dutasteride and Adenocarcinoma

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-alpha 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.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Androgens; Animals; Anticarcinogenic Agents; Apoptosis; Apoptosis Regulatory Proteins; Azasteroids; Dihydrotestosterone; Disease Progression; Dutasteride; Epithelial Cells; Finasteride; Humans; Isoenzymes; Male; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Patient Selection; Prostate; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Stromal Cells

As dihydrotestosterone (DHT) is the most potent androgen in the prostate, inhibition of the 5alpha-reductase isoenzymes, which convert testosterone to DHT, could be an appropriate target for the treatment of prostate cancer.. Eighty-one men with clinically localized prostate cancer received daily dutasteride 3.5 or 0.5 mg, or no therapy for 4 months before radical prostatectomy. Histopathological assessments were conducted on prostatectomy specimens.. Treatment with dutasteride was associated with reductions in serum and intraprostatic DHT of >or=90%, and a decrease in total prostate and tumor volumes. No effect of dutasteride was noted on Gleason grade. Histopathological effects on benign tissue were similar but less prominent than those seen with androgen ablation, whereas there was no significant difference in cancer histology among the groups.. Dutasteride treatment results in similar but less marked changes compared with androgen ablation.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Aged; Aged, 80 and over; Apoptosis; Azasteroids; Cell Proliferation; Dihydrotestosterone; Dose-Response Relationship, Drug; Double-Blind Method; Dutasteride; Enzyme Inhibitors; Humans; Male; Middle Aged; Pilot Projects; Prostate; Prostatectomy; Prostatic Neoplasms; Treatment Outcome

To perform the first evaluation of the effects of the 5-alpha-reductase inhibitor class of drugs on cancer histopathologic features at radical prostatectomy in a placebo-controlled multicenter trial.. We analyzed prostatectomy slides in a blinded manner from 17 men treated with dutasteride, an inhibitor of types 1 and 2 isoenzymes of 5-alpha-reductase, and 18 men treated with placebo for 5 to 11 weeks before radical prostatectomy. The histopathologic features of benign epithelium, high-grade prostatic intraepithelial neoplasia, and cancer were recorded, and the treatment effect was scored. Digital imaging analysis was used to measure the stroma/epithelium ratio and epithelial height, as well as the nuclear area in cancer.. In benign epithelium, treatment caused distinctive cytoarchitectural changes of atrophy and a decrease in the epithelial height (P = 0.053). The peripheral zone showed the most marked response to treatment. In cancer tissue, the tumor volume was significantly lower in the dutasteride-treated men than in the placebo-treated men (mean 15% versus 24%, respectively, P = 0.025), the percentage of atrophic epithelium was increased (P = 0.041), and the stroma/gland ratio was doubled (P = 0.046). The treatment alteration effect score was doubled (P = 0.055) and did not correlate with any Gleason score changes.. After short-term dutasteride treatment, benign epithelium showed involution and epithelial shrinkage, and prostate cancer tissue demonstrated a decrease in epithelium relative to stroma. These findings indicate that dutasteride induces significant phenotypic alterations in both the benign and the neoplastic prostate, supportive of a chemopreventive or chemoactive role.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Atrophy; Azasteroids; Combined Modality Therapy; Double-Blind Method; Dutasteride; Epithelial Cells; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Proteins; Pilot Projects; Prostate; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Stromal Cells

An 84-year-old man was referred to our hospital with swollen right cervical lymph nodes. Computed tomography showed right supraclavicular and mediastinal lymph node enlargement, and fluorodeoxyglucose positronemissiontomography showed multiple areas of abnormally increased radioactivity inthe right supraclavicular and mediastinal lymph nodes, right ninth rib, and left fifth and seventh ribs. Biopsy of the right supraclavicular lymph node revealed metastatic adenocarcinoma with partial immunohistochemical staining for prostate specific antigen (PSA). Serum PSA levels were not elevated (2.01 ng/ml). An 8-core transrectal prostatic biopsy was negative. Thus, we could not determine the primary site of the adenocarcinoma. The patient was diagnosed with carcinoma of an unknown primary site and followed without chemotherapy. Four years later, he was referred to our hospital due to right hydronephrosis. Serum PSA level was 31. 1 ng/ml. The tumor was not palpable by rectal examination. A 12-core transrectal prostatic biopsy revealed a poorly differentiated adenocarcinoma. Computed tomography revealed metastases in the left axilla, para-aortic, and pelvic lymph nodes as well as in the lung. We diagnosed the patient with prostate cancer, and combined androgen blockade (CAB) was administered. Metastases in the lymph nodes, lung, and bone were reduced on imaging after 1 month of therapy. Therefore, a definitive diagnosis of prostate cancer T1cN1M1c was made. Dutasteride had been administered as a benign prostate hyperplasia treatment 2 years before his first visit, which may have made the definitive diagnosis of prostate cancer difficult. In contrast, dutasteride may have delayed the progressionof prostate cancer inthis patient.

Topics: Adenocarcinoma; Aged, 80 and over; Disease Progression; Dutasteride; Humans; Lymphatic Metastasis; Male; Prostate-Specific Antigen; Prostatic Neoplasms

•To evaluate the effects of dutasteride on treatment-naïve prostate cancer in men using serial magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) in this pilot study.. •This investigator-initiated prospective single-arm study was approved by the institutional committee on human research ethics board. •The target accrual was 10 patients. Newly diagnosed prostate cancer patients with low risk disease either with symptomatic benign prostatic hypertrophy or deemed to require pre-brachytherapy androgen suppression therapy were eligible. In the latter group, dutasteride was used to achieve cytoreduction. •All patients received 6 months of dutasteride 3.5 mg daily and underwent baseline blood work, health-related quality of life indices and MRI/MRSI, which were repeated at 1, 3 and 6 months. •MRSI spectra were examined and scored as healthy or cancerous. The change in cancerous volumes over time was evaluated.. •Of the 10 patients enrolled, nine patients completed the entire study. One patient withdrew after 3 months because of drug-related toxicity. •Because a significant decrease in citrate and polyamines on MRSI spectra was noted at 1 month compared with baseline, healthy tissue appeared to be more like cancer and thus created a false impression that the cancer had grown after 1 month. To reduce this bias, comparisons were made between the 1-month and 6-month scans. •The median MR cancer volumes at 6 months and 3 months were 100% and 101% of the 1-month value, respectively. Three of the nine patients had a 30-45% decrease in cancer volume at 6 months relative to 1-month measures. Of the others, two had no change in cancer volume and four had an increase (range 65-167% of the 1-month value). •The median cancer volume (range) at baseline was only 0.5 (0.1-5.6) mL.. •The inclusion of only men with low volume disease may have limited our ability to accurately assess response rates after dutasteride due to the background effects on normal prostate metabolism. Despite this, one-third of patients had a 30-45% reduction in cancer volume at 6 months. •Future studies including men with larger volume disease may enable estimates of response rates to be made more accurately.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Aged; Azasteroids; Dutasteride; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Pilot Projects; Prospective Studies; Prostatic Neoplasms; Rectum