Three-year results of treatment for prostate cancer with low-dose rate temporary iridium-192 brachytherapy

Authors


Tetsuo Momma md, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokkyo 152-8902, Japan. Email: tmomma@ntmc.hosp.go.jp

Abstract

Aim:  To report the 3-year treatment results of definitive irradiation by using a temporary interstitial implant with low-dose rate iridium-192 with or without external beam radiotherapy in the treatment of localized prostate cancer.

Methods:  One-hundred and forty-three patients with pathologically defined prostate carcinoma were treated from December 1997 to April 2003. The patients were classified into a low-risk group (T2, PSA ≤ 20 ng/mL and Gleason score ≤ 6) or a high-risk group (T3, PSA > 20 ng/mL or Gleason score ≥ 7). Low-risk patients were treated with low-dose-rate iridium brachytherapy as monotherapy delivering 70 Gy. High-risk patients were treated with the combination of brachytherapy and external beam radiotherapy delivering 40 Gy and 36 Gy, respectively. Kaplan–Meier estimates of prostate-specific antigen (PSA) progression-free survival rate were analysed. To assess the treatment quality in different periods, PSA progression-free survival rates in late era (year of 2000 and after) and in early era (before 2000) were compared. Morbidity was graded according to the Radiation Therapy Oncology Group grading scale.

Results:  One hundred and nineteen patients were analysed, of which 86 patients underwent monotherapy with an iridium implant, and 33 were treated with the combination of external beam radiotherapy. Twenty-four patients were excluded from the analysis because the classification of risk group did not suit the criteria. The total (n = 119) PSA progression-free survival rate at 3 years was 80.3%. The PSA progression-free survival rate at 3 years for the monotherapy group (n = 86) and the combination therapy group (n = 33) were 78.2% and 86.9%, respectively. There were 23 patients who were followed for more than 36 to 63 months, and, during this period, only 1 patient who received the monotherapy was diagnosed as PSA failure at 50 months. The 3-year PSA progression-free survival rate of monotherapy in late era was significantly higher than that in early era; however, no significant difference was seen in the combination treatment. Morbidity for the combination treatment was low; however, for the monotherapy, three patients developed severe rectal ulcers, and colostomies were made.

Conclusions:  The PSA progression-free survival rate after low-dose rate iridium-192 brachytherapy with or without external beam radiotherapy can be satisfactory and longer follow up is necessary to compare the efficacy of other treatments.

Introduction

With widespread prostate-specific antigen (PSA) screening, prostate cancer can be diagnosed at an earlier stage than was previously possible. For early stage patients, brachytherapy with a permanent implant of iodine-125 (125I) or palladium-103 (103Pd) has more frequently been used, and a large number of papers have reported vigorous clinical study as to its efficacy and its potentially lower morbidity.1–3 In Japan, patients’ demands for brachytherapy have increased; however, permanent implants of radioactive materials, such as 125I or 103Pd was strictly restricted by the law and only available treatment was a temporary implant of iridium (192Ir). Brachytherapy using 192Ir is performed by two methods. One is continuous irradiation with low-dose-rate (LDR) 192Ir, and the other is intermittent irradiation with high-dose-rate (HDR) 192Ir. Brachytherapy with a temporary implant is not a worldwide trend; however, it has the advantage that implants are temporary, so that no foreign bodies stay in the prostate after the treatment. We have performed LDR 192Ir brachytherapy4 since 1997. The reason we chose LDR 192Ir was that it had the advantage that a temporary implant with LDR 192Ir could be completed in about 3 days with or without the combination of external beam radiotherapy (EBRT). We present our clinical results of LDR 192Ir brachytherapy, which include progression-free survival rates (PFS) and morbidity of monotherapy and EBRT combined therapy.

Methods

Patient population

Between 1997 and 2003, 143 patients received temporary LDR 192Ir implantation at the National Tokyo Medical Center, for clinically localized prostate cancer. The patients and tumor characteristics are shown in Table 1. Initial PSA rangeed from 1.7 to 141.0 ng/mL (Median 10.5, Mean 15.7). All patients were pathologically diagnosed as adenocarcinoma of prostate with Gleason score grading and 1997 American Joint Committee on Cancer clinical stage. Clinical stage was determined by digital rectal examination, computed tomography (CT) scan, bone scintigram and magnetic resonance imaging (MRI). On the basis of initial pretreatment PSA value and Gleason score, patients were stratified to low- or high-risk groups for recurrence. Patients with initial pretreatment PSA ≤ 20 ng/mL, Gleason score ≤ 6 and T2 were stratified to the low-risk group and those with pretreatment PSA > 20 ng/mL, Gleason score ≥ 7 or T3 were stratified to high-risk group.

Table 1.  Clinical characteristics of the 143 patients
 Number of patients% of patients
Gleason score
 ≤610472.3
 72215.4
 ≥8149.8
 Unknown32.1
Clinical Stage
 ≤T212386.0
 T3139.1
 Unknown74.9
Initial PSA
 <4.042.8
 4.1–10.06545.5
 10.1–20.04531.5
 >20.12920.3

Treatment

Patients were taken into the operation room and prepared in the dorsal lithotomy position under spinal anesthesia. The perineal lesion was sterilized, an 18-Fr Foley urethral catheter was indwelled and the scrotum was sutured to the groins if necessary. After draping, a bi-plane transrectal ultrasound probe (ProSound SSD-1700; Aloka, Tokyo, Japan) fixed to the stepping device (AccuSeed; Tayman Medical, MO, USA) was inserted. The address on the ultrasound image was synchronized with the holes on the template fixed to this stepping device. This template, which was specially made for this temporary implant, had the characteristics that its two supports could be separated and its shape facing the perineum was curved to fit the perineum. The transverse ultrasound image of the prostate was monitored every 5 mm from prostate base to apex and saved on the dosimetry calculation program (Prowess; SSGI, Chico, CA, USA). Using this software, a radiation oncologist made the plan of the location of the applicators (plastic needle; STS, Berlin, Germany). The plan was based on a modified peripheral loading method. Three stainless markers, 3 mm long and 1 mm in diameter, were inserted, two at the prostate base and one at apex. Applicators were inserted transperineally through the template holes to the designated position in the prostate from ventral to dorsal and from peripheral to central alternatively to both lobes. After completing insertion of all applicators, the actual location of applicators was marked and saved on the computer. Three-dimensional dosimetry was made and a dose-volume-histogram (DVH) was calculated. From these parameters, alignment of applicators had been adjusted until the planning target volume (PTV) covered up to 5 mm margin of the prostate and V150, which is the volume of the target organ that received 150% of the prescribed dose, of the rectum and the urethra became zero. After completing the insertion, the template was released from the stepping device and placed closely towards the perineum with adhesive tapes. Lithotomy position was released to supine position. This positional change sometimes caused applicators to slip. A CT scan was undergone to check the applicator position and slipped applicators were pushed back to the designated position. The patient was brought to the radiation-isolated room and 5 cm LDR 192Ir thin wires were introduced into each applicator and fixed to the template with adhesive tapes.

The monotherapy of temporary implants was planned to deliver a minimal dose of 70 Gy to the PTV for low-risk patients and they were required to stay in bed for about 70 h to complete the radiation. For high-risk patients as combination therapy, 40 Gy of brachytherapy was delivered to PTV followed by 36 Gy of EBRT in 18 fractions. For these patients, about 40 h with the implant is necessary.

In principle, neoadjuvant hormonal therapy (NHT) was not given unless the prostate volume was over 60 mL. There were 34 patients who had already received NHT before visiting our hospital; however, they participated in this study because NHT was not considered to have therapeutic benefits for intermediate and low-risk patients.5 After the treatment, hormonal therapy was not given for any patients until documented recurrence.

Follow up

Patients were monitored by serum PSA determination at 3–6 months intervals. PSA failure is defined accord-ing to American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel recommendation as patients who have an increasing serum PSA on three successive follow ups from the nadir.6 Survival rates were calculated from the date of treatment and statistical appraisal was performed by the Kaplan–Meier method. Morbidity was followed for 114 patients and it was graded according to Radiation Therapy Oncology Group (RTOG) grading scale.7

Results

The median age at treatment was 73 years old (range 40–86). Of the 143 total patients, 93 (65%) were classified as low risk and the remaining 50 (35%) patients were classified as high risk. Of the 93 patients in low-risk group, 86 patients (92%) were treated with monotherapy of brachytherapy, and 7 patients were treated with a combination of EBRT. The reason for this combination was chiefly that monotherapy was considered to be insufficient to cover the whole prostate due to the limitations of applicator alignment. Of the 50 in the high-risk group, 33 (66%) patients were treated with a combination of EBRT, and 17 (34%) patients were excluded from this study because they were treated with monotherapy of brachytherapy. The reason of performing this monotherapy for high-risk patients was chiefly that brachytherapy alone with LDR 192Ir was considered to be sufficient during the initial period of treatment because its energy is 10-fold higher than 125I. The median follow up for the observed patients was 28.9 months (range, 5–63 months). During this follow-up period, one patient died of prostate cancer and five patients died of other disease. Twenty-four patients (17%) were excluded from the survival analysis because seventeen patients (12%) in the high-risk group received the monotherapy of brachytherapy and seven patients (5%) in the low-risk group received the combination of EBRT.

Figure 1 shows PSA PFS rate for the total population. The PFS rate was 80.3% at the 36-month evaluation point. There are 23 patients who were followed from more than 36 months to 63 months and, during this period, only 1 patient who received monotherapy was diagnosed with PSA failure at 50 months. Figure 2 shows the PFS rate for the monotherapy and combination treatment. The PFS rate at the 36 months point for the monotherapy and combination treatment were 78.2% and 86.9%, respectively.

Figure 1.

Prostate-specific antigen progression-free survival rate for all 119 patients.

Figure 2.

Prostate-specific antigen progression-free survival with monotherapy (n = 86) as compared with combination therapy (n = 33). N.S., not significant.

Since 1997–2000, new instruments, such as the stepping device (AccuSeed), real-time dosimetry calculation program (Prowess) and plastic applicator, had been introduced to upgrade the treatment quality. PFS rate with different era is shown in Figure 3 (monotherapy) and Figure 4 (combination therapy). The PFS rate in the late era (year 2000 and after) was significantly higher than that in the early era (before year 2000); however, no difference was seen in the combination treatment.

Figure 3.

Prostate-specific antigen progression-free survival of monotherapy in the early era (n = 26; before 2000) as compared with the late era (n = 60; year of 2000 and after).

Figure 4.

Prostate-specific antigen progression-free survival of combination therapy in the early era (n = 7; before 2000) as compared with the late era (n = 26; year of 2000 and after).

Acute urinary symptoms such as urinary difficulty, frequency or urgency were common but mostly self-limiting. To improve urinary difficulty, α1-blockers seemed to be helpful. Urinary retention was occurred in eight patients (7.0%) and urethral catheters were temporarily placed. One patient (0.9%) developed incontinence. Late genitourinary and gastrointestinal complications were stratified according to RTOG Grade and are shown in Tables 2 and 3. Grade 2 genitourological (GU) symptoms were almost the same as acute symptoms, and they were relieved by α1-blockers or anticholinergic agents. Grade 3 GU symptoms appeared in five patients, out of whom four had urethral stricture and one had urethral bleeding. One of the four urethral stricture patients was managed with urethral dilation on an outpatient basis, and three needed an internal urethrotomy as an inpatient. The urethral bleeding patient was managed with temporarily continuous catheterization and no cauterization was done.

Table 2.  Late genitourological complications of the 114 patients
 Number of patients% of patients
Grade 1
 Monotherapy54.3
 Combination10.9
Grade 2
 Monotherapy2421.0
 Combination32.6
Grade 3
 Monotherapy21.8
 Combination32.6
Grade 4
 Monotherapy00.0
 Combination00.0
Grade 5
 Monotherapy00.0
 Combination00.0
Table 3.  Late gastrointestinal complications of the 114 patients
 Number of patients% of patients
Grade 1
 Monotherapy87.0
 Combination10.9
Grade 2
 Monotherapy76.1
 Combination00.0
Grade 3
 Monotherapy10.9
 Combination00.0
Grade 4
 Monotherapy32.6
 Combination00.0
Grade 5
 Monotherapy00.0
 Combination00.0

A grade 2 gastrointestinal (GI) complication was proctitis, and grades 3 and 4 were rectal ulcer. All patients who had GI morbidity grade 2 or more were those who previously treated with the monotherapy. Three rectal ulcer patients required colostomies because of persistent pain and urethral fistula. There were no grade 5 (fatal morbidity) patients.

Discussion

Progression-free survival outcomes are reported on 119 consecutively treated prostate cancer patients. These patients were treated with transperineal temporary LDR 192Ir implantation with or without EBRT. As to this treatment, few reports were seen where the patients were treated with combination of EBRT.8 Our study is unique in terms of performing LDR 192Ir brachytherapy which can be performed without EBRT for low-risk patients. As shown in Figures 3 and 4, our 3-year PFS outcome after the recent establishment of the treatment method achieved 82.8% for low-risk patients with monotherapy and 90.9% for high-risk patients with EBRT combination therapy. It is interesting to clarify the necessity of EBRT for low-risk patients with our technique. And it is interesting also to compare the results with other treatment modalites. D’Amico et al.9 reported the 5-year PFS after surgery as 85%, 65% or 32% for low, intermediate or high-risk patients, respectively, and Zelefsky et al.10 showed 5-year PFS after EBRT as 85%, 79% or 55% for favorable, intermediate or poor-risk patients, respectively. Our results with this improved technique have not reached the stage of 5-year follow up, so it is too early to draw conclusions yet. As for permanent implants with 125I or 103Pd, Blasko et al.11 reported 5-year PFS as 94%, 82% or 65% for each risk patients. However, as Sylvester et al.12 mentioned 10-year PFS as 85%, 77% or 47% for each risk patients, the recent discussion about this treatment results has been shifted to 10-year PFS rather than 5-year.

As for permanent implants, several criteria about risk group classification has been proposed. Seattle risk groupings12 are as follows: (i) the low-risk group is categorized with initial PSA ≤ 10.0 ng/mL, Gleason score 2–6 and clinical stage (1992 American Joint Committee on Cancer staging system) by digital rectal examination <T2c (no unfavorable risk factors); (ii) the intermediate-risk group is initial PSA > 10.0 ng/mL, Gleason score ≥7 or ≥T2c stage disease (one unfavorable risk factor); and (iii) the high-risk group have two or three of the preceding unfavorable risk factors. An alternative risk classification used by the Mt Sinai group13 is as follows: (i) the low-risk group is categorized with initial PSA ≤ 10.0 ng/mL, Gleason score 2–6 and clinical stage by digital rectal examination T1–T2a; (ii) the intermediate-risk group is initial PSA 10.0–20.0 ng/mL, Gleason score = 7 or T2b stage disease; and (iii) the high-risk group have two or three of the preceding unfavorable risk factors. With either the Seattle or Mt Sinai groups, monotherapy is indicated for low-risk group and combination therapy with EBRT is indicated for high-risk group; however, there has been no general consensus yet about treatment selection for the intermediate-risk group. According to the American Brachytherapy Society recommendations,14 T1 to T2a patients with PSA < 10 ng/mL and Gleason score 2–6 would generally be good candidates for permanent implant brachytherapy alone, and patients with stage T2c and higher or Gleason score of 8–10 or PSA > 20 ng/mL should receive combined EBRT and brachytherapy. Patients falling between two risk groups must be evaluated individually and other factors such as perineural invasion, multiple positive biopsies, tumor location, and MRI findings may influence the decision to add EBRT and/or hormonal therapy. As seen in these two criteria, PSA value is under 10 for the low-risk group; however, PSA value for the low-risk group was defined as under 20 in our criteria. The reasons why we set PSA at under 20 for low-risk patients are based on the following pathological and physical grounds. On the pathological basis, Davis et al.15 reported that 1.5% of patients whose PSA ranged from 10–20 had an extra capsular extension (ECE) lesion longer than 3 mm. Teh et al.16 reported that, among patients with PSA between 10 and 20, 9.2% had an ECE less than 2 mm, 19.2% had 2–5 mm and 4.2% had over 5 mm. Only 1.5% of patients with PSA 10–20 had an ECE lesion greater than 3 mm. On the physical basis, LDR 192Ir can provide high gamma energy with 340 kiloelectron volts (keV), which is much higher than 125I which emits a low energy of only 27 keV. Therefore we considered that peripheral loading of LDR 192Ir can cover 5 mm surrounding of prostatic capsule. From these considerations, we hypothesised that LDR 192Ir monotherapy for patients with a PSA value from 10 to 20 can control a local tumor more effectively than a permanent seed implant. The last, but not at least, reason in this discussion, the relation between ECE and PSA, is critical and, in the literature we are referring to, most patients are US citizens; however, our cases are all Japanese except one. It must be taken into consideration that racial differences in malignant potential, including differences between African-American and Caucasian, are still unknown.17

Comparing the results of the early and late eras, there was significant improvement of PFS rate. This may be due to the improvement of both soft and hard aspects because the key of this treatment is the accurate placement of the applicators at the adequate position which provides minimum cold spot of irradiation in the prostate. We consider that the most crucial improvement is the change of the applicator. During insertion, they should be advanced in the right direction through the prostate without moving it. For this purpose, they should have a rigid shaft, a sharp top and a smooth surface. Once inserted, they should stay in the right position without giving a painful feeling to the patient. For this purpose, they should have a soft shaft, a dull top and a rough surface also. Therefore the applicators in our treatment demanded higher quality in balance than those used in the permanent implant which does not need to be indwelled.

Acute urinary irritative symptom is commonly observed for a few months after brachytherapy. As shown in Table 2, Grade 2 toxicity was still seen in 23% of the patients evaluated after 6 months. Ninety-three of the patients with Grade 2 toxicity were taking α1-blockers for urinary obstructive symptoms and 80% of them were relieved. Prophylactic use of α1-blockers results in significantly less urinary morbidity than either the absence or therapeutic use of it.18 Seven percent of the patients experienced urinary retention. They were all relieved with temporary catheterization and transurethral resection was not required. Crook et al.19 reported the major determinant of this retention rate was the prostate volume, and implant quality such as D90, V100, V200, urethral dose and International Prostatic Symptom Score (IPSS) score did not predict retention after an 125I implant. Prophylactic use of α1-blocker had no benefit to avoid retention18 and corticosteroid use after brachytherapy was reported to reduce the risk by the relief of prostatic edema.20

Late rectal morbidity tends to deteriorate patients’ quality of life. Unfortunately three patients developed rectal ulcer and colostomies were made. Its rate was higher than the results of 125I brachytherapy. It is generally known that GI complications including proctitis tend to occur to the patient with the combination treatment; however, in our study, all patients had received monotherapy. We speculated this adverse phenomenon might be induced by not only sensitivity of the patients but also the high dose irradiation by the partially high concentration of applicators at the apex of the prostate. Waterman et al.21 reported that the percentage of the rectal surface that receives a dose over 100 Gy is predictive of Grade 2 late rectal morbidity after 125I prostate brachytherapy. Each patients who developed Grade 4 toxicity received 80 Gy, 95 Gy and 100 Gy in the rectal wall and no tendency could not be found yet.

Permanent 125I or 103Pd seed implantation has become a popular treatment for localized prostate cancer and a major alternative treatment to surgery. Permanent implants had been restricted by legislation in Japan until 2003 and only 192Ir temporary implantation was available as brachytherapy. Since the law was changed in Japan in 2004, permanent seed implantation with 125I has replaced LDR 192Ir treatment in our institute although it achieved acceptable treatment benefit.

Ancillary