Adjuvant androgen deprivation therapy for prostate cancer treated with radiation therapy

Siddiqui, Z.A.; Krauss, Daniel

doi:10.21037/tau.2018.01.06

Cited by 29 publications

(24 citation statements)

References 72 publications

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“…Alternatively, an enhanced immune response has been suggested as another possible mechanism of the synergistic effect of AdT and RT (15,16). Despite these benefits, treatment with ADT can result in a multitude of iatrogenic conditions including increased risk for diabetes, cardiovascular diseases, sexual health dysfunction, depression, cognitive and mood dysfunction (11,17). These treatment-related conditions can greatly reduce health-related quality of life (18).…”

Section: Cancer-related Fatigue During Combined Treatment Of Androgenmentioning

confidence: 99%

Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

et al. 2019

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combined androgen deprivation therapy (AdT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. A total of 64 participants with NMPc were enrolled. Fatigue was assessed using the Functional Assessment of cancer Therapy-Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMcs) extracted from participants' whole blood. An AdT/RT-induced fatigue mouse model was developed, with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the AdT/RT mouse brains using western blot analysis of glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). The results demonstrated that fatigue in the AdT group was exacerbated during RT compared with the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMcs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The AdT/RT mice demonstrated the synergistic effect of AdT and RT in decreasing VWRA. Brain tissues of AdT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. In conclusion, these findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (cNS). The synergistic effect of AdT/RT is behaviorally reproducible in a mouse model and its mechanism may be related to bioenergetics in the cNS.

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Section: Cancer-related Fatigue During Combined Treatment Of Androgenmentioning

confidence: 99%

Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

et al. 2019

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“…Results of the OABSS questionnaire indicated that the majority of patients (88%) had mild urinary symptoms with an average value of 3.2 (range, 1-5). According to the IPSS questionnaire, 27% of patients had mild symptoms with an average score of 5 (range, 4-6), and the majority of patients (62%) demonstrated moderate symptoms with an average score of 12.8 (range, [8][9][10][11][12][13][14][15][16][17][18][19]. There was no statistically significant difference between 18 Gy and 21 Gy arms, except in baseline quality of life, which included more patients who answered "delighted" in 18 Gy arm.…”

Section: Resultsmentioning

confidence: 99%

“…Most patients enrolled in the present study received ADT over 1 year. Usual recovery of testosterone occurs slowly over 1–2 years [ 16 ]. The median follow-up time of 35 months (range of 19 to 43 months) is insufficient to determine the exact long-term tumor control rate after testosterone recovery.…”

Section: Resultsmentioning

confidence: 99%

Phase I/IIa trial of androgen deprivation therapy, external beam radiotherapy, and stereotactic body radiotherapy boost for high-risk prostate cancer (ADEBAR)

et al. 2020

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Background To evaluate the clinical outcomes of combination of androgen deprivation therapy (ADT), whole pelvic radiotherapy (WPRT), and stereotactic body radiotherapy (SBRT) boost in high-risk prostate cancer patients. Methods This prospective phase I/IIa study was conducted between 2016 and 2017. Following WPRT of 44 Gy in 20 fractions, patients were randomized to two boost doses, 18 Gy and 21 Gy, in 3 fractions using the Cyberknife system. Primary endpoints were incidences of acute toxicities and short-term biochemical recurrence-free survival (BCRFS). Secondary endpoints included late toxicities and short-term clinical progression-free survival (CPFS). Results A total of 26 patients were enrolled. Twelve patients received a boost dose of 18 Gy, and the rest received 21 Gy. The Median follow-up duration was 35 months. There were no grade ≥ 3 genitourinary (GU) or gastrointestinal (GI) toxicities. Sixty-one and 4% of patients experienced grade 1–2 acute GU and GI toxicities, respectively. There were 12% late grade 1–2 GU toxicities and 8% late grade 1–2 GI toxicities. Patient-reported outcomes of urinary symptoms were aggravated after WPRT and SBRT boost. However, they resolved at 1 month and returned to the baseline level at 4 months. Three-year BCRFS was 88.1%, and CPFS was 92.3%. Conclusions The present study protocol demonstrated that the combination of ADT, WPRT, and SBRT boosts for high-risk prostate cancer is safe and feasible, and may reduce total treatment time to 5 weeks. Boost dose of 21 Gy in 3 fractions seems appropriate. Trial registration ClinicalTrials.gov, ID; NCT03322020 - Retrospectively registered on 26 October 2017.

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“…Presence of lymph-node (LN) metastasis in patients with PC undergoing radical prostatectomy (RP) is the strongest risk factor for both, tumor recurrence and cancer-specific mortality [2,3]. In patients with LN-positive PC, adjuvant treatment after RP with either androgen-deprivation therapy (ADT) alone or ADT in combination with pelvic radiation therapy (RT) has shown a benefit in overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) [4][5][6][7]. LN staging is crucial to assign node-positive patients to adjuvant treatment and thereby prolong CSS in these patients [8,9].…”

Section: Introductionmentioning

confidence: 99%

KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy

Lunger

Retz

Bandur

et al. 2020

Prostate Cancer Prostatic Dis

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Background Lymph-node (LN) metastasis in prostate cancer (PC) is a main risk factor for tumor recurrence after radical prostatectomy (RP). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP. Methods The expression of kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostate-specific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2) and transient receptor potential cation channel subfamily M member 8 (TRPM8) was assessed using qPCR. We analyzed LNs from 111 patients (intermediate PC, n = 32 (29%); high-risk PC, n = 79 (71%)) who underwent RP and extended pelvic lymph-node dissection without neoadjuvant treatment. Results Overall, 2411 LNs were examined by molecular and histopathologic examination. Histopathology detected 69 LN metastases in 28 (25%) patients. KLK2 and KLK3 diagnostically performed best and classified all pN1-patients correctly as molecular node-positive (molN1/pN1). The concordance on LN level was best for KLK3 (96%). KLK2, KLK3, KLK4, PSMA, TMPRSS2, and TRPM8 reclassified 27 (24%), 32 (29%), 29 (26%), 8 (7%), 13 (12%), and 23 (21%) pN0-patients, respectively, as node-positive (pN0/molN1). On multivariable cox regression analysis molecular LN status (molN1 vs. molN0) using KLK3 (HR 4.0, p = 0.04) and TMPRSS2 (HR 5.1, p = 0.02) were independent predictors of bRFS. Median bRFS was shorter in patients with only molecular positive LNs (molN1/pN0) for KLK3 (24 months, p = 0.001) and for TMPRSS2 (12 months, p < 0.001) compared to patients with negative nodes (molN0/pN0) (median bRFS not reached). Conclusions For diagnostic purposes, KLK3 showed highest concordance with histopathology for detection of LN metastases in PC patients undergoing RP. For prognostic purposes, KLK3 and TMPRSS2 expression were superior to histopathologic LN status and other transcripts tested for molecular LN status. We suggest a combined KLK3/TMPRSS2 panel as a valuable diagnostic and prognostic tool for molecular LN analysis.

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Adjuvant androgen deprivation therapy for prostate cancer treated with radiation therapy

Cited by 29 publications

References 72 publications

Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

Phase I/IIa trial of androgen deprivation therapy, external beam radiotherapy, and stereotactic body radiotherapy boost for high-risk prostate cancer (ADEBAR)

KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy

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