Gastrointestinal toxicity of transperineal interstitial prostate brachytherapy

Int. J. Radiation Oncology Biol. Phys., Vol. 53, No. 1, pp. 99 –103, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter

PII S0360-3016(01)02811-5

CLINICAL INVESTIGATION

Prostate

GASTROINTESTINAL TOXICITY OF TRANSPERINEAL INTERSTITIAL PROSTATE BRACHYTHERAPY SONG K. KANG, M.D.,* RACHEL H. CHOU, M.D.,*† RICHARD K. DODGE, M.S.,* ROBERT W. CLOUGH, B.A.,* HI-SUNG L. KANG, B.A.,* CAROL A. HAHN, M.D.,*† ARTHUR W. WHITEHURST, M.D.,† NIALL J. BUCKLEY, M.D.,† JAY H. KIM, M.D.,† RAYMOND E. JOYNER, M.D.,† GUSTAVO S. MONTANA, M.D.,* SALLY S. INGRAM, M.D.,* † AND MITCHELL S. ANSCHER, M.D.* *Duke University Medical Center, Durham, NC; †Durham Regional Hospital, Durham, NC Purpose: To characterize the severity and time course of rectal toxicity following transperineal prostate brachytherapy using prospectively recorded data, and to determine factors associated with toxicity. Methods and Materials: One hundred thirty-four patients with prostate cancer treated with transperineal brachytherapy from 1997 to 1999 had rectal toxicity data available for analysis. Patients with Gleason score (GS) > 6, prostate-specific antigen (PSA) > 6, or stage > T2a were treated initially with external beam radiation therapy followed by brachytherapy boost; patients with none of these features were treated with brachytherapy alone. Both iodine-125 and palladium-103 sources were used, and loaded according to a modified Quimby distribution. At each follow-up, toxicity was recorded according to a modified RTOG gastrointestinal scale. Results: Thirty-nine percent of patients experienced gastrointestinal toxicity, mostly Grade 1. Median duration of symptoms was 6 months. Two patients experienced Grade 3 toxicity, both of whom had minimal symptoms until their 12-month follow-up. There was no Grade 4 or 5 toxicity. The addition of external beam radiation therapy (p ⴝ 0.003), higher clinical stage (p ⴝ 0.006), and Caucasian race (p ⴝ 0.01) were associated with increased incidence of toxicity. Conclusion: Most patients with rectal toxicity have very mild symptoms. There is a small risk of severe late toxicity. External beam radiation, higher stage, and race are associated with toxicity. © 2002 Elsevier Science Inc. Prostate cancer, Brachytherapy, Complications, Rectal.

We also analyze several factors that may be associated with toxicity.

INTRODUCTION Transperineal interstitial prostate brachytherapy (TIPB) is being used with increasing frequency for the treatment of men with localized prostate cancer (1). Despite the increasing frequency of TIPB, its long-term efficacy has not been proven (2), and toxicity has not been well described. Recent reports have better described urinary toxicity (3); however, few detailed reports of rectal toxicity have been published (4, 5). Rectal toxicity following external-beam radiation therapy (EBRT) is considered to be relatively infrequent (6, 7). As patients with early-stage prostate cancer have more therapeutic options, the frequency and severity of side effects associated with each modality becomes more important. In this report, we describe the frequency, severity, and duration of rectal toxicity, recorded prospectively, in a cohort of patients treated with TIPB at a single institution.

One hundred forty-seven patients with prostate adenocarcinoma were treated with ultrasound-guided TIPB at Duke University Medical Center (DUMC) and Durham Regional Hospital (DRH) from 1997 to 1999. Of those, 134 had follow-up visits and gastrointestinal toxicity records available for review. Thirteen patients did not have follow-up and were excluded from the study. The complete methods and materials have been previously described in detail (3), and the most salient points are described below. Fifty-eight patients were treated with brachytherapy alone, while 76 received EBRT plus a brachytherapy boost. Patients selected for TIPB monotherapy included those with prostate-specific antigen (PSA) ⱕ 6, Gleason score (GS) ⱕ

Reprint requests to: Song K. Kang, M.D., Duke University Medical Center, Department of Radiation Oncology, Box 3085, Durham, NC 27710. Tel: (919) 660-2100; Fax: (919) 684-3953; E-mail: [email protected]

Presented at the 83rd Annual Meeting of the American Radium Society, San Diego, CA, April 2001. Received Aug 24, 2001, and in revised form Dec 10, 2001. Accepted for publication Dec 11, 2001.

METHODS AND MATERIALS

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Table 2. Patient characteristics

Table 1. Modified RTOG lower gastrointestinal toxicity scale Grade I Increased frequency not requiring medications, or completely controlled with medications Rectal discomfort not requiring analgesics Minimal, infrequent bleeding/discharge Grade II Diarrhea not completely controlled with parasympatholytic drugs Rectal discomfort requiring analgesics Bleeding/discharge not requiring regular use of pads Grade III Diarrhea requiring parenteral support Rectal pain requiring narcotics Bleeding/discharge requiring regular use of pads Grade IV Bleeding requiring transfusion Tenesmus requiring tube decompression Complication requiring surgical intervention Grade V Fatal complication

6, clinical stage ⱕ T2a. All others were treated with combination therapy consisting of 4,600 cGy via EBRT (8) followed by TIPB boost. All patients underwent a pretreatment ultrasound-based prostate volume study. Implanted patients generally had prostates less than 40 cc. Patients with glands larger than 40 cc were given a 3– 4-month trial of Depo Leuprolide (luteinizing hormone-releasing hormone agonist), then reassesed. Patients with prior transurethral resection of the prostate (TURP) were not considered for brachytherapy. One hundred six patients were treated with iodine-125 (I-125), and 28 patients with palladium-103 (Pd-103). Patients were implanted with either I-125 or Pd-103 based on availability of the isotope, without regard to patient characteristics. The minimum peripheral dose (MPD) for TIPB monotherapy with I-125 was 160 Gy (pre-TG43) and 115 Gy for Pd-103. Doses for the brachytherapy as a boost were 120 Gy and 90 Gy, respectively. Sources were loaded according to a modified uniform method (9) to keep the urethral dose ⬍ 400 Gy, as recommended by Wallner et al. (10). The transperineal implant was performed with the patient in lithotomy position and under general anesthesia. Preloaded needles were inserted transperineally to predetermined coordinates. Postimplant cystoscopy was performed in all patients to remove any seeds inadvertently deposited in the bladder or urethra. Following the procedure, the patients were taken to the recovery room and generally discharged the same day. Foley catheters were used after TIPB at the discretion of the urologist. In general, patients were seen at 2– 6 weeks postimplant, then every 3– 6 months thereafter. At each follow-up, toxicity was recorded by the physician and graded according to a modified RTOG toxicity scale (Table 1). The RTOG toxicity scale was modified to better describe the toxicities associated with prostate brachytherapy. Other authors have used similar modifications or supplements (5, 11). Only

Pretreatment characteristic

Median (range) or no. of patients (%)

Age Race Caucasian Non-Caucasian Clincal stage I II Gleason score 2–4 5–6 7 8–10 PSA 0–4 4.1–10 10.1–20 ⬎20 Volume (cc)

65 (43–78) 91 (68%) 43 (32%) 88 (66%) 46 (34%) 6 (4%) 74 (55%) 42 (31%) 6 (4%) 8 (6%) 95 (71%) 24 (18%) 7 (5%) 29.4 (13.6–85.0)

patients with a minimum follow-up of 3– 4 weeks were included in this analysis. Statistical analysis Duration of symptoms was defined as the interval between the first and last day of GI toxicity for those patients with Grade 1–3 toxicity. Patients who had not resolved their symptoms at last follow-up were counted as censored observations at that time. The Kaplan–Meier method was used to estimate the duration of symptoms for each of the implant groups, and the log–rank test was used to compare these durations. Factors related to the probability of Grade 1–3 GI toxicity were analyzed using Fisher’s 2-sided exact test. These factors were considered jointly using the multivariate logistic regression model. RESULTS Treatment data and patient characteristics The median follow-up was 11 months (range 1–34), with a mean of 13 months. Median age was 65 years (range 43–78). Sixty-eight percent of the patients were Caucasian, and 32% were non-Caucasian. Median pretreatment PSA and GS were 6.6 and 6, respectively (Table 2). Most patients had a GS of 5– 6, and a PSA between 4.1–10. The GS could not be determined in 6 patients because there was minimal volume of tumor. All 6 patients were described as having “well-” or “moderately–well-differentiated” adenocarcinomas. Fifty-two patients received antiandrogen therapy, with a mean volume reduction of 38%. The median preimplant volume was 29.7 cc (range 11.7– 85). The median number of implanted seeds was 92 (range 40 –143). The median total activity for patients treated with I-125 was 27.2 mCi, and 104.4 mCi for Pd-103. The median activity/seed was 0.290 mCi for I-125, and 1.10 mCi for Pd-103 (Table 3).

Prostate brachytherapy toxicity

Table 3. Treatment data Treatment data Antiandrogen therapy No Yes Brachytherapy Alone EBRT ⫹ boost Isotope I-125 Pd-103 No. of seeds Activity with I-125 (mCi) Activity with Pd-103 (mCi)

Median (range) or no. of patients (%) 82 (61%) 52 (39%) 58 (43%) 76 (57%) 106 (79%) 28 (21%) 92 (40–143) 27.2 (16.4–41.6) 104.4 (63.8–154.0)

Gastrointestinal toxicity Overall, 39% of patients experienced gastrointestinal toxicity; 22% (30/134) Grade 1, 13% (17/134) Grade 2, and 1.5% (2/134) Grade 3. Median duration of symptoms for all patients was 6 months (Fig. 1). Patients treated with combination EBRT and brachytherapy boost had a longer median duration of symptoms than patients treated with brachytherapy alone (8.6 vs. 5.1 months, p ⫽ 0.03) (Fig. 2). Toxicity grade was also plotted according to the duration of follow-up (Fig. 3). The two patients with Grade 3 toxicity did well until their 12-month follow-up, at which time they presented severe rectal spasms and bleeding. Both patients had documented radiation-induced proctitis by colonoscopy. There was no Grade 4 or 5 toxicity. Clinical factors associated with toxicity Several factors were analyzed using the logistic regression model to examine possible associations with increased

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incidence of gastrointestinal toxicity. The factors considered were age (ⱕ 65 vs. ⬎ 65), race (Caucasian vs. nonCaucasian), 1992 AJCC clinical stage (I vs. II ⫹ III), Gleason score (3– 6 vs. 7–9), pretreatment PSA level (ⱕ 10 vs. ⬎ 10), pretreatment volume (⬍ 30 cc vs. ⱖ 30 cc), use of EBRT, and type of isotope (I-125 vs. Pd-103). The results of this univariate analysis are shown in Table 4, demonstrating that the addition of EBRT (p ⫽ 0.004), higher clinical stage (p ⫽ 0.008), and Caucasian race (p ⫽ 0.03) were associated with higher incidence of toxicity. All patients with a Gleason score above 6 and a pretreatment PSA value greater than 6 received external beam radiation. Therefore, these two factors were adjusted for in a multivariate logistic regression model. After adjusting for Gleason score and PSA, the addition of EBRT (p ⫽ 0.003), higher clinical stage (p ⫽ 0.006), and Caucasian race (p ⫽ 0.01) all remained significant factors associated with increased incidence of toxicity. DISCUSSION Our data demonstrate that approximately one-third of patients undergoing TIPB with a modified homogeneous loading method experience rectal toxicity, with most limited to a severity of Grade 1. Half of those patients with toxicity had resolution of symptoms at the 6-month follow-up. There may be a small risk of late severe toxicity. Multivariate analysis demonstrates an increased incidence and duration of rectal toxicity with combined EBRT plus brachytherapy compared to brachytherapy alone. Increasing clinical stage and Caucasian race were also found to be associated with increased incidence of toxicity.

Fig. 1. Kaplan–Meier curve of all patients who developed gastrointestinal toxicity following prostate brachytherapy.

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Fig. 2. Kaplan–Meier curves of gastrointestinal toxicity for patients treated with brachytherapy alone and patients treated with EBRT ⫹ brachytherapy.

Other reports of GI toxicity have reported overall toxicity rates ranging from 5% to 31% (Table 5) (4, 5, 11–14). Our series presents a higher incidence of toxicity, which is explained by the fact that our toxicity data were collected and graded prospectively. In the present series, there were two patients who did well with regard to GI toxicity, until 12 months, when each suddenly developed Grade 3 toxicity. This finding is consistent with other reports. Gelblum and Potters (5) report four cases in their series with Grade 3 complications developing at 12–23 months following implant. Hu and Wallner (4) report seven patients developing rectal ulcers, and two developing fistulas at 24 and 37 months. Wallner et al. (13) report five cases of radiation-induced rectal ulcerations overlying the area of the prostate, ranging from 11 to 22 months after implant. In addition, three patients required colostomies for a fistula. They also noted that the incidence of rectal ulceration was significantly higher during their earlier experience from 1988 –

Fig. 3. Proportion of patients with Grades 1, 2, and 3 gastrointestinal toxicity according to duration of follow-up.

Table 4. Parameters associated with incidence of gastrointestinal toxicity Factor Age ⱕ65 ⬎65 Race Caucasian Non-Caucasian Clinical stage 1 2 Gleason score 3–6 7–9 PSA ⱕ10 ⬎10 Volume ⬍30 ⱖ30 Hormones No Yes Brachytherapy Alone Boost ⫹ EBRT Isotope I-125 Pd-103 No. seeds ⱕ92 ⬎92

GI toxicity (%)

p-value

37 36

1.00

43 23

0.03

28 52

0.008

35 40

0.71

33 48

0.14

33 41

0.37

33 42

0.28

22 47

0.004

38 32

0.66

32 41

0.37

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Table 5. Literature summary of gastrointestinal toxicity First author (ref. no.)

No. of patients

Hu (4) Gelblum (5) Kleinberg (11) Nag (12) Wallner (13) Stone (14) Current

109 825 31 32 92 109 134

Incidence of GI toxicity 19% bleeding 17% overall 31% bleeding 19% overall 5% ulceration 5% Grade 1–2 39% overall

Rectal ulceration

Latest onset of GI toxicity (months)

6.0% 0.5% 16.0% n.s. 5.0% n.s. 1.0%

28 23 18 n.s. 22 n.s. 12

n.s. ⫽ not stated.

1991 (10%), compared to 1991–1994 (2%). The sum of these data demonstrates a risk of late Grade 3 rectal toxicity in previously asymptomatic patients, suggesting that all patients should have close follow-up for at least 1 to 2 years. The underlying mechanism remains unclear. The study by Gelblum and Potters (5) did not find an association of GI toxicity with the addition of EBRT, isotope, or hormones. This is in contrast to our study, where EBRT, as well as stage and race, were found to be associated with higher toxicity. The addition of EBRT delivers a higher dose to a larger volume of the rectum, and would reasonably be expected to produce more low-grade toxicity. Patients with palpable disease by rectal examination are more often treated with the addition of EBRT, and seeds

may need to be placed closer to the rectum to adequately cover the tumor volume, thus explaining higher toxicity for advanced stage. The racial difference, although interesting, may simply reflect a difference in symptom reporting by patients, or may be a statistical aberration. To our knowledge, race has not been previously shown to predispose patients to normal tissue injury. This issue requires further study. In summary, brachytherapy for prostate cancer is generally well tolerated, with a small risk of severe GI complications. Future studies should focus on the impact of treatment-related toxicities on patient quality of life using prospectively collected data from validated, patient-reported questionnaires (15, 16).

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no difference. Prostate Cancer Prostatic Diseases 1998;1: 216 –222. Merrick GS, Butler WM. Modified uniform seed loading for prostate brachytherapy: Rationale, design, and evaluation. Tech Urol 2000;6:78 – 84. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995;32:465– 471. Kleinberg L, Wallner K, Roy J, et al. Treatment-related symptoms during the first year following transperineal 125I prostate implantation. Int J Radiat Oncol Biol Phys 1994;28:985–990. Nag S, Scaperoth DD, Badalament R, et al. Transperineal palladium 103 prostate brachytherapy: Analysis of morbidity and seed migration. Urology 1995;45:87–92. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996;14:449 – 453. Stone NN, Stock RG. Prostate brachytherapy: Treatment strategies. J Urol 1999;162:421– 426. Johnstone PA, Gray C, Powell CR. Quality of life in T1–3N0 prostate cancer patients treated with radiation therapy with minimum 10-year follow-up. Int J Radiat Oncol Biol Phys 2000;46:833– 838. Lee WR, McQuellon RP, Harris-Henderson K, et al. A preliminary analysis of health-related quality of life in the first year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;46:77– 81.