EFFECT OF THE DUAL 5α-Reductase INHIBITOR DUTASTERIDE ON MARKERS OF TUMOR REGRESSION IN PROSTATE CANCER

Andriole, Gerald L.; Humphrey, Peter A.; Ray, Paul S.; Gleave, Martin; Trachtenberg, John; Thomas, Lynn N.; Lazier, Catherine B.; Rittmaster, Roger S.

doi:10.1097/01.ju.0000136430.37245.b9

Cited by 145 publications

(87 citation statements)

References 21 publications

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“…Although the effects of 5␣-reductase inhibitors on known tumors, as opposed to the prevention of new tumors, are unclear, some data suggest that treatment can result in tumor volume reductions. 13 Therefore, the scenario in which an equal reduction in tumor and prostate volume size occurred was also modeled.…”

Section: Modeling the Influence Of Prostate Volume And Tumor Size Redmentioning

confidence: 99%

Quantifying the Impact of Prostate Volumes, Number of Biopsy Cores and 5α-Reductase Inhibitor Therapy on the Probability of Prostate Cancer Detection Using Mathematical Modeling

et al. 2007

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Purpose: Previous studies demonstrated a negative correlation between prostate volume and biopsy yield. By decreasing prostate volume 5␣-reductase inhibitors may enhance cancer detection, which may explain the greater detection of high grade tumors in the finasteride arm of the Prostate Cancer Prevention Trial. Materials and Methods: A mathematical model was constructed to analyze the effects of prostate and tumor volumes, and biopsy core number on cancer detection. The effects of the volume reduction observed with finasteride in the Prostate Cancer Prevention Trial were also modeled, as was the potential reduction in tumor volume needed to explain the observed difference in prostate cancer detection. The model was also applied to the Reduction by Dutasteride of Prostate Cancer Events study. Results: A higher number of biopsies are required to ensure a detection probability of 0.90 or greater in larger glands or with smaller tumors. In the Prostate Cancer Prevention Trial for a tumor volume of 1 cc a 17% increase in the detection rate in the finasteride arm would be predicted if there was no change in tumor volume, likewise the rate would be 11% to 17% for the dutasteride arm of the Reduction by Dutasteride of Prostate Cancer Events study. The calculated reduction in tumor volume needed to explain the difference in cancer detection between the finasteride and placebo arms of the Prostate Cancer Prevention Trial would be 51% to 66%. Conclusions: This model provides guidance on the optimal number of biopsy cores that accord with an earlier model. These findings also suggest that, if there were no reduction in tumor volume, 5␣-reductase inhibitor therapy could lead to excess cancer detection, including high grade tumors.

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Section: Modeling the Influence Of Prostate Volume And Tumor Size Redmentioning

confidence: 99%

Quantifying the Impact of Prostate Volumes, Number of Biopsy Cores and 5α-Reductase Inhibitor Therapy on the Probability of Prostate Cancer Detection Using Mathematical Modeling

et al. 2007

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“…19). Clinical trials also indicated that the combined level of DHT and testosterone was 58% lower in dutasteride than placebo patients (19). Dutasteride similarly causes shrinkage of the prostate gland (20) and atrophy and apoptosis of benign prostatic epithelium and adenocarcinoma in patients with clinically organ-confined prostate cancer (19,20).…”

Section: Reducing the Dihydrotestosterone Environment Associated Withmentioning

confidence: 99%

“…As with finasteride, dutasteride significantly reduces DHT and increases testosterone (versus placebo; ref. 19). Clinical trials also indicated that the combined level of DHT and testosterone was 58% lower in dutasteride than placebo patients (19).…”

Section: Reducing the Dihydrotestosterone Environment Associated Withmentioning

confidence: 99%

“…Clinical trials also indicated that the combined level of DHT and testosterone was 58% lower in dutasteride than placebo patients (19). Dutasteride similarly causes shrinkage of the prostate gland (20) and atrophy and apoptosis of benign prostatic epithelium and adenocarcinoma in patients with clinically organ-confined prostate cancer (19,20). Two large multicenter clinical trials of dutasteride will advance our understanding of the effects of 5-α reductase inhibitors in preventing or inhibiting progression of clinically localized prostate cancer.…”

Section: Reducing the Dihydrotestosterone Environment Associated Withmentioning

confidence: 99%

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Molecular Profiles of Finasteride Effects on Prostate Carcinogenesis

Kim

2009

Cancer Prevention Research

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Our inability to distinguish between low-grade prostate cancers that pose no threat and those that can kill compels newly diagnosed early prostate cancer patients to make decisions that may negatively affect their lives needlessly for years afterward. To reliably stratify patients into different risk categories and apply appropriate treatment, we need a better molecular understanding of prostate cancer progression. Androgen ablation therapy and 5-α reductase inhibitors reduce dihydrotestosterone levels and increase apoptosis. Because of the differing biological potentials of tumor cells, however, these treatments may, in some cases, worsen outcome by selecting for or inducing adaptation of stronger androgen receptor signaling pathways. Reduced dihydrotestosterone also may be associated with altered survival pathways. Complicating treatment effects further, molecular adaptation may be accelerated by interactions between epithelial and stromal cells. The hypothesis that early prostate cancer cells with differing biological potential may respond differently to finasteride treatment is worth testing. Ongoing studies using a systems biology approach in a preoperative prostate cancer setting are testing this hypothesis toward developing more-rational clinical interventions.The Prostate Cancer Prevention Trial (PCPT; ref. 1) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (2-5) have shown that 5-α reductase inhibitors are the only agent class proven to be effective in preventing prostate cancer. These positive randomized controlled trials have important implications for understanding the biological potential of the tumor in cases of early prostate cancer as well as for the convergent management (treating and preventing microcancer) of men at a high risk of developing the disease.Morphologically identical prostate tumors can progress at dramatically different rates, and patients in the same cancer risk category can respond very differently to identical treatment. These differences are due in part to the biological heterogeneity of prostate cancer. Some low-risk tumors remain indolent for more than a decade, whereas others rapidly turn deadly. Accurate characterization of the biological potential of the tumor is needed for personalizing prostate cancer treatment. Although the term "risk" commonly connotes the risk of primary prostate cancer, the term is commonly applied in cases of early prostate cancer because of the unusual characteristic of a relatively high frequency of indolent prostate cancer that does not pose a threat of clinical consequences in a patient's lifetime.Categorizing prostate cancer into risk categories (low, intermediate, and high) depends on the available indicators. Prostate cancer patients are stratified into different risk groups and prescribed different treatments based on prostate-specific antigen level, Gleason score (GS), and clinical stage. Common management options for low-or intermediate-risk patients include watchful waiting, prostatectomy, and radiation ther...

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“…53 The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial showed a decreased volume of HGPIN in a randomized trial of 46 patients who underwent radical prostatectomy that approached statistical significance at P = 0.052. 54 Selective estrogen receptor modulators also show promise in prevent-ing the progression of HGPIN to PCa. In a large phase IIB clinical trial, men with HGPIN who were given 20 mg toremifene had a decreased incidence of PCa at 24.4% versus 31.2% with placebo at 1 year.…”

Section: Impact Of Initial Pathological Findings High Grade Prostaticmentioning

confidence: 99%

Prostate cancer detection after a negative prostate biopsy: Lessons learnt in the Cleveland Clinic experience

Zaytoun

Jones

2011

Int J of Urology

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Abstract:Urologists are often faced with the dilemma of managing patients with a negative initial prostate biopsy in whom clinical or pathological risk for prostate cancer still exists. Such real-life challenging scenarios might raise questions such as: Who should undergo further biopsies? What are the optimal predictors for prostate cancer on subsequent biopsies? What is the optimal biopsy protocol that should be used? When to stop the biopsy cascade? The last decade has witnessed numerous studies that have analyzed factors conferring a significant risk for cancer discovered on repeat biopsies. We and others have developed predictive models to aid decision-making regarding pursuing further biopsies. For decades, high-grade prostatic intraepithelial neoplasia has been considered a strong risk indicator for subsequent cancer. However, it has been recently shown that only through segmentation of this heterogeneous population does the real risk profile emerge. Biopsy templates underwent modification regarding the number and location of cores with emergence of the transrectal or brachytherapy grid transperineal saturation biopsy. However, the best biopsy protocol remains controversial. We have refined the initial biopsy template to a 14 core initial biopsy template that optimizes cancer detection, and have shown that transrectal saturation biopsy significantly improves cancer detection for repeat biopsy. Another concern is the overdiagnosis of clinically insignificant cancer on repeat biopsies, so we explored ways to limit this, and to deal with its ramifications. Through carrying out a Medline literature search, we critically evaluated pertinent articles together with emphasis of our own journey in this arena to assist in the decision-making process for repeat biopsy population.

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EFFECT OF THE DUAL 5α-Reductase INHIBITOR DUTASTERIDE ON MARKERS OF TUMOR REGRESSION IN PROSTATE CANCER

Abstract: In this pilot study dutasteride treatment resulted in almost complete suppression of intraprostatic DHT, increased apoptosis and a trend toward decreased MVD. These findings suggest that short-term treatment with dutasteride can cause regression in some prostate cancers.

Cited by 145 publications

References 21 publications

Quantifying the Impact of Prostate Volumes, Number of Biopsy Cores and 5α-Reductase Inhibitor Therapy on the Probability of Prostate Cancer Detection Using Mathematical Modeling

Quantifying the Impact of Prostate Volumes, Number of Biopsy Cores and 5α-Reductase Inhibitor Therapy on the Probability of Prostate Cancer Detection Using Mathematical Modeling

Molecular Profiles of Finasteride Effects on Prostate Carcinogenesis

Prostate cancer detection after a negative prostate biopsy: Lessons learnt in the Cleveland Clinic experience

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