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Japanese Journal of Clinical Oncology Advance Access originally published online on January 25, 2007
Japanese Journal of Clinical Oncology 2007 37(2):121-126; doi:10.1093/jjco/hyl133
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© 2007 Foundation for Promotion of Cancer Research

Rectal Morbidity Following I-125 Prostate Brachytherapy in Relation to Dosimetry

Toshio Ohashi1,, Atsunori Yorozu1, Kazuhito Toya1, Shiro Saito2, Tetsuo Momma2, Hirohiko Nagata2 and Michio Kosugi2

1 Department of Radiology
2 Department of Urology, Tokyo Medical Center, National Hospital Organization, Tokyo, Japan

For reprints and all correspondence: Toshio Ohashi, Department of Radiology, Tokyo Medical Center, National Hospital Organization, 5-1, Higashigaoka 2 chome, Meguro-ku, Tokyo 152-8902, Japan. E-mail: ohashi{at}rad.med.keio.ac.jp

Received May 31, 2006; accepted September 21, 2006


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Background: To investigate rectal morbidity after I-125 prostate brachytherapy and to analyze predictive factors of rectal morbidity.

Methods: A group of 227 consecutive patients with localized prostate cancer were treated with I-125 prostate brachytherapy with or without external beam radiotherapy (EBRT) between September 2003 and January 2005. Rectal morbidity (diarrhea, bleeding and pain) was evaluated using the Radiation Therapy Oncology Group (RTOG) criteria. Dosimetry was based on computerized tomography (CT) scan 1 month post-implant. The clinical, treatment-related and dosimetric factors were evaluated for the risk of grade 2 rectal morbidity. Rectal dosimetric factors included the rectal volume that received >100% and 150% of the prescribed dose, and the maximal rectal dose which was defined as the sum of the minimal dose received by 1% of the rectum volume and the prescribed dose of EBRT.

Results: Grade 2 rectal bleeding occurred in 10 (4.4%): for nine patients within the first year and for one patient between the first and second year. Grade 2 diarrhea occurred in one patient (0.4%) within the first year. No patient reported grade 2 pain. In the univariate analysis with grade 2 rectal bleeding, there were significant correlations with number of seeds, supplemental EBRT, and all of the rectal dosimetric parameters. On subsequent multivariate analysis, the only significant factor was the maximal rectal dose (P < 0.001). Rectal dose > 160 Gy was correlated to grade 2 rectal morbidity. All the patients with rectal dose > 160 Gy received EBRT.

Conclusions: Manifestations of rectal morbidity are acceptable events after I-125 prostate brachytherapy. Rectal dose–volume histogram for the brachytherapy is a predictive method for assessing the risk of developing grade 2 rectal bleeding. Delivery of the rectal dose should not exceed 160 Gy in order to avoid rectal complications.

Key Words: prostate cancer • brachytherapy • iodine-125 • rectal morbidity • proctitis • rectal bleeding


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Over decades, transperineal permanent prostate brachytherapy is a popular treatment option for localized prostate cancer. Recent evidence confirming equivalent biochemical control rates with permanent seed implantation in comparison to radical prostatectomy or external beam radiotherapy (1,2) has emphasized the need for careful evaluation. Whereas the increased dose has been shown to improve biochemical control, it also has the potential to increase morbidity. Given the close proximity of the prostate to the anterior rectal wall, the possible adverse events after brachytherapy include rectal side effects. Although severe rectal complications are rare, 4–12% of patients develop mild, self-limited proctitis and <1% progress to ulceration and/or fistula formation (3–7).

In Japan, the use of I-125 was legally permitted in July 2003, and the first performance of I-125 prostate brachytherapy took place at Tokyo Medical Center, National Hospital Organization, in September 2003. To our knowledge, there has been no report on the acute or late rectal morbidity after prostate brachytherapy with or without external beam radiotherapy (EBRT) in Japan. Here, we report for the first time on the rectal morbidity among the 227 consecutive patients in Japan and analyze the risk and the predictive factors of developing rectal morbidity.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
During the period of September 2003 through December 2004, we treated 227 consecutive patients with localized prostate cancer with I-125 permanent seed implantation at Tokyo Medical Center, National Hospital Organization. The clinical characteristics of these patients are shown in Table 1.


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  		Table 1. Clinical characteristics of the patients

 
According to the risk factors: prostate specific antigen (PSA), Gleason score and T-category (according to the 1997 American Joint Commission on Cancer), a low-risk group (T1-2a, PSA<10 ng/ml, and Gleason score ≤ 6), an intermediate-risk group (one adverse factor: T2b or greater, PSA ≥ 10 ng/ml or greater, or Gleason score ≥ 7), and a high-risk group (two or three adverse factors) were defined (8). For the low-risk group, seed implantation alone (monotherapy) was recommended, while for the high-risk group a combination of I-125 seed implantation at a reduced prescribed radiation dose and EBRT was preferred (combined therapy). In the intermediate-risk group, individual treatment decisions were made, although combined therapy was recommended in general.

A neoadjuvant hormonal treatment was prescribed in 142 patients (62.6%) for a median of 8 months, ranging from one to 48 months. Hormone therapy consisted of a luteinizing hormone releasing hormone (LHRH) agonist alone in 90 patients or in conjunction with an anti-androgen in 52 patients. Written informed consent was obtained from each patient before I-125 permanent seed implantation.

The pre-implant treatment planning was performed about 1 month before the implant procedure. Our preplanning technique has been previously described (9–11). The implantation was performed under spinal anesthesia, via TRUS guidance of the preplanned seeds, with the patient in the extended lithotomy position, similar to the pre-implant treatment planning. A Mick applicator (Mick Radionuclear Instruments, Bronx, NY, USA) was used to deposit the seeds. The treatment planning was performed using the planning system VariSeed 7.1 (Varian Medical Systems, Palo Alto, CA, USA). A modified peripheral loading technique was used. The prescribed dose was 145 Gy in the monotherapy group and 100 Gy in the combined therapy group.

For post-implant dosimetric analysis, a computerized tomography (CT) scan was obtained 1 month after implantation. Axial CT scan images of the pelvic area were taken at 5 mm intervals. Dose–volume histograms of the prostate and rectum were calculated using the outer prostatic and rectal margins identified on the CT scan by one investigator (AY). The rectum was contoured as a solid structure defined by the outer wall on all the slices showing seeds, without attempting to differentiate the inner wall or contents (Fig. 1A–C). In the combined therapy group, supplemental EBRT was started 1 month after the brachytherapy. The prescribed doses of EBRT were 45 Gy in 25 fractions of 1.8 Gy per fraction using 6 MV photons delivered by 3D-conformal technique in a supine position, including the prostate and seminal vesicles plus a 0.8 cm margin at a rectal side and a 1.5 m margin at the other sides.


Figure 1
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  		Figure 1. Example of how outer rectal wall is drawn, shown as white line. (A) prostatic base; (B) middle prostate; (C) prostatic apex.

 
The calculated dosimetry parameters used included the percent volume of the post-implant prostate receiving 100, 150 and 200% of the prescribed dose (V100, V150 and V200, respectively). The rectal dose expressed as the rectal volume in cubic centimeters that received > 100 and 150%, respectively of the prescribed dose (R100 and R150, respectively). Dose–volume histograms for the rectal EBRT dose were not available for most patients and the maximal rectal dose was defined as the sum of the minimal dose received by 1% of the rectum volume and the prescribed dose of EBRT (0 Gy in the monotherapy group and 45 Gy in the combined therapy group).

Treatment-related morbidity (diarrhea, bleeding and pain) was monitored using modified Radiation Therapy Oncology Group (RTOG) criteria (Table 2). The patients who reported persistent bleeding, occurring at least once a week for a minimum period of 1 month, were categorized as grade 2.


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  		Table 2. Modified RTOG rectal morbidity criteria

 
The clinical, treatment-related and dosimetric factors were assessed for univariate and multivariate correlations with the risk of grade 2 rectal morbidity. Clinical and treatment-related factors included patient age, pre-implant ultrasound (US) prostate volume, number of seeds inserted, hemorrhoid, diabetes mellitus, supplemental EBRT, and the utilization of neoadjuvant hormonal manipulation. Dosimetric factors included V100, V150, V200, R100, R150 and the maximal rectal doses. A univariate analysis was performed using the Mann–Whitney test. The variables that showed univariate significance (P ≤ 0.10) were then included in a multivariate analysis using the logistic regression test. Analyses were carried out using SPSS 14.0 (SPSS Inc., Chicago, IL, USA). Differences were regarded as statistically significant at P < 0.05.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Conflict of interest statement
 References
 
The implantation data and the post-implant dosimetric factors are shown in Table 3. The median follow-up was 22.0 months (range: 16.0–32.2 months).


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  		Table 3. Treatment-related and post-implant dosimetric factors

 
Table 4 summarized the rates of rectal morbidity by grade for each rectal event. Grade 2 diarrhea occurred in 1 patient (0.4%) of the 227 patients within the first year. Grade 2 rectal bleeding occurred in 10 patients (4.4%): nine patients within the first year and the one patient between the first and second year. No patients reported grade 2 pain. There were no patients with grade 3 rectal morbidity.


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  		Table 4. Rates of rectal morbidity by grade

 
On the basis of univariate analysis with grade 2 rectal bleeding (Table 5), there were significant correlations with number of seeds, supplemental EBRT, and all of the rectal dosimetric parameters (Fig. 2A–C). On subsequent multivariate analysis (Table 5), the only significant factor was the maximal rectal dose (P < 0.001).


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  		Table 5. Factors evaluated as possible contributors to grade 2 rectal bleeding

 

Figure 2
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  		Figure 2. (A) R100 in patients with or without grade 2 rectal bleeding; (B) R150 in patients with or without grade 2 rectal bleeding; (C) Maximal rectal dose in patients with or without grade 2 rectal bleeding. Error bars indicate the 95% confidence interval of the mean.

 
Table 6 shows the relationship between the maximal rectal dose and the risk of grade 2 rectal bleeding. The patients with the maximal rectal dose > 145 Gy had a grade 2 bleeding rate of 15.2% versus a rate of 0% for the patients with the maximal rectal dose ≤ 145 Gy (P < 0.001). Also, the patients with the maximal rectal dose > 160 Gy had a grade 2 rate of 15.0% versus a rate of 2.1% for the patients with the maximal rectal dose ≤ 160 Gy (P = 0.003; odds ratio [OR], 8.074; 95% confidence interval [CI], 2.16–30.13). All the patients with rectal dose > 160 Gy received EBRT. As for the other rectal dosimetric factors which were significant on the univariate analysis, the risk of grade 2 rectal bleeding was 3.3% if R100 ≤ 1.5 cm3, compared to a risk of 16.7% for R100 > 1.5 cm3 (P = 0.035; OR, 3.615; 95% CI, 1.35–24.62). The risk of grade 2 rectal bleeding was 2.8% if R150 ≤ 0.05 cm3, compared to a risk of 10.2% for R150 > 0.05 cm3 (P = 0.041; OR, 3.932; 95% CI, 1.09–14.18).


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  		Table 6. Relationship between the maximal rectal dose and the risk of grade 2 rectal bleeding

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Conflict of interest statement
 References
 
Previous reports have suggested an association between rectal dosimetric parameters and post-implant rectal toxicities. Although comparisons between series are hindered by different timing of the post-implant CT scans and variations in the way that rectal doses are described, nearly all investigators have shown a higher incidence of rectal bleeding with higher rectal doses.

Snyder et al. (3) reported on the relationship between the volume of rectal wall receiving a given dose and the risk of developing grade 2 radiation proctitis (defined as rectal bleeding occurring at least once a week for a minimum period of 1month) based on CT analysis. Grade 2 proctitis developed in 10.4%. The risk of grade 2 proctitis at 5 years was 5% if < 1.3 cm3 of rectal wall received the prescribed dose (160 Gy), compared to a risk of 18% for volumes > 1.3 cm3. The volume threshold reported for ≤ 5% risk of grade 2 proctitis at 5 years was 3.0 cm3 at 100 Gy, 2.0 cm3 at 140 Gy, 1.3 cm3 at 160 Gy, 1.2 cm3 at 180 Gy, 0.8 cm3 at 200 Gy, 0.5 cm3 at 220 Gy and 0.4 cm3 at 240 Gy. Waterman and Dicker (5) reported on 98 patients treated with I-125 monotherapy. Post-plan CT scans were performed 4–6 weeks after implantation. Ten patients (10.2%) developed grade 2 late rectal morbidity. The probability of late rectal morbidity increased with dose and with the percentage of the rectal surface receiving that dose. Maximal rectal doses of 150, 200 and 300 Gy were associated with a probability of 0.4%, 1.2% and 4.7% of proctitis, respectively. For percentage of the rectal surface, the risk was ≤ 5% with 31, 19 and 9% receiving 100, 150 and 200 Gy, respectively. Wallner et al. (12) concluded that the rectal surface dose should be maintained below 100 Gy to decrease the likelihood of RTOG grade 1–2 toxicity.

Zelefsky et al. and Merrick et al. considered rectal point doses and failed to find any significant relationships between such doses and the incidence of RTOG more than grade 2 rectal toxicity or the total rectal function impairment score on a rectal quality-of-life survey, respectively (13,14). However, in a subsequent report by Merrick et al. (15), the median rectal dose was correlated with rectal dysfunction measured by the Rectal Function Assessment Score. In another report, Merrick et al. (6) also described persistent rectal bleeding occurred in 44 (8.8%) of the 502 patients and rectal fistulas occurred in 0.4%.

Our data show that grade 2 rectal bleeding occurred in 10 patients (4.4%), which was a relatively favorable result compared to other reports and was statistically linked with all parameters of rectal dosimetry (R100, R150 and the maximal rectal dose) in univariate analysis. It is very difficult to validly evaluate the biologically effective dose values of the rectal wall for treatments involving both brachytherapy and EBRT. In this report, although we recognized that the dose of brachytherapy alone was not equal to the combination of the dose of implant and EBRT from the radiobiological basis, we defined the maximal rectal dose as the sum of the minimal dose received by 1% of the rectum volume and the prescribed dose of EBRT, as a simple predictive method. Rectal dose > 160 Gy was correlated to grade 2 rectal morbidity. All the patients with rectal dose > 160 Gy received EBRT. It seemed that there was a relationship between grade 2 rectal morbidity and EBRT, but our data did not prove a significant relation. This finding needs to be confirmed in a larger population.

The different ways of examining post-implant rectal dosimetry obviously created a question of what is the most practical and reliable technique for calculating the appropriate dose. Our approach entails performing the simple task of contouring the outer rectal wall on post-implant CT scan slices. By contrast, to most precisely determine rectal surface doses, one should place an obturator inside the rectum before the post-implant CT scan to accurately identify the rectal surface mucosa (16). Use of an obturator is not only uncomfortable but is likely to distort the rectal anatomy. Also, although rectal point doses can be determined relatively easily, Hilts et al. (17) have demonstrated that point doses are highly unreliable indicators of dose delivered to the rectum by prostate brachytherapy. They also showed that volume-based rectal dose measurements are highly correlated with surface-based ones; however, the former are obtained much more rapidly than the latter. Hilts et al. thus concluded that volume-based measures are the most practical and reliable rectal dose indicators, and should therefore be the standard method for assessing rectal dose after prostate brachytherapy.

In conclusion, there is little question, based on our report and others, that grade 2 rectal bleeding is related to high anterior rectal wall doses. Rectal dose–volume histogram analysis for the brachytherapy is a practical and predictive method for assessing the risk of developing grade 2 rectal bleeding after I-125 prostate brachytherapy. Rectal dose > 160 Gy was correlated to grade 2 rectal morbidity. All the patients with a rectal dose > 160 Gy received EBRT.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
References
 
None declared.


   Acknowledgment
 
This study was financially supported by the Budget for Nuclear Research of the Ministry of Education, Culture, Sports, Science and Technology, based on the screening and counseling by the Atomic Energy Commission.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
1 Blasko JC, Grimm PD, Sylvester JE, Badiozamani KR, Hoak D, Cavanagh W. (2000) Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 46 839–50.[CrossRef][Web of Science][Medline]

2 Ragde H, Elgamal AA, Snow PB, Brandt J, Bartolucci AA, Nadir BS, et al. (1998) Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-Gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma [see comments]. Cancer 83 989–1001.[CrossRef][Web of Science][Medline]

3 Snyder KM, Stock RG, Hong SM, Lo YC, Stone NN. (2001) Defining the risk of developing grade 2 proctitis following 125-I prostate brachytherapy using a rectal dose–volume histogram analysis. Int J Radiat Oncol Biol Phys 50 335–41.[CrossRef][Web of Science][Medline]

4 Gelblum DY and Potters L. (2000) Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 48 119–24.[Web of Science][Medline]

5 Waterman FM and Dicker AP. (2003) Probability of late rectal morbidity in 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 55 342–53.[CrossRef][Web of Science][Medline]

6 Tran A, Wallner K, Merrick G, Seeberger J, Armstrong J, Mueller A, et al. (2005) Rectal fistulas after prostate brachytherapy. Int J Radiat Oncol Biol Phys 63 150–4.[CrossRef][Web of Science][Medline]

7 Shah JN and Ennis RD. (2006) Rectal toxicity profile after transperineal interstitial permanent prostate brachytherapy: use of a comprehensive toxicity scoring and identification of rectal dosimetric toxicity predictors. Int J Radiat Oncol Biol Phys 64 817–24.[CrossRef][Web of Science][Medline]

8 Kwok Y, DiBiase SJ, Amin PP, Naslund M, Sklar G, Jacobs SC. (2002) Risk group stratification in patients undergoing permanent 125I prostate brachytherapy as monotherapy. Int J Radiat Oncol Biol Phys 53 588–94.[CrossRef][Web of Science][Medline]

9 Toya K, Yorozu A, Ohashi T, Okada M, Itoh R, Monma T, et al. (2005) Experience of brachytherapy using I-125 seed permanent implants for localized prostate cancer. Nippon Acta Radiologica 65 432–7.

10 Ohashi T, Yorozu A, Toya K, Saito S, Momma T. (2005) Acute urinary morbidity following I-125 prostate brachytherapy. Int J Clin Oncol 10 262–8.[CrossRef][Medline]

11 Ohashi T, Yorozu A, Toya K, Saito S, Momma T. (2006) Predictive factors of acute urinary retention requiring catheterization following 125I prostate brachytherapy. Jpn J Clin Oncol 36 285–9.[Abstract/Free Full Text]

12 Wallner K, Roy J, Harrison L. (1995) Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 32 465–71.[CrossRef][Web of Science][Medline]

13 Zelefsky MJ, Yamada Y, Marion C, Sim S, Cohen G, Ben Porat L, et al. (2003) Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal ultrasound-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 55 956–63.[CrossRef][Web of Science][Medline]

14 Merrick GS, Butler WM, Dorsey AT, Galbreath RW, Blatt H, Lief JH. (2000) Rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 48 667–74.[CrossRef][Web of Science][Medline]

15 Merrick GS, Butler WM, Wallner KE, Hines AL, Allen Z. (2003) Late rectal function after prostate brachytherapy. Int J Radiat Oncol Biol Phys 57 42–8.[Medline]

16 Merrick GS, Butler WM, Dorsey AT, Lief JH, Walbert HL, Blatt HJ. (1999) Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 43 1021–7.[CrossRef][Web of Science][Medline]

17 Hilts M, Spadinger I, Keyes M. (2002) Comparison of methods for calculating rectal dose after 125I prostate brachytherapy implants. Int J Radiat Oncol Biol Phys 53 775–85.[CrossRef][Web of Science][Medline]


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