

In the current study, the effects of dose escalation for localized prostate cancer treatment with intensity‐modulated radiotherapy (IMRT) or permanent transperineal brachytherapy (BRT) in comparison with conventional dose 3‐dimensional conformal radiotherapy (3D‐CRT) were evaluated.

METHODS:

This study included 853 patients; 270 received conventional dose 3D‐CRT, 314 received high‐dose IMRT, 225 received BRT, and 44 received external beam radiotherapy (EBRT) + BRT boost. The median radiation doses were 68.4 grays (Gy) for 3D‐CRT and 75.6 Gy for IMRT. BRT patients received a prescribed dose of 144 Gy with iodine‐125 (I‐125) or 120 Gy with palladium‐103 (Pd‐103), respectively. Patients treated with EBRT + BRT received 45 Gy of EBRT plus a boost of 110 Gy with I‐125 or 90 Gy with Pd‐103. Risk group categories were low risk (T1‐T2 disease, prostate‐specific antigen level ≤10 ng/mL, and a Gleason score ≤6), intermediate risk (increase in value of 1 of the factors), and high risk (increase in value of ≥2 factors).

RESULTS:

With a median follow‐up of 58 months, the 5‐year biochemical control (bNED) rates were 74% for 3D‐CRT, 87% for IMRT, 94% for BRT, and 94% for EBRT + BRT (P <.0001). For the intermediate‐risk group, high‐dose IMRT, BRT, or EBRT + BRT achieved significantly better bNED rates than 3D‐CRT (P <.0001), whereas no improvement was noted for the low‐risk group (P = .22). There was no increase in gastrointestinal (GI) toxicity from high‐dose IMRT compared with conventional dose 3D‐CRT, although there was more grade 2 genitourinary (GU) toxicity (toxicities were graded at the time of each follow‐up visit using a modified Radiation Therapy Oncology Group [RTOG] scale). BRT caused more GU but less GI toxicity, whereas EBRT + BRT caused more late GU and GI toxicity than IMRT or 3D‐CRT.

CONCLUSIONS:

The data from the current study indicate that radiation dose escalation improved the bNED rate for the intermediate‐risk group. IMRT caused less acute and late GU toxicity than BRT or EBRT + BRT. Cancer 2009. © 2009 American Cancer Society.     

Hypofractionated radiotherapy in prostate cancer

In regards to prostate cancer, the classic radiotherapy dose ranges from 70–80 Gy, administered in daily 2-Gy fractions. However, when taking into account the particular radiobiological model of prostate cancer cells, one realizes that there is a potential theoretical advantage to delivering a greater biological effective dose per treatment in a lower number of fractions. Both recent and older publications have attempted to explore this treatment option. This critical review comprehensively examines the current state of knowledge concerning hypofractionated radiotherapy in prostate cancer.     

Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer

BACKGROUND.

The authors investigated long‐term tumor control and toxicity outcomes after high‐dose, intensity‐modulated radiation therapy (IMRT) in patients who had clinically localized prostate cancer.

METHODS.

Between April 1996 and January 1998, 170 patients received 81 gray (Gy) using a 5‐field IMRT technique. Patients were classified according to the National Comprehensive Cancer Network‐defined risk groups. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse, distant metastases, and cause‐specific survival outcomes were calculated. The median follow‐up was 99 months.

RESULTS.

The 10‐year actuarial prostate‐specific antigen relapse‐free survival rates were 81% for the low‐risk group, 78% for the intermediate‐risk group, and 62% for the high‐risk group; the 10‐year distant metastases–free rates were 100%, 94%, and 90%, respectively; and the 10‐year cause‐specific mortality rates were 0%, 3%, and 14%, respectively. The 10‐year likelihood of developing grade 2 and 3 late genitourinary toxicity was 11% and 5%, respectively; and the 10‐year likelihood of developing grade 2 and 3 late gastrointestinal toxicity was 2% and 1%, respectively. No grade 4 toxicities were observed.

CONCLUSIONS.

To the authors' knowledge, this report represents the longest followed cohort of patients who received high‐dose radiation levels of 81 Gy using IMRT for localized prostate cancer. The findings indicated that high‐dose IMRT is well tolerated and is associated with excellent long‐term tumor‐control outcomes in patients with localized prostate cancer Cancer 2011. © 2010 American Cancer Society.     

Stereotactic body radiotherapy for primary prostate cancer: A systematic review

Stereotactic body radiotherapy (SBRT) for prostate cancer allows overall treatment times to be reduced to as little as 1 week while maintaining a non‐invasive approach. This study provides a comprehensive summary of the literature relating to SBRT in prostate cancer. A systematic review of the relevant literature was performed using structured search terms. Fourteen phase I–II trials and retrospective studies using SBRT for the treatment of prostate cancer were used. Three studies were identified which addressed cost. Dose fractionation, radiotherapy procedures, biochemical progression‐free survival, toxicity, cost and quality of life were critically appraised. A total of 1472 patients were examined across studies. Median follow‐up ranged from 11 to 60 months. The most common dose fractionation was 35–36.25 Gy in five fractions, used in nine out of 14 studies. Ten of 14 studies used CyberKnife. The overall biochemical progression‐free survival ranged 81–100%. Acute grade 2 urinary and rectal toxicities were reported in 5–42% and 0–27% of patients, respectively. Acute grade 3 or more urinary and rectal toxicity were 0.5% and 0%, respectively. Late grade 2 urinary toxicity was reported in 0–29% of patients, while 1.3% had a late grade 3 urinary toxicity. There were no late grade 4 urinary toxicities seen. Late grade 2 rectal toxicity was reported in 0–11%, while 0.5% had a late grade 3 rectal toxicity. Late grade 4 rectal toxicity was reported in 0.2% of patients.     

局限性前列腺癌调强适形放疗联合间歇性内分泌治疗的疗效评价

目的探讨调强适形放射治疗（intensity modulated radiation therapy,IMRT）联合间歇性内分泌治疗（intermittent hormonal therapy,IHT）方法治疗局限性前列腺癌的疗效评价。方法将72例同期局限性前列腺癌患者随机分为两组,分别进行调强适形放射治疗联合间歇性内分泌治疗（37例）和单纯调强适形放射治疗（35例）,分析比较两组患者的临床症状缓解率、前列腺体积变化、血清前列腺特异性抗原（PSA）值改变、肿瘤控制率、放疗不良反应发生率及生存率。结果随访5～118个月,平均56个月,联合治疗组与单纯治疗组比较,临床症状缓解率、前列腺体积差值、血清PSA〈0．2μg/L者所占比例及治疗后1年、3年、5年和8年的PSA无进展生存率差异均有统计学意义（P〈0．05）;治疗后1年、3年两组均无死亡病例,差异无统计学意义,治疗后5年、8年的生存率和早期放疗不良反应发生率两组间差异均有统计学意义（P〈0．05）。结论调强适形放射治疗联合间歇性内分泌治疗方法治疗局限性前列腺癌可明显缓解患者的临床症状,降低血清PSA水平,提高疾病控制率及生存率,降低放疗早期不良反应发生率,疗效优于单纯调强适形放射治疗,是一种安全、有效的治疗措施。