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Management of localized carcinoma of the prostate: Brachytherapy revisited
Clinical Oncology(1997) 9:219-221 © 1997 The Royal College of Radiologists
Clinical Oncology
Review Article Management of Localized Carcinoma of the Prostate: Brachytherapy Revisited D. V. A s h Cookridge Hospital, Leeds, UK
INTRODUCTION Brachytherapy already has a long history of trial and disappointment, starting in the early 1900s with the work of Pastean and Degrais [1], followed by Flocks et al. [2] in the 1950s and the extensive experience of the 1970s and 1980s from the Memorial Hospital, New York, where Hilaris, Whitmore and co-workers [3] implanted over 1000 patients with iodine-125 seeds. Unfortunately, it was very difficult with the early techniques of open operation and manual seed placement to achieve satisfactory seed implantation in the majority of patients. Once prostate specific antigent (PSA) monitoring became available, it was clear that the technique resulted in relatively poor local control rates and appreciable morbidity. As a result, brachytherapy for prostate cancer was largely abandoned. In 1981, Holm and Gammelgaard [4] described the technique of template-guided transrectal ultrasound percutaneous needle placement. This opened up the possibility of achieving satisfactory source placement within the prostate, using a simpler technique than the open operation described from the Memorial Hospital [5]. Unfortunately, early experience reported from Scandinavia using the new technique was unfavourable [6] and it seemed to be yet another false dawn. One of the problems may have been the decision to use a small number of high-activity iodine-125 seeds. This makes the placement of each seed an extremely critical factor, with a high probability of both hot spots and cold spots within the prostate. The team at the North West Tumor Institute, Seattle, adapted Holm's technique, using a large number of lowactivity seeds in order to reduce the critical importance of each seed placement [7]. This technique has proved to be effective and reproducible and has now been applied to several thousand patients in a number of centres [8-12]. Until recently, the diagnosis of early localized prostate cancer was a relatively rare event. Most patients presented with symptoms either from locally advanced disease or from metastases. The ready availability of serum PSA determination, coupled with transrectal ultrasound guided biopsy, has resulted in a huge increase in the diagnosis of early Correspondence and offprint requests to: Dr D. V. Ash, Cookridge Hospital, Leeds LS16 6QB, UK.
prostate cancer, with many cases now being picked up in the fifth and sixth decades of life rather than in the seventh and eighth, as before. The management of early prostate cancer has therefore become a significant public health problem. TREATMENT OPTIONS For the man in whom early localized prostate cancer is diagnosed, a number of treatment options have been proposed. All of these have limitations and it has been difficult to confirm any impact upon life expectancy in the absence of randomized trials against a 'no treatment' arm.
No Treatment/Watch and Wait This may be a very reasonable option for men over 75 years of age with low stage, low grade disease, for whom there is a much higher probability of dying from natural causes than from prostate cancer. For younger men, however, and those with less favourable prognostic factors, there is a high probability that prostate cancer will be a problem during their projected life expectancy. This makes a no treatment option much less acceptable. Not surprisingly, most of these men have refused entry into clinical trials having a no treatment control arm.
Hormone Therapy Hormone therapy, if given long term, will produce impotence in nearly all patients. This, and other side effects, such as hot flushes and gynaecomastia, are not readily accepted by men who have very few symptoms and those who are still sexually active.
Radical Prostatectomy Although the new nerve-sparing techniques have reduced the risk of impotence and incontinence, there are data to suggest that approximately 30% of patients may suffer incontinence and approximately 80% impotence after radical surgery [13,14]. It has also been found that, in spite of preoperative staging
220 investigations to exclude capsular invasion, up to 50% of patients have invasive tumour at the resection margins after radical prostatectomy [15-17]. For those who make an uncomplicated recovery following complete resection of the tumour, surgery is an attractive option, but many patients and many surgeons remain uncertain about whether the risks outweigh the benefits.
Radical External Beam Radiation There is considerable experience in the use of radical external beam radiation for localized prostate cancer. The treatment usually involves daily visits to the radiotherapy department for 6 or 7 weeks and it is usually impossible to avoid irradiation of the rectum and bladder base. Nevertheless, high rates of local control and survival have been reported [18,19]. Unfortunately, when these results are analysed using PSA relapse-free survival as an endpoint, they are often not as good as suggested in earlier reports [20]. There is a reasonable prospect that new techniques of conformal radiation may allow higher doses to be given to smaller volumes, thus improving local control without increasing complication rates. It is unlikely, however, that the dose/volume parameters will ever better those achieved by brachytherapy. The minimum treated volume achievable by conformal radiation is 200-300 cm a, which is four to six times greater than that achieved with brachytherapy for tumours of the same size. The dose by conformal treatment is approximately half that from iodine seed brachytherapy, although it is given in a shorter overall time.
Brachytherapy For patients who have disease confined within the prostate capsule, permanent implantation using iodine-125 seeds provides PSA relapse-free survival rates that appear to be equivalent to those achieved by radical surgery [8-12]. The incidence of incontinence is less than 1% in patients who have not had previous transurethral resection of the prostate and impotence occurs in less than 20% of patients who are treated before the age of 70 years [21-23]. The treatment can be delivered on a day-case basis, or with a single overnight stay. The majority of patients are able to return to work or normal activity within 1 week. The dose to the prostate capsule is usually 160 Gy, but 300 Gy or more may be delivered to more central portions of the gland. There is a more intense and prolonged urethral reaction than that seen with external beam radiation, but this settles completely within 12 months in over 95% of patients. There is minimal bowel or rectal reaction [21-23]. Permanent radioactive seed implants are suitable only for those patients who have disease confined within the capsule. For more advanced disease, temporary implants using iridium-192 can be used, but, because of the difficulty of delivering the whole treatment with temporary implants, they nearly
D.V. Ash always have to be combined with external beam radiation. High local control rates have, however, been reported with these techniques [24].
PROGNOSTIC FACTORS AND ASSESSMENT OF O U T C O M E The most significant prognostic factors in localized prostate cancer are age, stage, Gleason grade and PSA level. The older the patient, the more likely he is to die of causes other than prostate cancer. The higher the stage, Gleason grade and PSA, the more likely he is to develop distant metastases. Patients with T2C or T3 tumours, those with combined Gleason Grade 7 or greater, and those with an initial PSA greater than 20 have a relatively high rate of distant failure however they are treated. Nevertheless, 40%-50% of such patients treated by brachytherapy remain PSA relapse-free at 5 years. They can still be treated with hormones if they do relapse. Survival is a relatively insensitive endpoint by which to assess the success of treatment in prostate cancer. PSA relapse-free survival is much more sensitive. There remains some controversy, however, about what level of PSA should be accepted. Experience gained from the iodine implants at the Memorial Hospital have shown relapse to be extremely uncommon in those patients in whom the PSA has fallen to less than 1 #g/1 [25]. Relapses may still occur in those patients whose PSA falls to below 4/~g/1, which is the generally accepted normal limit. There is, however, no agreement yet on the PSA level to be used to define relapse-free survival or on the most useful time point to use. For those patients treated by radical surgery, the PSA falls within a few weeks. Those treated with permanent iodine seed implantation may, however, take a year or more to reach the PSA nadir. A negative prostate biopsy can be a useful indication of local cure, although it must be accepted that there is a certain risk of sampling error. For those patients treated by radiation, whichever technique is used, it must be recognized that regression rates are slow and there is little point in taking a biopsy less than 18 months after treatment [26]. It is also difficult to justify biopsy in patients in whom the PSA is < 1 #g/l, when there are no other suspicious symptoms or clinical findings.
CONCLUSION Early prostate cancer is being diagnosed with increasing frequency, and in younger and younger men. While there still remains uncertainty about the optimum treatment, randomized controlled clinical trials should be performed in order to resolve the dilemma. Experience has shown, however, that a no treatment control arm is not acceptable to patients who are giving informed consent, and that many will not consent to the risks posed by current surgical techniques. It seems unlikely, therefore, that clinical trials will resolve the problem, certainly not within
Localized Carcinoma of the Prostate: Brachytherapy Revisited
the next 10 years. During this time, many thousands of patients, clinicians and health care purchasers will continue to be faced with deciding what to do, while informed patients will increasingly demand a choice of treatment. There will also be a number of patients for whom surgery or external beam radiation is contraindicated, but for whom brachytherapy is still appropriate. Under the circumstances, the best way forward may be for all those who treat localized prostate cancer, by whatever modality, to agree on how to describe the patients they have treated (or not) and how to analyse outcome by agreed criteria, which should include quality of life assessment. In the meantime, brachytherapy seems to provide a convenient, effective and relatively non-toxic form of treatment, which deserves further evaluation using the new techniques that have been developed over the last few years.
References 1. Pasteau O, Degrais P. De l'emploi du radium dans le traitement des cancers de la prostate. J Urol Med Chir 1913;4:341-66. 2. Flocks RH, Kerr HD, Elkins HB, et al. Treatment of carcinoma of the prostate by interstitial radiation with radioactive gold-198: a preliminary report. J Urol 1952;68:510-22. 3. Whitmore WF, Hilaris BS, Grabstald H. Retropubic implantation of iodine-125 in the treatment of prostatic cancer. J Urol 1972;108:918-20. 4. Holm HH, Gammelgaard J. Ultrasonically guided precise needle placement in the prostate and seminal vesicles. J Urol 1981;125:385-87. 5. Holm HH, Juul N, Pedersen JF. Transperineal 125-iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130:283-6. 6. Iversen P, Bak M, Juul N. Ultrasonically guided 1-125 seed implantation with external radiation in management of localised prostatic carcinoma. Urology 1989;4a:181-6. 7. Blasko JC, Ragde H, Schumacher D. Transperineal percutaneous iodine-125 implantation for prostate carcinoma using transrectal ultrasound and template guidance. Endocnriether Hypertherm Oncol 1987;3:131 8. Priestley JB, Beyer DC. Guided bracytherapy for treatment of confined prostate cancer. Urology 1992;40:127-32. 9. Wallner K, Roy J, Harrison L. Tumour control and morbidity following transperineal iodine-125 implantation for stage T1/ T2 prostatic carcinoma. J Clin Oncol 1996;14:449-53. 10. Kaye KW, Olson DJ, Payne JT. Detailed preliminary analysis
221
11. 12.
13. 14. 15. 16.
17. 18.
19. 20.
21. 22. 23. 24.
25.
26.
of iodine-125 implantation for localised prostate cancer using percutaneous approach. J Urol 1995; 153:1020-5. Wallner K, Roy J, Zelefsky M, et al. Short term freedom from disease progression after iodine-125 prostate implantation. Int J Radiat Oncol Biol Phys 1994;30:405-9. Blasko JC, Wallner K, Grimm PD, et al. Prostate specific antigen based disease control following ultrasound guided iodine-125 implantation for Stage T1/T2 prostatic carcinoma. J Urol 1995;154:1096-9. Fowler FJ, Barry MJ, Lu-Yoa GL, et al, Patient reported complications and follow up treatment after radical prostatectomy. Urology 1993;42:622-9. Pederson KV, Carlsson P, Rahmquist M, et al. Quality of life after radical retropubic prostatectomy for carcinoma of the prostate. Eur Urol 1993;24:7-11. Catalona WJ, Smith DS. Five-year tumour recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837-42. Stein A, deKernion JB, Smith RB, et al. Prostate specific antigen levels after radical prostatectomy in patients with organ confined and locally extensive prostate cancer. J Urol 1992;147:942-6. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy: the John Hopkins experience after 10 years. Urol Clin North Am 1993;20:713-25. Perez CA, Hanks GE, Liebel SA, et al. Localised carcinoma of the prostate (Stages T1B, TIC, T2 and T3): review of management with external beam radiation therapy. Cancer 1993;72:3156-73. Kaplan ID, Cox RS, Bagshaw MA. Prostate specific antigen after external beam radiotherapy for prostate cancer: follow up. J Urol 1993;149:519-22. Stamey TA, Ferrari MK, Schmid H. The value of serial prostate specific antigen determinations 5 years after radiotherapy: steeply increasing values characterise 80% of patients. J Urol 1993;150:1856-9. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasound guided implantation of the prostate: morbidity and complications. Scan J Urol Nephrol 1991; Suppl 137:113-8. Stock RG, Stone NN, Iannuzzi C. Sexual potency following interactive ultrasound guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996;35:267-72. Arterbery VE, Wallner K, Roy J, et al. Short term morbidity from CT planned transperineal iodine-125 prostate implants. Int J Radiat Oncol Biol Phys 1993;25:661-7. Stromberg J, Martinez A, Benson R, et al. Improved local control and survival for surgically staged patients with locally advanced prostate cancer treated with up-front low dose rate iridium-192 prostate implantation and external beam radiation. Int J Radiat Oncol Biol Phys 1994;28:67-75. Zelefksy MJ, Leibel SA, Wallner KE, et al. Significance of normal serum prostate specific antigen in the follow-up period after definitive radiation therapy for prostate cancer. J Clin Oncol 1995;13:459-63. Kuban DA, El-Mahdi AM, Schellhammer PF. The significance of post irradiation prostate biopsy with long term follow up. Int J Radiat Oncol Biol Phys 1992;24:409-14.
Clinical Oncology
Review Article Management of Localized Carcinoma of the Prostate: Brachytherapy Revisited D. V. A s h Cookridge Hospital, Leeds, UK
INTRODUCTION Brachytherapy already has a long history of trial and disappointment, starting in the early 1900s with the work of Pastean and Degrais [1], followed by Flocks et al. [2] in the 1950s and the extensive experience of the 1970s and 1980s from the Memorial Hospital, New York, where Hilaris, Whitmore and co-workers [3] implanted over 1000 patients with iodine-125 seeds. Unfortunately, it was very difficult with the early techniques of open operation and manual seed placement to achieve satisfactory seed implantation in the majority of patients. Once prostate specific antigent (PSA) monitoring became available, it was clear that the technique resulted in relatively poor local control rates and appreciable morbidity. As a result, brachytherapy for prostate cancer was largely abandoned. In 1981, Holm and Gammelgaard [4] described the technique of template-guided transrectal ultrasound percutaneous needle placement. This opened up the possibility of achieving satisfactory source placement within the prostate, using a simpler technique than the open operation described from the Memorial Hospital [5]. Unfortunately, early experience reported from Scandinavia using the new technique was unfavourable [6] and it seemed to be yet another false dawn. One of the problems may have been the decision to use a small number of high-activity iodine-125 seeds. This makes the placement of each seed an extremely critical factor, with a high probability of both hot spots and cold spots within the prostate. The team at the North West Tumor Institute, Seattle, adapted Holm's technique, using a large number of lowactivity seeds in order to reduce the critical importance of each seed placement [7]. This technique has proved to be effective and reproducible and has now been applied to several thousand patients in a number of centres [8-12]. Until recently, the diagnosis of early localized prostate cancer was a relatively rare event. Most patients presented with symptoms either from locally advanced disease or from metastases. The ready availability of serum PSA determination, coupled with transrectal ultrasound guided biopsy, has resulted in a huge increase in the diagnosis of early Correspondence and offprint requests to: Dr D. V. Ash, Cookridge Hospital, Leeds LS16 6QB, UK.
prostate cancer, with many cases now being picked up in the fifth and sixth decades of life rather than in the seventh and eighth, as before. The management of early prostate cancer has therefore become a significant public health problem. TREATMENT OPTIONS For the man in whom early localized prostate cancer is diagnosed, a number of treatment options have been proposed. All of these have limitations and it has been difficult to confirm any impact upon life expectancy in the absence of randomized trials against a 'no treatment' arm.
No Treatment/Watch and Wait This may be a very reasonable option for men over 75 years of age with low stage, low grade disease, for whom there is a much higher probability of dying from natural causes than from prostate cancer. For younger men, however, and those with less favourable prognostic factors, there is a high probability that prostate cancer will be a problem during their projected life expectancy. This makes a no treatment option much less acceptable. Not surprisingly, most of these men have refused entry into clinical trials having a no treatment control arm.
Hormone Therapy Hormone therapy, if given long term, will produce impotence in nearly all patients. This, and other side effects, such as hot flushes and gynaecomastia, are not readily accepted by men who have very few symptoms and those who are still sexually active.
Radical Prostatectomy Although the new nerve-sparing techniques have reduced the risk of impotence and incontinence, there are data to suggest that approximately 30% of patients may suffer incontinence and approximately 80% impotence after radical surgery [13,14]. It has also been found that, in spite of preoperative staging
220 investigations to exclude capsular invasion, up to 50% of patients have invasive tumour at the resection margins after radical prostatectomy [15-17]. For those who make an uncomplicated recovery following complete resection of the tumour, surgery is an attractive option, but many patients and many surgeons remain uncertain about whether the risks outweigh the benefits.
Radical External Beam Radiation There is considerable experience in the use of radical external beam radiation for localized prostate cancer. The treatment usually involves daily visits to the radiotherapy department for 6 or 7 weeks and it is usually impossible to avoid irradiation of the rectum and bladder base. Nevertheless, high rates of local control and survival have been reported [18,19]. Unfortunately, when these results are analysed using PSA relapse-free survival as an endpoint, they are often not as good as suggested in earlier reports [20]. There is a reasonable prospect that new techniques of conformal radiation may allow higher doses to be given to smaller volumes, thus improving local control without increasing complication rates. It is unlikely, however, that the dose/volume parameters will ever better those achieved by brachytherapy. The minimum treated volume achievable by conformal radiation is 200-300 cm a, which is four to six times greater than that achieved with brachytherapy for tumours of the same size. The dose by conformal treatment is approximately half that from iodine seed brachytherapy, although it is given in a shorter overall time.
Brachytherapy For patients who have disease confined within the prostate capsule, permanent implantation using iodine-125 seeds provides PSA relapse-free survival rates that appear to be equivalent to those achieved by radical surgery [8-12]. The incidence of incontinence is less than 1% in patients who have not had previous transurethral resection of the prostate and impotence occurs in less than 20% of patients who are treated before the age of 70 years [21-23]. The treatment can be delivered on a day-case basis, or with a single overnight stay. The majority of patients are able to return to work or normal activity within 1 week. The dose to the prostate capsule is usually 160 Gy, but 300 Gy or more may be delivered to more central portions of the gland. There is a more intense and prolonged urethral reaction than that seen with external beam radiation, but this settles completely within 12 months in over 95% of patients. There is minimal bowel or rectal reaction [21-23]. Permanent radioactive seed implants are suitable only for those patients who have disease confined within the capsule. For more advanced disease, temporary implants using iridium-192 can be used, but, because of the difficulty of delivering the whole treatment with temporary implants, they nearly
D.V. Ash always have to be combined with external beam radiation. High local control rates have, however, been reported with these techniques [24].
PROGNOSTIC FACTORS AND ASSESSMENT OF O U T C O M E The most significant prognostic factors in localized prostate cancer are age, stage, Gleason grade and PSA level. The older the patient, the more likely he is to die of causes other than prostate cancer. The higher the stage, Gleason grade and PSA, the more likely he is to develop distant metastases. Patients with T2C or T3 tumours, those with combined Gleason Grade 7 or greater, and those with an initial PSA greater than 20 have a relatively high rate of distant failure however they are treated. Nevertheless, 40%-50% of such patients treated by brachytherapy remain PSA relapse-free at 5 years. They can still be treated with hormones if they do relapse. Survival is a relatively insensitive endpoint by which to assess the success of treatment in prostate cancer. PSA relapse-free survival is much more sensitive. There remains some controversy, however, about what level of PSA should be accepted. Experience gained from the iodine implants at the Memorial Hospital have shown relapse to be extremely uncommon in those patients in whom the PSA has fallen to less than 1 #g/1 [25]. Relapses may still occur in those patients whose PSA falls to below 4/~g/1, which is the generally accepted normal limit. There is, however, no agreement yet on the PSA level to be used to define relapse-free survival or on the most useful time point to use. For those patients treated by radical surgery, the PSA falls within a few weeks. Those treated with permanent iodine seed implantation may, however, take a year or more to reach the PSA nadir. A negative prostate biopsy can be a useful indication of local cure, although it must be accepted that there is a certain risk of sampling error. For those patients treated by radiation, whichever technique is used, it must be recognized that regression rates are slow and there is little point in taking a biopsy less than 18 months after treatment [26]. It is also difficult to justify biopsy in patients in whom the PSA is < 1 #g/l, when there are no other suspicious symptoms or clinical findings.
CONCLUSION Early prostate cancer is being diagnosed with increasing frequency, and in younger and younger men. While there still remains uncertainty about the optimum treatment, randomized controlled clinical trials should be performed in order to resolve the dilemma. Experience has shown, however, that a no treatment control arm is not acceptable to patients who are giving informed consent, and that many will not consent to the risks posed by current surgical techniques. It seems unlikely, therefore, that clinical trials will resolve the problem, certainly not within
Localized Carcinoma of the Prostate: Brachytherapy Revisited
the next 10 years. During this time, many thousands of patients, clinicians and health care purchasers will continue to be faced with deciding what to do, while informed patients will increasingly demand a choice of treatment. There will also be a number of patients for whom surgery or external beam radiation is contraindicated, but for whom brachytherapy is still appropriate. Under the circumstances, the best way forward may be for all those who treat localized prostate cancer, by whatever modality, to agree on how to describe the patients they have treated (or not) and how to analyse outcome by agreed criteria, which should include quality of life assessment. In the meantime, brachytherapy seems to provide a convenient, effective and relatively non-toxic form of treatment, which deserves further evaluation using the new techniques that have been developed over the last few years.
References 1. Pasteau O, Degrais P. De l'emploi du radium dans le traitement des cancers de la prostate. J Urol Med Chir 1913;4:341-66. 2. Flocks RH, Kerr HD, Elkins HB, et al. Treatment of carcinoma of the prostate by interstitial radiation with radioactive gold-198: a preliminary report. J Urol 1952;68:510-22. 3. Whitmore WF, Hilaris BS, Grabstald H. Retropubic implantation of iodine-125 in the treatment of prostatic cancer. J Urol 1972;108:918-20. 4. Holm HH, Gammelgaard J. Ultrasonically guided precise needle placement in the prostate and seminal vesicles. J Urol 1981;125:385-87. 5. Holm HH, Juul N, Pedersen JF. Transperineal 125-iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130:283-6. 6. Iversen P, Bak M, Juul N. Ultrasonically guided 1-125 seed implantation with external radiation in management of localised prostatic carcinoma. Urology 1989;4a:181-6. 7. Blasko JC, Ragde H, Schumacher D. Transperineal percutaneous iodine-125 implantation for prostate carcinoma using transrectal ultrasound and template guidance. Endocnriether Hypertherm Oncol 1987;3:131 8. Priestley JB, Beyer DC. Guided bracytherapy for treatment of confined prostate cancer. Urology 1992;40:127-32. 9. Wallner K, Roy J, Harrison L. Tumour control and morbidity following transperineal iodine-125 implantation for stage T1/ T2 prostatic carcinoma. J Clin Oncol 1996;14:449-53. 10. Kaye KW, Olson DJ, Payne JT. Detailed preliminary analysis
221
11. 12.
13. 14. 15. 16.
17. 18.
19. 20.
21. 22. 23. 24.
25.
26.
of iodine-125 implantation for localised prostate cancer using percutaneous approach. J Urol 1995; 153:1020-5. Wallner K, Roy J, Zelefsky M, et al. Short term freedom from disease progression after iodine-125 prostate implantation. Int J Radiat Oncol Biol Phys 1994;30:405-9. Blasko JC, Wallner K, Grimm PD, et al. Prostate specific antigen based disease control following ultrasound guided iodine-125 implantation for Stage T1/T2 prostatic carcinoma. J Urol 1995;154:1096-9. Fowler FJ, Barry MJ, Lu-Yoa GL, et al, Patient reported complications and follow up treatment after radical prostatectomy. Urology 1993;42:622-9. Pederson KV, Carlsson P, Rahmquist M, et al. Quality of life after radical retropubic prostatectomy for carcinoma of the prostate. Eur Urol 1993;24:7-11. Catalona WJ, Smith DS. Five-year tumour recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837-42. Stein A, deKernion JB, Smith RB, et al. Prostate specific antigen levels after radical prostatectomy in patients with organ confined and locally extensive prostate cancer. J Urol 1992;147:942-6. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy: the John Hopkins experience after 10 years. Urol Clin North Am 1993;20:713-25. Perez CA, Hanks GE, Liebel SA, et al. Localised carcinoma of the prostate (Stages T1B, TIC, T2 and T3): review of management with external beam radiation therapy. Cancer 1993;72:3156-73. Kaplan ID, Cox RS, Bagshaw MA. Prostate specific antigen after external beam radiotherapy for prostate cancer: follow up. J Urol 1993;149:519-22. Stamey TA, Ferrari MK, Schmid H. The value of serial prostate specific antigen determinations 5 years after radiotherapy: steeply increasing values characterise 80% of patients. J Urol 1993;150:1856-9. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasound guided implantation of the prostate: morbidity and complications. Scan J Urol Nephrol 1991; Suppl 137:113-8. Stock RG, Stone NN, Iannuzzi C. Sexual potency following interactive ultrasound guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996;35:267-72. Arterbery VE, Wallner K, Roy J, et al. Short term morbidity from CT planned transperineal iodine-125 prostate implants. Int J Radiat Oncol Biol Phys 1993;25:661-7. Stromberg J, Martinez A, Benson R, et al. Improved local control and survival for surgically staged patients with locally advanced prostate cancer treated with up-front low dose rate iridium-192 prostate implantation and external beam radiation. Int J Radiat Oncol Biol Phys 1994;28:67-75. Zelefksy MJ, Leibel SA, Wallner KE, et al. Significance of normal serum prostate specific antigen in the follow-up period after definitive radiation therapy for prostate cancer. J Clin Oncol 1995;13:459-63. Kuban DA, El-Mahdi AM, Schellhammer PF. The significance of post irradiation prostate biopsy with long term follow up. Int J Radiat Oncol Biol Phys 1992;24:409-14.