Risk factors for rectal bleeding associated with I-125 brachytherapy for prostate cancer

doi:10.1093/jrr/rrs059

J Radiat Res. 2012 November; 53(6): 923–929.

Published online 2012 August 1. doi: 10.1093/jrr/rrs059

PMCID: PMC3483856

Risk factors for rectal bleeding associated with I-125 brachytherapy for prostate cancer

Kosaku Harada,¹^* Hitoshi Ishikawa,¹ Yoshitaka Saito,² Soken Nakamoto,¹ Hidemasa Kawamura,³ Masaru Wakatsuki,³ Toru Etsunaga,² Yutaka Takezawa,² Mikio Kobayashi,² and Takashi Nakano³

¹Department of Radiation Oncology, Isesaki Municipal Hospital, 12-1, Tsunatorimoto-machi, Isesaki-shi, Gunma 372-0802, Japan

²Department of Urology, Isesaki Municipal Hospital, 12-1, Tsunatorimoto-machi, Isesaki-shi, Gunma 372-0802, Japan

³Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

^*Corresponding author. Department of Radiation Oncology, Isesaki Municipal Hospital, 12-1, Tsunatorimoto-machi, Isesaki-shi, Gunma 372-0802, Japan. Tel: +81-270-25-5022; Fax: +81-270-25-5023; Email: kusauko/at/showa.gunma-u.ac.jp

Received April 3, 2012; Revised June 26, 2012; Accepted June 26, 2012.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The purpose of this study was to determine the risk factors for rectal bleeding after prostate brachytherapy. Between April 2005 and September 2009, 89 patients with T1c-2cN0M0 prostate cancer were treated with permanent I-125 seed implantation alone. The prostate prescription dose was 145 Gy, and the grade of rectal bleeding was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Post-treatment planning was performed with fusion images of computerized tomography and magnetic resonance imaging 4–5 weeks after brachytherapy. Patient characteristics and dosimetric parameters were evaluated to determine risk factors for bleeding. The calculated parameters included the rectal volume in cubic centimeters that received >50–200% of the prescribed dose (RV50–200) and the minimal doses received by 1–30% of the rectal volume (RD1–30). The median follow-up time was 42 months (ranging 18–73 months). Grade 1 rectal bleeding occurred in 24 (27.0%) patients, but no Grade 2 or severe bleeding was observed. Usage of anticoagulants had a significant correlation with the occurrence of bleeding (P = 0.007). The RV100–150 and RD1–10 were significantly higher in patients with rectal bleeding than in those without bleeding. The RV100 was identified as a possible threshold value; the 3-year rectal bleeding rate in patients with an RV100 > 1.0 cm³ was 36%, whereas that with an RV100 ≤ 1.0 cm³ was 14% (P < 0.05). Although no Grade 2 morbidity developed in this study, the RV100 should be kept below 1.0 cm³, especially in additional dose-escalated brachytherapy.

Keywords: prostate cancer, brachytherapy, rectal bleeding, dose-volume-histogram, anticoagulant

INTRODUCTION

The incidence of prostate cancer in Japan has been increasing in recent years [1]. Radiation therapy (RT) has been playing an important role in the curative treatment of prostate cancer, because recent novel RT techniques, such as intensity-modulated radiotherapy (IMRT), stereotactic radiotherapy, and particle radiotherapy with protons and carbon ions, can deliver a large dose to the target while sparing the surrounding normal tissues.

Permanent implants for prostate cancer have proved to be useful as an alternative highly conformal and high-dose RT approach. Since the Japanese government legalized the use of the iodine-125 (¹²⁵I) seed source in July 2003, ¹²⁵I-brachytherapy has been a popular treatment method, mainly for low- to intermediate-risk prostate cancer in Japan. It is well known that the actual benefits of prostate brachytherapy compared with external beam radiation therapy (EBRT) are lower incidences of sexual dysfunction and incontinence and a shorter treatment period [2]. Regarding rectal morbidity, however, radiation-induced rectal bleeding is still a problem in brachytherapy as well as in EBRT because of the close borders of the rectum and the prostate. Several reports have shown improved outcomes of prostate cancer when higher irradiation doses are delivered both in EBRT and brachytherapy [3–9]. It is possible that increasing the irradiation dose to the target volume improves biochemical disease control, but it has a risk of increasing the rectal morbidity of RT for prostate cancer. Therefore, the purpose of this study was to identify predictive factors associated with rectal bleeding after brachytherapy to carry out future dose escalation safely.

MATERIALS AND METHODS

A total of 98 patients with T1–T2 prostate cancer (according to the International Union Against Cancer TNM Classification of Malignant Tumours 6th edition [10]) underwent ¹²⁵I permanent radioactive seed implantation between April 2005 and September 2009 at Isesaki Municipal Hospital. Among them, 90 patients who did not receive adjuvant EBRT were followed up for more than 36 months. One was excluded from this study, because the computed tomography (CT) data for post-implant dosimetry could not be used. Hence, 89 patients were evaluated, and their clinical and treatment characteristics are shown in Table 1. According to the National Comprehensive Cancer Network Guidelines [11], 48 and 39 patients had low-risk and intermediate-risk prostate cancer, respectively. The median age was 70 years (range 51–80 years), and the median initial prostate specific antigen (PSA) level before biopsy was 5.5 ng/ml (range 3.0–34.0 ng/ml). A total of 17 patients (19%) received anticoagulant therapy for various reasons. Neoadjuvant androgen deprivation therapy (ADT) was given to 43 patients (48.3%) for a median of 9 months (range 1–39 months). ADT consisted of a luteinizing hormone releasing hormone agonist alone in 40 patients or in conjunction with an anti-androgen in 2 patients or an anti-androgen alone in 1 patient. Written informed consent was obtained from each patient before treatment.

Table 1.

Clinical characteristics of patients

About one month before the actual implant procedure, a volumetric study of the prostate was performed for all patients with transrectal ultrasound (TRUS) with patients in the dorsal lithotomy position. The prostate was scanned at 5-mm intervals from the proximal seminal vesicles to the apex. The captured images were digitized with a planning computer. Treatment planning was performed with the brachytherapy planning system VariSeed 7.1 (Varian Medical Systems, Palo Alto, CA, USA) to calculate the well-designed dose volume histogram (DVH). The gross target volume (GTV) was defined as the prostate itself visualized on the TRUS images. The planning target volume (PTV) was determined from the GTV plus a treatment margin of 3 mm in the bilateral and anterior directions but no margin posteriorly. We set the treated volume to include the PTV within the prescribed isodose (145 Gy), using a modified peripheral loading technique. Implantation was performed under general anesthesia, via TRUS guidance of the preplanned seeds, with the patient in the extended lithotomy position, similar to the volumetric study. A Mick applicator (Mick Radionuclear Instruments, Bronx, NY, USA) was used to deposit the seeds.

One month after implantation, both computerized tomography (CT) and magnetic resonance imaging (MRI) were carried out for dosimetric analysis. A urinary catheter was placed during these examinations. Axial CT images 2.5 mm in thickness were obtained at 1.25-mm intervals, and T2-weighted images 2 mm in thickness were acquired within 1 h after CT examination. The CT and MR images were electronically fused using the manual-fusion procedure of the Variseed fusion system by fitting the urethra, and then the prostate, rectum and urethra were contoured. To provide consistency in defining rectal volumes, all rectal outlining was redone by one person (K.H.). Volumes were contoured as a solid structure defined by the outer wall from one slice above and below the prostate.

The calculated dosimetric parameters included the % volume of the post-implant prostate receiving 100 and 150% of the prescribed dose (V100 and V150, respectively) and values of the minimal dose received by 90% of the prostate volume (D90). The urethral dose was expressed as values of the minimal dose received by 5% of the urethral volume (UD5). The rectal volumes in cubic centimeters that received >50, 75, 100, 125, 150, 175 and 200% of the prescribed dose (RV50, RV75, RV100, RV125, RV150, RV175 and RV200, respectively) and the minimal doses received by 1, 2, 5, 10 and 30% of the rectum volume (RD1, RD2, RD5, RD10 and RD30, respectively) were determined.

After brachytherapy, patients were followed-up at 3-month intervals to record information concerning disease status, rectal bleeding and cause of death. If patients were unable to visit our hospital due to various reasons, the information was obtained through letters or telephone contact directly with patients or relatives or through communication with the referring physicians. Rectal bleeding was confirmed by rectal digital examination and endoscopy and was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [12] (Table 2). All time intervals were measured from the day of brachytherapy to occurrence of the rectal bleeding. The median follow-up time for this study was 42 months (range 18–73 months).

Table 2.

CTCAE version 4.0 rectal hemorrhage criteria

The student's t test and a chi-square test were used to compare the distribution of clinical and dosimetric parameters between the two groups. The cumulative incidence of rectal bleeding was calculated with the Kaplan-Meier method, and differences in cumulative incidence were compared with the log-rank test. Statistical significance was set at P < 0.05.

RESULTS

One patient died of cerebral infarction 43 months after brachytherapy. Biochemical PSA failures as defined by the nadir + 2 definition were observed in two patients (2.2%). No Grade 2 or greater rectal bleeding was observed, but 24 (27.0%) patients developed Grade 1 bleeding. The median onset of the bleeding was 20 months (range 3–63 months), and it was resolved without treatment from 1–33 months (median 11 months). Post-treatment planning data showed that D90, V100 and V150 of the implanted prostate were 157.5 ± 13.4 Gy, 92.9 ± 3.4%, and 58.1 ± 12.0%, respectively.

The distributions of clinical parameters and treatment-related factors were compared between patients who did or did not develop rectal bleeding (Table 3). There was a significant relationship between the occurrence of bleeding and taking anticoagulants (P = 0.007). There was no significant difference between the two groups regarding age, medical history of diabetes mellitus (DM), neoadjuvant hormonal therapy, prostate volume and number of seeds.

Table 3.

Correlation of clinical parameters

The comparison of the mean values of dosimetric parameters between the 24 patients who presented with rectal bleeding and the 65 patients who did not is shown in Table 4. There were significant differences in the RD1 and RD2 between the two groups. Dosimetric risk factors for rectal bleeding were further analyzed in 72 patients who did not take anticoagulants, and a comparison of the mean values of dosimetric parameters between the 15 patients with and the 57 patients without rectal bleeding is shown in Table 5. The means of the RV100, RV125, R150, RD1, RD2, RD5 and RD10 in patients with rectal bleeding were significantly higher than in those without bleeding. The most significant statistical difference was observed in the RV100 (P = 0.02). An RV100 > 1.0 cm³ was possibly a threshold value; the cumulative incidence of rectal bleeding in patients with an RV100 > 1.0 cm³ was significantly higher than that with an RV100 ≤ 1.0 cm³ (36% vs 14% at 36 months, P < 0.05; Fig. 1). Table 6 shows dosimetric parameters of patients taking anticoagulants. There was no significant difference between the two groups.

Table 4.

Correlation of dosimetric parameters with rectal bleeding in all patients

Table 5.

Correlation of dosimetric parameters with rectal bleeding in patients not taking anticoagulants

Fig. 1.

Cumulative late Grade 1 rectal bleeding rates according to receipt of 100% of the prescribed dose to the rectum (RV100) in patients who did not receive anticoagulation therapy (n = 72). The 3-year bleeding rate of patients with an RV100 > 1.0 cm (more ...)

Table 6.

Correlation of dosimstric parameters with rectal bleeding in patients not taking anticoagulants

DISCUSSION

Rectal bleeding is one of the major dose-limiting factors in curative RT for prostate cancer. Table 7 summarizes the results of the incidence of rectal morbidities after prostate brachytherapy without EBRT reported by several investigators. The rates of Grade 1, 2 and > 3 rectal morbidities ranged from 4.2–16.7%, 0–10.4% and 0–1.4%, respectively [13–19]. The incidence of morbidities in the current study was almost comparable (Grade 1, 27% and Grade 2–4, 0%). In addition, the rates were lower than those observed after 3D-conformal RT and similar to those after current IMRT studies [3–5, 20–22]. In brachytherapy, the incidence of rectal bleeding seems to be tolerable because most cases can be managed with conservative therapy.

Table 7.

Reports of late rectal morbidity after prostate brachytherapy

Several randomized trials have shown improved outcomes when higher external beam radiation doses are delivered [3–5, 23]. In general, dose levels of 78 Gy or higher were associated with better biochemical no evidence of disease rates for prostate cancer. Similarly to EBRT, dose-response relationships were found in brachytherapy [6–9]. Stock et al. [6] demonstrated that higher doses resulted in a lower incidence of positive cancer cells from post-radiation biopsies. Positive biopsies were found in 24% of patients who received a D90 < 140 Gy, 6% for 140–160 Gy, 7% for 160–180 Gy, and 1–3% for > 180 Gy. In this study, no cases of Grade 2 or worse rectal bleeding were observed. However, the rate of bleeding would probably increase if higher prescription doses to the prostate were given. As dose escalation to D90 = 160 Gy was actually performed in our institution based on Stone's data [7–9], identification of risk factors for mild bleeding at the rectum with the prescription dose of D90 = 145 Gy is very important for safe delivery of higher doses to the prostate.

In this study, the RV75–125 and RD1–10 were predictors for rectal bleeding, and RV100 was thought to be the most significant predictor (P = 0.02). The cumulative incidence of rectal bleeding in patients with an RV100 > 1.0 cm³ was significantly higher than that with an RV100 ≤ 1.0 cm³ (36% vs 14% at 36 months, P < 0.05; Fig. 1). Snyder et al. [13] reported that the risk of developing Grade 2 proctitis following ¹²⁵I brachytherapy with rectal DVH analysis, and the volume thresholds for < 5% risk of morbidity were 3 cm³ at 100 Gy, 2 cm³ at 140 Gy, 1.3 cm³ at 160 Gy, and 0.8 cm³ at 200 Gy. Furthermore, Waterman et al. [18] showed that the rectum could tolerate doses of 100, 150, and 200 Gy to approximately 30%, 20% and 10% of the rectal surface, respectively, with a <5% risk of late morbidity. It is difficult to compare our results with theirs because a different definition of rectal dose and a different grade of criteria for rectal bleeding were used. However, to a varying degree, our results agree with theirs from the viewpoint of prediction for rectum morbidity.

Recent studies have shown that patients taking anticoagulation therapy have a substantial risk of bleeding toxicity with EBRT [24, 25]. Our results show that rectal bleeding occurred in 9 of 17 patients with anticoagulation therapy, and usage of anticoagulants was one of the predictors for bleeding induced by irradiation. DVH parameters of the rectum were associated with the incidence of bleeding in all patients as well as in patients not taking anticoagulants, but this observation was not detected in patients taking anticogulants . Taking these findings into consideration, it is important to evaluate DVH parameters of the rectum to predict rectal bleeding. Additionally, a usage of anticoagulants seems to be an independent risk factor for the occurrence of bleeding after brachytherapy using this dose level.

Several investigators have shown that DM and ADT are risk factors for rectal bleeding in RT for prostate cancer [26–29]. However, no relationship of bleeding with DM and ADT was observed in our study. This discrepancy is probably explained by the following reasons: (i) this study included a small number of cases, (ii) other studies focused on Grade 2 but not Grade 1 rectal bleeding, and (iii) ADT was used as only short-term neoadjuvant therapy in this study. A previous Phase II trial of carbon-ion RT, which can deliver excellently localized irradiation doses to the target like brachytherapy, also revealed that the use of short-term ADT was not correlated with rectal and urogenital complications [24].

Brachytherapy with ¹²⁵I is an effective treatment modality for localized prostate cancer. Rectal DVH analysis is a practical and predictive method for assessing the risks of late rectal morbidity after treatment. To maintain less than 1 cm³ of the RV100 is very important to decrease rectal morbidity after brachytherapy. Although we used a prescribed dose of 145 Gy, the predictive risk factors proposed in this analysis may be useful tools for safely and effectively delivering higher doses to the target when dose escalation to 160 Gy is also included.

REFERENCES

1. Matsuda T, Marugame T, Kamo K, et al. Cancer incidence and incidence rates in Japan in 2004: based on data from 14 population-based cancer registries in the Monitoring of Cancer Incidence in Japan (MCIJ) Project. Jpn J Clin Oncol. 2010;40:1192–200. [PubMed]

2. Frank SJ, Pisters LL, Davis J, et al. An assessment of quality of life following radical prostatectomy, high dose external beam radiation therapy and brachytherapy iodine implantation as monotherapies for localized prostate cancer. J Urol. 2007;177:2151–6. [PubMed]

3. Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol. 2006;24:1990–6. [PubMed]

4. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233–9. [PubMed]

5. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:67–74. [PubMed]

6. Stock RG, Stone NN, Cesaretti JA, et al. Biologically effective dose values for prostate brachytherapy: effects on PSA failure and posttreatment biopsy results. Int J Radiat Oncol Biol Phys. 2006;64:527–33. [PubMed]

7. Stone NN, Potters L, Davis BJ, et al. Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes. Int J Radiat Oncol Biol Phys. 2007;69:1472–7. [PubMed]

8. Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2009;73:341–6. [PubMed]

9. Stone NN, Stock RG, Cesaretti JA, et al. Local control following permanent prostate brachytherapy: effect of high biologically effective dose on biopsy results and oncologic outcomes. Int J Radiat Oncol Biol Phys. 2010;76:355–60. [PubMed]

10. Sobin LH, Wittekind C, editors. International Union Against. Cancer. Prostate. In. 6th edn. New York: Wiley-Liss; 2002. pp. 184–7. Classification of Malignant Tumours.

11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. (19 July 2012, date last accessed)

12. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events. version 4.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. (23 June 2012, date last accessed)

13. Snyder KM, Stock RG, Hong SM, et al. Defining the risk of developing grade 2 proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys. 2001;50:335–41. [PubMed]

14. Shah JN, Ennis RD. Rectal toxicity profile after transperineal interstitial permanent prostate brachytherapy: use of a comprehensive toxicity scoring system and identification of rectal dosimetric toxicity predictors. Int J Radiat Oncol Biol Phys. 2006;64:817–24. [PubMed]

15. Zelefsky MJ, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys. 2000;47:1261–6. [PubMed]

16. Zelefsky MJ, Yamada Y, Cohen GN, et al. Five-year outcome of intraoperative conformal permanent I-125 interstitial implantation for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2007;67:65–70. [PubMed]

17. Gelblum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2000;48:119–24. [PubMed]

18. Waterman FM, Dicker AP. Probability of late rectal morbidity in 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2003;55:342–53. [PubMed]

19. Martin AG, Roy J, Beaulieu L, et al. Permanent prostate implant using high activity seeds and inverse planning with fast simulated annealing algorithm: A 12-year Canadian experience. Int J Radiat Oncol Biol Phys. 2007;67:334–41. [PubMed]

20. Eade TN, Guo L, Forde E, et al. Image-guided dose-escalated intensity-modulated radiation therapy for prostate cancer: treating to doses beyond 78 Gy. BJU Int. 2012;109:1655–60. [PubMed]

21. Zelefsky MJ, Kollmeier M, Cox B, et al. (11 Feb 2012) Improved clinical outcomes with high-dose image guided radiotherapy compared with non-IGRT for the treatment of clinically localized prostate cancer. Int J Radiat Oncol Biol Phys, [doi:10.1016/j.ijrobp.2011.11.047] [PubMed]

22. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys. 2002;53:1111–6. [PubMed]

23. Zelefsky MJ, Reuter VE, Fuks Z, et al. Influence of local tumor control on distant metastases and cancer related mortality after external beam radiotherapy for prostate cancer. J Urol. 2008;179:1368–73. [PMC free article] [PubMed]

24. Ishikawa H, Tsuji H, Kamada T, et al. Risk factors of late rectal bleeding after carbon ion therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2006;66:1084–91. [PubMed]

25. Choe KS, Jani AB, Liauw SL. External beam radiotherapy for prostate cancer patients on anticoagulation therapy: how significant is the bleeding toxicity? Int J Radiat Oncol Biol Phys. 2010;76:755–60. [PubMed]

26. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys. 2000;47:103–13. [PubMed]

27. Herold DM, Hanlon AL, Hanks GE. Diabetes mellitus: a predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys. 1999;43:475–9. [PubMed]

28. Feigenberg SJ, Hanlon AL, Horwitz EM, et al. Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2005;62:397–405. [PubMed]

29. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003;21:3972–8. [PubMed]

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