Pre-treatment nomogram for biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for clinically localised prostate cancer

Phase III studies have demonstrated the clinical benefit of adding neo-adjuvant androgen deprivation to radical radiotherapy for clinically localised prostate cancer. We have developed a nomogram to describe the probability of PSA control for patients treated in this way. Five hundred and seventeen men with clinically localised prostate cancer were treated with 3-6 months of neo-adjuvant androgen deprivation and radical radiotherapy (64Gy in 32#) between 1988 and 1998. Median presenting PSA was 20 ng x ml(-1), and 56% of patients had T3/4 disease. Multivariate analysis of pre-treatment factors was performed, and a nomogram developed to describe PSA-failure-free survival probability. At a median follow-up of 44 months, 233 men had developed PSA failure. Presenting PSA, histological grade and clinical T stage were all highly predictive of PSA failure on multivariate analysis. The nomogram score for an individual patient is given by the summation of PSA (<10=0, 10-19=16, 20-49=44, > or =50=100), grade (Gleason 2-4=0, 5-7=44, 8-10=81) and T stage (T1/2=0, T3/4=35). For a nomogram score of 0, 50, 100 and 150 points the 2 year PSA control rate was 93, 87, 75 and 54%, and the 5 year PSA control rate was 82, 67, 44 and 18%. These results are comparable to those using surgery or higher doses of radical radiotherapy alone. The nomogram illustrates the results of multivariate analysis in a visually-striking way, and facilitates comparisons with other treatment methods.     

A novel BRCA2 mutation in prostate cancer sensitive to combined radiotherapy and androgen deprivation therapy

Genetic factors contribute to more than 40% of prostate cancer risk, and mutations in BRCA1 and BRCA2 are well-established risk factors. By using target capture-based deep sequencing to identify potential pathogenic germline mutations, followed by Sanger sequencing to determine the loci of the mutations, we identified a novel pathogenic BRCA2 mutation caused by a cytosine-to-guanine base substitution at position 4211, resulting in protein truncation (p.Ser1404Ter), which was confirmed by immunohistochemistry. Analysis of peripheral blood also identified benign polymorphisms in BRCA2 (c.7397T>C, p.Val2466Ala) and SRD5A2 (c.87G>C, p.Lys29Asn). Analysis of tumor tissues revealed seven somatic mutations in prostate tumor tissue and nine somatic mutations in esophageal squamous carcinoma tissue (single nucleotide polymorphisms, insertions, and deletions). Five-year follow-up results indicate that ADT combined with radiotherapy successfully treated the prostate cancer. To our knowledge, we are the first to report the germline BRCA2 mutation c.4211C>G (p.Ser1404Ter) in prostate cancer. Combined ADT and radiotherapy may be effective in treating other patients with prostate cancer caused by this or similar mutations.     

Androgen deprivation therapy in nonmetastatic prostate cancer patients: Indications,treatment effects,and new predictive biomarkers

Men with prostate cancer with positive margins, extraprostatic extension, positive lymph nodes, high prostate‐specific antigen, or high Gleason Score are at high risk of recurrence following primary therapy. Androgen deprivation therapy (ADT), which includes medical/surgical castration, antiandrogen therapy, and combined androgen blockade, can be combined with primary therapy to shrink the tumor, reduce margin positivity, and reduce the risk of recurrence. However, many problems still remain, such as optimizing the application of ADT in the treatment of prostate cancer, for example, ideal patient population and optimal timing and duration of therapy. To investigate these problems, we searched PubMed for relevant publications on clinical studies of deprivation therapy for nonmetastatic prostate cancer. In this review, we discuss our findings on the role of ADT in the treatment of castrate‐sensitive nonmetastatic prostate cancer and the adverse effects associated with ADT. We also examine the recent advances in new predictive biomarkers for ADT, many of which are currently in the exploratory phase. Overall, the addition of ADT to primary therapy improves outcomes for patients with intermediate‐ or high‐risk prostate cancer.     

Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer

BACKGROUND: The use of androgen deprivation therapy (ADT) in the treatment of men with prostate cancer has risen sharply. Although cardiovascular disease is the most common reason for death among men with prostate cancer who do not die of the disease itself, data regarding the effect of ADT on cardiovascular morbidity and mortality in men with prostate cancer are limited. In the current study, the authors attempted to measure the risk for subsequent cardiovascular morbidity in men with prostate cancer who received ADT. METHODS: A cohort of newly diagnosed men in a population-based registry who were diagnosed between 1992 and 1996 were identified retrospectively. A total of 22,816 subjects were identified after exclusion criteria were applied. Using a multivariate model, the authors calculated the risk of subsequent cardiovascular morbidity in men with prostate cancer who were treated with ADT, as defined using Medicare claims. RESULTS: Newly diagnosed prostate cancer patients who received ADT for at least 1 year were found to have a 20% higher risk of serious cardiovascular morbidity compared with similar men who did not receive ADT. Subjects began incurring this higher risk within 12 months of treatment. However, Hispanic men were found to have a lowered risk for cardiovascular morbidity. CONCLUSIONS: ADT is associated with significantly increased cardiovascular morbidity in men with prostate cancer and may lower overall survival in men with low-risk disease. These data have particular relevance to decisions regarding the use of ADT in men with prostate cancer in settings in which the benefit has not been clearly established. For men with metastatic disease, focused efforts to reduce cardiac risk factors through diet, exercise, or the use of lipid-lowering agents may mitigate some of the risks of ADT.     

Combining radiation therapy and androgen deprivation for localized prostate cancer-a critical review

Interest has been increasing in the use of androgen deprivation therapy (ADT) combined with radiation therapy (RT) in the management of localized prostate cancer. Preclinical studies have provided some rationale for the use of this combination. In patients with high-risk disease, the benefit of a combined approach, with the addition of adjuvant hormonal therapy, is supported by results of randomized trials. In contrast, for patients with low-risk disease, there is no obvious therapeutic advantage except for cytoreduction. The usefulness of short-term hormonal therapy in association with rt for intermediate-risk patients is still debatable, particularly in the context of doseescalated RT. The optimal timing and duration of ADT, in the neoadjuvant and adjuvant settings alike, are still under investigation. In view of the potential side effects with ADT, further studies are being performed to better identify subsets of patients who will definitely benefit from this therapy in combination with rt.     

Androgen deprivation and cognition in prostate cancer

Androgen deprivation (AD) is commonly used in neoadjuvant and adjuvant setting with prostate cancer (PC) radiotherapy. This prospective study assessed whether cognitive functioning is impaired during 12 months of AD therapy. Longitudinal testing of 25 patients treated with AD and curative radiotherapy was undertaken at baseline, and at 6 and 12 months. CogniSpeed software was used for measuring attentional performances. Other cognitive performances were evaluated using verbal, visuomotor and memory tests. The Beck depression inventory was employed to evaluate depressive mood and EORTC QLQ-C30 for quality of life (QoL). During longitudinal testing of the AD group, no impairment in cognitive performances was found. Instead, improvement was observed in object recall (immediate, P=0.035; delayed, P<0.001), and in semantic memory (P=0.037). In QoL, impairment in physical function was observed. Androgen deprivation of 12 months appears to be associated with preserved cognitive functioning, although physical impairment occurs. These results have implications for counseling and psychosocial support of patients in the context of treatment options in PC.     

多学科综合治疗——改善高危前列腺癌患者的预后

手术和放疗是局限性前列腺癌主要的治疗方法,但对于高危前列腺癌单用局部治疗预后不佳,超过50％的患者会复发。手术、放疗、内分泌治疗和化疗的联合应用目前被认为是提高高危前列腺癌疗效的重要途径。本文总结了目前高危前列腺癌综合治疗的相关文献,期望能为我国高危前列腺癌综合治疗方案的选择提供借鉴和参考。     

Androgen deprivation therapy prevents bladder cancer recurrence

Although accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development, its clinical relevance remains unclear. We aimed to evaluate the predictive role of androgen deprivation therapy (ADT) in BC recurrence in prostate cancer (PC) patients.We retrospectively reviewed 20,328 patients with PC diagnosed during 1991–2013 and identified 239 (1.2%) men having primary BC. After excluding ineligible patients, 162 patients made up a final cohort.With a median follow-up of 62 months, 38 (50%) of 76 control patients without ADT experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT for their PC showed a significantly lower risk of BC recurrence (5-year actuarial recurrence-free survival: 76% v 40%; P < 0.001) and also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001), compared to the control patients. A multivariable analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17–0.49) for BC recurrence.This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence.     

Zoledronic acid to prevent bone loss in Chinese men receiving androgen deprivation therapy for prostate cancer

Aim: To explore the bone mineral density (BMD) preservation effect of zoledronic acid and its renal safety and tolerability in Chinese patients with prostate cancer on androgen deprivation therapy (ADT). Methods: Overall 26 prostate cancer patients with ADT were given zoledronic acid 4 mg by a 15‐min i.v. infusion every 3 months for up to 12 months. Assessment was made at baseline and at 3, 6, 9 and 12 months. Dual‐energy X‐ray absorptiometry was used to measure the BMD of the lumbar spine and the femoral neck at baseline and 12 months. Results: A total of 23 of 26 recruited patients completed the study. Seven patients had bone metastases. The overall mean increase in BMD (T‐score) of the lumbar spine and femoral head from baseline to follow up at 12 months was significant (−2.32 ± 0.98 to −2.03 ± 1.08, P = 0.02 and −1.77 ± 0.72 to −1.63 ± 0.76, P = 0.01, respectively). In subgroup analyses, significant BMD improvement was observed independent of the status of bone metastasis and the means of ADT. Zoledronic acid had no adverse effect on renal function. Adverse events related to zoledronic acid were minimal. Conclusion: Zoledronic acid administered every 3 months significantly increased BMD in prostate cancer patients receiving ADT. It had a satisfactory adverse event profile and imposed minimal risk on patients' renal function.     

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.     

局部晚期食管癌的围手术期治疗策略

我国是食管癌的高发地区之一,目前手术仍是局部晚期食管癌治疗的主要手段。为降低手术患者复发、转移的几率,延长其生存期,寻求最佳的治疗方法,已有多个临床研究对围手术期联合化、放疗的综合治疗方法进行了探索。本文对近年来针对围手术期治疗的主要临床研究做一综述。     

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.     

Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial

Stereotactic body radiotherapy (SBRT) can delay escalation to systemic treatment in men with oligometastatic prostate cancer (PCa). However, large, prospective studies are still required to evaluate the efficacy of this approach in different patient groups. This is the interim analysis of a prospective, single institution study of men relapsing with up to five synchronous lesions following definitive local treatment for primary PCa. Our aim was to determine the proportion of patients not requiring treatment escalation following SBRT. In total, 199 patients were enrolled to receive fractionated SBRT (50 Gray in 10 fractions) to each visible lesion. Fourteen patients were castration resistant at enrolment. The proportion of patients not requiring treatment escalation 2 years following SBRT was 51.7% (95% CI: 44.1–59.3%). The median length of treatment escalation-free survival over the entire follow-up period was 27.1 months (95% CI; 21.8–29.4 months). Prior androgen deprivation therapy (ADT) predicted a significantly lower rate of freedom from treatment escalation at 2 years compared to no prior ADT (odds ratio = 0.21, 95% CI: 0.08–0.54, p = 0.001). There was no difference in the efficacy of SBRT when treating 4–5 vs. 1–3 initial lesions. A prostate-specific antigen (PSA) decline was induced in 75% of patients, with PSA readings falling to an undetectable level in six patients. No late grade three toxicities were observed. These interim results suggest that SBRT can be used to treat up to five synchronous PCa oligometastases to delay treatment escalation.     

Current trends for the use of androgen deprivation therapy in conjunction with radiotherapy for patients with unfavorable intermediate‐risk,high‐risk,localized, and locally advanced prostate cancer

Androgen deprivation therapy (ADT) is now a well‐established standard of care in combination with definitive radiotherapy for patients with unfavorable intermediate‐risk to high‐risk locally advanced prostate cancer. It is also well established that combination modality treatment with ADT and radiotherapy is superior to either of these modalities alone for the treatment of patients with high‐risk locally advanced disease. Current treatment guidelines for prostate cancer in the United States are based on the estimated risk of recurrence and death. This review examines the clinical evidence underpinning the use of ADT and radiotherapy among patients with high‐risk localized and locally advanced disease in the United States. This review also considers the rationale for moving from traditional luteinizing hormone‐releasing hormone agonists to more recently developed gonadotrophin‐releasing hormone antagonists. Cancer 2014;120:1620–1629 . © 2014 American Cancer Society.