A PSM is well established as an independent predictor for BCR.[20
] Pathologic downstaging and a reduction in positive margins should be associated with reduced BCR and improved disease-specific survival. However, despite the decreased positive margin rate demonstrated in our initial study,[18
] we continue to see no BCR benefit from NHT after a median followup of 8 years.
Our findings are consistent with previous randomized prospective studies that demonstrate a reduction in positive margin rates, but no difference in overall BCR-free survival ().[7
] Soloway et al.
reported no difference in BCR rates between cT2b patients in the RP only and 3-month NHT (leuprolide and flutamide) groups at 5 years followup.[10
] Similarly, at a median followup of almost 7 years, Aus et al.
found no improvement in BCR-free rates in clinically localized prostate cancer patients given 3 months of NHT (triptorelin and cyproterone acetate).[7
] Furthermore, Klotz et al.
showed no BCR benefit in the 3-month NHT (cyproterone acetate) group overall, though improved BCR-free survival was seen in the highest risk PSA group (PSA > 20 ng/mL) on subgroup analyses.[19
Literature review of prospective randomized trials on biochemical recurrence free rates in patients treated with and without 3 months of neoadjuvant hormone therapy before radical prostatectomy
Several limitations and factors may account for the lack of difference in BCR rates despite improved positive margin rates. Approximately 40% of the patients in this study had “low risk” tumors (PSA < 10 ng/mL, biopsy Gleason score ≤6: n=50) with an associated low risk of BCR after RP alone; such patients may derive little benefit from the addition of NHT. Similar to prior studies, this trial was also initially designed to identify differences in pathologic stage and not powered to detect differences in BCR. Thus, the lack of a demonstrable BCR benefit for NHT on long-term followup may be due to insufficient sample size. However, even in a recent meta-analysis combining several studies on 1,129 men, NHT did not improve BCR rates (OR 1.20, 95% CI, 0.95 – 1.52; p = 0.13).[21
Another factor in the failure of 3-month NHT to reduce BCR rates may result from insufficient duration of NHT. In an early pilot study, Gleave et al.
showed that serum PSA does not reach nadir or undetectable levels in most patients during this period. While serum PSA decreased by 84% after 1 month of NHT, significant reductions continued to occur between 3 and 8 months of treatment. PSA decreased to nadir or undetectable levels in 22% of patients after 3 months, 42% at 5 months, and 84% after 8 months of therapy.[1
] In another study of 156 patients treated with 8 months of NHT, Gleave et al.
reported low positive margin (6%) and BCR (12.2%) rates at a mean postoperative followup of 54 months.[22
] These observations suggest that the optimal duration of NHT may be longer than 3 months.[1
In a prospective cohort study of 756 men, Meyer et al.
reported a BCR survival advantage seen in patients treated with NHT > 3 months compared with those treated by RP only or with those who received a similar treatment for ≤3 months.[25
] This benefit of longer NHT became statistically significant after year 3, reached its greatest magnitude in year 4 and was still present 8 years after RP. Concerns with this study’s findings include the lack of randomization and the differences in baseline BCR risk between the RP only and NHT groups.
These data led to the Canadian Urologic Oncology Group P95A study, a prospective randomized trial of 547 men comparing 3 versus 8 months of NHT (leuprolide and flutamide). On preliminary analysis, Gleave et al.
reported significantly lower positive margin rates in the 8-month group compared to the 3-month group (12% versus 23%).[23
] Analyzing BCR outcomes among all patients at 3 years showed no significant difference in outcome between the 2 treatment groups.[26
] However, when stratified by surgical volume, BCR rates in high-volume centers were significantly lower in the 8-month group (16%) compared to the 3-month group (25%). In addition, patients who received surgery at high-volume centers did better than those at low-volume centers regardless of NHT duration. Thus, surgical site proved a strong independent predictor of BCR. Now that we better understand the optimal duration of NHT and patient selection, an ideal trial might include intermediate and high risk patients randomized to no NHT versus 8 months of NHT and stratified by surgeon volume.
Another reason for the lack of apparent difference in BCR rates may be that the reduction in positive margin status is artifactual. The decrease in margin positivity may partially result from an inability to recognize cells and architecture after androgen deprivation, as morphological changes include loss of glandular architecture, cytoplasmic vacuolization, and nuclear pyknosis. Pathologists unaware of these changes may have difficulty in identifying residual disease. In addition, Gleason grading by conventional methods may be misleading and is discouraged.[27
Bazinet et al.
compared routine hematoxylin and eosin staining with cytokeratin immunohistochemistry in 22 whole mount prostatectomy specimens from patients treated with 3 months of NHT.[28
] Hematoxylin and eosin staining compared to cytokeratin immunohistochemistry overestimated organ confinement (46% versus 27%) and underestimated capsular penetration (45% versus 68%) and PSMs (14% versus 23%). Standard histology also identified as tumor-free 2 specimens for which cytokeratin staining later confirmed adenocarcinoma. Thus, morphological tissue changes by NHT may obscure tumor cells and cause underreporting of positive margins. In the current series, the 7-year BCR-free probabilities for those with negative surgical margins were similar by treatment group (84% for no NHT versus 82% for NHT).
Even if improvement in positive margin rates with NHT is real, it may not produce the same effect in contemporary RP series. In the randomized prospective studies that showed a significant difference in positive margin rates, positive margins in the RP only group occurred in 34% to 65% of patients.[12
] These values are high compared with those in contemporary RP series, which report positive margin rates of 9% to 13%.[20
] This marked decrease in positive margin rates in current RP series may greatly reduce any possible BCR benefit of NHT.
If NHT increases prostate cancer cell death or decreases the progression rate, its effects should also be seen on the seminal vesicles and lymph nodes.[30
] However, none of the randomized prospective studies which examined this aspect showed an advantage for NHT with respect to seminal vesicle invasion rate.[11
] Similarly, the rate of lymph node metastases was decreased with NHT in only 1 of the 3 randomized prospective studies reporting this aspect.[12
The cost of NHT is not insignificant, particularly when randomized prospective studies have not shown a clear survival advantage. Scolieri et al.
reported the 3-month cost of a luteinizing hormone-releasing hormone agonist and antiandrogen at $2,131.[30
] Additional costs associated with NHT include additional preoperative office visits and PSA measurements. Another disadvantage to NHT may be increased patient anxiety due to delaying definitive cancer treatment. Patients may also suffer from common adverse effects of androgen deprivation, including decreased libido, impotence, vasomotor symptoms, impairment of cognitive function, and risk of osteoporosis. NHT may also increase operative difficulty by inducing a desmoplastic reaction.[13
] Furthermore, a potential disadvantage is the theoretical continued proliferation of androgen resistant cells.[30
Although our study was not originally powered to detect differences in BCR, 3 months of NHT did not show a benefit in BCR-free probability, local recurrence, and metastasis with 8 years of followup. The side effects and added cost of NHT, patient anxiety from delay of definitive therapy, and theoretical risk of androgen resistant cell proliferation makes its use difficult to justify. A prospective randomized trial of intermediate and high risk patients randomized to 0 versus 8 months of NHT stratified by surgeon volume may shed further light into its utility. Pending evidence of improvement in patient outcomes, NHT before RP appears unjustified outside of clinical trials.