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Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer
Radiotherapy and Oncology 74 (2005) 157–161 www.elsevier.com/locate/radonline
Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer ˚ stro¨ma,1,*, Dorte Pedersena, Claes Merckea, Sten Holma¨ngb, Karl Axel Johanssonc Lennart A a Department of Oncology, University of Gothenburg, Gothenburg, Sweden Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden c Department of Medical Radiophysics, Sahlgrenska University Hospital, Gothenburg, Sweden b
Received 3 November 2003; received in revised form 13 October 2004; accepted 29 October 2004 Available online 25 November 2004
Abstract Background and purpose: High dose rate brachytherapy (HDR-BT) in prostate cancer (PC) is receiving increasing interest. The steep dose gradient gives a possibility to escalate the dose to the prostate. If the a/b ratio is low for PC, hypofractionation will be of advantage. A retrospective analysis of outcome in patients (pts) consecutively treated with combined HDR-BT and conformal external beam radiotherapy (ERT) was performed. Material and methods: Data from 214 pts treated consecutively from 1988 to 2000 were analysed. The median age was 64 years (50–77). Median follow up was 4 years (12–165 months). Pre-irradiatory endocrine therapy was given to 150 pts (70%). The pts were divided into low-, intermediate- and high (80/87/47 pts) risk groups according to the occurrence of none, one, or more risk factors defined by T-classification, PSA and histopathology. ERT was given with 2 Gy fractions to 50 Gy. HDR-BT consisted of two 10 Gy fractions. Results: Overall 5-year biochemical no evidence of disease (bNED) was 82%, and for the low-, intermediate-, and high-risk group bNED was 92, 88 and 61%, respectively. PSA-relapse was found in 17, local recurrence in 3 and distant metastases in 13 pts. Five pts died of PC. No recurrences were observed after 5 years. Severe late complications were few. Urethral stricture (13 pts) was the most frequent. No severe rectal complications were seen. Conclusion: Dose escalation with HDR-BT is safe and effective in radiotherapy of localised PC. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Prostate cancer; Radiotherapy; Brachytherapy; High dose rate
1. Introduction High dose rate brachytherapy (HDR-BT) in prostate cancer (PC) is receiving increasing interest. The steep dose gradient in BT gives a possibility for dose escalation with sparing of normal tissue [10]. A dose– response relationship with higher doses corresponding to higher response rates has been demonstrated in PC [8]. Recent data suggest a low a/b-ratio in PC [4], implicating a higher tumour sensitivity if higher doses per fraction are given. Hypofractioned HDR-BT could consequently be of advantage with the possibility of
higher local tumour control [12] without increased normal tissue toxicity. In Gothenburg combined treatment with HDR-BT and external beam radiotherapy (ERT) in PC began in 1988 [2]. The HDR-BT was developed from the Kiel-technique [7], but modified extensively [3]. The outcome for a cohort of pts with PC treated consecutively with combined HDR-BT and conformal ERT is presented here.
2. Patients and methods 2.1. Patients
* Corresponding author. 1 Present address: The Norwegian Radium Hospital, Oslo, Norway. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.10.014
Data from the first 214 pts treated consecutively from 1988 to 2000 were analysed. The patient characteristics are
L. A˚stro¨m et al. / Radiotherapy and Oncology 74 (2005) 157–161
158
listed in Table 1. The median age was 64 years (range 50– 77). T-classification was based on digital rectal examination. Bone scintigram and pelvic lymph node dissection were performed if PSA was more than 10 ng/ml. Pretreatment PSA was assessed in 211 pts (99%) and the median PSA was 9.6 (range 1.2–93). Gleason scoreO7, PSAO10 ng/ml, and T-classificationOT2b (UICC 2002) were considered as negative prognostic factors. Pts were divided into three risk groups according to prognostic factors. No negative prognostic factors implicated low risk disease. One negative factor intermediate- and two or more factors high risk disease [16]. The number of pts in each risk group is shown in Table 1. If the tumour cell differentiation was graded according to Table 1 Patient characteristics Number T-classification (UICC 2002) T1 45 a 4 b 5 c 36 T2 137 a 71 b 36 c 30 T3 32 a 30 b 2 N-classification pN0 113 NX 101 M-classification M0 169 MX 45 Gleason score 2–5 39 6 48 7 20 8–10 10 Not available 97 WHO tumour grade Low 63 Intermediate 126 High 25 PSA (ng/ml) !10 108 10–20 53 O20 50 Not available 3 Risk group* Low1 80 Intermediate2 87 High3 47 Previous TURP# Yes 19 No 195 Total 214
Percent 21
64
15
53 47 79 21 18 22 9 5 45 29 59 12 50 25 24 1 37 41 22 9 91 100
*Risk group according to occurrence of 1no, 2one or 3two or more negative prognostic factors (OT2b, PSAO10, Gleason scoreO7). #TURP, transurethral resection of prostate.
WHO, low differentiated adenocarcinoma was considered as a negative prognostic factor. Missing PSA (3 pts) was not considered as a negative factor. 2.2. Treatment 2.2.1. Endocrine therapy Preirradiatory endocrine therapy (HT) was given to 150 pts (70%) in a median time of 5 months. Three to 6 months combined androgen blockade (TAB) consisting of antiandrogen and gonadotropine releasing hormone analogue (GnRH) was used routinely from 1997. TAB was given to 94 pts. Two pts had orchiectomy performed at diagnosis, 21 pts received antiandrogen monotherapy and 33 had treatment with GnRH alone. 2.2.2. Radiotherapy Treatment details and schedule have been described previously [3]. Briefly, ERT was given in 2 Gy fractions to a total dose of 50 Gy. From 1988 to 1993, the pelvic lymph nodes were included in the clinical target volume (CTV). After 1993, the CTV was confined to the prostate gland. For T3-tumours, the seminal vesicles were included in CTV. The planning target volume (PTV) was defined as CTV with a 2 cm margin. Dorsally to the rectum the margin was reduced to 1.5 cm. HDR-BT was given in two separate 10 Gy fractions in a pause halfway in the ERT. A dose plan was constructed based on ultrasound images. The HDR-BT PTV was equal to the CTV and was defined as the prostate gland with a margin of 2 mm. The number of applicators and their positions were defined in such a way that CTV was covered by the 10 Gy isodose line. The BT was performed under spinal anaesthesia with the patient in lithotomy position. The pts remained in situ from applicator insertion to treatment delivery. Six to 21 applicators were inserted transperineally guided by transrectal ultrasound. The ultrasound transducer had a water stand-off, which was deflated after needle insertion to retract the anterior rectal wall from the prostate. A remote afterloading technique was used with an HDR Ir-192 source. The total treatment time of ERT and HDR-BT was 7 weeks. 2.2.3. Follow up Patients were followed with PSA and regular visits after completion of ERT. PSA failure was defined according to the ASTRO consensus definition [1]. Recording of complications was performed retrospectively from patient records. Type of complication, time of appearance, and necessary therapy were recorded [13]. If there was no information about symptoms the pt was considered to be free from complication. If surgical intervention or hospitalisation was required, the complication was graded as severe. Complications requiring medical therapy were graded as moderate, and if no therapy was necessary, the grade was defined as mild. Erectile dysfunction was classified as severe if there
L. A˚stro¨m et al. / Radiotherapy and Oncology 74 (2005) 157–161 Table 2 Actuarial estimates of 5-year survival in low, intermediate, and high-risk prostate cancer Risk group Low1 BNED Clinical failurefree survival Disease specific survival Overall survival
All patients Intermediate2
High3
92 94
87 93
56 80
82 91
100
100
86
97
94
92
74
89
bNED, biochemical no evidence of disease. Risk group defined according to occurrence of 1no, 2one or 3two or more negative prognostic factors (OT2b, PSAO10, Gleason scoreO7).
was total impotence. Late complications were those appearing more than 3 months after end of radiotherapy. 2.2.4. Statistics Overall survival, disease specific survival, clinical failure free survival (FFS, defined as no local progression and no distant metastases), biochemical no evidence of disease (bNED) and complication risks were estimated according to the Kaplan Meier method [11]. Levels of significance were calculated with the log-rank test. A difference between groups was considered significant if the P-value was !0.05.
3. Results The mean- and median follow up was 48 months (12– 165). Actuarial 5-year estimates of overall survival, disease specific survival, clinical FFS and bNED for the low, intermediate, and high risk groups are shown in Table 2. The bNED survival in relation to risk groups is shown in Fig. 1.
Fig. 1. Actuarial estimates of bNED in low-, intermediate- and high risk prostate cancer. bNED, biochemical no evidence of disease. Low/ intermediate/high risk: no/one/two or more negative prognostic factors (OT2b, PSAO10, Gleason scoreO7).
159
Table 3 Actuarial 5-year estimates of late complication risks Complication grade
Urological (%)
Gastrointestinal (%)
Sexual dysfunction
Mild Moderate Severe
45 26 10
24 17 0
55 41 14
Complication grading: mild—no therapy. Moderate—medical therapy necessary. Severe—surgery or hospitalisation required. Severe sexual dysfunction: total impotence.
The difference between 5-year estimates of bNED in relation to risk group was significant (P!0.0001). There was no significant difference in bNED between hormonally treated and untreated pts (PZ0.24) or between shorter (!Z3 months) or longer duration of the endocrine treatment (PZ0.54). Disease recurrence was seen in 32 pts (15%) of whom 17 had PSA-relapse only. Local recurrences were seen in 3 and distant metastases in 13 pts. Five pts died of PC. No recurrences were found after 5 years with 68 pts followed more than 5 years and 25 pts more than 8 years. Early complications were few. Three pts had postoperative fever requiring antibiotics. Transient hematuria (!3 days) was seen in 36 pts (17%). Three pts had perineal paresthesia, which resolved spontaneously. The 5-year actuarial estimates of late complications are shown in Table 3. No severe rectal complications were seen. The most frequent severe urological complication was urethral stricture (13 pts) with a 5-year actuarial risk of 7% (Fig. 2) and median latency of three years. One of these pts underwent transurethral resection of the prostate (TURP) before radiotherapy. Two pts required urinary diversion, and 3 pts were subjected to TURP after radiotherapy. Also, two pts with recurrent hematuria and 3 with recurrent urinary retention required TURP. The risk for erectile dysfunction was significantly higher in pts treated with endocrine therapy (PZ0.02) compared to those who did not receive HT.
Fig. 2. Actuarial estimate of risk of urethral stricture.
160
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from the prostate by deflation of the probe water stand-off before the BT treatment. After dose escalation with ERT alone from 70 to 78 Gy, Pollack reported an increase in rectal toxicity from 12 to 26% [14]. The most frequent late severe complication observed here was urethral stricture, as has also been reported by other investigators. Deger reports a similar cumulative incidence of 8% with a shorter follow-up [5]. Martinez reports a 5 year actuarial risk of 7% [12]. Galalae observed high complication rates for pts in whom TURP was performed less than 6 months before treatment [7]. No relation to previously undergone TURP was seen in our material. Most urethral strictures were seen in pts treated in the beginning of the study where manual dose planning and few needles were used. The introduction of on-line dose planning and visualisation of urethra resulted in lower doses to normal urethral tissue. The lower risk of complications seen in the later period of the study could, therefore, be related not only to a shorter follow up but to optimisation of the treatment. Fig. 3. Equivalent dose in 2 Gy fractions (EQD2). (A) and (B) 70–78 Gy external radiotherapy (ERT), (C)–(E) two 10 Gy fractions HDR brachytherapy (BT) combined with 50 Gy ERT for different values of a/b.
4. Discussion This report with more patients and a long follow up confirms the earlier published promising results by Borghede [2]. Galalae et al. report a 5 year bNED estimate of 73% in PC after combined ERT and HDR-BT and 8 years of follow up [7]. Martinez et al. report a 5 year bNED of 74% [12]. These results are in agreement with the result of 5-years overall bNED of 82% in our study. In the present study no pt developed recurrence after 5 years follow up, as indicated by a ‘plateau’ in the bNED survival curves in all three risk groups. The ‘plateau’ might suggest that long term cure has been achieved. Zagars et al. have previously shown a survival curve plateau after ERT in prostatic T1-2 tumours, but was not able to demonstrate this finding in T3-4 tumours [15]. According to the linear quadratic formalism [6] the a/b ratio is used to assess response after radiotherapy in different tissues. Recent data suggest a low a/b ratio for PC which would imply a high sensitivity for fraction size [4]. Hence, the addition of large fractions of HDR BT to the ERT would result in a biological dose escalation (Fig. 3). Such a high dose cannot be delivered to the prostate gland by ERT alone and might be an explanation of the good results found in our study. The fact that few local recurrences were observed could also support this hypothesis. No severe rectal complications were seen in our material. This might be explained by our BT technique in which the pt was not moved during the procedure, thereby reducing the risk for applicator displacement [9]. Probably more important was the retraction of the anterior rectal wall
5. Conclusion HDR BT in combination with ERT showed high bNED rates for low-, intermediate-, as well as high-risk prostate cancer. Actuarial complication risks were low and no severe early or late rectal complications were found.
References [1] ASTRO. Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997;37:1035–41. [2] Borghede G, Hedelin H, Holmang S, et al. Combined treatment with temporary short-term high dose rate iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiother Oncol 1997;44:237–44. [3] 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 definitions and dose levels inside the prostate gland. Radiother Oncol 1997;44:245–50. [4] Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52:6–13. [5] Deger S, Boehmer D, Turk I, et al. High dose rate brachytherapy of localized prostate cancer. Eur Urol 2002;41:420–6. [6] Fowler JF. The Linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–94. [7] Galalae RM, Kovacs G, Schultze J, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002;52:81–90. [8] Hanks G, Martz KL, Diamond JJ. The effect of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys 1988;15:1299–305.
L. A˚stro¨m et al. / Radiotherapy and Oncology 74 (2005) 157–161 [9] Hoskin PJ, Bownes PJ, Ostler P, Walker K, Bryant L. High dose rate afterloading brachytherapy for prostate cancer: catheter and gland movement between fractions. Radiother Oncol 2003;68: 285–8. [10] Hsu I-CJ, Pickett B, Shinohara K, et al. Normal tissue dosimetric comparison between hdr prostate implant boost and conformal external beam radiotherapy boost: potential for dose escalation. Int J Radiat Oncol Biol Phys 2000;46:851–8. [11] Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81. [12] Martinez A, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause specific survival in patients with prostate cancer and poor prognostic factors. J Urol 2003;169:974–9.
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[13] Pedersen D, Bentzen SM, Overgaard J. Early and late radiotherapeutic morbidity in 442 consecutive patients with locally advanced carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1994; 29:941–52. [14] Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097–105. [15] Zagars GK, Pollack A, Kavadi VS, von Eschenbach AC. Prostatespecific antigen and radiation therapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1995;32:293–306. [16] Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53: 1111–6.
Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer ˚ stro¨ma,1,*, Dorte Pedersena, Claes Merckea, Sten Holma¨ngb, Karl Axel Johanssonc Lennart A a Department of Oncology, University of Gothenburg, Gothenburg, Sweden Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden c Department of Medical Radiophysics, Sahlgrenska University Hospital, Gothenburg, Sweden b
Received 3 November 2003; received in revised form 13 October 2004; accepted 29 October 2004 Available online 25 November 2004
Abstract Background and purpose: High dose rate brachytherapy (HDR-BT) in prostate cancer (PC) is receiving increasing interest. The steep dose gradient gives a possibility to escalate the dose to the prostate. If the a/b ratio is low for PC, hypofractionation will be of advantage. A retrospective analysis of outcome in patients (pts) consecutively treated with combined HDR-BT and conformal external beam radiotherapy (ERT) was performed. Material and methods: Data from 214 pts treated consecutively from 1988 to 2000 were analysed. The median age was 64 years (50–77). Median follow up was 4 years (12–165 months). Pre-irradiatory endocrine therapy was given to 150 pts (70%). The pts were divided into low-, intermediate- and high (80/87/47 pts) risk groups according to the occurrence of none, one, or more risk factors defined by T-classification, PSA and histopathology. ERT was given with 2 Gy fractions to 50 Gy. HDR-BT consisted of two 10 Gy fractions. Results: Overall 5-year biochemical no evidence of disease (bNED) was 82%, and for the low-, intermediate-, and high-risk group bNED was 92, 88 and 61%, respectively. PSA-relapse was found in 17, local recurrence in 3 and distant metastases in 13 pts. Five pts died of PC. No recurrences were observed after 5 years. Severe late complications were few. Urethral stricture (13 pts) was the most frequent. No severe rectal complications were seen. Conclusion: Dose escalation with HDR-BT is safe and effective in radiotherapy of localised PC. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Prostate cancer; Radiotherapy; Brachytherapy; High dose rate
1. Introduction High dose rate brachytherapy (HDR-BT) in prostate cancer (PC) is receiving increasing interest. The steep dose gradient in BT gives a possibility for dose escalation with sparing of normal tissue [10]. A dose– response relationship with higher doses corresponding to higher response rates has been demonstrated in PC [8]. Recent data suggest a low a/b-ratio in PC [4], implicating a higher tumour sensitivity if higher doses per fraction are given. Hypofractioned HDR-BT could consequently be of advantage with the possibility of
higher local tumour control [12] without increased normal tissue toxicity. In Gothenburg combined treatment with HDR-BT and external beam radiotherapy (ERT) in PC began in 1988 [2]. The HDR-BT was developed from the Kiel-technique [7], but modified extensively [3]. The outcome for a cohort of pts with PC treated consecutively with combined HDR-BT and conformal ERT is presented here.
2. Patients and methods 2.1. Patients
* Corresponding author. 1 Present address: The Norwegian Radium Hospital, Oslo, Norway. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.10.014
Data from the first 214 pts treated consecutively from 1988 to 2000 were analysed. The patient characteristics are
L. A˚stro¨m et al. / Radiotherapy and Oncology 74 (2005) 157–161
158
listed in Table 1. The median age was 64 years (range 50– 77). T-classification was based on digital rectal examination. Bone scintigram and pelvic lymph node dissection were performed if PSA was more than 10 ng/ml. Pretreatment PSA was assessed in 211 pts (99%) and the median PSA was 9.6 (range 1.2–93). Gleason scoreO7, PSAO10 ng/ml, and T-classificationOT2b (UICC 2002) were considered as negative prognostic factors. Pts were divided into three risk groups according to prognostic factors. No negative prognostic factors implicated low risk disease. One negative factor intermediate- and two or more factors high risk disease [16]. The number of pts in each risk group is shown in Table 1. If the tumour cell differentiation was graded according to Table 1 Patient characteristics Number T-classification (UICC 2002) T1 45 a 4 b 5 c 36 T2 137 a 71 b 36 c 30 T3 32 a 30 b 2 N-classification pN0 113 NX 101 M-classification M0 169 MX 45 Gleason score 2–5 39 6 48 7 20 8–10 10 Not available 97 WHO tumour grade Low 63 Intermediate 126 High 25 PSA (ng/ml) !10 108 10–20 53 O20 50 Not available 3 Risk group* Low1 80 Intermediate2 87 High3 47 Previous TURP# Yes 19 No 195 Total 214
Percent 21
64
15
53 47 79 21 18 22 9 5 45 29 59 12 50 25 24 1 37 41 22 9 91 100
*Risk group according to occurrence of 1no, 2one or 3two or more negative prognostic factors (OT2b, PSAO10, Gleason scoreO7). #TURP, transurethral resection of prostate.
WHO, low differentiated adenocarcinoma was considered as a negative prognostic factor. Missing PSA (3 pts) was not considered as a negative factor. 2.2. Treatment 2.2.1. Endocrine therapy Preirradiatory endocrine therapy (HT) was given to 150 pts (70%) in a median time of 5 months. Three to 6 months combined androgen blockade (TAB) consisting of antiandrogen and gonadotropine releasing hormone analogue (GnRH) was used routinely from 1997. TAB was given to 94 pts. Two pts had orchiectomy performed at diagnosis, 21 pts received antiandrogen monotherapy and 33 had treatment with GnRH alone. 2.2.2. Radiotherapy Treatment details and schedule have been described previously [3]. Briefly, ERT was given in 2 Gy fractions to a total dose of 50 Gy. From 1988 to 1993, the pelvic lymph nodes were included in the clinical target volume (CTV). After 1993, the CTV was confined to the prostate gland. For T3-tumours, the seminal vesicles were included in CTV. The planning target volume (PTV) was defined as CTV with a 2 cm margin. Dorsally to the rectum the margin was reduced to 1.5 cm. HDR-BT was given in two separate 10 Gy fractions in a pause halfway in the ERT. A dose plan was constructed based on ultrasound images. The HDR-BT PTV was equal to the CTV and was defined as the prostate gland with a margin of 2 mm. The number of applicators and their positions were defined in such a way that CTV was covered by the 10 Gy isodose line. The BT was performed under spinal anaesthesia with the patient in lithotomy position. The pts remained in situ from applicator insertion to treatment delivery. Six to 21 applicators were inserted transperineally guided by transrectal ultrasound. The ultrasound transducer had a water stand-off, which was deflated after needle insertion to retract the anterior rectal wall from the prostate. A remote afterloading technique was used with an HDR Ir-192 source. The total treatment time of ERT and HDR-BT was 7 weeks. 2.2.3. Follow up Patients were followed with PSA and regular visits after completion of ERT. PSA failure was defined according to the ASTRO consensus definition [1]. Recording of complications was performed retrospectively from patient records. Type of complication, time of appearance, and necessary therapy were recorded [13]. If there was no information about symptoms the pt was considered to be free from complication. If surgical intervention or hospitalisation was required, the complication was graded as severe. Complications requiring medical therapy were graded as moderate, and if no therapy was necessary, the grade was defined as mild. Erectile dysfunction was classified as severe if there
L. A˚stro¨m et al. / Radiotherapy and Oncology 74 (2005) 157–161 Table 2 Actuarial estimates of 5-year survival in low, intermediate, and high-risk prostate cancer Risk group Low1 BNED Clinical failurefree survival Disease specific survival Overall survival
All patients Intermediate2
High3
92 94
87 93
56 80
82 91
100
100
86
97
94
92
74
89
bNED, biochemical no evidence of disease. Risk group defined according to occurrence of 1no, 2one or 3two or more negative prognostic factors (OT2b, PSAO10, Gleason scoreO7).
was total impotence. Late complications were those appearing more than 3 months after end of radiotherapy. 2.2.4. Statistics Overall survival, disease specific survival, clinical failure free survival (FFS, defined as no local progression and no distant metastases), biochemical no evidence of disease (bNED) and complication risks were estimated according to the Kaplan Meier method [11]. Levels of significance were calculated with the log-rank test. A difference between groups was considered significant if the P-value was !0.05.
3. Results The mean- and median follow up was 48 months (12– 165). Actuarial 5-year estimates of overall survival, disease specific survival, clinical FFS and bNED for the low, intermediate, and high risk groups are shown in Table 2. The bNED survival in relation to risk groups is shown in Fig. 1.
Fig. 1. Actuarial estimates of bNED in low-, intermediate- and high risk prostate cancer. bNED, biochemical no evidence of disease. Low/ intermediate/high risk: no/one/two or more negative prognostic factors (OT2b, PSAO10, Gleason scoreO7).
159
Table 3 Actuarial 5-year estimates of late complication risks Complication grade
Urological (%)
Gastrointestinal (%)
Sexual dysfunction
Mild Moderate Severe
45 26 10
24 17 0
55 41 14
Complication grading: mild—no therapy. Moderate—medical therapy necessary. Severe—surgery or hospitalisation required. Severe sexual dysfunction: total impotence.
The difference between 5-year estimates of bNED in relation to risk group was significant (P!0.0001). There was no significant difference in bNED between hormonally treated and untreated pts (PZ0.24) or between shorter (!Z3 months) or longer duration of the endocrine treatment (PZ0.54). Disease recurrence was seen in 32 pts (15%) of whom 17 had PSA-relapse only. Local recurrences were seen in 3 and distant metastases in 13 pts. Five pts died of PC. No recurrences were found after 5 years with 68 pts followed more than 5 years and 25 pts more than 8 years. Early complications were few. Three pts had postoperative fever requiring antibiotics. Transient hematuria (!3 days) was seen in 36 pts (17%). Three pts had perineal paresthesia, which resolved spontaneously. The 5-year actuarial estimates of late complications are shown in Table 3. No severe rectal complications were seen. The most frequent severe urological complication was urethral stricture (13 pts) with a 5-year actuarial risk of 7% (Fig. 2) and median latency of three years. One of these pts underwent transurethral resection of the prostate (TURP) before radiotherapy. Two pts required urinary diversion, and 3 pts were subjected to TURP after radiotherapy. Also, two pts with recurrent hematuria and 3 with recurrent urinary retention required TURP. The risk for erectile dysfunction was significantly higher in pts treated with endocrine therapy (PZ0.02) compared to those who did not receive HT.
Fig. 2. Actuarial estimate of risk of urethral stricture.
160
L. A˚stro¨m et al. / Radiotherapy and Oncology 74 (2005) 157–161
from the prostate by deflation of the probe water stand-off before the BT treatment. After dose escalation with ERT alone from 70 to 78 Gy, Pollack reported an increase in rectal toxicity from 12 to 26% [14]. The most frequent late severe complication observed here was urethral stricture, as has also been reported by other investigators. Deger reports a similar cumulative incidence of 8% with a shorter follow-up [5]. Martinez reports a 5 year actuarial risk of 7% [12]. Galalae observed high complication rates for pts in whom TURP was performed less than 6 months before treatment [7]. No relation to previously undergone TURP was seen in our material. Most urethral strictures were seen in pts treated in the beginning of the study where manual dose planning and few needles were used. The introduction of on-line dose planning and visualisation of urethra resulted in lower doses to normal urethral tissue. The lower risk of complications seen in the later period of the study could, therefore, be related not only to a shorter follow up but to optimisation of the treatment. Fig. 3. Equivalent dose in 2 Gy fractions (EQD2). (A) and (B) 70–78 Gy external radiotherapy (ERT), (C)–(E) two 10 Gy fractions HDR brachytherapy (BT) combined with 50 Gy ERT for different values of a/b.
4. Discussion This report with more patients and a long follow up confirms the earlier published promising results by Borghede [2]. Galalae et al. report a 5 year bNED estimate of 73% in PC after combined ERT and HDR-BT and 8 years of follow up [7]. Martinez et al. report a 5 year bNED of 74% [12]. These results are in agreement with the result of 5-years overall bNED of 82% in our study. In the present study no pt developed recurrence after 5 years follow up, as indicated by a ‘plateau’ in the bNED survival curves in all three risk groups. The ‘plateau’ might suggest that long term cure has been achieved. Zagars et al. have previously shown a survival curve plateau after ERT in prostatic T1-2 tumours, but was not able to demonstrate this finding in T3-4 tumours [15]. According to the linear quadratic formalism [6] the a/b ratio is used to assess response after radiotherapy in different tissues. Recent data suggest a low a/b ratio for PC which would imply a high sensitivity for fraction size [4]. Hence, the addition of large fractions of HDR BT to the ERT would result in a biological dose escalation (Fig. 3). Such a high dose cannot be delivered to the prostate gland by ERT alone and might be an explanation of the good results found in our study. The fact that few local recurrences were observed could also support this hypothesis. No severe rectal complications were seen in our material. This might be explained by our BT technique in which the pt was not moved during the procedure, thereby reducing the risk for applicator displacement [9]. Probably more important was the retraction of the anterior rectal wall
5. Conclusion HDR BT in combination with ERT showed high bNED rates for low-, intermediate-, as well as high-risk prostate cancer. Actuarial complication risks were low and no severe early or late rectal complications were found.
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