External beam Radiation Therapy and Brachytherapy
The addition of EBT to brachytherapy remains a popular method for treating high-risk prostate cancer patients. Some authors have even suggested that all patients undergoing brachytherapy should receive combined therapy. Unfortunately, a review of the current literature does not allow one to generate any firm conclusions on this subject (Table 3). Blasko et. al. have compared their patients treated with combination EBRT and brachytherapy verses brachytherapy monotherapy and identified an improvement in the biochemical freedom form failure for the monotherapy subset as compared to the combined therapy subset (88% versus 79% 8-year PSA-FFR, respectively) 79. The stratification of risk factors in their series predicts for this outcome based on the pretreatment PSA values and Gleason sum for each treatment group.
Further, when these authors stratified their patients into three basic risk categories, no difference in outcome was observed between the treatment groups within each category, respectively. Another study from Ragde et. al. that has been used to assert the need for combined therapy in all patients, presents 12-year crude biochemical control rates of 79% in the combined therapy group as compared to 66% for those treated with monotherapy 5. Although multivariate analysis was not performed in the Ragde study, it appears that the combined therapy patients had higher risk disease as compared with the monotherapy group. This counterintuitive result may be explained on the basis of not achieving a desired dosimetry in the monotherapy group of patients. Potters et al recently updated their results on combined therapy versus monotherapy 14. When multivariate analysis was performed and included the D90 dose as a variable, the addition of EBRT to an implant was not identified as significant. By stratifying the patients in the Potters study based on the established dosimetry cut point, one is able to mimic both the intuitive and counterintuitive results of Blasko et. al. and Ragde et. al., respectively (Table 4), suggesting that implant quality may be a more important factor for predicting outcome than the actual need for combined therapy, even in high risk patients.
Androgen Deprivation and Brachytherapy
Another controversial topic remains the exact role for androgen deprivation therapy as an adjunct treatment to permanent prostate brachytherapy. The classic role for AD remains that of prostate reduction with about a 35% volume reduction expected over 3-4 months. Several studies report the use of LHRH agonist with an anti-androgen to achieve prostate volume reduction before placing the seeds 22, 80, 81. Whittington et. al. demonstrated a median prostate volume decrease of 33% following 3-6 months of AD 82. Stone et. al. and Potters et. al. each found a mean decrease of 35% 22, 83. Patients with glands larger than 40 cc had significantly greater gland reduction than those with smaller glands (41% vs 29%). Blasko et. al. noted similar findings, with a greater reduction seen in patients receiving combination AD than in those receiving an LHRH analogue alone 57.
Prostate volume reduction can serve a number of purposes. A smaller prostate might diminish the risk of encountering pubic arch interference 84. However, other factors such as implant technique may eliminate pubic arch interference without the need to reduce the prostate size. Stone et. al. has shown that 98.5% of patients with prostates > 50 cc achieved planned doses when implanted by the real-time technique 85. Nonetheless, as already noted, a higher incidence of grade 2 urinary morbidity is generally seen in patients with prostate volumes > 35 cc at the time of implant 24 and it is not clear whether such a volume reduction with AD will prevent post-implant urinary morbidity 23.
The potential advantage of AD as an adjunctive therapy to brachytherapy is extrapolated from randomized data from the RTOG data that reported favorable survival advantage when AD was added to external radiation in patients with locally advanced or metastatic disease 86, 87. Controlled clinical trials from the RTOG and EORTC comparing EBRT with or without the addition of AD have demonstrated a benefit in disease-specific survival in patients with locally advanced, bulky tumors 36, 87. Only the trial from the EORTC shows a survival advantage. Thus it appears that patients with locally advanced bulky tumors may benefit from AD if their Gleason sum is 8-10 88-91. However, in clinically confined disease, when using 3-Dimensional conformal radiotherapy or intensity modulated radiotherapy with doses in excess of 72 Gy, the advantage of neoadjuvant AD appears to be negated 92.
There are few studies evaluating biochemical control in patients undergoing brachytherapy combined with AD. Sylvester et. al. 93 failed to show a significant improvement in PSA progression-free survival at 5 years when AD was added to patients receiving EBRT to 45 Gy and an 125I or 103Pd implant. Potters et. al. 22 did a matched-pair analysis on 612 implant patients and did not observe any difference of PSA progression-free survival between patients who received AD and those who did not. In contrast, Lee et. al. found that AD was the most significant predictor of 5-year freedom from biochemical failure in a multivariate analysis of intermediate and high-risk prostate cancer patients 94. Positive post-implant biopsy results were lower in patients treated with AD. No randomized data is available with brachytherapy.
The potential benefits of AD have to be weighed against its toxicity. Impotence, fatigue, hot flashes, breast swelling and tenderness, and decreased libido occur in many patients . Less common effects include anemia, muscle wasting and osteoporosis. These toxicities can continue for a variable period even after stopping the AD, as the return to normal testosterone levels may take as long as 8-14 months following a 3 month depot injection, or longer following long-term administration of AD 95. Alternative androgen depriving approaches using either high dose anti-antiandrogens alone or in combination with finasteride may reduce some of the side effects.