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A Phase II Study of High-Dose-Rate Afterloading Brachytherapy as Monotherapy for the Treatment of Localized Prostate Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 2, pp. 441–446, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2007.12.026
CLINICAL INVESTIGATION
Prostate
A PHASE II STUDY OF HIGH-DOSE-RATE AFTERLOADING BRACHYTHERAPY AS MONOTHERAPY FOR THE TREATMENT OF LOCALIZED PROSTATE CANCER CARIE CORNER, F.R.C.R., ANA MARIA ROJAS, PH.D., LINDA BRYANT, D.C.R.(T.), PETER OSTLER, F.R.C.R., AND PETER HOSKIN, M.D., F.R.C.R. Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK Purpose: A Phase II dose escalation study has been undertaken to evaluate high-dose-rate brachytherapy (HDRBT) monotherapy for prostate cancer. Methods and Materials: A total of 110 patients have been entered, all with locally advanced cancer. Three dose levels have been used; 34 Gy in four fractions, 36 Gy in four fractions, and 31.5 Gy in three fractions. These equate to 226Gy1.5, 252Gy1.5, and 252Gy1.5, respectively. Thirty patients have received 34 Gy, 25 received 36 Gy, and 55 patients received 31.5 Gy. Acute and late toxicity was analyzed using the International Prostate Symptom Score, and urologic and rectal events were scored using the Radiation Therapy Oncology Group/Common Terminology Criteria scoring systems. Results: Seven patients required urethral catheterization at 2 weeks; 3 receiving 34 Gy, 1 receiving 36 Gy, and 3 receiving 31.5 Gy. Only 3 patients remained catheterized at 12 weeks. Radiation Therapy Oncology Group 1 and 2 gastrointestinal toxicity at 2 weeks was seen in 61%, 68%, and 77%, respectively. Grade 3 bladder toxicity was seen in 2 patients at 6 months, 1 each from the 36 Gy and 31.5 Gy arms. One patient from the 31.5-Gy cohort reported Grade 2 bowel toxicity at 6 months. Prostate-specific antigen (PSA), stratified for androgen deprivation therapy (ADT) and no-ADT patients ranged from 16.1–22.9 mg/L and 11.1–12.5 mg/L, respectively. This fell at 12 months to 0.2–0.6 mg/L and 0.5–1.4 mg/L, respectively. No PSA relapses have yet been seen with a median follow-up of 30 months (34 Gy), 18 months (36 Gy), and 11.8 months (31.5 Gy). Conclusions: Early results suggest an excellent biochemical response with no differences seen in acute and late toxicity between doses of 34 Gy/four fractions, 36 Gy/four fractions, or 31.5 Gy/three fractions. Ó 2008 Elsevier Inc. Phase II study, Dose escalation, High-dose-rate monotherapy, Afterloading brachytherapy, Localized prostate cancer.
INTRODUCTION There is now established evidence that dose escalating external beam radiotherapy (>70 Gy) in the treatment of localized prostate cancer improves biochemical disease control (1). Dose escalation, however, is often at the expense of an increase in genitourinary and gastrointestinal toxicity (2). Brachytherapy delivers a high localized dose to the tumor while minimizing normal tissue toxicity. The techniques available to deliver interstitial brachytherapy use either permanent low-dose-rate (LDR) seeds or high-dose-rate (HDR) afterloading. Numerous studies have reported excellent biochemical disease control in favorable risk disease using iodine-125 seeds with a prescription dose of 145 Gy (3–5) or using LDR palladium-103 seeds (6, 7). HDR brachytherapy
for prostate cancer has been predominantly used as a boost after external beam radiation therapy in unfavorable risk disease (8–11). In recent years, HDR monotherapy has been explored as an alternative to seed monotherapy in favorable risk prostate cancer (12). From the published data on the radiobiology of prostate cancer, it is believed to be a tumor with a low alpha beta (a/b) ratio 1.5 Gy (13–15). A recent overview of the literature supports lower a/b values for prostate tumor than for rectum or bladder (16, 17). As a result, prostate cancers will be significantly more sensitive to radiation fraction size, which means that a small number of larger fractions will exploit this radiobiologic advantage and achieve biologic dose escalation.
Reprint requests to: Carie Corner, F.R.C.R., Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK. Tel: (+44) 1923 844533; Fax: (+44) 1923 844167; E-mail: [email protected] Presented in part at the Groupe Europeen de Curitherapie–European Society for Therapeutic Radiology and Oncology–International Society of Intraoperative Radiotherapy-Europe (GEC-ESTRO-ISO-
IORT Europe) joint meeting, 2007, Montpellier, France, May 12, 2007. Conflict of interest: none. Acknowledgments—We are grateful to Mr. Y. Tsang for assistance with the statistical analyses. Received Oct 5, 2007, and in revised form Dec 16, 2007. Accepted for publication Dec 17, 2007. 441
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Large fraction treatments however may result in severe late damage to the normal tissues included in the treatment volume. HDR afterloading brachytherapy enables concentration of dose in the planning target volume minimizing the volume of normal tissue irradiated. Pilot studies of HDR brachytherapy monotherapy for early prostate cancer using relatively small numbers of patients have shown no excessive toxicity at a follow up of 2 years. Tumor control data are awaited (18–20). MATERIALS AND METHODS Study design This study was a prospective, successive dose escalation study of HDR brachytherapy in locally advanced prostate cancer. The first group received 34 Gy in four fractions over 3 days at a dose of 8.5 Gy per fraction. Using an a/b ratio of 1.5 Gy for prostate cancer, the calculated biologic effective dose (BED) in equivalent 2 Gy fractions was 97.1 Gy. In the absence of excessive toxicity in the first 20 patients treated with 34 Gy in four fractions, the second group was dose-escalated to receive 36 Gy in four fractions over 3 days using a dose of 9 Gy per fraction. This gave a calculated BED 2 Gy equivalent of 108 Gy. Treatment was then delivered to the third dose group who received 31.5 Gy in three fractions over 2 days at a dose of 10.5 Gy per fraction, giving a 2-Gy equivalent dose to the second group of 108 Gy, but in a shorter overall time. Dose–limiting toxicity in this study was defined as any toxicity of Radiation Therapy Oncology Group (RTOG) Grade 3 or more occurring with an incidence of 10%.
Inclusion and exclusion criteria The study had approval from the Hertfordshire Local Research Ethics Committee. Inclusion criteria were localized prostate cancer with no distant metastases, with a prostate-specific antigen (PSA) <40 mg/L and a staging pelvic magnetic resonance imaging scan before study entry to confirm node-negative disease. Patients were staged using the UICC/TNM 2002 staging system. Any stage up to T3b disease was permitted as this method of treatment delivery allows for successful implantation of the seminal vesicles. For those patients with a PSA >20 mg/L, a normal isotope bone scan was required. All patients had to be fit for a general anaesthetic and able to give written informed consent. Patients who had previous transurethral resection of the prostate were excluded.
Treatment and schedule The technique of HDR afterloading has been previously described (11, 20, 21). After implantation, computed tomography imaging was undertaken and the implant reconstructed using a three dimensional planning system (Brachyvision, Varian Medical System, Crawley, UK). The clinical target volume was defined by the prostate capsule with extension to cover extracapsular disease and seminal vesicle disease where demonstrated on staging magnetic resonance imaging. The planning target volume was a 2–3 mm volumetric expansion from the clinical target volume, constrained to the anterior rectal wall. On the day of the implant, patients received their first fraction of radiotherapy, Day 1. Fractions two and three were given the following day, with a minimum of 6 h between fractions. For those patients
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receiving a four-fraction regimen, this was given on the third day. Computed tomography scans were performed before the second and fourth fractions to assess catheter movement so that appropriate adjustments could be made to catheter dwell times or position to optimize dose distribution (22). Normal tissue constraints were defined for the urethra D30 to receive less than 125% of the prescribed dose and the anterior rectal wall D2mL to receive less than 100%. The primary end points were acute and late radiation toxicity. Acute toxicity was assessed using the RTOG scores for urologic and rectal toxicity, and the International Prostate Symptom Score urinary function scores (23). These were assessed at 2 weeks, 4 weeks, and 12 weeks. Late toxicity was measured by the Common Toxicity Criteria v 3.0 (24) in addition to RTOG scores at 6 months and then every 6 months thereafter. The secondary end point was biochemical relapse free survival; PSA was measured at 6 months after the implant and then every 6 months thereafter.
Statistical analysis Statistical comparisons were performed using version 5.1.2 JMP (SAS Institute, Cary, NC). Differences in Gleason scores and tumor stages between treatment schedules were compared using a contingency platform. Fisher’s exact test was used to test for significance between treatments from which two-tailed p values were obtained. Similarly, statistical differences in the prevalence of toxicity before HDR brachytherapy and at 6 and 12 months after treatment were tested using the same contingency platform. One-way analysis of variance was used to calculate mean PSA values and a Student’s t test was used to test for differences between dose groups.
RESULTS A total of 110 patients entered the study between November 2003 and December 2006: 30 receiving 34 Gy/four fractions, 25 receiving 36 Gy/four fractions, and the remaining 55 receiving 31.5 Gy/three fractions. The mean age of the treated patients was similar in the three groups ranging from 66 to 68 years. Follow-up ranged from a mean of 11.8 months in the 31.5 Gy dose group to 27 months in the 34 Gy dose group. This study therefore reports late toxicity for all three dose groups at 6 months. There were no statistically significant differences among the three dose groups in initial PSA (p $ 0.1) or Gleason score as shown in Tables 1, 2, and 3 respectively. The 31.5 Gy dose group had a significantly higher number of patients with stage T2 disease (p # 0.006) compared with the 34 Gy or 36 Gy dose group. There were significantly fewer patients with stage T1c disease in the 31.5 Gy dose group compared with the 34 Gy group (p = 0.0012). There were no significant differences among the three dose groups for stage T3 disease, as shown in Table 4. Urinary toxicity as measured by mean IPSS scores is shown in Fig 1. These did not differ significantly before treatment. At 2 weeks, acute urinary toxicity peaks reflected in a rise in the mean IPSS scores in all three groups, 12.2 (34 Gy), 13.1 (36 Gy), 9.6 (31.5 Gy); by 12 weeks, mean IPSS scores are back to pretreatment levels. No statistically significant difference was seen among the three dose levels. No data exist on the use of an alpha blocker during treatment, but its use was permitted in this study.
High-Dose-Rate Afterloading Brachytherapy as Monotherapy d C. CORNER et al.
Table 1. Mean ( 1 SEM) and median PSA (mg/L) in patients treated with androgen deprivation therapy Dose group 34 Gy Mean Median n 36 Gy Mean Median n 31.5 Gy Mean Median n p value
Pre-Rx
6 months
12 months
22.9 5.4 18.2 14
0.4 0.1 0.2 13
0.4 0.1 0.1 14
# 0.00001
23.7 5.7 12.3 15
0.08 0.02 0.02 14
0.2 0.1 0.1 15
# 0.00001
Dose Group
Grades 4–6
Grade 7
Grades 8–10
34 Gy 36 Gy 31.5 Gy p value
37% (11) 24% (6) 20% (11) $ 0.12
50% (15) 60% (15) 69% (37) $ 0.12
30% (4) 16% (4) 11% (6) $ 0.72
16.1 1.5 12.9 38 $ 0.1
0.6 0.3 0.1 26 $ 0.1
0.6 0.2 0.1 35 $ 0.2
# 0.0002
Number of patients in parentheses.
Table 2. Mean ( 1 SEM) and median PSA (mg/L) in patients not treated with androgen deprivation therapy
34 Gy Mean Median n 36 Gy Mean Median n 31.5 Gy Mean Median n p value
Table 3. Distribution of Gleason grades between groups
p value
Acute Grade 1 and 2 gastrointestinal toxicity peaked at 2 weeks after treatment affecting 61% (34 Gy), 68% (36 Gy), and 71% (31.5 Gy) of patients. By 12 weeks, this fell to 25%, 54%, and 27%, respectively (p = 0.560), as shown in Fig. 2. The urethral catheterization rate overall was low with seven patients (6%) requiring a urethral catheter at 2 weeks after the implant: 3 patients (34 Gy), 1 patient (36 Gy), and 3 patients (31.5 Gy). This improved with time and, by week 12 after implant, just 3 patients remained with a urethral catheter, all from the 31.5 Gy dose group. By 6 months, none of the patients in the study required a urethral catheter. The incidence of late bladder toxicity at 6 months was low with only 25% (34 Gy), 31% (36 Gy), and 28% (31.5 Gy) reporting RTOG Grade 1 toxicity or more. Two patients reported Grade 3 bladder toxicity at 6 months, 1 patient from 36 Gy group and 1 patient from the 31.5 Gy group. There was no significant difference in the incidence of late bladder toxicity among the three groups (p = 0.844). The incidence of late gastrointestinal toxicity assessed at 6 months was low; Grade 1 toxicity was seen in 20% (34 Gy), 8% (36 Gy), and 22% (31.5 Gy) of patients, respectively, and did not differ significantly among the three dose groups
Dose group
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Pre Rx
6 months
12 months
p value
11.8 1.8 9.8 16
1.5 0.4 0.8 15
1.5 0.5 0.7 15
# 0.00001
11.1 1.7 9.4 9
3.0 1.8 1.4 10
0.9 0.2 1.0 9
# 0.001
15.7 4.0 12.5 14 $ 0.3
0.9 0.7 0.1 11 $ 0.2
0.5 0.2 0.1 9 $ 0.06
# 0.001
(p = 0.710). One patient reported Grade 2 toxicity from the 31.5 Gy group; this was intermittent rectal bleeding. There were no cases of Grade 3 late intestinal toxicity. A total of 67 patients were receiving antiandrogen therapy in the form of a luteinizing hormone-releasing hormone agonist. Patients commenced neoadjuvant androgen deprivation therapy (ADT) at a median of 4 months (34 Gy and 36 Gy, respectively) and 3 months (31.5 Gy) before commencing HDR brachytherapy. The proposed end of ADT ranged from a median of 15 months (31.5 Gy) to 24 months (34 Gy), as shown in Table 5. The recommended duration of ADT was determined at the start of treatment by the Gleason score, T stage, and initial PSA. Patients with Gleason score 7, T2 disease, or PSA 10–20 mg/L were recommended 6 months’ total ADT. Patients with Gleason score 8–10, T3 disease, or PSA >20 mg/L were recommended 24 months’ total ADT. Biochemical response to treatment was stratified by ADT and no ADT as shown in Tables 1 and 2, respectively, and is assessable at 6 months and 12 months for the three dose groups. Median PSA (mg/L) for the ADT and no-ADT patients across the three dose groups at 6 months was 0.2 and 0.8, 0.02 and 1.4, and 0.1 and 0.1, respectively. At 12 months, this was 0.1 and 0.7, 0.1 and 1.0, and 0.1 and 0.1, respectively. There was no significant difference in the biochemical response observed among the three dose groups for both the ADT and no-ADT patients at 6 months p $ 0.1/p $ 0.2 and at 12 months p $ 0.2/p $ 0.06, respectively. DISCUSSION There is increasing evidence to support the view that prostate cancer has a low a/b ratio, in the 1.2–3.1 range (12–14). Hypofractionated regimes may be expected to produce improved tumor control. Predictions from radiobiologic models suggest brachytherapy as monotherapy or as a boost may Table 4. Distribution of tumor T stage among the three dose groups Dose group
T1c
T2
T3
34 Gy 36 Gy 31.5 Gy Comparisons 36 Gy vs. 31.5 Gy 34 Gy vs. 31.5 Gy
50% (14) 28% (7) 14% (6)
25% (7) 32% (8) 68% (30)
25% (7) 40% (10) 18% (8)
p = 0.201 p = 0.001
p = 0.006 p = 0.0006
p = 0.08 p = 0.56
There was no statistically significant difference between the T stages comparing 34 Gy with 36Gy dose group (p $ 0.16).
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Mean IPSS ± 1 SEM
444 16
Table 5. Initiation and planned end of androgen deprivation therapy
12
Dose group Mean (months) Median (months) Range (months)
8 4 0
Pre-RT
2
4
12
Time from treatment (week)
Fig. 1. Mean International Prostate Symptom Score (IPSS) for patients treated with 34 Gy (solid circles and line), 36 Gy (open squares, dot-dashed line), or 31.5 Gy (solid triangles, dotted line) and determined before the start of treatment and at 2, 4, and 12 weeks after high-dose rate brachytherapy. Errors are 1 standard error of mean (SEM).
achieve superior tumor control compared with dose escalation using three-dimensional conformal external beam radiotherapy (25). High-dose-rate brachytherapy has been extensively studied as a boost after external beam radiation therapy in intermediate- to high-risk prostate cancer to achieve improved biochemical disease control (8–11). The published data on HDR monotherapy for intermediate- to high-risk prostate cancer is limited. Yoshioka et al. (19) studied 43 patients with localized disease, 38 of whom were of intermediate to high risk. Their results suggested crude biochemical control rates for intermediate risk patients of 80% and for high risk 61%. One patient experienced Grade 4 acute toxicity. High-dose-rate afterloading brachytherapy is the optimal method of delivering high doses per fraction to the tumor with low dose to normal tissues as the dose distribution obeys the inverse square law. Furthermore, temporary implant techniques result in a conformal localized dose to an immobilized target in contrast to the additional setup errors and internal organ motion encountered in external beam therapy. Based on an a/b ratio of 1.5 Gy the 2 Gy fraction equivalent doses received in this study in the 34 Gy, 36 Gy, and 31.5 Gy groups were 97.1 Gy, 108 Gy, and 108 Gy, respec100 80
Incidence (%)
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60 40 20 0
Week 2
Week 4
Week 12
Fig. 2. Bar histogram representing the incidence of acute Grade 1 and 2 gastrointestinal toxicity ( 1 standard deviation) at 2, 4, and 12 weeks after high-dose-rate brachytherapy with 34 Gy (gray bar), 36 Gy (black), or 31.5 Gy (open bars).
34 Gy Initiation End 36 Gy Initiation End 31.5 Gy Initiation End
4.5 18.6
4 24
2–8 6–24
3.7 20
4 24
0–8 6–24
3.9 14.9
3 15
1–11 3–24
tively. If the a/b ratio were 3.5 Gy, the relative 2 Gy fraction equivalent doses would be 74.2 Gy, 81.8 Gy, and 80.2 Gy, respectively. If the a/b ratio for prostate cancer is lower than that of critical normal tissues, then the risk of late normal tissue damage cannot be reduced by fractionation (17). Therefore ,to minimize late effects, the volume of critical normal tissue treated must be kept as low as possible. In a recent study by Kupelian et al. (26) morbidity was reported with hypofractionated external beam radiotherapy after 70 Gy in 2.5-Gy fractions. RTOG late rectal toxicity was reported as Grade 2 or more in 4.5% of patients and late urinary toxicity scores were 2 or more in 5.2%. This is higher than reported in this study, in which late rectal toxicity at 6 months was seen in 0.01% (1 patient) and late urinary toxicity in 0.02% (2 patients). Brachytherapy is the optimal technique to minimize the irradiated volume of the rectum and urethra, with a steep dose gradient within the planning target volume. Because of the large combination of dwell times and positions possible with the HDR afterloading technique, complex dose distributions can be designed to provide a relative cold spot around the urethra and also limit the rectal dose (27). Given the incidence of late rectal toxicity seen with hypofractionated external beam radiotherapy (26), HDR brachytherapy appears to be a more effective way of sparing the urethra and anterior rectal wall, therefore minimizing significant late toxicity. Additional advantages of HDR monotherapy as given in this study is that radical treatment can be completed in just three fractions, which is more convenient for patients and more cost-effective for the treating hospital. The interfraction interval of at least 6 h was stipulated to allow for normal tissue repair. There are very limited data on the radiobiologic characteristics of prostate cancer. A relatively long cell-cycle time and potential volume doubling time ranging from 16 to 61 days is reported (28). This suggests that time-dependent factors such as repopulation, reoxygenation, and reassortment may not be important in the response of prostate cancer to radiotherapy, and that acceleration alone will have no benefits. High-dose-rate brachytherapy has been reported to cause less acute genitourinary toxicity, less acute rectal pain, and less late urinary toxicity than LDR brachytherapy (10) and fewer late effects also.
High-Dose-Rate Afterloading Brachytherapy as Monotherapy d C. CORNER et al.
In this Phase II study of 110 patients, we confirm that toxicity with hypofractionated HDR monotherapy is low. Because mean follow-up varies among the three dose groups, acute and late toxicity is reported for all three dose groups up to 6 months. Acute urinary toxicity peaks in week 2 after the implant, but by week 12 has returned to baseline. This is in contrast to the pattern seen after LDR seed brachytherapy when acute symptoms persist for 6 months or more (10). The urinary catheterization rate was 6% in this study, which compares favorably with the 10–15% urinary catheterization rates observed with LDR. The 3 patients in this study that remained with a urethral catheter at 12 weeks were all from the higher dose per fraction cohort receiving 31.5 Gy. None of the patients required a urethral catheter at 6 months. It is feasible that the higher dose fractions (10.5 Gy) in this group may correlate with an increased risk of catheter dependency at 12 weeks. However, by 6 months, this has resolved. Acute gastrointestinal toxicity was low grade and short lived, with no reported cases of Grade 3 toxicity. Few patients experienced more than Grade 1 late bladder or intestinal toxicity. There was one case of late Grade 2 intestinal toxicity from the 31.5-Gy dose group arising at 6 months. Because this group has the shortest mean follow-up (11.8 months), future toxicity data will determine if this is an effect of the
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higher BED or whether this toxicity resolves. In this study, there was no statistically significant difference seen in the toxicity data at 6 months among the three dose groups. Sixty-seven patients were receiving ADT with a luteinizing hormone-releasing hormone agonist during treatment with a mean proposed duration of 14.9–20 months. This may impact favorably on the PSA nadir at 6 months and 12 months. However, our results show equivalent median biochemical responses for the ADT and no-ADT patients in the higher BED group of 31.5 Gy: at 6 months 0.1 mg/L and 12 months 0.1 mg/L, respectively. CONCLUSION The results from this study show equivalent low rates of acute and late urinary and rectal toxicity across the three dose groups. Initial biochemical disease control is excellent and appears equivalent among the three groups when stratified for ADT and no-ADT treated patients; however, longer follow-up is required to evaluate this further. The low toxicity seen with this approach suggests further dose escalation could be possible, although longer term follow-up to confirm late toxicity events is required before proceeding in this way.
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doi:10.1016/j.ijrobp.2007.12.026
CLINICAL INVESTIGATION
Prostate
A PHASE II STUDY OF HIGH-DOSE-RATE AFTERLOADING BRACHYTHERAPY AS MONOTHERAPY FOR THE TREATMENT OF LOCALIZED PROSTATE CANCER CARIE CORNER, F.R.C.R., ANA MARIA ROJAS, PH.D., LINDA BRYANT, D.C.R.(T.), PETER OSTLER, F.R.C.R., AND PETER HOSKIN, M.D., F.R.C.R. Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK Purpose: A Phase II dose escalation study has been undertaken to evaluate high-dose-rate brachytherapy (HDRBT) monotherapy for prostate cancer. Methods and Materials: A total of 110 patients have been entered, all with locally advanced cancer. Three dose levels have been used; 34 Gy in four fractions, 36 Gy in four fractions, and 31.5 Gy in three fractions. These equate to 226Gy1.5, 252Gy1.5, and 252Gy1.5, respectively. Thirty patients have received 34 Gy, 25 received 36 Gy, and 55 patients received 31.5 Gy. Acute and late toxicity was analyzed using the International Prostate Symptom Score, and urologic and rectal events were scored using the Radiation Therapy Oncology Group/Common Terminology Criteria scoring systems. Results: Seven patients required urethral catheterization at 2 weeks; 3 receiving 34 Gy, 1 receiving 36 Gy, and 3 receiving 31.5 Gy. Only 3 patients remained catheterized at 12 weeks. Radiation Therapy Oncology Group 1 and 2 gastrointestinal toxicity at 2 weeks was seen in 61%, 68%, and 77%, respectively. Grade 3 bladder toxicity was seen in 2 patients at 6 months, 1 each from the 36 Gy and 31.5 Gy arms. One patient from the 31.5-Gy cohort reported Grade 2 bowel toxicity at 6 months. Prostate-specific antigen (PSA), stratified for androgen deprivation therapy (ADT) and no-ADT patients ranged from 16.1–22.9 mg/L and 11.1–12.5 mg/L, respectively. This fell at 12 months to 0.2–0.6 mg/L and 0.5–1.4 mg/L, respectively. No PSA relapses have yet been seen with a median follow-up of 30 months (34 Gy), 18 months (36 Gy), and 11.8 months (31.5 Gy). Conclusions: Early results suggest an excellent biochemical response with no differences seen in acute and late toxicity between doses of 34 Gy/four fractions, 36 Gy/four fractions, or 31.5 Gy/three fractions. Ó 2008 Elsevier Inc. Phase II study, Dose escalation, High-dose-rate monotherapy, Afterloading brachytherapy, Localized prostate cancer.
INTRODUCTION There is now established evidence that dose escalating external beam radiotherapy (>70 Gy) in the treatment of localized prostate cancer improves biochemical disease control (1). Dose escalation, however, is often at the expense of an increase in genitourinary and gastrointestinal toxicity (2). Brachytherapy delivers a high localized dose to the tumor while minimizing normal tissue toxicity. The techniques available to deliver interstitial brachytherapy use either permanent low-dose-rate (LDR) seeds or high-dose-rate (HDR) afterloading. Numerous studies have reported excellent biochemical disease control in favorable risk disease using iodine-125 seeds with a prescription dose of 145 Gy (3–5) or using LDR palladium-103 seeds (6, 7). HDR brachytherapy
for prostate cancer has been predominantly used as a boost after external beam radiation therapy in unfavorable risk disease (8–11). In recent years, HDR monotherapy has been explored as an alternative to seed monotherapy in favorable risk prostate cancer (12). From the published data on the radiobiology of prostate cancer, it is believed to be a tumor with a low alpha beta (a/b) ratio 1.5 Gy (13–15). A recent overview of the literature supports lower a/b values for prostate tumor than for rectum or bladder (16, 17). As a result, prostate cancers will be significantly more sensitive to radiation fraction size, which means that a small number of larger fractions will exploit this radiobiologic advantage and achieve biologic dose escalation.
Reprint requests to: Carie Corner, F.R.C.R., Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK. Tel: (+44) 1923 844533; Fax: (+44) 1923 844167; E-mail: [email protected] Presented in part at the Groupe Europeen de Curitherapie–European Society for Therapeutic Radiology and Oncology–International Society of Intraoperative Radiotherapy-Europe (GEC-ESTRO-ISO-
IORT Europe) joint meeting, 2007, Montpellier, France, May 12, 2007. Conflict of interest: none. Acknowledgments—We are grateful to Mr. Y. Tsang for assistance with the statistical analyses. Received Oct 5, 2007, and in revised form Dec 16, 2007. Accepted for publication Dec 17, 2007. 441
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Large fraction treatments however may result in severe late damage to the normal tissues included in the treatment volume. HDR afterloading brachytherapy enables concentration of dose in the planning target volume minimizing the volume of normal tissue irradiated. Pilot studies of HDR brachytherapy monotherapy for early prostate cancer using relatively small numbers of patients have shown no excessive toxicity at a follow up of 2 years. Tumor control data are awaited (18–20). MATERIALS AND METHODS Study design This study was a prospective, successive dose escalation study of HDR brachytherapy in locally advanced prostate cancer. The first group received 34 Gy in four fractions over 3 days at a dose of 8.5 Gy per fraction. Using an a/b ratio of 1.5 Gy for prostate cancer, the calculated biologic effective dose (BED) in equivalent 2 Gy fractions was 97.1 Gy. In the absence of excessive toxicity in the first 20 patients treated with 34 Gy in four fractions, the second group was dose-escalated to receive 36 Gy in four fractions over 3 days using a dose of 9 Gy per fraction. This gave a calculated BED 2 Gy equivalent of 108 Gy. Treatment was then delivered to the third dose group who received 31.5 Gy in three fractions over 2 days at a dose of 10.5 Gy per fraction, giving a 2-Gy equivalent dose to the second group of 108 Gy, but in a shorter overall time. Dose–limiting toxicity in this study was defined as any toxicity of Radiation Therapy Oncology Group (RTOG) Grade 3 or more occurring with an incidence of 10%.
Inclusion and exclusion criteria The study had approval from the Hertfordshire Local Research Ethics Committee. Inclusion criteria were localized prostate cancer with no distant metastases, with a prostate-specific antigen (PSA) <40 mg/L and a staging pelvic magnetic resonance imaging scan before study entry to confirm node-negative disease. Patients were staged using the UICC/TNM 2002 staging system. Any stage up to T3b disease was permitted as this method of treatment delivery allows for successful implantation of the seminal vesicles. For those patients with a PSA >20 mg/L, a normal isotope bone scan was required. All patients had to be fit for a general anaesthetic and able to give written informed consent. Patients who had previous transurethral resection of the prostate were excluded.
Treatment and schedule The technique of HDR afterloading has been previously described (11, 20, 21). After implantation, computed tomography imaging was undertaken and the implant reconstructed using a three dimensional planning system (Brachyvision, Varian Medical System, Crawley, UK). The clinical target volume was defined by the prostate capsule with extension to cover extracapsular disease and seminal vesicle disease where demonstrated on staging magnetic resonance imaging. The planning target volume was a 2–3 mm volumetric expansion from the clinical target volume, constrained to the anterior rectal wall. On the day of the implant, patients received their first fraction of radiotherapy, Day 1. Fractions two and three were given the following day, with a minimum of 6 h between fractions. For those patients
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receiving a four-fraction regimen, this was given on the third day. Computed tomography scans were performed before the second and fourth fractions to assess catheter movement so that appropriate adjustments could be made to catheter dwell times or position to optimize dose distribution (22). Normal tissue constraints were defined for the urethra D30 to receive less than 125% of the prescribed dose and the anterior rectal wall D2mL to receive less than 100%. The primary end points were acute and late radiation toxicity. Acute toxicity was assessed using the RTOG scores for urologic and rectal toxicity, and the International Prostate Symptom Score urinary function scores (23). These were assessed at 2 weeks, 4 weeks, and 12 weeks. Late toxicity was measured by the Common Toxicity Criteria v 3.0 (24) in addition to RTOG scores at 6 months and then every 6 months thereafter. The secondary end point was biochemical relapse free survival; PSA was measured at 6 months after the implant and then every 6 months thereafter.
Statistical analysis Statistical comparisons were performed using version 5.1.2 JMP (SAS Institute, Cary, NC). Differences in Gleason scores and tumor stages between treatment schedules were compared using a contingency platform. Fisher’s exact test was used to test for significance between treatments from which two-tailed p values were obtained. Similarly, statistical differences in the prevalence of toxicity before HDR brachytherapy and at 6 and 12 months after treatment were tested using the same contingency platform. One-way analysis of variance was used to calculate mean PSA values and a Student’s t test was used to test for differences between dose groups.
RESULTS A total of 110 patients entered the study between November 2003 and December 2006: 30 receiving 34 Gy/four fractions, 25 receiving 36 Gy/four fractions, and the remaining 55 receiving 31.5 Gy/three fractions. The mean age of the treated patients was similar in the three groups ranging from 66 to 68 years. Follow-up ranged from a mean of 11.8 months in the 31.5 Gy dose group to 27 months in the 34 Gy dose group. This study therefore reports late toxicity for all three dose groups at 6 months. There were no statistically significant differences among the three dose groups in initial PSA (p $ 0.1) or Gleason score as shown in Tables 1, 2, and 3 respectively. The 31.5 Gy dose group had a significantly higher number of patients with stage T2 disease (p # 0.006) compared with the 34 Gy or 36 Gy dose group. There were significantly fewer patients with stage T1c disease in the 31.5 Gy dose group compared with the 34 Gy group (p = 0.0012). There were no significant differences among the three dose groups for stage T3 disease, as shown in Table 4. Urinary toxicity as measured by mean IPSS scores is shown in Fig 1. These did not differ significantly before treatment. At 2 weeks, acute urinary toxicity peaks reflected in a rise in the mean IPSS scores in all three groups, 12.2 (34 Gy), 13.1 (36 Gy), 9.6 (31.5 Gy); by 12 weeks, mean IPSS scores are back to pretreatment levels. No statistically significant difference was seen among the three dose levels. No data exist on the use of an alpha blocker during treatment, but its use was permitted in this study.
High-Dose-Rate Afterloading Brachytherapy as Monotherapy d C. CORNER et al.
Table 1. Mean ( 1 SEM) and median PSA (mg/L) in patients treated with androgen deprivation therapy Dose group 34 Gy Mean Median n 36 Gy Mean Median n 31.5 Gy Mean Median n p value
Pre-Rx
6 months
12 months
22.9 5.4 18.2 14
0.4 0.1 0.2 13
0.4 0.1 0.1 14
# 0.00001
23.7 5.7 12.3 15
0.08 0.02 0.02 14
0.2 0.1 0.1 15
# 0.00001
Dose Group
Grades 4–6
Grade 7
Grades 8–10
34 Gy 36 Gy 31.5 Gy p value
37% (11) 24% (6) 20% (11) $ 0.12
50% (15) 60% (15) 69% (37) $ 0.12
30% (4) 16% (4) 11% (6) $ 0.72
16.1 1.5 12.9 38 $ 0.1
0.6 0.3 0.1 26 $ 0.1
0.6 0.2 0.1 35 $ 0.2
# 0.0002
Number of patients in parentheses.
Table 2. Mean ( 1 SEM) and median PSA (mg/L) in patients not treated with androgen deprivation therapy
34 Gy Mean Median n 36 Gy Mean Median n 31.5 Gy Mean Median n p value
Table 3. Distribution of Gleason grades between groups
p value
Acute Grade 1 and 2 gastrointestinal toxicity peaked at 2 weeks after treatment affecting 61% (34 Gy), 68% (36 Gy), and 71% (31.5 Gy) of patients. By 12 weeks, this fell to 25%, 54%, and 27%, respectively (p = 0.560), as shown in Fig. 2. The urethral catheterization rate overall was low with seven patients (6%) requiring a urethral catheter at 2 weeks after the implant: 3 patients (34 Gy), 1 patient (36 Gy), and 3 patients (31.5 Gy). This improved with time and, by week 12 after implant, just 3 patients remained with a urethral catheter, all from the 31.5 Gy dose group. By 6 months, none of the patients in the study required a urethral catheter. The incidence of late bladder toxicity at 6 months was low with only 25% (34 Gy), 31% (36 Gy), and 28% (31.5 Gy) reporting RTOG Grade 1 toxicity or more. Two patients reported Grade 3 bladder toxicity at 6 months, 1 patient from 36 Gy group and 1 patient from the 31.5 Gy group. There was no significant difference in the incidence of late bladder toxicity among the three groups (p = 0.844). The incidence of late gastrointestinal toxicity assessed at 6 months was low; Grade 1 toxicity was seen in 20% (34 Gy), 8% (36 Gy), and 22% (31.5 Gy) of patients, respectively, and did not differ significantly among the three dose groups
Dose group
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Pre Rx
6 months
12 months
p value
11.8 1.8 9.8 16
1.5 0.4 0.8 15
1.5 0.5 0.7 15
# 0.00001
11.1 1.7 9.4 9
3.0 1.8 1.4 10
0.9 0.2 1.0 9
# 0.001
15.7 4.0 12.5 14 $ 0.3
0.9 0.7 0.1 11 $ 0.2
0.5 0.2 0.1 9 $ 0.06
# 0.001
(p = 0.710). One patient reported Grade 2 toxicity from the 31.5 Gy group; this was intermittent rectal bleeding. There were no cases of Grade 3 late intestinal toxicity. A total of 67 patients were receiving antiandrogen therapy in the form of a luteinizing hormone-releasing hormone agonist. Patients commenced neoadjuvant androgen deprivation therapy (ADT) at a median of 4 months (34 Gy and 36 Gy, respectively) and 3 months (31.5 Gy) before commencing HDR brachytherapy. The proposed end of ADT ranged from a median of 15 months (31.5 Gy) to 24 months (34 Gy), as shown in Table 5. The recommended duration of ADT was determined at the start of treatment by the Gleason score, T stage, and initial PSA. Patients with Gleason score 7, T2 disease, or PSA 10–20 mg/L were recommended 6 months’ total ADT. Patients with Gleason score 8–10, T3 disease, or PSA >20 mg/L were recommended 24 months’ total ADT. Biochemical response to treatment was stratified by ADT and no ADT as shown in Tables 1 and 2, respectively, and is assessable at 6 months and 12 months for the three dose groups. Median PSA (mg/L) for the ADT and no-ADT patients across the three dose groups at 6 months was 0.2 and 0.8, 0.02 and 1.4, and 0.1 and 0.1, respectively. At 12 months, this was 0.1 and 0.7, 0.1 and 1.0, and 0.1 and 0.1, respectively. There was no significant difference in the biochemical response observed among the three dose groups for both the ADT and no-ADT patients at 6 months p $ 0.1/p $ 0.2 and at 12 months p $ 0.2/p $ 0.06, respectively. DISCUSSION There is increasing evidence to support the view that prostate cancer has a low a/b ratio, in the 1.2–3.1 range (12–14). Hypofractionated regimes may be expected to produce improved tumor control. Predictions from radiobiologic models suggest brachytherapy as monotherapy or as a boost may Table 4. Distribution of tumor T stage among the three dose groups Dose group
T1c
T2
T3
34 Gy 36 Gy 31.5 Gy Comparisons 36 Gy vs. 31.5 Gy 34 Gy vs. 31.5 Gy
50% (14) 28% (7) 14% (6)
25% (7) 32% (8) 68% (30)
25% (7) 40% (10) 18% (8)
p = 0.201 p = 0.001
p = 0.006 p = 0.0006
p = 0.08 p = 0.56
There was no statistically significant difference between the T stages comparing 34 Gy with 36Gy dose group (p $ 0.16).
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Mean IPSS ± 1 SEM
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Table 5. Initiation and planned end of androgen deprivation therapy
12
Dose group Mean (months) Median (months) Range (months)
8 4 0
Pre-RT
2
4
12
Time from treatment (week)
Fig. 1. Mean International Prostate Symptom Score (IPSS) for patients treated with 34 Gy (solid circles and line), 36 Gy (open squares, dot-dashed line), or 31.5 Gy (solid triangles, dotted line) and determined before the start of treatment and at 2, 4, and 12 weeks after high-dose rate brachytherapy. Errors are 1 standard error of mean (SEM).
achieve superior tumor control compared with dose escalation using three-dimensional conformal external beam radiotherapy (25). High-dose-rate brachytherapy has been extensively studied as a boost after external beam radiation therapy in intermediate- to high-risk prostate cancer to achieve improved biochemical disease control (8–11). The published data on HDR monotherapy for intermediate- to high-risk prostate cancer is limited. Yoshioka et al. (19) studied 43 patients with localized disease, 38 of whom were of intermediate to high risk. Their results suggested crude biochemical control rates for intermediate risk patients of 80% and for high risk 61%. One patient experienced Grade 4 acute toxicity. High-dose-rate afterloading brachytherapy is the optimal method of delivering high doses per fraction to the tumor with low dose to normal tissues as the dose distribution obeys the inverse square law. Furthermore, temporary implant techniques result in a conformal localized dose to an immobilized target in contrast to the additional setup errors and internal organ motion encountered in external beam therapy. Based on an a/b ratio of 1.5 Gy the 2 Gy fraction equivalent doses received in this study in the 34 Gy, 36 Gy, and 31.5 Gy groups were 97.1 Gy, 108 Gy, and 108 Gy, respec100 80
Incidence (%)
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60 40 20 0
Week 2
Week 4
Week 12
Fig. 2. Bar histogram representing the incidence of acute Grade 1 and 2 gastrointestinal toxicity ( 1 standard deviation) at 2, 4, and 12 weeks after high-dose-rate brachytherapy with 34 Gy (gray bar), 36 Gy (black), or 31.5 Gy (open bars).
34 Gy Initiation End 36 Gy Initiation End 31.5 Gy Initiation End
4.5 18.6
4 24
2–8 6–24
3.7 20
4 24
0–8 6–24
3.9 14.9
3 15
1–11 3–24
tively. If the a/b ratio were 3.5 Gy, the relative 2 Gy fraction equivalent doses would be 74.2 Gy, 81.8 Gy, and 80.2 Gy, respectively. If the a/b ratio for prostate cancer is lower than that of critical normal tissues, then the risk of late normal tissue damage cannot be reduced by fractionation (17). Therefore ,to minimize late effects, the volume of critical normal tissue treated must be kept as low as possible. In a recent study by Kupelian et al. (26) morbidity was reported with hypofractionated external beam radiotherapy after 70 Gy in 2.5-Gy fractions. RTOG late rectal toxicity was reported as Grade 2 or more in 4.5% of patients and late urinary toxicity scores were 2 or more in 5.2%. This is higher than reported in this study, in which late rectal toxicity at 6 months was seen in 0.01% (1 patient) and late urinary toxicity in 0.02% (2 patients). Brachytherapy is the optimal technique to minimize the irradiated volume of the rectum and urethra, with a steep dose gradient within the planning target volume. Because of the large combination of dwell times and positions possible with the HDR afterloading technique, complex dose distributions can be designed to provide a relative cold spot around the urethra and also limit the rectal dose (27). Given the incidence of late rectal toxicity seen with hypofractionated external beam radiotherapy (26), HDR brachytherapy appears to be a more effective way of sparing the urethra and anterior rectal wall, therefore minimizing significant late toxicity. Additional advantages of HDR monotherapy as given in this study is that radical treatment can be completed in just three fractions, which is more convenient for patients and more cost-effective for the treating hospital. The interfraction interval of at least 6 h was stipulated to allow for normal tissue repair. There are very limited data on the radiobiologic characteristics of prostate cancer. A relatively long cell-cycle time and potential volume doubling time ranging from 16 to 61 days is reported (28). This suggests that time-dependent factors such as repopulation, reoxygenation, and reassortment may not be important in the response of prostate cancer to radiotherapy, and that acceleration alone will have no benefits. High-dose-rate brachytherapy has been reported to cause less acute genitourinary toxicity, less acute rectal pain, and less late urinary toxicity than LDR brachytherapy (10) and fewer late effects also.
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In this Phase II study of 110 patients, we confirm that toxicity with hypofractionated HDR monotherapy is low. Because mean follow-up varies among the three dose groups, acute and late toxicity is reported for all three dose groups up to 6 months. Acute urinary toxicity peaks in week 2 after the implant, but by week 12 has returned to baseline. This is in contrast to the pattern seen after LDR seed brachytherapy when acute symptoms persist for 6 months or more (10). The urinary catheterization rate was 6% in this study, which compares favorably with the 10–15% urinary catheterization rates observed with LDR. The 3 patients in this study that remained with a urethral catheter at 12 weeks were all from the higher dose per fraction cohort receiving 31.5 Gy. None of the patients required a urethral catheter at 6 months. It is feasible that the higher dose fractions (10.5 Gy) in this group may correlate with an increased risk of catheter dependency at 12 weeks. However, by 6 months, this has resolved. Acute gastrointestinal toxicity was low grade and short lived, with no reported cases of Grade 3 toxicity. Few patients experienced more than Grade 1 late bladder or intestinal toxicity. There was one case of late Grade 2 intestinal toxicity from the 31.5-Gy dose group arising at 6 months. Because this group has the shortest mean follow-up (11.8 months), future toxicity data will determine if this is an effect of the
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higher BED or whether this toxicity resolves. In this study, there was no statistically significant difference seen in the toxicity data at 6 months among the three dose groups. Sixty-seven patients were receiving ADT with a luteinizing hormone-releasing hormone agonist during treatment with a mean proposed duration of 14.9–20 months. This may impact favorably on the PSA nadir at 6 months and 12 months. However, our results show equivalent median biochemical responses for the ADT and no-ADT patients in the higher BED group of 31.5 Gy: at 6 months 0.1 mg/L and 12 months 0.1 mg/L, respectively. CONCLUSION The results from this study show equivalent low rates of acute and late urinary and rectal toxicity across the three dose groups. Initial biochemical disease control is excellent and appears equivalent among the three groups when stratified for ADT and no-ADT treated patients; however, longer follow-up is required to evaluate this further. The low toxicity seen with this approach suggests further dose escalation could be possible, although longer term follow-up to confirm late toxicity events is required before proceeding in this way.
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