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High dose rate brachytherapy boost treatment in radical radiotherapy for prostate cancer
Radiotherapy and Oncology 57 (2000) 285±288
www.elsevier.com/locate/radonline
High dose rate brachytherapy boost treatment in radical radiotherapy for prostate cancer Peter J. Hoskin Mount Vernon Centre for Cancer Treatment, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK Received 10 February 2000; accepted 20 July 2000
Abstract The natural history of prostate cancer is for early invasion of the prostatic capsule and seminal vesicles. This will be present in the majority of patients presenting with a prostate speci®c antigen (PSA) .10 or Gleason score .7. In these patients a combination of external beam treatment to provide a regional dose of radiation followed by a high dose rate afterloading brachytherapy boost to enable conformal dose escalation within the prostate gland presents an attractive option in local treatment. Accurate placement of catheters is now possible using transrectal ultrasound to provide high quality implants. A number of centres have now developed this technique as a routine clinical tool. There remains variation in the optimal dose fractionation with a range of BED10 values from 100 to 77 and BED3 values from 246.6 to 122.5. This does not, however, take into account geometric variations in dose distribution exploiting the physical advantage of BT in achieving a rapid dose fall off close to critical structures such as the rectum. Early results show PSA response levels of around 90% with grade III toxicity in 5±9% of patients. Critical evaluation of this technique in prospective, randomized trials is required. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: High dose rate brachytherapy; Prostate cancer; Radiotherapy
1. Introduction The main advantage of brachytherapy (BT) over external beam treatment is its ability to deliver a high dose of radiation within a well-de®ned volume, but with a rapid fall-off of dose outside the implanted area. This approach is ideal for the treatment of prostate cancer where the target organ lies very close to critical normal tissues, in particular the anterior rectal wall and bladder base. Modern techniques using transrectal ultrasound-guided insertion of applicators in conjunction with high dose rate (HDR) afterloading enables BT to be delivered accurately and safely to the prostate gland. The general principle of combining external beam treatment and BT as a means of delivering a radical dose of radiation is well established in other sites. In gynaecological [5] and head and neck cancers [9] superior results have been reported in patients who had BT as a component of their treatment compared with those who received external beam treatment alone. As a means of concentrating a high radiation dose within a de®ned volume, BT is superior to external beam treatment, even using sophisticated conformal techniques. A localized accessible tumour with a known clinical dose response [6], particularly for the more bulky tumours, is therefore an ideal candidate for BT.
However, the advantage of accurate localized dose observed with BT is also a potential disadvantage for patients who may have microscopic spread outside the implantation volume. External beam treatment can encompass a safety margin outside the prostate gland and include seminal vesicles to provide treatment to potential areas of microscopic spread. One of the main predictors of extracapsular and seminal vesical involvement is T stage, but it is these very patients with bulky local disease who are most likely to bene®t from the dose escalation achieved with BT. Combination therapy, therefore, allows a dose adequate for control of microscopic disease to be delivered with external beam treatment, followed by a boost using HDR afterloading to the site of macroscopic disease within the prostate. The probability of spread outside the gland can be predicted with some accuracy using the Partin tables [11], which are based on histological examination of a large number of prostatectomy specimens. Using a combination of T stage, prostate speci®c antigen (PSA) level and Gleason score, estimates of capsular penetration and seminal vesicle invasion can be obtained. These reveal that even early tumours with low Gleason scores and a PSA .10 ng/ml, or with a Gleason score .7, regardless of T stage or PSA level, have a high probability (.50%) of microscopic regional spread. It would seem from this data that only
0167-8140/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0167-814 0(00)00290-5
286
P.J. Hoskin / Radiotherapy and Oncology 57 (2000) 285±288
patients with T1b or T2a tumours with a Gleason score of ,6 and PSA of ,10 ng/ml have an 80% or greater probability of truly localized disease. For these patients BT alone may be optimal, exploiting the biological advantages of low dose rate BT using I-125 seed implantation. Patients with localized disease who fall outside these criteria may be best served by including an external beam component to enable full coverage of locoregional disease. On this basis a programme of combined external beam radiotherapy and BT has been developed at Mount Vernon Hospital and is now being evaluated in a prospective, randomized, controlled trial. 2. HDR afterloading BT boost treatment is nothing new. Twenty years ago individual centres were electing to include a BT boost using iridium wire, I-125 seeds and, before this, radon seeds [3]. Two recent developments, however, have resulted in a renaissance for prostate implantation in this setting. First, the development of transrectal ultrasound coupled with a perineal template enabled accurate source placement, a major criticism of earlier techniques being the need for direct placement transperineally or retropubically using only ¯uoroscopic guidance. Second, the development of HDR afterloading provides the advantage of small, highactivity iridium sources, ¯exible catheters and short treatment times. The use of HDR afterloading does not carry the same biological advantages of low dose rate treatment seen with iodine seed I-125 implants. The dose rate of a modern iridium afterloading machine, at about 1 Gy/min, is similar to that of a linear accelerator. Radical radiotherapy doses can only be delivered safely using multiple small fraction sizes to achieve biological sparing of normal tissues. Alternatively, a hypofractionated schedule employing large fraction sizes with a lower total dose to remain within normal tissue tolerance can also be used. For these biological reasons HDR afterloading has been considered less than ideal for the sole treatment of prostate cancer. The current role of HDR afterloading is as a boost treatment in conjunction with external beam treatment. However, recent clinical data has challenged the fraction sensitivity of prostate cancer and suggested that prostate cancer cells may have a low a:b ratio of around 1.5 [2]. This signi®cantly reduces any therapeutic advantage based on fraction size as the a:b ratio is similar to that of late responding tissues. Indeed, the a:b ratio for the anterior rectal wall has been shown to be around 3 [10]. This suggests that fractionation designed to achieve an acceptable level of rectal morbidity would, in fact, spare prostate cancer cells. Brenner and Hall [2] proposed that large fraction sizes, such as those employed in HDR afterloading (.2 Gy), may be more bene®cial by exploiting a differential in acute toxicity between this approach and conventional 2 Gy
fractions. This sparing is ampli®ed when the reduced volume of rectal tissue achieved in BT is included as a factor. Thus, HDR-BT using large fraction sizes of 5±10 Gy may have both physical and biological advantages over standard fractionated external beam radiotherapy. 3. Method The protocol at Mount Vernon Hospital delivers the HDR afterloading BT boost within 1 week of completion of external beam treatment. Patients undergo a transrectal ultrasound volume study in the lithotomy position and under general anaesthetic. The prostate template is aligned to ensure that the urethra is positioned midway between the rows of applicator settings and that the baseplane runs along the required inferior border of the implanted volume. An indwelling catheter allows demarcation of the bladder base and urethra on ultrasound. Standard 2 mm diameter HDR afterloading ¯exible applicator tubes are inserted transperineally using the prostate ultrasound template. With a combination of transverse and sagittal views the applicators can be placed accurately using a 1 cm square grid within the prostate volume. A ¯exible template is used against the perineal skin ®xed with adhesive and containing rubber O rings, which hold the ¯exible afterloading catheters in position. At completion of the implant procedure the rigid template is removed and the applicator ends are capped to protect the afterloading channel. The applicator positions are checked by measurement from the rubber O ring, enabling their position to be veri®ed before each treatment exposure. Following recovery from anaesthetic, 5 mm transverse CT images are taken through the implant volume, and the target volume is de®ned on each scan. Dwell positions and times are then calculated along the length of each applicator to ensure a homogeneous dose within the target volume, aiming for a cold spot around the urethra. Manchesterbased dosimetry is used, using dwell times in place of mg/h of radium [7] and differential loading between the periphery and core of the volume according to Manchester rules. These may then be adjusted manually for optimization. Treatment is given on the day of implant, with a further two fractions given the following day. Following the second fraction, the applicator tubes are removed manually without the need for additional anaesthetic and the ¯exible template is also removed. Typically, the patient will return home the same day. 4. Dose prescription The technique of external beam and BT boost for radical prostate treatment is not unique and has been adopted in a number of centres across Europe and the US. The dose prescription used at Mount Vernon Hospital delivers a dose of 35.7 Gy in 13 fractions, treating daily, Monday to
P.J. Hoskin / Radiotherapy and Oncology 57 (2000) 285±288 Table 1 Comparison of BED equivalents for the Mount Vernon schedules BED10
BED3
287
Table 3 Dose fractionation schedules reported at different centres a BED1.5
External beam alone 55 Gy in 20 fractions
70.1
105.4
155.8
External beam and HDR 35.7 Gy in 13 fractions HDR 17 Gy in two fractions HDR 10 Gy in two fractions
45.5 31.5 15.0
68.4 65.2 26.7
101.1 113.3 43.3
Friday, followed by 17 Gy in two fractions with HDR afterloading BT. This is based on our standard external beam radical treatment dose of 55 Gy in 20 daily fractions. The use of isoeffect formulae in this setting is controversial but provides a basis for comparing schedules. It is recognized that this may be, at best, an estimate and it does not take into account repair, proliferation and volume effects, which may be of considerable importance in de®ning the total radiobiological impact of a radiation schedule. A comparison of the BED equivalents for the Mount Vernon schedule is shown in Table 1. The nominal dose to the rectum and urethra expected from 8.5 Gy to the tumour isodose is 5 and 10.5 Gy, respectively. This prescription, therefore, was designed to achieve a 10% dose escalation to the tumour volume with a 10% reduction in rectal dose. A number of different dose fractionation schedules have emerged from different centres (Table 2). Reported data is still relatively immature but a comparison of the published reports from Michigan [12], Kiel [8] and Berlin [4] suggest that each of the schedules is effective, with acceptable morbidity rates, which are comparable with those observed with external beam treatment (Table 2). However, these series contained signi®cant numbers of patients with T3 tumours and with high PSA levels of .20 ng/ml. Comparison of the BED10 and BED1.5 estimate for the different schedules is shown in Table 3, including the data from Gothenberg [1] for which clinical outcome data are not yet available, using a simple summation of the external beam and BT components. This demonstrates the considerable variability and the dif®culty which emerges when comparing ef®cacy data from different centres. Comparison of the BED is more dif®cult when considering late toxicity, as each centre may employ different criteria for dose distri-
Kiel Berlin Gothenberg Michigan Mount Vernon
BED10
BED1.5
BED3
BED3 60%
130 87.3 100 83.1 77
446.7 225 270 193.3 214.4
263.3 144 170 122.5 133.6
191.3 115.2 135.3 103.3 107.5
a For comparison 64 Gy in 32 fractions gives values of BED10 76.8, BED3 106.7, BED1.5 149.3.
bution within the treated volume, and limitations on dose and volume to the rectum will vary between individual impants. However, Table 3 shows the BED3 values for the full tumour dose and the 60% tumour dose, which is probably a realistic estimate of the target rectal dose in most circumstances.
5. Conclusion There is a strong and sound rationale for the use of combined external beam radiotherapy and BT schedules in the radical treatment of carcinoma of the prostate for all tumours of stage T1b or above which are localized on staging investigations but have a Gleason score of .6 or PSA . 10 ng/ml. These parameters carry a signi®cant risk of extracapsular or seminal vesicle invasion, for which an external beam component is required to cover regional microscopic spread. Techniques are now well established in a number of European and US centres, but consensus on dose fractionation is lacking, with potentially signi®cant variations in both external beam and HDR fractionation. Formal comparison with state of the art external beam treatment is urgently required. A retrospective analysis of successive cohorts of patients treated between 1987 and 1991 with external beam alone and between 1991 and 1995 with a combined schedule [13] suggests that the combined therapy is superior with 3-year actuarial biochemical control rates of 86.5% compared with 53% with external beam alone in an apparently well matched population. Proponents of external beam treatment, however, will correctly point out the shortcomings of such historical controls particularly using external beam techniques of the 1980s compared with current high
Table 2 Comparison of results BED10
Kiel Berlin Michigan a
130 87.3 83.1
79.5% negative biopsy at 2 years.
BED1.5
446.7 225 193.3
Patient numbers
PSA response (%)
T2
T3
Level de®ning response
26 21 112
7 61 59
88 (,1) 53 (,1) a 91 (,4)
Grade 3 toxicity (%)
9 7 5
288
P.J. Hoskin / Radiotherapy and Oncology 57 (2000) 285±288
dose conformal techniques. There is an urgent need for randomized controlled trials to compare this approach with external beam treatment alone before widespread adoption of HDR boost BT can be fully justi®ed.
[7] [8]
References [1] Borghede G, Hedelin H, Holmang S, et al. Irradiation of localized prostatic carcinoma with a combination of high dose rate iridium-192 brachytherapy and external beam radiotherapy with three target de®nitions and dose levels inside the prostate gland. Radiother Oncol 1997;44:245±250. [2] Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095± 1101. [3] Crawford ED, Johnson EL. Transperineal percutaneous iridium-192 implant of the prostate. Int J Radiat Oncol Biol Phys 1983;9:1391± 1395. [4] Dinges S, Deger S, Koswig S, et al. High-dose rate interstitial with external beam irradiation for localized prostate cancer: results of a prospective trial. Radiother Oncol 1998;48:197±202. [5] Hanks GE, Kerring DF, Kramer S. Patterns of care outcome studies: results of the national practice in cancer of the cervix. Cancer 1983;51:959±967. [6] Hanks GE, Leibel SA, Krall JM, et al. Patterns of care studies: dose-
[9] [10]
[11] [12]
[13]
response observations for local control of adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1985;11:153±157. Hoskin PJ, Rembowska A. Dosimetry rules for brachytherapy using high dose rate remote afterloading implants. Clin Oncol 1998;10:226± 230. Kovacs G, Wirth B, Bertermann H, et al. Prostate preservation by combined external beam and HDR brachytherapy at nodal negative prostate cancer patients: an intermediate analysis after ten years experience. Int J Radiat Oncol Biol Phys 1996;36(S80):198. Lusinchi A, Eskandari J, Son Y, et al. External irradiation plus curietherapy boost in 108 base of tongue carcinomas. Int J Radiat Oncol Biol Phys 1989;17:1191±1197. MacKay RI, Hendry JH, Moore CJ, et al. Predicting late rectal complications following prostate conformal radiotherapy using biologically effective doses and normalized dose-surface histograms. Br J Radiol 1997;70:517±526. Partin AW, Subong ENP, Walsh PC, et al. Clinical stage and Gleason score to predict pathological stage of localized prostate cancer. J Am Med Assoc 1997;277:1445±1451. Stromberg J, Martinez A, Gonzalez J, et al. Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a Phase I/II clinical trial. Int J Radiat Oncol Biol Phys 1995;33:161±171. Stromberg JS, Martinez AA, Horwitz EM, et al. Conformal high dose rate iridium-192 boost brachtherapy in locally advanced prostate cancer: superior prostate-speci®c antigen response compared with external beam treatment. Cancer J Sci Am 1997;3:346±352.
www.elsevier.com/locate/radonline
High dose rate brachytherapy boost treatment in radical radiotherapy for prostate cancer Peter J. Hoskin Mount Vernon Centre for Cancer Treatment, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK Received 10 February 2000; accepted 20 July 2000
Abstract The natural history of prostate cancer is for early invasion of the prostatic capsule and seminal vesicles. This will be present in the majority of patients presenting with a prostate speci®c antigen (PSA) .10 or Gleason score .7. In these patients a combination of external beam treatment to provide a regional dose of radiation followed by a high dose rate afterloading brachytherapy boost to enable conformal dose escalation within the prostate gland presents an attractive option in local treatment. Accurate placement of catheters is now possible using transrectal ultrasound to provide high quality implants. A number of centres have now developed this technique as a routine clinical tool. There remains variation in the optimal dose fractionation with a range of BED10 values from 100 to 77 and BED3 values from 246.6 to 122.5. This does not, however, take into account geometric variations in dose distribution exploiting the physical advantage of BT in achieving a rapid dose fall off close to critical structures such as the rectum. Early results show PSA response levels of around 90% with grade III toxicity in 5±9% of patients. Critical evaluation of this technique in prospective, randomized trials is required. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: High dose rate brachytherapy; Prostate cancer; Radiotherapy
1. Introduction The main advantage of brachytherapy (BT) over external beam treatment is its ability to deliver a high dose of radiation within a well-de®ned volume, but with a rapid fall-off of dose outside the implanted area. This approach is ideal for the treatment of prostate cancer where the target organ lies very close to critical normal tissues, in particular the anterior rectal wall and bladder base. Modern techniques using transrectal ultrasound-guided insertion of applicators in conjunction with high dose rate (HDR) afterloading enables BT to be delivered accurately and safely to the prostate gland. The general principle of combining external beam treatment and BT as a means of delivering a radical dose of radiation is well established in other sites. In gynaecological [5] and head and neck cancers [9] superior results have been reported in patients who had BT as a component of their treatment compared with those who received external beam treatment alone. As a means of concentrating a high radiation dose within a de®ned volume, BT is superior to external beam treatment, even using sophisticated conformal techniques. A localized accessible tumour with a known clinical dose response [6], particularly for the more bulky tumours, is therefore an ideal candidate for BT.
However, the advantage of accurate localized dose observed with BT is also a potential disadvantage for patients who may have microscopic spread outside the implantation volume. External beam treatment can encompass a safety margin outside the prostate gland and include seminal vesicles to provide treatment to potential areas of microscopic spread. One of the main predictors of extracapsular and seminal vesical involvement is T stage, but it is these very patients with bulky local disease who are most likely to bene®t from the dose escalation achieved with BT. Combination therapy, therefore, allows a dose adequate for control of microscopic disease to be delivered with external beam treatment, followed by a boost using HDR afterloading to the site of macroscopic disease within the prostate. The probability of spread outside the gland can be predicted with some accuracy using the Partin tables [11], which are based on histological examination of a large number of prostatectomy specimens. Using a combination of T stage, prostate speci®c antigen (PSA) level and Gleason score, estimates of capsular penetration and seminal vesicle invasion can be obtained. These reveal that even early tumours with low Gleason scores and a PSA .10 ng/ml, or with a Gleason score .7, regardless of T stage or PSA level, have a high probability (.50%) of microscopic regional spread. It would seem from this data that only
0167-8140/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0167-814 0(00)00290-5
286
P.J. Hoskin / Radiotherapy and Oncology 57 (2000) 285±288
patients with T1b or T2a tumours with a Gleason score of ,6 and PSA of ,10 ng/ml have an 80% or greater probability of truly localized disease. For these patients BT alone may be optimal, exploiting the biological advantages of low dose rate BT using I-125 seed implantation. Patients with localized disease who fall outside these criteria may be best served by including an external beam component to enable full coverage of locoregional disease. On this basis a programme of combined external beam radiotherapy and BT has been developed at Mount Vernon Hospital and is now being evaluated in a prospective, randomized, controlled trial. 2. HDR afterloading BT boost treatment is nothing new. Twenty years ago individual centres were electing to include a BT boost using iridium wire, I-125 seeds and, before this, radon seeds [3]. Two recent developments, however, have resulted in a renaissance for prostate implantation in this setting. First, the development of transrectal ultrasound coupled with a perineal template enabled accurate source placement, a major criticism of earlier techniques being the need for direct placement transperineally or retropubically using only ¯uoroscopic guidance. Second, the development of HDR afterloading provides the advantage of small, highactivity iridium sources, ¯exible catheters and short treatment times. The use of HDR afterloading does not carry the same biological advantages of low dose rate treatment seen with iodine seed I-125 implants. The dose rate of a modern iridium afterloading machine, at about 1 Gy/min, is similar to that of a linear accelerator. Radical radiotherapy doses can only be delivered safely using multiple small fraction sizes to achieve biological sparing of normal tissues. Alternatively, a hypofractionated schedule employing large fraction sizes with a lower total dose to remain within normal tissue tolerance can also be used. For these biological reasons HDR afterloading has been considered less than ideal for the sole treatment of prostate cancer. The current role of HDR afterloading is as a boost treatment in conjunction with external beam treatment. However, recent clinical data has challenged the fraction sensitivity of prostate cancer and suggested that prostate cancer cells may have a low a:b ratio of around 1.5 [2]. This signi®cantly reduces any therapeutic advantage based on fraction size as the a:b ratio is similar to that of late responding tissues. Indeed, the a:b ratio for the anterior rectal wall has been shown to be around 3 [10]. This suggests that fractionation designed to achieve an acceptable level of rectal morbidity would, in fact, spare prostate cancer cells. Brenner and Hall [2] proposed that large fraction sizes, such as those employed in HDR afterloading (.2 Gy), may be more bene®cial by exploiting a differential in acute toxicity between this approach and conventional 2 Gy
fractions. This sparing is ampli®ed when the reduced volume of rectal tissue achieved in BT is included as a factor. Thus, HDR-BT using large fraction sizes of 5±10 Gy may have both physical and biological advantages over standard fractionated external beam radiotherapy. 3. Method The protocol at Mount Vernon Hospital delivers the HDR afterloading BT boost within 1 week of completion of external beam treatment. Patients undergo a transrectal ultrasound volume study in the lithotomy position and under general anaesthetic. The prostate template is aligned to ensure that the urethra is positioned midway between the rows of applicator settings and that the baseplane runs along the required inferior border of the implanted volume. An indwelling catheter allows demarcation of the bladder base and urethra on ultrasound. Standard 2 mm diameter HDR afterloading ¯exible applicator tubes are inserted transperineally using the prostate ultrasound template. With a combination of transverse and sagittal views the applicators can be placed accurately using a 1 cm square grid within the prostate volume. A ¯exible template is used against the perineal skin ®xed with adhesive and containing rubber O rings, which hold the ¯exible afterloading catheters in position. At completion of the implant procedure the rigid template is removed and the applicator ends are capped to protect the afterloading channel. The applicator positions are checked by measurement from the rubber O ring, enabling their position to be veri®ed before each treatment exposure. Following recovery from anaesthetic, 5 mm transverse CT images are taken through the implant volume, and the target volume is de®ned on each scan. Dwell positions and times are then calculated along the length of each applicator to ensure a homogeneous dose within the target volume, aiming for a cold spot around the urethra. Manchesterbased dosimetry is used, using dwell times in place of mg/h of radium [7] and differential loading between the periphery and core of the volume according to Manchester rules. These may then be adjusted manually for optimization. Treatment is given on the day of implant, with a further two fractions given the following day. Following the second fraction, the applicator tubes are removed manually without the need for additional anaesthetic and the ¯exible template is also removed. Typically, the patient will return home the same day. 4. Dose prescription The technique of external beam and BT boost for radical prostate treatment is not unique and has been adopted in a number of centres across Europe and the US. The dose prescription used at Mount Vernon Hospital delivers a dose of 35.7 Gy in 13 fractions, treating daily, Monday to
P.J. Hoskin / Radiotherapy and Oncology 57 (2000) 285±288 Table 1 Comparison of BED equivalents for the Mount Vernon schedules BED10
BED3
287
Table 3 Dose fractionation schedules reported at different centres a BED1.5
External beam alone 55 Gy in 20 fractions
70.1
105.4
155.8
External beam and HDR 35.7 Gy in 13 fractions HDR 17 Gy in two fractions HDR 10 Gy in two fractions
45.5 31.5 15.0
68.4 65.2 26.7
101.1 113.3 43.3
Friday, followed by 17 Gy in two fractions with HDR afterloading BT. This is based on our standard external beam radical treatment dose of 55 Gy in 20 daily fractions. The use of isoeffect formulae in this setting is controversial but provides a basis for comparing schedules. It is recognized that this may be, at best, an estimate and it does not take into account repair, proliferation and volume effects, which may be of considerable importance in de®ning the total radiobiological impact of a radiation schedule. A comparison of the BED equivalents for the Mount Vernon schedule is shown in Table 1. The nominal dose to the rectum and urethra expected from 8.5 Gy to the tumour isodose is 5 and 10.5 Gy, respectively. This prescription, therefore, was designed to achieve a 10% dose escalation to the tumour volume with a 10% reduction in rectal dose. A number of different dose fractionation schedules have emerged from different centres (Table 2). Reported data is still relatively immature but a comparison of the published reports from Michigan [12], Kiel [8] and Berlin [4] suggest that each of the schedules is effective, with acceptable morbidity rates, which are comparable with those observed with external beam treatment (Table 2). However, these series contained signi®cant numbers of patients with T3 tumours and with high PSA levels of .20 ng/ml. Comparison of the BED10 and BED1.5 estimate for the different schedules is shown in Table 3, including the data from Gothenberg [1] for which clinical outcome data are not yet available, using a simple summation of the external beam and BT components. This demonstrates the considerable variability and the dif®culty which emerges when comparing ef®cacy data from different centres. Comparison of the BED is more dif®cult when considering late toxicity, as each centre may employ different criteria for dose distri-
Kiel Berlin Gothenberg Michigan Mount Vernon
BED10
BED1.5
BED3
BED3 60%
130 87.3 100 83.1 77
446.7 225 270 193.3 214.4
263.3 144 170 122.5 133.6
191.3 115.2 135.3 103.3 107.5
a For comparison 64 Gy in 32 fractions gives values of BED10 76.8, BED3 106.7, BED1.5 149.3.
bution within the treated volume, and limitations on dose and volume to the rectum will vary between individual impants. However, Table 3 shows the BED3 values for the full tumour dose and the 60% tumour dose, which is probably a realistic estimate of the target rectal dose in most circumstances.
5. Conclusion There is a strong and sound rationale for the use of combined external beam radiotherapy and BT schedules in the radical treatment of carcinoma of the prostate for all tumours of stage T1b or above which are localized on staging investigations but have a Gleason score of .6 or PSA . 10 ng/ml. These parameters carry a signi®cant risk of extracapsular or seminal vesicle invasion, for which an external beam component is required to cover regional microscopic spread. Techniques are now well established in a number of European and US centres, but consensus on dose fractionation is lacking, with potentially signi®cant variations in both external beam and HDR fractionation. Formal comparison with state of the art external beam treatment is urgently required. A retrospective analysis of successive cohorts of patients treated between 1987 and 1991 with external beam alone and between 1991 and 1995 with a combined schedule [13] suggests that the combined therapy is superior with 3-year actuarial biochemical control rates of 86.5% compared with 53% with external beam alone in an apparently well matched population. Proponents of external beam treatment, however, will correctly point out the shortcomings of such historical controls particularly using external beam techniques of the 1980s compared with current high
Table 2 Comparison of results BED10
Kiel Berlin Michigan a
130 87.3 83.1
79.5% negative biopsy at 2 years.
BED1.5
446.7 225 193.3
Patient numbers
PSA response (%)
T2
T3
Level de®ning response
26 21 112
7 61 59
88 (,1) 53 (,1) a 91 (,4)
Grade 3 toxicity (%)
9 7 5
288
P.J. Hoskin / Radiotherapy and Oncology 57 (2000) 285±288
dose conformal techniques. There is an urgent need for randomized controlled trials to compare this approach with external beam treatment alone before widespread adoption of HDR boost BT can be fully justi®ed.
[7] [8]
References [1] Borghede G, Hedelin H, Holmang S, et al. Irradiation of localized prostatic carcinoma with a combination of high dose rate iridium-192 brachytherapy and external beam radiotherapy with three target de®nitions and dose levels inside the prostate gland. Radiother Oncol 1997;44:245±250. [2] Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43:1095± 1101. [3] Crawford ED, Johnson EL. Transperineal percutaneous iridium-192 implant of the prostate. Int J Radiat Oncol Biol Phys 1983;9:1391± 1395. [4] Dinges S, Deger S, Koswig S, et al. High-dose rate interstitial with external beam irradiation for localized prostate cancer: results of a prospective trial. Radiother Oncol 1998;48:197±202. [5] Hanks GE, Kerring DF, Kramer S. Patterns of care outcome studies: results of the national practice in cancer of the cervix. Cancer 1983;51:959±967. [6] Hanks GE, Leibel SA, Krall JM, et al. Patterns of care studies: dose-
[9] [10]
[11] [12]
[13]
response observations for local control of adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1985;11:153±157. Hoskin PJ, Rembowska A. Dosimetry rules for brachytherapy using high dose rate remote afterloading implants. Clin Oncol 1998;10:226± 230. Kovacs G, Wirth B, Bertermann H, et al. Prostate preservation by combined external beam and HDR brachytherapy at nodal negative prostate cancer patients: an intermediate analysis after ten years experience. Int J Radiat Oncol Biol Phys 1996;36(S80):198. Lusinchi A, Eskandari J, Son Y, et al. External irradiation plus curietherapy boost in 108 base of tongue carcinomas. Int J Radiat Oncol Biol Phys 1989;17:1191±1197. MacKay RI, Hendry JH, Moore CJ, et al. Predicting late rectal complications following prostate conformal radiotherapy using biologically effective doses and normalized dose-surface histograms. Br J Radiol 1997;70:517±526. Partin AW, Subong ENP, Walsh PC, et al. Clinical stage and Gleason score to predict pathological stage of localized prostate cancer. J Am Med Assoc 1997;277:1445±1451. Stromberg J, Martinez A, Gonzalez J, et al. Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a Phase I/II clinical trial. Int J Radiat Oncol Biol Phys 1995;33:161±171. Stromberg JS, Martinez AA, Horwitz EM, et al. Conformal high dose rate iridium-192 boost brachtherapy in locally advanced prostate cancer: superior prostate-speci®c antigen response compared with external beam treatment. Cancer J Sci Am 1997;3:346±352.