Continuous Finasteride Therapy for Benign Prostate Hypertrophy Upgrades Both Neuroendorcine Differentiation and Aggressive Prostate Cancer

Discussion

Maximal effect of finasteride on prostate volume and prostate-specific antigen value is achieved within a period of 6 to 9 months (4) thus being in accord with clinical standards for BPH therapy (14, 15). Conjointly, the acquisition of NED during Mab (5), expressed as the significant elevation in CgA concentration, was ratified after 9 months of study and respective data were fully documented after 15 months of the therapy taken for an overall period of 3 years (5). Since finasteride treatmet changes androgen environment within the prostate, although differently than Mab, it was decided to mimic the conditions required for finasteride efficiency in intermittendly treated subjects (4, 14, 15) and to hold them sufficiently long for the possible NED expression to take place during continuous therapy (5). Thus, both acquisition data of NED and PC together with the respective GSs in resulting PC patients were identically compared in group A patients as well as in group B BPH patients. Placebo-referred BPH patients served as controls (group C). Data from 125 patients in all groups during the 3-years study are presented in Table I.

Tabulated data (Table I) were discussed here in terms of the acquisition of both PC and CgA-elevation, the distribution of GS 6 and GS>6 in acquired PC throughout studied groups and the relationship of acquired PC in patients with elevated versus patients with normal CgA concentration in all three groups. Finally, the above data were compared with the PCPT results (11).

Total PC prevalance in group A is 22% lower in comparison to controls (Table I). This result is roughly in harmony with the one published by the PCPT group (25%) (11). Thus, the 3 year-study period is seemingly a long enough interval for making the right conclusions especially in terms of their resemblance with PCPT group data. Intermittent therapy (group B) yielded an even lower cancer incidence (37%) compared to controls. This result might be potentially important and should be controled by a comprehensive and multicentric study. Overall incidence of PC GS>6 is highest in continuously treated patients (44.5%) and lowest in controls (18.2%) (p<0.01) thus also resembling PCPT data (11) rather closely.

The acquired NED is markedly higher in group A (13.6%) than in groups B and C (5.6% and 6.4%, respectively) indicating continuous finasteride therapy as a possible if not a critical reason for an increase in NED compared to discontinuous treatment.

In patients with the raise in CgA concentration the percentage of acquired PC was smallest in group A (35.3%) and rather higher in groups B and C (71.4% and 63.5%, respectively). However, the PC GS> distribution among these patients was highest in group A (50%) and significantly lower in the two other groups (20% and 25%, respectively). Thus the capacity of NED provoked by a continuous finasteride therapy seems to be responsible for a decrease in PC prevalance and possibly, due to higher incidence in serum CgA elevation, for the promotion of aggressive PC.

To understand more closely the interrelationship between the two modes of therapy and untreated patients the acquired PC and the distribution of respective GS in patients with the retained normal CgA level should be analyzed.

The PC incidence in patients with retained normal CgA level differs insignificantly in groups A and B (3/108, 2.8% and 3/118, 2.5%, respectively) but is much higher in controls (6/112, 5.1%). Identical number of PC GS>6 patients was acquired in all three studied groups (Table I). A slightly lower percent in respective controls came from a larger number of patients entered in this subgroup (Table I). Expectedly, free of NED capacity sporadic PC showed no preferences towards tumor aggressiveness expressed as GS >6. However, the reduced intracellular DHT level in treated patients with normal CgA level remained the only determinant for downgrading PC incidence compared to the controls (Table I).

Overall, the acquired NED, detected as a raise in CgA, is responsible for the recorded higher GS in finasteride treated patients relative to the controls. In continuously treated patients NED is more advanced than it is in patients referred to a discontinuous treatment and thus in the former PC patients GS>6 are a more abundant category. This same phenomenon might also be responsible for the higher percent of PC GS>6 in PCPT study although it has not been recognized there. However, differences in PC prevalance between untreated and finasteride treated patients arise not from the acquired NED but might be a consequence of finasteride-induced reduction in DHT that downregulates PC promotion. Data in Table I seem to favor such a view since PC incidence in untreated controls with elevated CgA is 1.77-fold higher than in continuously treated subjects and slightly lower (0.87-fold) compared to respective patients referred to intermittent therapy. These results might be additional proofs in favor of discountinuous androgen deprivation in all hormone-therapy protocols including chemoprevention.

Parallel to the work on the link between positive margins after radical prostatectomy (RP) and the recorded NED data (16) other studies have found positive association of time to progression and NED positivity versus Gleason's score, extracapsular extension, seminal vesicle invasion, surgical margin infiltration and tumor volume in prostate cancer patients following radical prostatectomy. All these data clearly indicate the effects of NED even in very early stages of the natural history of PC activating a dramatic increase in the biological potential of the disease (6, 17, 18). The large body of evidence implies NED not only as a paracrine stimulus for the propagation of local carcinoma cells and their possible dedifferentiation (6, 7) but in later stages represents a keystone of PC progression toward an androgen-independent state (7). There is also a great deal of evidence on neuropeptides conferring antiapoptotic capabilities on adenocarcinoma cells thus influencing their survival and further proliferation (17, 18). Consequently, NED makes inoperative a critical intracellular defence mechanism against a tumorigenic growth (18). All these events may contribute to the aggressive clinical course of PC having neuroendocrine elements (7, 17, 18).

Recently, an ascertainment bias has been proposed to account for an increase in high grade PC found at the end of PCPT finasteride treatment for chemoprevention. The higher sensitivity for PSA of higher GS disease should make more likely the detection of a high-grade disease respecting the true result of such cases (19). This assumption was statistically confirmed by logistic regression due to effects of finasteride on prostatic volume. However, reports neglecting the NED factor (11, 19) can hardly endure the challenge of data indicating NED-provided PC as highly resistant to apoptosis (20), the fact that breakes free an avenue for a PC hormonal refractoriness.

In addition, statistical analysis (19) can hardly explain differences in CgA data in conjunction with GS PC recordings during continuous and intermittend finasteride treatment (Table I) since both treatments put forth identical effects on both prostatic volume and PSA concentration. The NED data offer an ample correlation with high-grade GS recordings that are for real and not only statistical. Indeed, current chemoprevention protocols as well as those for BPH therapy need to be carefully reconsidered prior to choosing between continuous and intermittent finasteride treatment. Other authors express the same attitude (20).

In addition, already ongoing studies (21) examine both type 1 and 2 5alpha reductase inhibitors (finasteride and dutasteride) in several scenarios (general population studies, subjects with elevated PSA and a negative biopsy). It would be interesting to challenge the results of these studies on NED versus GS data.