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High-Dose-Rate Brachytherapy as a Monotherapy for Favorable-Risk Prostate Cancer: A Phase II Trial
Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 5, pp. 1889–1896, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter
doi:10.1016/j.ijrobp.2010.09.006
CLINICAL INVESTIGATION
Genitourinary Cancer
HIGH-DOSE-RATE BRACHYTHERAPY AS A MONOTHERAPY FOR FAVORABLE-RISK PROSTATE CANCER: A PHASE II TRIAL MAROIE BARKATI, F.R.C.P.C.,* SCOTT G. WILLIAMS, M.D., F.R.A.N.Z.C.R.,*z FARSHAD FOROUDI, F.R.A.N.Z.C.R.,*z KEEN HUN TAI, F.R.A.N.Z.C.R.,*z SARAT CHANDER, F.R.A.N.Z.C.R.,*z SYLVIA VAN DYK, D.APP.SC.,* ANDREW SEE, F.R.A.N.Z.C.R.,y z AND GILLIAN M. DUCHESNE, M.D., F.R.C.R., F.R.A.N.Z.C.R.* *Division of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Australia; yBallarat Austin Radiation Oncology Centre, Ballarat, Australia; and zDepartment of Pathology, University of Melbourne, Melbourne, Australia Purpose: There are multiple treatment options for favorable-risk prostate cancer. High-dose-rate (HDR) brachytherapy as a monotherapy is appealing, but its use is still investigational. A Phase II trial was undertaken to explore the value of such treatment in low-to-intermediate risk prostate cancer. Methods and Materials: This was a single-institution, prospective study. Eligible patients had low-risk prostate cancer features but also Gleason scores of 7 (51% of patients) and stage T2b to T2c cancer. Treatment with HDR brachytherapy with a single implant was administered over 2 days. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10, 10.5, 11, or 11.5 Gy. Patients were assessed with the Common Terminology Criteria for Adverse Events version 2.0 for urinary toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring schema for rectal toxicity, and the Expanded Prostate Cancer Index Composite (EPIC) questionnaire to measure patient-reported health-related quality of life. Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/ml. Results: Between 2003 and 2008, 79 patients were enrolled. With a median follow-up of 39.5 months, biochemical relapse occurred in 7 patients. Three- and 5-year actuarial biochemical control rates were 88.4% (95% confidence interval [CI], 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Acute grade 3 urinary toxicity was seen in only 1 patient. There was no instance of acute grade 3 rectal toxicity. Rates of late grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were 0%, 10.3%, 1.3%, 9.0%, and 0%, respectively. No grade 4 or greater toxicity was recorded. Among the four (urinary, bowel, sexual, and hormonal) domains assessed with the EPIC questionnaire, only the sexual domain did not recover with time. Conclusions: HDR brachytherapy as a monotherapy for favorable-risk prostate cancer, administered using a single implant over 2 days, is feasible and has acceptable acute and late toxicities. Further follow-up is still required to better evaluate the efficacy of such treatment. Ó 2012 Elsevier Inc. High-dose rate, Brachytherapy, Prostate cancer, Toxicity, Quality of life.
INTRODUCTION
high-dose-rate (HDR) boosts using iridium-192 within needles for intermediate- and high-risk disease. Most of the data published in the literature relate to HDR brachytherapy as a boost given before or after a course of external beam radiotherapy for intermediate- or high-risk prostate cancer (1). HDR brachytherapy as a monotherapy is still in a clinical trial phase, although there have been a few publications since the year 2000 that have shown promising outcomes (2–7). HDR monotherapy seems to be associated with decreased rates of acute and late toxicity compared to LDR palladium brachytherapy for low-risk prostate cancer (8, 9). However, iodine-125 seeds are more commonly
There are multiple treatment options for favorable-risk prostate cancer, including radical prostatectomy, external beam radiotherapy, brachytherapy, and watchful waiting. In the absence of randomized trials showing superior efficacy of one modality over another, treatment assignment is usually influenced by physician bias and patient preference. With the refinement of transrectal ultrasound (TRUS) imaging from the mid 1980s onward, there has been renewed interest in interstitial brachytherapy techniques. These include permanent low-dose-rate (LDR) iodine or palladium seed implantation for favorable-risk disease and temporary
Presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium, San Francisco, CA, March 5-7 2010. Conflict of interest: none. Received March 17, 2010, and in revised form Sept 1, 2010. Accepted for publication Sept 15, 2010.
Reprint requests to: Scott G. Williams, Division of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Victoria 8006, Australia. Tel: (+61) 3 9656 1111; Fax: (+61) 3 9656 1424; E-mail: scott.williams@ petermac.org 1889
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used today, and it is unknown whether these results can be extrapolated. HDR monotherapy for prostate cancer is appealing for many reasons. It is convenient for the patient, with the total dose being delivered in less than 1 week; the treatment is cheaper than permanent seed brachytherapy (8); optimization is possible by altering both the source dwell times and positions to provide an acceptable dose distribution (although real-time inverse optimization is now commonly used for LDR brachytherapy); the sharp dose fall-off allows for relative sparing of adjacent critical organs; there are fewer radioprotection issues as the radioactive source does not remain in the patient, and the medical staff are free from radiation exposure. Also, since many publications about the radiobiology of prostate cancer converge to a low alpha-beta ratio (10–13), general interest in hypofractionated schedules has increased. In that context, a Phase II trial was initiated at Peter MacCallum Cancer Centre (Melbourne, Australia) to explore the value of HDR brachytherapy used as a monotherapy for men presenting with favorable-risk prostate cancer. This study is a preliminary report of feasibility, acute and chronic toxicity, quality of life, as well as early biochemical control rates. METHODS AND MATERIALS Study design This is a Phase II, single-institution, prospective study. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10 Gy, 10.5 Gy, 11 Gy, or 11.5 Gy. These dose levels represented the minimal peripheral dose to the target volume. The treatment was given via a single implant and delivered over 2 days. Once 20 patients had been recruited to the first dose level, acute toxicity (i.e., the maximum grade demonstrated within 3 months of treatment with the Common Terminology Criteria for Adverse Events [CTCAE] version 2.0 and Radiation Therapy Oncology Group acute radiation morbidity scoring systems) was evaluated prior to initiating recruitment to the next dose level. Twenty patients were to be recruited for each dose level for a total of 80 patients. Consideration was given to stopping the trial early or to reducing the dose if the severity of toxicity was unacceptable or if the accrual was poor. This study received approval from the Peter MacCallum Cancer Centre Human Research Ethics Committee.
Selection criteria Eligible patients were referred for radiotherapy with histologically proven favorable-risk adenocarcinoma of the prostate, with clinical stage T1c to T2c disease (2002 TNM palpation staging system) and without clinical or radiographic evidence of metastases. Favorable risk was defined as a Gleason score of 7 or less, clinical stage T2c or less, and prostate-specific antigen (PSA) concentration of 10 ng/ml or less. Patients had to have a projected life expectancy greater than 10 years and an Eastern Cooperative Oncology Group performance status of 0 or 1. Written informed consent was required. Exclusion criteria included prior pelvic radiotherapy; clinical, radiological, or pathologic evidence of nodal or distant metastatic disease; concurrent active malignancy other than nonmetastatic skin cancer or early-stage lymphocytic leukemia (previous malignancy in remission for $5 years was not an exclusion criterion); transurethral resection of the prostate (TURP) within 5
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years prior to registration (patients who underwent TURP more than 5 years prior to registration were eligible provided they had a small residual TURP defect); prostate volume of >60 cc (at time of implantation); baseline International Prostate Symptom Score (IPSS) of $9 (relative contraindication); and peak urinary flow rate of <15 ml/sec. Previous androgen deprivation therapy was allowed in the beginning of the trial, but the protocol was amended in 2005 to exclude these patients based on the lack of benefit of such treatment in favorable-risk prostate cancer patients.
Pretreatment evaluation Complete history and physical examination findings were recorded for all patients. Serum PSA and testosterone level tests were repeated if the latest ones had been done more than 4 weeks and 3 months, respectively, prior to registration. A bone scan and computed tomography (CT) scan of the pelvis were performed to exclude metastatic disease. The modified Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire was administered to each patient prior to treatment to measure health-related quality of life (HRQOL). A central review of the pathology at the time of registration and for all posttreatment biopsies was undertaken.
Treatment Under spinal anesthesia, patients were placed in a high lithotomy position. The perineum was shaved and prepared with antiseptic solution. A 16-F single-lumen Foley catheter was then passed into the bladder, and dilute contrast solution was used to inflate the balloon. All patients received gram-negative intravenous antibiotic cover at induction. Using TRUS guidance, we determined the maximum prostate length, width, and height, and gland volume was approximated using the formula: gland volume (cc) = 0.54 length (cm) height (cm) width (cm). Pro-guide needles (Nucletron, Veenendal, The Netherlands) were then inserted into the prostate under TRUS guidance. Needles were spaced to ensure sufficient gland coverage with the prescription dose and to allow for central urethral sparing. Needle depth was determined from sagittal plane imaging, with tips commonly placed beyond the prostate base, given the potential for caudal needle displacement, and to compensate for a 5mm dosimetric dead space between the needle tips and the first dwell position. After the implantation, patients underwent planning CT scanning. The dataset was exported to a Nucletron BPS version 14.1 unit for physician contouring and forward planning. The target (prostate, from base to apex, plus a 2- to 5-mm margin, except posteriorly where there was no margin) and the urethra and rectum were contoured. The base of seminal vesicles was contoured in men with a risk of seminal vesicle involvement of more than 15%, using the Roach formula (14). The plan was accepted if the volume of the target receiving at least 95% of the prescribed dose (V95) was more than 95% and if the dose received by at least 90% of the target (D90) was more than 90% of the prescribed dose. Also, an effort was made to minimize the contiguity of 150% isodose lines and to keep the volume of the target receiving at least 200% of the prescribed dose (V200) to less than 15%. Normal tissue constraints were defined for the urethra and rectum. The urethra received less than 120% of the prescribed dose. The 70% isodose line did not penetrate beyond 3 mm into the anterior rectal wall. HDR brachytherapy was delivered using an iridium-192 stepping source unit (MicroSelectron, Nucletron NV, The Netherlands). The minimal interfraction interval was 6 h. Needle position verification for each fraction was initially assessed by measuring the external catheter length. While the protocol was still active, the technique evolved to include fiducial seed placement and
HDR monotherapy for prostate cancer d M. BARKATI et al.
pretreatment fluoroscopic imaging. In the case of needle slippage inferiorly, catheter length parameters were adjusted to correct for the implant movement relative to the prostate. This new verification technique was used for the last 22 patients.
Patient follow-up Patients were assessed prior to treatment, at 1 month after HDR brachytherapy, then at 3 and 6 months, and thereafter every 6 months for up to 60 months. A history and physical examination, a serum PSA test, and a toxicity assessment using the National Cancer Institute’s CTCAE were obtained at each visit. Quality of life assessment using the patient-reported EPIC questionnaire was done prior to treatment and then again at 1, 3, 6, 12, 24, 36, 48, and 60 months after HDR brachytherapy. The specific questions concerning ability to achieve an erection and the quality of erections were dichotomized at levels of 3 or more and 4 or more, implying good or very good ability to achieve an erection and erections adequate for intercourse, respectively. Adequate sexual function was defined as a sexual function subdomain score of 65 (15). Biochemical relapse was defined according to American Society for Radiation Oncology (ASTRO) consensus guidelines (16) at the beginning of the study and then according to the Phoenix definition (PSA nadir plus 2 ng/ml) (17). Patients with a PSA level rise followed by a drop to a level below PSA nadir plus 2 ng/ml were considered to be having a PSA bounce. When used for comparative purposes, the prior ASTRO consensus definition was defined as three consecutive PSA rises above the last nonrising value and was backdated to the midpoint between the first PSA rise and the previous PSA value (16). Biochemical relapse would have prompted an investigation with a bone scan and a CT scan of the pelvis. A prostate biopsy was undertaken to confirm local recurrence when it was suspected, according to clinical examination or radiological imaging.
Statistical analysis The primary endpoint was biochemical control. Secondary endpoints included quality of life assessment and acute and chronic toxicity. Differences in covariate distributions were assessed using chi-square and Kruskal-Wallis tests for categorical and continuous covariates, respectively. Actuarial biochemical control rates were measured using the Kaplan-Meier method with confidence intervals obtained by bootstrap resampling (n = 1,000). Time to failure was measured from the date of commencement of brachytherapy to the date of first failure. Quality of life and toxicity are reported using summary descriptive statistics and actuarial rates of potency. Statistical analyses were performed with R version 2.9.2 software (R Foundation for Statistical Computing, Vienna, Austria). Statistical tests were always two-sided and deemed to be significant at a p value of 0.05.
RESULTS Between June 2003 and October 2008, 79 patients met the eligibility criteria and were enrolled in this trial. Patients’ characteristics are shown in Table 1. The first 19 patients received 30 Gy in 3 fractions, the following 19 eligible patients were treated with 31.5 Gy in 3 fractions, the following 19 patients received 33 Gy in 3 fractions, and the last 22 patients received a total dose of 34.5 Gy in 3 fractions. There were no statistically significant differences among age distributions, PSA levels, Gleason scores, or disease stages across the four
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Table 1. Patients characteristics Characteristic No. of patients Median age (range) T stage
PSA at diagnosis (ng/ml) Gleason score Neoadjuvant hormone therapy Brachytherapy dose level
Grade or score
No. of patients or test value (range)
1c 2a 2b 2c Mean Median Range 5 6 7 Yes No 3 10 Gy 3 10.5 Gy 3 11Gy 3 11.5 Gy
79 66 (47–77) 34 23 18 4 6.8 6.8 2–10 1 38 40 7 72 19 19 19 22
dose levels. The use of neoadjuvant androgen deprivation therapy (nADT) did vary across the dose cohorts, with 5 patients being treated with nADT in the 10-Gy arm and 2 patients treated in the 10.5-Gy arm; however, no patients received nADT in the 11-Gy or 11.5-Gy arm (p = 0.005). A total of 6 patients were not eligible for this study for the following reasons: Gleason score of 8 on pathology review (n = 2), prostate volume of 74 cc, urinary flow rate of <10 ml/sec, cerebral vascular accident before the procedure, and severe anxiety. Median follow-up for the whole group was 39.5 months (range, 1-64 months). Median follow-up for each dose level group was 56 months for the 30-Gy arm, 49 months for the 31.5-Gy arm, 36 months for the 33-Gy arm, and 13 months for the 34.5-Gy arm. Clinical outcome In total, there were 7 patients who had biochemical relapses according to the Phoenix definition (17) (5 of whom had a Gleason score of 7), excluding 6 patients with likely PSA bounces. Of those patients who relapsed, 3 patients were treated with 30 Gy and 4 patients with 31.5 Gy. Of these patients, 3 patients had clinical relapse: 1 patient had a local relapse, 1 patient had bone metastases, and 1 patient had an enlarged pelvic lymph node on CT scan. The patient with a local recurrence relapsed 5 years after prostate HDR brachytherapy. He underwent magnetic resonance imaging and a biopsy. Pathology showed a carcinosarcoma of the prostate that was thought to be a radiation-induced tumor possibly related to previous radiotherapy he had undergone in the 1970s for testis cancer. Three- and 5-year actuarial biochemical control rates for the whole group were 88.4% (95% CI, 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Corresponding values for the original ASTRO definition were 80.2% (95% CI, 68.4-90.3%) and 76.6% (95% CI, 63.6-88.1%), respectively. Figure 1a–c shows biochemical control rates for the whole group, for each dose level, and for Gleason score groups, respectively. Median
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(a)
(b)
(c)
Fig. 1. (a) Biochemical control is shown for the whole group of patients (N = 79), using the Phoenix definition, including and excluding patients with likely PSA bounces. (b) Biochemical control is shown for patients treated at each dose level (3 fractions of 10 Gy, 10.5 Gy, 11 Gy and 11.5 Gy). (c) Biochemical control shown according to Gleason score (GS) group. Five-year estimated biochemical control rates are shown for patients with GS of #6; and a GS of 7 is 89.1% (95% CI, 74.6-100%) and 78.0% (95% CI, 56.0-94.1%), respectively (p = 0.43).
time to biochemical failure was 33 months (range, 15-55 months). Of all the patients, 2 patients required hormone treatment. Toxicity Data for acute and late toxicity were available for 73 and 78 patients, respectively. Toxicities are detailed in Tables 2
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and 3. Acute toxicity was assessed in the first 3 months following treatment. Acute grade 3 urinary toxicity (dysuria) occurred in 1 patient (1.3%). There was no acute grade 3 rectal toxicity. Late toxicity was assessed at 3 months after treatment. Rates of late grade 3 rectal toxicity were 0%, 10.3% for dysuria, 1.3% for hematuria, 9.0% for urinary retention, and 0% for urinary incontinence. All patients with late grade 3 urinary retention had urethral strictures requiring either dilatation (n = 2) or urethrotomy (n = 5). Median time to diagnosis of urethral stricture was 19 months (range, 12-40 months). There was no acute or late grade 4 toxicity. Health-related quality of life Table 4 shows quality of life scores for four domains, urinary, bowel, sexual, and hormonal, as well as IPSS scores. Prior to treatment, 78% of patients had completed the HRQOL questionnaire. Compliance rate was 52% at 1 month following treatment, decreased to 36% at 6 months, and reached 67% at 48 months. In general, after a drop, most scores seemed to recover, at least partially. Only the sexual domain scores did not seem to recover with time. As for the urinary domain, IPSS scores appeared to improve with follow-up compared to the early posttreatment period. However, they did not reach the baseline scores (Fig. 2). Sexual function assessment The median pretreatment sexual function subdomain score was 64, implying that most men had less than satisfactory function. Overall, 63 patients (80%) had experienced a loss in sexual desire at some point during follow-up. Erectile dysfunction, defined as an erectile function inadequate for intercourse, was present in 42 men (53%) prior to therapy. In the remaining 37 men with adequate function, the cumulative incidence of inadequate erections reported at 36 months was 71% (95% CI, 55-87%). For the 31 men who reported good or very good ability to have an erection prior to brachytherapy, 89% (95% CI, 75-97%) had reported a decline in this function to lower levels at 36 months. Of all the patients, 37 patients (47%) used erectile aids at some point after treatment, including 1 patient who was already using erectile aids before brachytherapy. At the last follow-up, 20 patients (25%) were still using erectile aids, and only 4 men had what was termed acceptable sexual function (defined as 65 points on the EPIC sexual function subdomain) at last follow-up of the 27 patients with levels higher than that at pretreatment. Hematospermia and orgasmalgia occurred in 32% and 27% of patients, respectively. DISCUSSION HDR brachytherapy as a monotherapy was initiated in Japan in 1995, and results were published for the first time in 2000 (7). To date, only five institutions have published their results, with median follow-up ranging from 8 months to 4.8 years (2–9, 18, 19). Patients treated in these institutions had low-, intermediate-, or high-risk disease and received
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Table 2. Acute toxicity Dose group (no. of patients) Grade
All patients (n = 73)
3 10 Gy (n = 18)
3 10.5 Gy (n = 17)
3 11 Gy (n = 18)
3 11.5 Gy (n = 20)
0 1 2 3 Data not available 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
52 18 1 0 2 34 31 7 1 69 2 2 0 47 24 2 0 68 4 1 0
15 3 0 0 0 11 6 1 0 17 1 0 0 14 4 0 0 16 2 0 0
9 7 1 0 0 7 8 2 0 16 0 1 0 11 5 1 0 17 0 0 0
12 4 0 0 2 8 8 2 0 16 1 1 0 10 7 1 0 17 0 1 0
16 4 0 0 0 8 9 2 1 20 0 0 0 12 8 0 0 18 2 0 0
Toxicity Rectal toxicity
Dysuria
Gross hematuria
Urinary retention
Urinary incontinence
This Phase II study of 79 patients treated at Peter MacCallum Cancer Centre with HDR brachytherapy as a monotherapy for favorable-risk prostate cancer showed that dose escalation was feasible and that treatments were well tolerated. Toxicity rates were equally distributed among the different dose fractionation schemes, as shown in Tables 2 and 3. Even though the last dose level (34.5-Gy) group had a short median follow-up (13 months), acute toxicity
different dose fractionation schedules. Despite the inclusion of patients with locally advanced cancers, the reported biochemical control rates ranged from 83% to 100% at 3 years. Toxicity reports were also promising. High-grade gastrointestinal toxicity (grade, $3) was rare, and rates of highgrade acute and late urinary toxicity ranged from 3% to 10% and from 2% to 11%, respectively. None of these studies reported HRQOL data.
Table 3. Late toxicity Dose group (no. of patients) Toxicity Rectal
Dysuria
Gross hematuria
Urinary retention
Urinary incontinence
Grade
All patients (n = 78)
3 10 Gy (n = 19)
3 10.5 Gy (n = 19)
3 11 Gy (n = 19)
3 11.5 Gy (n = 21)
0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
45 29 4 0 30 28 12 8 57 6 14 1 40 31 0 7 64 10 4 0
17 2 0 0 12 6 1 0 16 1 2 0 10 7 0 2 18 1 0 0
1 15 3 0 4 5 5 5 11 1 6 1 6 9 0 4 12 5 2 0
11 7 1 0 3 11 3 2 12 4 3 0 9 9 0 1 14 3 2 0
16 5 0 0 11 6 3 1 18 0 3 0 15 6 0 0 20 1 0 0
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Table 4. Health-related quality of life scores using EPIC Mean follow-up score (range) Domain
Baseline (n = 62)
1 month (n = 41)
3 months (n = 35)
6 months (n = 26)
12 months (n = 29)
48 months (n = 20)
Urinary Bowel Sexual Hormonal IPSS
93.1 (70.6–100) 96.4 (72.2–100) 70.2 (8.2–94.7) 93.2 (72.6–100) 2 (0–13)
66.7 (26.1–93.6) 85.7 (50.0–100) 39.8 (0–82.9) 84.1 (57.2–100) 14 (2–31)
88.9 (62.2–97.3) 96.4 (68.7–100) 37.8 (15.1–87.2) 93.2 (61.6–100) 6 (0.9–17.8)
89.1 (65.4–97.3) 94.6 (58.9–100) 37.2 (10.2–82.7) 90.9 (71.8–100) 5 (0–24.8)
80.3 (41.9–95.9) 92.0 (71.9–100) 32.7 (5.7–67.6) 95.5 (76.5–100) 7 (1–23)
84.1 (54.3–97.3) 94.6 (64.9–100) 35.9 (6.3–67.3) 95.5 (71.5–100) 6 (0.5–26.1)
Abbreviations: EPIC = Expanded Prostate Cancer Index Composite; IPSS = International Prostate Symptom Score.
rates were not increased compared to the lower-dose levels. Corner et al. (2) published a similar Phase II trial in which the highest dose level was 31.5 Gy in 3 fractions. Because of short follow-up, they reported acute and late toxicity at 6 months and found no significant differences among their three dose groups. Their median follow-up for the group of patients treated with 31.5 Gy in 3 fractions was only 11.8 months, and they concluded that further toxicity data are required, with longer follow-up. In our study, patients treated with 30 Gy, 31.5 Gy, 33 Gy, and 34.5 Gy had median followup times of 56, 49, 36, and 13 months, respectively. In our series, we report only 1 patient with acute grade 3 toxicity (dysuria). Excluding the last dose level group (with shorter follow-up), chronic grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were reported for 0%, 12.2%, 1.7%, 12.3%, and 0% of patients, respectively. Despite using a different fractionation scheme (4 fractions of 9.5 Gy), Ghadjar et al. (3) found similar rates of acute and late grade 3 urinary toxicity, with 1.3 % of patients having acute grade 3 urinary frequency/urgency and 11.1% of patients having late grade 3 urinary retention. HDR brachytherapy as prostate cancer monotherapy has been compared to LDR permanent seed brachytherapy in two retrospective studies from William Beaumont Hospital and the California Endocurietherapy Cancer Center (8, 9). Although the 5-year biochemical control rates were the same for both modalities (88% and 89%, respectively), acute and chronic toxicities were decreased with HDR
100 90 80 70 60 50 40 30 20 10 0 35 30 25 20 15 10 5 0
0
6
12
18
24
30
36
42
48
Months
Fig. 2. Health-related quality of life was recorded using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire and the International Prostate Symptom Score (IPSS).
brachytherapy. In a more recent report of 248 patients treated with HDR and 206 patients treated with LDR palladium-103 (9), there was less acute grade 1 to 3 dysuria (60% vs. 39%, p < 0.001, respectively), urinary frequency/ urgency (90% vs. 58%, p < 0.001, respectively), and rectal pain (17% vs. 6.5%, p < 0.001, respectively). Similarly, long-term dysuria and urinary frequency/urgency were significantly reduced with HDR, from 22% to 15% and from 54% to 43%, respectively. The rate of impotence was also reduced from 30% for LDR to 20% for HDR, but it did not reach statistical significance. The rate of urethral stricture was higher with HDR (8% vs. 3%, respectively), although it was not statistically significant (9). In a publication by Crook et al. (20), urinary stricture rate was 1.7% in patients treated with iodine-125 prostate brachytherapy, with a median follow-up of 41 months. This rate is lower than the rate of urethral stricture in our patients treated with HDR brachytherapy (9% for the whole group and 12.3% when patients with short follow-up are excluded). This rate is in agreement with the rate of 8% published previously by our group for patients treated with either HDR monotherapy or HDR brachytherapy boost to external beam radiotherapy (21). As follow-up matures, a higher rate of urethral strictures could possibly be seen, although the median time to diagnosis of urethral stricture was 19 months in our study. Interestingly, urethral strictures occurred more commonly at the level of the bulbomembranous urethra, which is beyond the high-dose region. In this study, we measured HRQOL by using the patientreported modified EPIC questionnaire. It assesses diseasespecific aspects of prostate cancer and its therapies, emphasizing urinary, bowel, sexual, and hormonal aspects. Test-retest reliability and internal consistency are high (22). To date, there are no HRQOL data for patients treated with HDR monotherapy. A few prospective multicenter cohort studies have used validated HRQOL instruments to measure HRQOL outcomes after prostatectomy, external beam radiotherapy, and LDR permanent seed brachytherapy (23–26). Unfortunately, brachytherapy data are limited to early follow-up (less than 1 year). All treatment modalities seem to affect HRQOL in a few domains. The sexual domain was the most commonly affected HRQOL domain, and the impact was shown beyond 1 year after treatment. Urinary and bowel domains seem to be affected similarly, with symptoms more commonly seen early after treatment. Data for the
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hormonal domain were not available in these studies (27). Our quality of life results from patients treated with HDR monotherapy compare favorably with results published for radical prostatectomy, external beam radiotherapy, and LDR brachytherapy (27). We also found that the sexual domain was the most affected and recovered little with time, reaching a plateau after 12 months of follow-up. The ability to achieve an erection was almost universally compromised, and erections had become inadequate in over 70% of patients at the 3-year mark, and only 4 men had acceptable global sexual function at last follow-up. The other three domains (urinary, bowel, and hormonal) recovered at least partially in our cohort of patients. In this trial of favorable-risk prostate cancer patients (in which 51% of patients had Gleason scores of 7), we report 3- and 5-year actuarial biochemical control rates of 88% and 85%, respectively. However, follow-up is still too short for patients treated at the high-dose level. Most outcomes for HDR monotherapy are reported at 3 years in the literature, and biochemical control rates ranged from 83% to 100% with median follow-up times between 11.8 and 36 months (2, 3, 6, 8). Five-year biochemical control rates were reported in two studies and ranged between 70% and 91% (6, 9). Comparisons with our results are difficult to make as inclusion criteria differ among studies, as some studies included patients with intermediate- and high-risk prostate
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cancer. In our cohort, the 7 patients with biochemical failures according to the Phoenix definition, and excluding patients with likely PSA bounces, were in the first two dose levels (30 Gy and 31.5 Gy). However, it is too early to conclude a dose response relationship as PSA level failures occurred at a median of 33 months, and longer follow-up is required for the group of patients treated at higher doses. Also, further follow-up will determine the dose level with the best treatment outcomes and reasonable toxicity.
CONCLUSIONS HDR brachytherapy as a monotherapy for low- and lowto-intermediate risk prostate cancer patients, using a single implant, and administered over 2 days is feasible and well tolerated. Acute and late toxicities are acceptable; the main late grade 3 toxicities being dysuria and urinary retention (urethral stricture). Except for the sexual domain, only mild changes occurred in HRQOL measurements. Longterm follow-up is required to assess the outcome after such treatment and to determine the appropriate dose. Also, a prospective trial in a multiinstitutional setting is warranted to compare HDR monotherapy with other standard treatments before adding it to the arsenal of treatments available for favorable-risk prostate cancer patients.
REFERENCES 1. Morton GC. The emerging role of high-dose-rate brachytherapy for prostate cancer. Clin Oncol (R Coll Radiol) 2005;17: 219–227. 2. Corner C, Rojas AM, Bryant L, et al. A Phase II study of highdose-rate afterloading brachytherapy as monotherapy for the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72:441–446. 3. Ghadjar P, Keller T, Rentsch CA, et al. Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy. Brachytherapy 2009;8:45–51. 4. Martin T, Baltas D, Kurek R, et al. 3-D conformal HDR brachytherapy as monotherapy for localized prostate cancer. A pilot study. Strahlenther Onkol 2004;180:225–232. 5. Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61–69. 6. Yoshioka Y, Konishi K, Oh RJ, et al. High-dose-rate brachytherapy without external beam irradiation for locally advanced prostate cancer. Radiother Oncol 2006;80:62–68. 7. Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial. Int J Radiat Oncol Biol Phys 2000;48:675– 681. 8. Grills IS, Martinez AA, Hollander M, et al. High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds. J Urol 2004;171: 1098–1104. 9. Martinez AA, Demanes J, Vargas C, et al. High-dose-rate prostate brachytherapy: An excellent accelerated-hypofractionated
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treatment for favorable prostate cancer. Am J Clin Oncol 2010; 33:481–488. 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. Duchesne GM, Peters LJ. What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 1999;44:747–748. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001;51:213–214. Williams SG, Taylor JM, Liu N, et al. Use of individual fraction size data from 3756 patients to directly determine the alpha/ beta ratio of prostate cancer. Int J Radiat Oncol Biol Phys 2007;68:24–33. Diaz A, Roach M 3rd, Marquez C, et al. Indications for and the significance of seminal vesicle irradiation during 3D conformal radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 1994;30:323–329. Levinson AW, Ward NT, Sanda MG, et al. Comparison of validated instruments measuring sexual function in men. Urology 2010;76:380–386. 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: 1035–1041. Roach M III, Hanks G, Thames H Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006; 65:965–974.
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18. Konishi K, Yoshioka Y, Isohashi F, et al. Correlation between dosimetric parameters and late rectal and urinary toxicities in patients treated with high-dose-rate brachytherapy used as monotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2009;75:1003–1007. 19. Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate brachytherapy as monotherapy for localized prostate cancer: a retrospective analysis with special focus on tolerance and chronic toxicity. Int J Radiat Oncol Biol Phys 2003;56:213–220. 20. Crook J, Fleshner N, Roberts C, et al. Long-term urinary sequelae following 125iodine prostate brachytherapy. J Urol 2008;179:141–146. 21. Sullivan L, Williams SG, Tai KH, et al. Urethral stricture following high dose rate brachytherapy for prostate cancer. Radiother Oncol 2009;91:232–236. 22. Wei JT, Dunn RL, Litwin MS, et al. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000;56:899–905.
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23. Downs TM, Sadetsky N, Pasta DJ, et al. Health related quality of life patterns in patients treated with interstitial prostate brachytherapy for localized prostate cancer: Data from CaPSURE. J Urol 2003;170:1822–1827. 24. Madalinska JB, Essink-Bot ML, de Koning HJ, et al. Healthrelated quality-of-life effects of radical prostatectomy and primary radiotherapy for screen-detected or clinically diagnosed localized prostate cancer. J Clin Oncol 2001;19: 1619–1628. 25. Potosky AL, Davis WW, Hoffman RM, et al. Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: The prostate cancer outcomes study. J Natl Cancer Inst 2004; 96:1358–1367. 26. Talcott JA, Manola J, Clark JA, et al. Time course and predictors of symptoms after primary prostate cancer therapy. J Clin Oncol 2003;21:3979–3986. 27. Dandapani SV, Sanda MG. Measuring health-related quality of life consequences from primary treatment for early-stage prostate cancer. Semin Radiat Oncol 2008;18:67–72.
doi:10.1016/j.ijrobp.2010.09.006
CLINICAL INVESTIGATION
Genitourinary Cancer
HIGH-DOSE-RATE BRACHYTHERAPY AS A MONOTHERAPY FOR FAVORABLE-RISK PROSTATE CANCER: A PHASE II TRIAL MAROIE BARKATI, F.R.C.P.C.,* SCOTT G. WILLIAMS, M.D., F.R.A.N.Z.C.R.,*z FARSHAD FOROUDI, F.R.A.N.Z.C.R.,*z KEEN HUN TAI, F.R.A.N.Z.C.R.,*z SARAT CHANDER, F.R.A.N.Z.C.R.,*z SYLVIA VAN DYK, D.APP.SC.,* ANDREW SEE, F.R.A.N.Z.C.R.,y z AND GILLIAN M. DUCHESNE, M.D., F.R.C.R., F.R.A.N.Z.C.R.* *Division of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Australia; yBallarat Austin Radiation Oncology Centre, Ballarat, Australia; and zDepartment of Pathology, University of Melbourne, Melbourne, Australia Purpose: There are multiple treatment options for favorable-risk prostate cancer. High-dose-rate (HDR) brachytherapy as a monotherapy is appealing, but its use is still investigational. A Phase II trial was undertaken to explore the value of such treatment in low-to-intermediate risk prostate cancer. Methods and Materials: This was a single-institution, prospective study. Eligible patients had low-risk prostate cancer features but also Gleason scores of 7 (51% of patients) and stage T2b to T2c cancer. Treatment with HDR brachytherapy with a single implant was administered over 2 days. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10, 10.5, 11, or 11.5 Gy. Patients were assessed with the Common Terminology Criteria for Adverse Events version 2.0 for urinary toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring schema for rectal toxicity, and the Expanded Prostate Cancer Index Composite (EPIC) questionnaire to measure patient-reported health-related quality of life. Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/ml. Results: Between 2003 and 2008, 79 patients were enrolled. With a median follow-up of 39.5 months, biochemical relapse occurred in 7 patients. Three- and 5-year actuarial biochemical control rates were 88.4% (95% confidence interval [CI], 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Acute grade 3 urinary toxicity was seen in only 1 patient. There was no instance of acute grade 3 rectal toxicity. Rates of late grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were 0%, 10.3%, 1.3%, 9.0%, and 0%, respectively. No grade 4 or greater toxicity was recorded. Among the four (urinary, bowel, sexual, and hormonal) domains assessed with the EPIC questionnaire, only the sexual domain did not recover with time. Conclusions: HDR brachytherapy as a monotherapy for favorable-risk prostate cancer, administered using a single implant over 2 days, is feasible and has acceptable acute and late toxicities. Further follow-up is still required to better evaluate the efficacy of such treatment. Ó 2012 Elsevier Inc. High-dose rate, Brachytherapy, Prostate cancer, Toxicity, Quality of life.
INTRODUCTION
high-dose-rate (HDR) boosts using iridium-192 within needles for intermediate- and high-risk disease. Most of the data published in the literature relate to HDR brachytherapy as a boost given before or after a course of external beam radiotherapy for intermediate- or high-risk prostate cancer (1). HDR brachytherapy as a monotherapy is still in a clinical trial phase, although there have been a few publications since the year 2000 that have shown promising outcomes (2–7). HDR monotherapy seems to be associated with decreased rates of acute and late toxicity compared to LDR palladium brachytherapy for low-risk prostate cancer (8, 9). However, iodine-125 seeds are more commonly
There are multiple treatment options for favorable-risk prostate cancer, including radical prostatectomy, external beam radiotherapy, brachytherapy, and watchful waiting. In the absence of randomized trials showing superior efficacy of one modality over another, treatment assignment is usually influenced by physician bias and patient preference. With the refinement of transrectal ultrasound (TRUS) imaging from the mid 1980s onward, there has been renewed interest in interstitial brachytherapy techniques. These include permanent low-dose-rate (LDR) iodine or palladium seed implantation for favorable-risk disease and temporary
Presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium, San Francisco, CA, March 5-7 2010. Conflict of interest: none. Received March 17, 2010, and in revised form Sept 1, 2010. Accepted for publication Sept 15, 2010.
Reprint requests to: Scott G. Williams, Division of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Victoria 8006, Australia. Tel: (+61) 3 9656 1111; Fax: (+61) 3 9656 1424; E-mail: scott.williams@ petermac.org 1889
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used today, and it is unknown whether these results can be extrapolated. HDR monotherapy for prostate cancer is appealing for many reasons. It is convenient for the patient, with the total dose being delivered in less than 1 week; the treatment is cheaper than permanent seed brachytherapy (8); optimization is possible by altering both the source dwell times and positions to provide an acceptable dose distribution (although real-time inverse optimization is now commonly used for LDR brachytherapy); the sharp dose fall-off allows for relative sparing of adjacent critical organs; there are fewer radioprotection issues as the radioactive source does not remain in the patient, and the medical staff are free from radiation exposure. Also, since many publications about the radiobiology of prostate cancer converge to a low alpha-beta ratio (10–13), general interest in hypofractionated schedules has increased. In that context, a Phase II trial was initiated at Peter MacCallum Cancer Centre (Melbourne, Australia) to explore the value of HDR brachytherapy used as a monotherapy for men presenting with favorable-risk prostate cancer. This study is a preliminary report of feasibility, acute and chronic toxicity, quality of life, as well as early biochemical control rates. METHODS AND MATERIALS Study design This is a Phase II, single-institution, prospective study. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10 Gy, 10.5 Gy, 11 Gy, or 11.5 Gy. These dose levels represented the minimal peripheral dose to the target volume. The treatment was given via a single implant and delivered over 2 days. Once 20 patients had been recruited to the first dose level, acute toxicity (i.e., the maximum grade demonstrated within 3 months of treatment with the Common Terminology Criteria for Adverse Events [CTCAE] version 2.0 and Radiation Therapy Oncology Group acute radiation morbidity scoring systems) was evaluated prior to initiating recruitment to the next dose level. Twenty patients were to be recruited for each dose level for a total of 80 patients. Consideration was given to stopping the trial early or to reducing the dose if the severity of toxicity was unacceptable or if the accrual was poor. This study received approval from the Peter MacCallum Cancer Centre Human Research Ethics Committee.
Selection criteria Eligible patients were referred for radiotherapy with histologically proven favorable-risk adenocarcinoma of the prostate, with clinical stage T1c to T2c disease (2002 TNM palpation staging system) and without clinical or radiographic evidence of metastases. Favorable risk was defined as a Gleason score of 7 or less, clinical stage T2c or less, and prostate-specific antigen (PSA) concentration of 10 ng/ml or less. Patients had to have a projected life expectancy greater than 10 years and an Eastern Cooperative Oncology Group performance status of 0 or 1. Written informed consent was required. Exclusion criteria included prior pelvic radiotherapy; clinical, radiological, or pathologic evidence of nodal or distant metastatic disease; concurrent active malignancy other than nonmetastatic skin cancer or early-stage lymphocytic leukemia (previous malignancy in remission for $5 years was not an exclusion criterion); transurethral resection of the prostate (TURP) within 5
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years prior to registration (patients who underwent TURP more than 5 years prior to registration were eligible provided they had a small residual TURP defect); prostate volume of >60 cc (at time of implantation); baseline International Prostate Symptom Score (IPSS) of $9 (relative contraindication); and peak urinary flow rate of <15 ml/sec. Previous androgen deprivation therapy was allowed in the beginning of the trial, but the protocol was amended in 2005 to exclude these patients based on the lack of benefit of such treatment in favorable-risk prostate cancer patients.
Pretreatment evaluation Complete history and physical examination findings were recorded for all patients. Serum PSA and testosterone level tests were repeated if the latest ones had been done more than 4 weeks and 3 months, respectively, prior to registration. A bone scan and computed tomography (CT) scan of the pelvis were performed to exclude metastatic disease. The modified Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire was administered to each patient prior to treatment to measure health-related quality of life (HRQOL). A central review of the pathology at the time of registration and for all posttreatment biopsies was undertaken.
Treatment Under spinal anesthesia, patients were placed in a high lithotomy position. The perineum was shaved and prepared with antiseptic solution. A 16-F single-lumen Foley catheter was then passed into the bladder, and dilute contrast solution was used to inflate the balloon. All patients received gram-negative intravenous antibiotic cover at induction. Using TRUS guidance, we determined the maximum prostate length, width, and height, and gland volume was approximated using the formula: gland volume (cc) = 0.54 length (cm) height (cm) width (cm). Pro-guide needles (Nucletron, Veenendal, The Netherlands) were then inserted into the prostate under TRUS guidance. Needles were spaced to ensure sufficient gland coverage with the prescription dose and to allow for central urethral sparing. Needle depth was determined from sagittal plane imaging, with tips commonly placed beyond the prostate base, given the potential for caudal needle displacement, and to compensate for a 5mm dosimetric dead space between the needle tips and the first dwell position. After the implantation, patients underwent planning CT scanning. The dataset was exported to a Nucletron BPS version 14.1 unit for physician contouring and forward planning. The target (prostate, from base to apex, plus a 2- to 5-mm margin, except posteriorly where there was no margin) and the urethra and rectum were contoured. The base of seminal vesicles was contoured in men with a risk of seminal vesicle involvement of more than 15%, using the Roach formula (14). The plan was accepted if the volume of the target receiving at least 95% of the prescribed dose (V95) was more than 95% and if the dose received by at least 90% of the target (D90) was more than 90% of the prescribed dose. Also, an effort was made to minimize the contiguity of 150% isodose lines and to keep the volume of the target receiving at least 200% of the prescribed dose (V200) to less than 15%. Normal tissue constraints were defined for the urethra and rectum. The urethra received less than 120% of the prescribed dose. The 70% isodose line did not penetrate beyond 3 mm into the anterior rectal wall. HDR brachytherapy was delivered using an iridium-192 stepping source unit (MicroSelectron, Nucletron NV, The Netherlands). The minimal interfraction interval was 6 h. Needle position verification for each fraction was initially assessed by measuring the external catheter length. While the protocol was still active, the technique evolved to include fiducial seed placement and
HDR monotherapy for prostate cancer d M. BARKATI et al.
pretreatment fluoroscopic imaging. In the case of needle slippage inferiorly, catheter length parameters were adjusted to correct for the implant movement relative to the prostate. This new verification technique was used for the last 22 patients.
Patient follow-up Patients were assessed prior to treatment, at 1 month after HDR brachytherapy, then at 3 and 6 months, and thereafter every 6 months for up to 60 months. A history and physical examination, a serum PSA test, and a toxicity assessment using the National Cancer Institute’s CTCAE were obtained at each visit. Quality of life assessment using the patient-reported EPIC questionnaire was done prior to treatment and then again at 1, 3, 6, 12, 24, 36, 48, and 60 months after HDR brachytherapy. The specific questions concerning ability to achieve an erection and the quality of erections were dichotomized at levels of 3 or more and 4 or more, implying good or very good ability to achieve an erection and erections adequate for intercourse, respectively. Adequate sexual function was defined as a sexual function subdomain score of 65 (15). Biochemical relapse was defined according to American Society for Radiation Oncology (ASTRO) consensus guidelines (16) at the beginning of the study and then according to the Phoenix definition (PSA nadir plus 2 ng/ml) (17). Patients with a PSA level rise followed by a drop to a level below PSA nadir plus 2 ng/ml were considered to be having a PSA bounce. When used for comparative purposes, the prior ASTRO consensus definition was defined as three consecutive PSA rises above the last nonrising value and was backdated to the midpoint between the first PSA rise and the previous PSA value (16). Biochemical relapse would have prompted an investigation with a bone scan and a CT scan of the pelvis. A prostate biopsy was undertaken to confirm local recurrence when it was suspected, according to clinical examination or radiological imaging.
Statistical analysis The primary endpoint was biochemical control. Secondary endpoints included quality of life assessment and acute and chronic toxicity. Differences in covariate distributions were assessed using chi-square and Kruskal-Wallis tests for categorical and continuous covariates, respectively. Actuarial biochemical control rates were measured using the Kaplan-Meier method with confidence intervals obtained by bootstrap resampling (n = 1,000). Time to failure was measured from the date of commencement of brachytherapy to the date of first failure. Quality of life and toxicity are reported using summary descriptive statistics and actuarial rates of potency. Statistical analyses were performed with R version 2.9.2 software (R Foundation for Statistical Computing, Vienna, Austria). Statistical tests were always two-sided and deemed to be significant at a p value of 0.05.
RESULTS Between June 2003 and October 2008, 79 patients met the eligibility criteria and were enrolled in this trial. Patients’ characteristics are shown in Table 1. The first 19 patients received 30 Gy in 3 fractions, the following 19 eligible patients were treated with 31.5 Gy in 3 fractions, the following 19 patients received 33 Gy in 3 fractions, and the last 22 patients received a total dose of 34.5 Gy in 3 fractions. There were no statistically significant differences among age distributions, PSA levels, Gleason scores, or disease stages across the four
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Table 1. Patients characteristics Characteristic No. of patients Median age (range) T stage
PSA at diagnosis (ng/ml) Gleason score Neoadjuvant hormone therapy Brachytherapy dose level
Grade or score
No. of patients or test value (range)
1c 2a 2b 2c Mean Median Range 5 6 7 Yes No 3 10 Gy 3 10.5 Gy 3 11Gy 3 11.5 Gy
79 66 (47–77) 34 23 18 4 6.8 6.8 2–10 1 38 40 7 72 19 19 19 22
dose levels. The use of neoadjuvant androgen deprivation therapy (nADT) did vary across the dose cohorts, with 5 patients being treated with nADT in the 10-Gy arm and 2 patients treated in the 10.5-Gy arm; however, no patients received nADT in the 11-Gy or 11.5-Gy arm (p = 0.005). A total of 6 patients were not eligible for this study for the following reasons: Gleason score of 8 on pathology review (n = 2), prostate volume of 74 cc, urinary flow rate of <10 ml/sec, cerebral vascular accident before the procedure, and severe anxiety. Median follow-up for the whole group was 39.5 months (range, 1-64 months). Median follow-up for each dose level group was 56 months for the 30-Gy arm, 49 months for the 31.5-Gy arm, 36 months for the 33-Gy arm, and 13 months for the 34.5-Gy arm. Clinical outcome In total, there were 7 patients who had biochemical relapses according to the Phoenix definition (17) (5 of whom had a Gleason score of 7), excluding 6 patients with likely PSA bounces. Of those patients who relapsed, 3 patients were treated with 30 Gy and 4 patients with 31.5 Gy. Of these patients, 3 patients had clinical relapse: 1 patient had a local relapse, 1 patient had bone metastases, and 1 patient had an enlarged pelvic lymph node on CT scan. The patient with a local recurrence relapsed 5 years after prostate HDR brachytherapy. He underwent magnetic resonance imaging and a biopsy. Pathology showed a carcinosarcoma of the prostate that was thought to be a radiation-induced tumor possibly related to previous radiotherapy he had undergone in the 1970s for testis cancer. Three- and 5-year actuarial biochemical control rates for the whole group were 88.4% (95% CI, 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Corresponding values for the original ASTRO definition were 80.2% (95% CI, 68.4-90.3%) and 76.6% (95% CI, 63.6-88.1%), respectively. Figure 1a–c shows biochemical control rates for the whole group, for each dose level, and for Gleason score groups, respectively. Median
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(b)
(c)
Fig. 1. (a) Biochemical control is shown for the whole group of patients (N = 79), using the Phoenix definition, including and excluding patients with likely PSA bounces. (b) Biochemical control is shown for patients treated at each dose level (3 fractions of 10 Gy, 10.5 Gy, 11 Gy and 11.5 Gy). (c) Biochemical control shown according to Gleason score (GS) group. Five-year estimated biochemical control rates are shown for patients with GS of #6; and a GS of 7 is 89.1% (95% CI, 74.6-100%) and 78.0% (95% CI, 56.0-94.1%), respectively (p = 0.43).
time to biochemical failure was 33 months (range, 15-55 months). Of all the patients, 2 patients required hormone treatment. Toxicity Data for acute and late toxicity were available for 73 and 78 patients, respectively. Toxicities are detailed in Tables 2
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and 3. Acute toxicity was assessed in the first 3 months following treatment. Acute grade 3 urinary toxicity (dysuria) occurred in 1 patient (1.3%). There was no acute grade 3 rectal toxicity. Late toxicity was assessed at 3 months after treatment. Rates of late grade 3 rectal toxicity were 0%, 10.3% for dysuria, 1.3% for hematuria, 9.0% for urinary retention, and 0% for urinary incontinence. All patients with late grade 3 urinary retention had urethral strictures requiring either dilatation (n = 2) or urethrotomy (n = 5). Median time to diagnosis of urethral stricture was 19 months (range, 12-40 months). There was no acute or late grade 4 toxicity. Health-related quality of life Table 4 shows quality of life scores for four domains, urinary, bowel, sexual, and hormonal, as well as IPSS scores. Prior to treatment, 78% of patients had completed the HRQOL questionnaire. Compliance rate was 52% at 1 month following treatment, decreased to 36% at 6 months, and reached 67% at 48 months. In general, after a drop, most scores seemed to recover, at least partially. Only the sexual domain scores did not seem to recover with time. As for the urinary domain, IPSS scores appeared to improve with follow-up compared to the early posttreatment period. However, they did not reach the baseline scores (Fig. 2). Sexual function assessment The median pretreatment sexual function subdomain score was 64, implying that most men had less than satisfactory function. Overall, 63 patients (80%) had experienced a loss in sexual desire at some point during follow-up. Erectile dysfunction, defined as an erectile function inadequate for intercourse, was present in 42 men (53%) prior to therapy. In the remaining 37 men with adequate function, the cumulative incidence of inadequate erections reported at 36 months was 71% (95% CI, 55-87%). For the 31 men who reported good or very good ability to have an erection prior to brachytherapy, 89% (95% CI, 75-97%) had reported a decline in this function to lower levels at 36 months. Of all the patients, 37 patients (47%) used erectile aids at some point after treatment, including 1 patient who was already using erectile aids before brachytherapy. At the last follow-up, 20 patients (25%) were still using erectile aids, and only 4 men had what was termed acceptable sexual function (defined as 65 points on the EPIC sexual function subdomain) at last follow-up of the 27 patients with levels higher than that at pretreatment. Hematospermia and orgasmalgia occurred in 32% and 27% of patients, respectively. DISCUSSION HDR brachytherapy as a monotherapy was initiated in Japan in 1995, and results were published for the first time in 2000 (7). To date, only five institutions have published their results, with median follow-up ranging from 8 months to 4.8 years (2–9, 18, 19). Patients treated in these institutions had low-, intermediate-, or high-risk disease and received
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Table 2. Acute toxicity Dose group (no. of patients) Grade
All patients (n = 73)
3 10 Gy (n = 18)
3 10.5 Gy (n = 17)
3 11 Gy (n = 18)
3 11.5 Gy (n = 20)
0 1 2 3 Data not available 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
52 18 1 0 2 34 31 7 1 69 2 2 0 47 24 2 0 68 4 1 0
15 3 0 0 0 11 6 1 0 17 1 0 0 14 4 0 0 16 2 0 0
9 7 1 0 0 7 8 2 0 16 0 1 0 11 5 1 0 17 0 0 0
12 4 0 0 2 8 8 2 0 16 1 1 0 10 7 1 0 17 0 1 0
16 4 0 0 0 8 9 2 1 20 0 0 0 12 8 0 0 18 2 0 0
Toxicity Rectal toxicity
Dysuria
Gross hematuria
Urinary retention
Urinary incontinence
This Phase II study of 79 patients treated at Peter MacCallum Cancer Centre with HDR brachytherapy as a monotherapy for favorable-risk prostate cancer showed that dose escalation was feasible and that treatments were well tolerated. Toxicity rates were equally distributed among the different dose fractionation schemes, as shown in Tables 2 and 3. Even though the last dose level (34.5-Gy) group had a short median follow-up (13 months), acute toxicity
different dose fractionation schedules. Despite the inclusion of patients with locally advanced cancers, the reported biochemical control rates ranged from 83% to 100% at 3 years. Toxicity reports were also promising. High-grade gastrointestinal toxicity (grade, $3) was rare, and rates of highgrade acute and late urinary toxicity ranged from 3% to 10% and from 2% to 11%, respectively. None of these studies reported HRQOL data.
Table 3. Late toxicity Dose group (no. of patients) Toxicity Rectal
Dysuria
Gross hematuria
Urinary retention
Urinary incontinence
Grade
All patients (n = 78)
3 10 Gy (n = 19)
3 10.5 Gy (n = 19)
3 11 Gy (n = 19)
3 11.5 Gy (n = 21)
0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
45 29 4 0 30 28 12 8 57 6 14 1 40 31 0 7 64 10 4 0
17 2 0 0 12 6 1 0 16 1 2 0 10 7 0 2 18 1 0 0
1 15 3 0 4 5 5 5 11 1 6 1 6 9 0 4 12 5 2 0
11 7 1 0 3 11 3 2 12 4 3 0 9 9 0 1 14 3 2 0
16 5 0 0 11 6 3 1 18 0 3 0 15 6 0 0 20 1 0 0
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Table 4. Health-related quality of life scores using EPIC Mean follow-up score (range) Domain
Baseline (n = 62)
1 month (n = 41)
3 months (n = 35)
6 months (n = 26)
12 months (n = 29)
48 months (n = 20)
Urinary Bowel Sexual Hormonal IPSS
93.1 (70.6–100) 96.4 (72.2–100) 70.2 (8.2–94.7) 93.2 (72.6–100) 2 (0–13)
66.7 (26.1–93.6) 85.7 (50.0–100) 39.8 (0–82.9) 84.1 (57.2–100) 14 (2–31)
88.9 (62.2–97.3) 96.4 (68.7–100) 37.8 (15.1–87.2) 93.2 (61.6–100) 6 (0.9–17.8)
89.1 (65.4–97.3) 94.6 (58.9–100) 37.2 (10.2–82.7) 90.9 (71.8–100) 5 (0–24.8)
80.3 (41.9–95.9) 92.0 (71.9–100) 32.7 (5.7–67.6) 95.5 (76.5–100) 7 (1–23)
84.1 (54.3–97.3) 94.6 (64.9–100) 35.9 (6.3–67.3) 95.5 (71.5–100) 6 (0.5–26.1)
Abbreviations: EPIC = Expanded Prostate Cancer Index Composite; IPSS = International Prostate Symptom Score.
rates were not increased compared to the lower-dose levels. Corner et al. (2) published a similar Phase II trial in which the highest dose level was 31.5 Gy in 3 fractions. Because of short follow-up, they reported acute and late toxicity at 6 months and found no significant differences among their three dose groups. Their median follow-up for the group of patients treated with 31.5 Gy in 3 fractions was only 11.8 months, and they concluded that further toxicity data are required, with longer follow-up. In our study, patients treated with 30 Gy, 31.5 Gy, 33 Gy, and 34.5 Gy had median followup times of 56, 49, 36, and 13 months, respectively. In our series, we report only 1 patient with acute grade 3 toxicity (dysuria). Excluding the last dose level group (with shorter follow-up), chronic grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were reported for 0%, 12.2%, 1.7%, 12.3%, and 0% of patients, respectively. Despite using a different fractionation scheme (4 fractions of 9.5 Gy), Ghadjar et al. (3) found similar rates of acute and late grade 3 urinary toxicity, with 1.3 % of patients having acute grade 3 urinary frequency/urgency and 11.1% of patients having late grade 3 urinary retention. HDR brachytherapy as prostate cancer monotherapy has been compared to LDR permanent seed brachytherapy in two retrospective studies from William Beaumont Hospital and the California Endocurietherapy Cancer Center (8, 9). Although the 5-year biochemical control rates were the same for both modalities (88% and 89%, respectively), acute and chronic toxicities were decreased with HDR
100 90 80 70 60 50 40 30 20 10 0 35 30 25 20 15 10 5 0
0
6
12
18
24
30
36
42
48
Months
Fig. 2. Health-related quality of life was recorded using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire and the International Prostate Symptom Score (IPSS).
brachytherapy. In a more recent report of 248 patients treated with HDR and 206 patients treated with LDR palladium-103 (9), there was less acute grade 1 to 3 dysuria (60% vs. 39%, p < 0.001, respectively), urinary frequency/ urgency (90% vs. 58%, p < 0.001, respectively), and rectal pain (17% vs. 6.5%, p < 0.001, respectively). Similarly, long-term dysuria and urinary frequency/urgency were significantly reduced with HDR, from 22% to 15% and from 54% to 43%, respectively. The rate of impotence was also reduced from 30% for LDR to 20% for HDR, but it did not reach statistical significance. The rate of urethral stricture was higher with HDR (8% vs. 3%, respectively), although it was not statistically significant (9). In a publication by Crook et al. (20), urinary stricture rate was 1.7% in patients treated with iodine-125 prostate brachytherapy, with a median follow-up of 41 months. This rate is lower than the rate of urethral stricture in our patients treated with HDR brachytherapy (9% for the whole group and 12.3% when patients with short follow-up are excluded). This rate is in agreement with the rate of 8% published previously by our group for patients treated with either HDR monotherapy or HDR brachytherapy boost to external beam radiotherapy (21). As follow-up matures, a higher rate of urethral strictures could possibly be seen, although the median time to diagnosis of urethral stricture was 19 months in our study. Interestingly, urethral strictures occurred more commonly at the level of the bulbomembranous urethra, which is beyond the high-dose region. In this study, we measured HRQOL by using the patientreported modified EPIC questionnaire. It assesses diseasespecific aspects of prostate cancer and its therapies, emphasizing urinary, bowel, sexual, and hormonal aspects. Test-retest reliability and internal consistency are high (22). To date, there are no HRQOL data for patients treated with HDR monotherapy. A few prospective multicenter cohort studies have used validated HRQOL instruments to measure HRQOL outcomes after prostatectomy, external beam radiotherapy, and LDR permanent seed brachytherapy (23–26). Unfortunately, brachytherapy data are limited to early follow-up (less than 1 year). All treatment modalities seem to affect HRQOL in a few domains. The sexual domain was the most commonly affected HRQOL domain, and the impact was shown beyond 1 year after treatment. Urinary and bowel domains seem to be affected similarly, with symptoms more commonly seen early after treatment. Data for the
HDR monotherapy for prostate cancer d M. BARKATI et al.
hormonal domain were not available in these studies (27). Our quality of life results from patients treated with HDR monotherapy compare favorably with results published for radical prostatectomy, external beam radiotherapy, and LDR brachytherapy (27). We also found that the sexual domain was the most affected and recovered little with time, reaching a plateau after 12 months of follow-up. The ability to achieve an erection was almost universally compromised, and erections had become inadequate in over 70% of patients at the 3-year mark, and only 4 men had acceptable global sexual function at last follow-up. The other three domains (urinary, bowel, and hormonal) recovered at least partially in our cohort of patients. In this trial of favorable-risk prostate cancer patients (in which 51% of patients had Gleason scores of 7), we report 3- and 5-year actuarial biochemical control rates of 88% and 85%, respectively. However, follow-up is still too short for patients treated at the high-dose level. Most outcomes for HDR monotherapy are reported at 3 years in the literature, and biochemical control rates ranged from 83% to 100% with median follow-up times between 11.8 and 36 months (2, 3, 6, 8). Five-year biochemical control rates were reported in two studies and ranged between 70% and 91% (6, 9). Comparisons with our results are difficult to make as inclusion criteria differ among studies, as some studies included patients with intermediate- and high-risk prostate
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cancer. In our cohort, the 7 patients with biochemical failures according to the Phoenix definition, and excluding patients with likely PSA bounces, were in the first two dose levels (30 Gy and 31.5 Gy). However, it is too early to conclude a dose response relationship as PSA level failures occurred at a median of 33 months, and longer follow-up is required for the group of patients treated at higher doses. Also, further follow-up will determine the dose level with the best treatment outcomes and reasonable toxicity.
CONCLUSIONS HDR brachytherapy as a monotherapy for low- and lowto-intermediate risk prostate cancer patients, using a single implant, and administered over 2 days is feasible and well tolerated. Acute and late toxicities are acceptable; the main late grade 3 toxicities being dysuria and urinary retention (urethral stricture). Except for the sexual domain, only mild changes occurred in HRQOL measurements. Longterm follow-up is required to assess the outcome after such treatment and to determine the appropriate dose. Also, a prospective trial in a multiinstitutional setting is warranted to compare HDR monotherapy with other standard treatments before adding it to the arsenal of treatments available for favorable-risk prostate cancer patients.
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18. Konishi K, Yoshioka Y, Isohashi F, et al. Correlation between dosimetric parameters and late rectal and urinary toxicities in patients treated with high-dose-rate brachytherapy used as monotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2009;75:1003–1007. 19. Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate brachytherapy as monotherapy for localized prostate cancer: a retrospective analysis with special focus on tolerance and chronic toxicity. Int J Radiat Oncol Biol Phys 2003;56:213–220. 20. Crook J, Fleshner N, Roberts C, et al. Long-term urinary sequelae following 125iodine prostate brachytherapy. J Urol 2008;179:141–146. 21. Sullivan L, Williams SG, Tai KH, et al. Urethral stricture following high dose rate brachytherapy for prostate cancer. Radiother Oncol 2009;91:232–236. 22. Wei JT, Dunn RL, Litwin MS, et al. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000;56:899–905.
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23. Downs TM, Sadetsky N, Pasta DJ, et al. Health related quality of life patterns in patients treated with interstitial prostate brachytherapy for localized prostate cancer: Data from CaPSURE. J Urol 2003;170:1822–1827. 24. Madalinska JB, Essink-Bot ML, de Koning HJ, et al. Healthrelated quality-of-life effects of radical prostatectomy and primary radiotherapy for screen-detected or clinically diagnosed localized prostate cancer. J Clin Oncol 2001;19: 1619–1628. 25. Potosky AL, Davis WW, Hoffman RM, et al. Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: The prostate cancer outcomes study. J Natl Cancer Inst 2004; 96:1358–1367. 26. Talcott JA, Manola J, Clark JA, et al. Time course and predictors of symptoms after primary prostate cancer therapy. J Clin Oncol 2003;21:3979–3986. 27. Dandapani SV, Sanda MG. Measuring health-related quality of life consequences from primary treatment for early-stage prostate cancer. Semin Radiat Oncol 2008;18:67–72.