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Defining the risk of developing Grade 2 proctitis following 125I prostate brachytherapy using a rectal dose–volume histogram analysis
Int. J. Radiation Oncology Biol. Phys., Vol. 50, No. 2, pp. 335–341, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/01/$–see front matter
PII S0360-3016(01)01442-0
CLINICAL INVESTIGATION
Prostate
DEFINING THE RISK OF DEVELOPING GRADE 2 PROCTITIS FOLLOWING 125 I PROSTATE BRACHYTHERAPY USING A RECTAL DOSE–VOLUME HISTOGRAM ANALYSIS KURT M. SNYDER, M.D.,* RICHARD G. STOCK, M.D.,* SUZANNE M. HONG, M.A.,* YEH CHI LO, PH.D.,* AND NELSON N. STONE, M.D.† Departments of *Radiation Oncology and †Urology, Mount Sinai School of Medicine, New York, NY Objective: To determine the rectal tolerance for developing Grade 2 radiation proctitis after 125I prostate implantation based on the rectal dose–volume histogram. Methods and Materials: Two hundred twelve patients with T1–T2 prostate cancer underwent 125I implantation without external beam irradiation. One month after the procedure, all patients underwent CT-based postimplant dosimetry (3-mm abutting slices). The rectal volumes, defined by an inner and outer wall, were determined from 9 mm above the seminal vesicles to 9 mm below the prostate apex. All doses were calculated by TG43 formalism. The prostate prescription dose was 160 Gy. A dose response analysis was undertaken for volumes of rectal tissue receiving a given dose. Dose levels examined were 80 Gy, 100 Gy, 120 Gy, 140 Gy, 160 Gy, 180 Gy, 200 Gy, 220 Gy, and 240 Gy. Grade 2 proctitis was defined as rectal bleeding occurring at least once a week for a minimum period of one month. The risk of proctitis was calculated using actuarial methods. For each dose level, a critical volume cutpoint was chosen to define a low and high volume group of patients. The cutpoint was determined based on two goals: minimizing the p value and finding a <5% risk of proctitis in the low volume group. Patients were followed from 12 to 61 months (median: 28 months) after implantation. Results: Twenty-two patients developed Grade 2 proctitis: 14% within the first year, 72% between the first and second year, and 14% during the third year after the implant date. After the third year postimplantation, no cases of proctitis were reported. Proctitis was found to be significantly volume dependent for a given dose. The prescription dose (160 Gy) delivered to <1.3 cc of rectal tissue resulted in a 5% rate of proctitis at 5 years vs. 18% for volumes >1.3 cc (p ⴝ 0.001). Similar results were found for all doses examined. As the rectal volume receiving the prescription dose (160 Gy) increased, so did the proctitis rate: 0% for <0.8 cc, 7% for >0.8 –1.3 cc, 8% for >1.3–1.8 cc, 24% for >1.8 –2.3 cc, and 25.5% for >2.3cc (p ⴝ 0.002). Conclusions: Rectal dose–volume histogram analysis is a practical and predictive method of assessing the risk of developing Grade 2 proctitis after 125I prostate implantation. Delivered dose should be kept below defined rectal volume thresholds to minimize this risk. This information can allow one to decrease rectal morbidity by modifying prostate implant technique. © 2001 Elsevier Science Inc. Prostate brachytherapy, Rectal dosimetry, Proctitis.
INTRODUCTION
intermittent painless rectal bleeding to more severe cases of ulceration and fistula formation. Initial reports in the literature reveal proctitis rates ranging from 1.0% to 5.0% with implant alone (2– 4). Although these rates are low, one might expect rates to increase with longer follow-up and improved implant technique. Our initial experience revealed a Grade 2 proctitis rate of 1.0% (5). We began to observe an increased rate of rectal bleeding as our implants became more accurate and prostate doses increased. Due to this observation, we undertook this study to better define the risk of developing proctitis and to develop a practical and easily reproducible tool for assessing this risk. The goal of this analysis was to provide guidelines that would enable physicians to modify planning
As prostate brachytherapy has evolved, the ability to more precisely place seeds has improved. Postimplant dosimetry analysis has also helped physicians perfect the technique. These factors have resulted in increased dose delivered to the prostate (1). Whereas this increased dose has been shown to improve biochemical control, it also has the potential to increase morbidity. One potential late complication of prostate brachytherapy is radiation proctitis. This complication results from the difficulty inherent in sparing the anterior rectal wall from high radiation dose due to its close proximity to the prostate. Radiation proctitis is variable in its presentation and can range in severity from Reprint requests to: Richard G. Stock, M.D., Department of Radiation Oncology, Box 1236, Mount Sinai Hospital, 1184 Fifth Avenue, New York, NY 10029. Tel: (212) 241-7502; Fax: (212)
410-7194; E-mail: [email protected] Accepted for publication 20 December 2000. 335
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and implantation technique to decrease this treatment-related side effect.
METHODS AND MATERIALS A total of 229 patients underwent 125I (Nycomed Amersham Model 6711) permanent radioactive seed implants for T1–T2 prostate cancer and had postimplant CT-based dosimetry. Seed activities ranged from 0.264 mCi to 0.556 mCi, with the median being 0.405 mCi. The study period was from 1/95 to 6/98. This time frame was selected so that all dosimetric analyses could be performed on the same planning system. Implants done before this time could not be converted over to the new system to allow for a uniform method of defining rectal volumes. Of these patients, 223 had a minimum follow-up of one year and did not receive adjuvant external beam irradiation. An additional 11 patients were eliminated from the study for the following reasons: bilateral hip prosthesis, movement during the CT scan making seed identification difficult, or unattainable or unusable CT scan. The remaining 212 patients were analyzed for the study. Patients were followed from 12 to 61 months (median: 28 months) after implantation by the urologist or radiation oncologist. Those patients who had not been seen in the past 6 months, approximately 10%, were contacted via phone and asked detailed questions concerning rectal bleeding by the author (R.S.). Patients with rectal bleeding were sent to a gastroenterologist for endoscopic evaluation of the proctitis. Patients who developed rectal bleeding were treated with Metamucil and corticosteroid suppositories or foams. A typical regimen involved daily medication for 3 to 4 weeks. Treatment All patients were implanted using the real time interactive ultrasound-guided transperineal technique. Details of this technique have been previously reported (6). The basic plan involved a two-phased peripheral loaded implant. The prostate volume was measured using ultrasound planemetry. The total amount of activity to implant was determined from an activity-per-volume table to achieve a prostate prescription dose of 160 Gy. Needle and seed deposition were guided by transrectal ultrasound. The first phase was peripheral implantation. This involved placing needles (average 13–17) 0.75 to 1 cm apart in the periphery of the largest transverse diameter of the prostate. These needles were used to implant 75% of the total activity using longitudinal ultrasound guidance. The second phase involved interior needles that were inserted into the prostate so that they covered the periphery of the apex and base and were no closer than 0.5 cm from the urethra. Twenty-five percent of the remaining activity was inserted into the prostate via these needles (average 6 – 8). Seeds were inserted using a Mick applicator. Most of this activity was deposited near the apex and base, keeping the interior of the gland relatively free of seeds.
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Postimplant dosimetry One month after implantation, in the absence of a pre-CT bowel prep or GI contrast, a CT scan of the implanted area was performed using 3-mm abutting slices. This time period was selected to allow for the acute swelling of the prostate after implantation to subside. Studies have demonstrated that this time for analysis provides the most accurate assessment of actual delivered doses (7, 8). Dosimetry was performed using the ADAC Pinnacle system, and all doses were defined using TG43 formulism (9). To provide a consistency in defining rectal volumes, all rectal outlining was redone by one person (K.S.). Volumes were outlined from 9 mm above the seminal vesicles to 9 mm below the prostate apex. Both inner and outer walls were drawn to define the volume. The inner wall of the rectum was defined by the edge of the lumen, taking care to exclude any feces. If the lumen was absent, the inner wall was approximated based on the diameter of the outer rectal wall and the thickness of the rectal wall in abutting slices. A dose– volume histogram (DVH) of the rectum was generated for each patient. Study parameters and analysis Grade 2 proctitis was defined as rectal bleeding occurring at least once a week for a minimum period of one month. Grade 3– 4 toxicity was defined using the Radiation Therapy and Oncology Group (RTOG) scale (10). Proctitis rates were calculated using the methods of Kaplan and Meier (11). The log-rank test was used to compare rates (12, 13). Dose levels examined were 80 Gy, 100 Gy, 120 Gy, 140 Gy, 160 Gy, 180 Gy, 200 Gy, 220 Gy, and 240 Gy. For each dose level, the risk of proctitis was calculated for patients in whom the given dose covered above or below a given amount of rectal tissue. By examining different rectal volume cutpoints for a given dose, patients were separated into two groups (less than or equal to or above the volume threshold). This volume threshold was determined based on two goals: minimizing the p value in a univariate comparison and finding a ⱕ5% risk of proctitis in the low-volume group. RESULTS Twenty-two patients developed Grade 2 proctitis: 14% within the first year, 72% between the first and second year, and 14% during the third year after the implant date. After the third year postimplantation, no cases of proctitis were reported. No patient developed Grade 3– 4 toxicity. The risks of developing Grade 2 proctitis at 5 years using volume cutpoints for the above dose levels are listed in Table 1. Actuarial risk curves for doses 80 Gy (50% of prescription dose), 160 Gy (prescription dose), and 240 Gy (150% of prescription dose) can be found in Figs. 1–3. Figure 4 shows graphically the volume cutpoints by dose that demonstrate a ⱕ5% risk of proctitis at 5 years. The development of proctitis was found to be significantly volume dependent for a given dose. The prescription
Proctitis after prostate brachytherapy
Table 1. Relationship between volume of rectal wall receiving a given dose and 5-year risk of developing Grade 2 radiation proctitis 5-Year actuarial Grade 2 proctitis rate (%) Dose (Gy)
Rectal volume cutpoint (cc)
ⱕVolume cutpoint
⬎Volume cutpoint
p value
80 100 120 140 160 180 200 220 240
4.0 3.0 2.5 2.0 1.3 1.2 0.8 0.5 0.4
5 4 5 5 5 5 6 5 5
21.0 20.0 21.0 23.6 18.0 22.0 20.0 18.0 20.0
0.0007 0.0006 0.0002 0.0001 0.0010 0.0002 0.0009 0.0040 0.0009
dose (160 Gy) delivered to ⱕ1.3 cc of rectal tissue resulted in a 5% rate of proctitis at 5 years vs. 18% for volumes ⬎1.3 cc (p ⫽ 0.001). As the rectal volume receiving the prescription dose (160 Gy) increased, so did the proctitis rate: 0% for ⱕ0.8 cc, 7% for ⬎0.8 –1.3 cc, 8% for ⬎1.3–1.8 cc, 24% for ⬎1.8 –2.3 cc, and 25.5% for ⬎2.3 cc. There also appeared to be a strong correlation between dose levels and volume of rectum irradiated. For example, the dose cutpoint for 240 Gy was 0.4 cc and increased to 4 cc for 80 Gy. In addition, the following factors were analyzed using univariate analyses for their effects on proctitis: diabetes, age, ultrasound prostate volume, and dose delivered to 90% of the prostate (D90) (Table 2). Of these factors, only
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prostate volume significantly affected the development of proctitis. The 5-year freedom from proctitis rate was 94% for prostate volumes ⱕ40 cc vs. 73% for volumes ⬎40 cc (p ⫽ 0.001). Prostate volumes as well as dose levels were tested using multivariate analysis (Table 3). Only the amount of rectum receiving 80 Gy was significant in multivariate analysis. This finding is probably due to the larger amount of rectal tissue receiving this dose as opposed to higher doses. The large volume allows for greater variation among patients and can better separate out hot vs. cold rectums. DISCUSSION A common side effect of radiation therapy in the treatment of prostate carcinoma is the development of radiation proctitis. This late morbidity is a result of the close proximity of the anterior rectal wall to the prostate. As greater doses of radiation are being delivered to the prostate to improve biochemical control, the risk of rectal morbidity increases. Hanks et al. conducted the first study examining the relationship between escalating prostate prescription doses and radiation proctitis (14). In comparing the dose response curves for biochemical freedom of disease and Grade 2 proctitis in patients with an initial PSA ⬎10, they found that the slope of the dose response curve for Grade 2 proctitis became steeper than the curve for cancer control after a prescription dose of 72–75 Gy. They recommended reducing the area of rectum treated above 72 Gy during treatment planning to reduce the risk of developing this morbidity.
Fig. 1. Effect of rectal volume receiving 80 Gy on Grade 2 proctitis.
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Fig. 2. Effect of rectal volume receiving 160 Gy on Grade 2 proctitis.
A dose response for developing radiation proctitis was confirmed by Zelefsky et al. (15) in a multivariate analysis of 743 patients examining predictors of rectal morbidity after external beam radiation treatment for prostate carcinoma. In this study, they found that the following factors
were independent predictors for developing Grade ⱖ2 proctitis: prostate doses ⱖ75.6 Gy, a history of diabetes, and presence of acute gastrointestinal symptoms during treatment. A more extensive study carried out on the same patients by Skwarchuk et al. (16) found the following fac-
Fig. 3. Effect of rectal volume receiving 240 Gy on Grade 2 proctitis.
Proctitis after prostate brachytherapy
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Fig. 4. Rectal volume thresholds associated with ⱕ5% risk of Grade 2 proctitis at 5 years.
tors to be significant for developing Grade ⱖ2 proctitis after a prostate dose of ⱖ75.6 Gy: smaller anatomically defined rectal wall volume, higher rectal Dmax (maximum dose to the rectal wall), enclosure of the outer rectal wall by the 50% isodose line on the central CT slice, patient age, history of diabetes mellitus, and acute rectal toxicity. Although several of these parameters are fixed (age, diabetes, rectal wall volume), modification of dose factors (rectal Dmax, enclosure of the outer rectal wall by the 50% isodose line, higher treatment doses) offers the possibility of decreasing radiation proctitis. Although these studies did not specifically address DVH analysis, Skwarchuk et al. (16) reported that DVH parameters were highly correlated with late rectal bleeding in univariate analysis. Other studies have specifically examined the relationship between the rectal dose–volume histogram and late rectal Table 2. The effect of diabetes, age, prostate ultrasound volume, and D90 on developing Grade 2 proctitis
Factor Diabetes Yes No Age ⱕ65 ⬎65 Prostate ultrasound volume ⱕ40 cc ⬎40 cc D90 ⱕ160 Gy ⬎160 Gy
Number of patients
5-Year freedom from Grade 2 proctitis (%)
14 198
85 88
0.660
105 107
89 86
0.780
139 73
94 73
0.001
75 137
94 84
0.070
p value
toxicity. Boersma et al. looked at 130 patients who underwent conformal radiation therapy and failed to observe any correlation between Grade 2 radiation proctitis and any of the examined DVH parameters (17). However, the study found an association between the percentage of rectal volume receiving a given dose and severe rectal bleeding (defined as requiring a blood transfusion or laser therapy). There was an association between several consecutive DVH cutoff levels and the percentage of rectal volume receiving a particular dose. Similarly, Hartford et al. found a statistical correlation between the percentage of anterior rectal volume receiving various doses and Grade 1 radiation proctitis (18). These studies confirm a correlation between dose delivered to the rectum and proctitis. Whereas there are multiple reports examining radiation proctitis after external beam radiation treatment, only two studies have addressed rectal toxicity after prostate brachytherapy. Wallner et al. looked at 45 patients who underwent 125 I implantation without supplemental external beam radiation therapy (19). Patients with rectal complications had, on average, 17 mm2 of rectal wall irradiated to doses greater than 100 Gy vs. 11 mm2 in those without rectal morbidity. There was no relationship seen between radiation proctitis and matched peripheral dose, mCi/source, or total mCi implanted. This study validated the notion that there is a Table 3. Multivariate analysis of factors affecting proctitis Factor Prostate volume Volume (cc) of rectum receiving 80 Gy 140 Gy 160 Gy 240 Gy
p value 0.8 ⬍0.0001 0.6 0.5 0.08
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dose effect involved with proctitis. However, there are several limitations to this study. First, the number of patients involved in the study was small (45), and there were only 6 patients with rectal complications. Second, the guideline to limit radiation proctitis was to decrease the surface area of the anterior rectal wall receiving 100 Gy (preTG43). The data generated for a dose–surface relationship cannot be converted into the more widely used dose–volume relationship to predict complications. A second study by Merrick et al. took an alternative approach to calculating rectal dose by examining the relationship between point doses on the anterior rectal wall and radiation proctitis (20). This study set parameters involving the average rectal mucosa point dose and the length of the rectum receiving percentages of the prescribed dose in which the incidence of serious rectal complications would be rare. However, due to a lack of significant rectal complications in the study, no conclusions were made regarding rectal tolerance. The findings of this study are difficult to apply to general practice as well. First, the study was small in number, and the treatment regimens were not consistent. Patients were treated with either 125I or 103Pd alone or as a boost after 45 Gy of external beam radiotherapy. Radiobiologic differences in dose rate and fractionation among the different therapies make extrapolation of the data difficult. In addition, a rectal obturator was inserted before the CT scan to identify the anterior rectal mucosa on each CT slice. The obturator is not practical for large groups of patients, and it can be argued that it distorts the rectum. In our study, we attempted to correct for some of these limitations and develop an accurate and practical method for ascertaining the risk of developing proctitis. To analyze patients undergoing the same treatment, only patients treated with 125I monotherapy were selected. We utilized the rectal dose–volume histogram in our analysis, since it is
Volume 50, Number 2, 2001
available on all major brachytherapy-planning systems. Absolute volume was used as opposed to the percentage volume for two reasons. One, it was hypothesized that proctitis depends only on the absolute amount of rectal tissue receiving a given dose rather than the percentage of entire rectal tissue receiving that same dose. Second, it reduces the possible error in underestimating or overestimating the total rectal volume when deciding where the rectum begins and ends or in outlining the inner wall of the rectum. This approach is less dependent on the total rectal volume. Through this analysis, we were able to define a volume threshold for a range of doses that can be found in a tabular DVH for the rectum that would limit Grade 2 proctitis to a rate less than or equal to 5% at 5 years (Table 1). The information provided by this analysis can be used to help modify implant technique. This type of rectal DVH data can be used in both preplanning as well as postimplant dosimetry analysis. Reviewing rectal DVH data from postimplant dosimetry can allow physicians to learn from their implants and hopefully use this information to improve future prostate brachytherapy procedures. In addition, we have begun to develop an intraoperative dosimetry system to optimize dose distributions (21). We plan to use this rectal DVH data in the intraoperative setting to help minimize rectal morbidity as well as achieve the planned prostate dose. CONCLUSION Rectal dose–volume histogram analysis is a practical and predictive method for assessing the risk of developing Grade 2 proctitis after 125I prostate implantation. Delivered dose should be kept below defined rectal volume thresholds to minimize the risk. This information can allow one to decrease rectal morbidity by modifying prostate implant technique.
REFERENCES 1. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41:101–108. 2. Beyer DC, Priestley JB Jr. Biochemical disease-free survival following 125I prostate implantation. Int J Radiat Oncol Biol Phys 1997;37:559 –563. 3. Blasko JC, Ragde H, Luse RW, et al. Should brachytherapy be considered a therapeutic option in localized prostate cancer? Urol Clin North Am 1996;23:633– 650. 4. 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. 5. Stock RG, Stone NN, DeWyngaert JK. Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer 1996;77:2386 –2392. 6. Stock RG, Stone NN, Wesson MF, et al. A modified technique allowing interactive ultrasound-guided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995;32:219 –225. 7. Prestidge BR, Bice WS, Kiefer EJ, et al. Timing of computed
8.
9.
10. 11. 12. 13.
14.
tomography-based postimplant assessment following permanent transperineal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998;40:1111–1115. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46:221–230. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995;22:209 –234. Winchester DP, Cox JD. Standards for breast conservation treatment. Ca Center J Clin 1992;2:134 –162. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. Cox DR, Oakes D. Analysis of survival data. Chapman and Hall. 1984. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–170. Hanks GE, Schultheiss TE, Hanlon AL, et al. Optimization of
Proctitis after prostate brachytherapy
conformal radiation treatment of prostate cancer: Report of a dose escalation study. Int J Radiat Oncol Biol Phys 1997;37:543–550. 15. Zelefsky MJ, Cowen DM, Fuks Z, et al. Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate cancer. Cancer 1999;85: 2460 –2468. 16. 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;47:103–113. 17. Boersma LJ, van den Brink M, Bruce AM, et al. Estimation of the incidence of late bladder and rectum complications after high-dose (70 –78 Gy) conformal radiotherapy for prostate cancer, using dose-volume histograms. Int J Radiat Oncol Biol Phys 1998;41:83–92.
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18. Hartford AC, Niemierko A, Adams JA, et al. Conformal irradiation of the prostate: Estimating long-term rectal bleeding risk using dose-volume histograms. Int J Radiat Oncol Biol Phys 1996;36:721–730. 19. 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. 20. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999;43:1021–1027. 21. Stock RG, Stone NN, Lo YC. Intraoperative dosimetric representation of the real-time ultrasound-guided prostate implant. Techniques in Urology 2000;6:95–98.
PII S0360-3016(01)01442-0
CLINICAL INVESTIGATION
Prostate
DEFINING THE RISK OF DEVELOPING GRADE 2 PROCTITIS FOLLOWING 125 I PROSTATE BRACHYTHERAPY USING A RECTAL DOSE–VOLUME HISTOGRAM ANALYSIS KURT M. SNYDER, M.D.,* RICHARD G. STOCK, M.D.,* SUZANNE M. HONG, M.A.,* YEH CHI LO, PH.D.,* AND NELSON N. STONE, M.D.† Departments of *Radiation Oncology and †Urology, Mount Sinai School of Medicine, New York, NY Objective: To determine the rectal tolerance for developing Grade 2 radiation proctitis after 125I prostate implantation based on the rectal dose–volume histogram. Methods and Materials: Two hundred twelve patients with T1–T2 prostate cancer underwent 125I implantation without external beam irradiation. One month after the procedure, all patients underwent CT-based postimplant dosimetry (3-mm abutting slices). The rectal volumes, defined by an inner and outer wall, were determined from 9 mm above the seminal vesicles to 9 mm below the prostate apex. All doses were calculated by TG43 formalism. The prostate prescription dose was 160 Gy. A dose response analysis was undertaken for volumes of rectal tissue receiving a given dose. Dose levels examined were 80 Gy, 100 Gy, 120 Gy, 140 Gy, 160 Gy, 180 Gy, 200 Gy, 220 Gy, and 240 Gy. Grade 2 proctitis was defined as rectal bleeding occurring at least once a week for a minimum period of one month. The risk of proctitis was calculated using actuarial methods. For each dose level, a critical volume cutpoint was chosen to define a low and high volume group of patients. The cutpoint was determined based on two goals: minimizing the p value and finding a <5% risk of proctitis in the low volume group. Patients were followed from 12 to 61 months (median: 28 months) after implantation. Results: Twenty-two patients developed Grade 2 proctitis: 14% within the first year, 72% between the first and second year, and 14% during the third year after the implant date. After the third year postimplantation, no cases of proctitis were reported. Proctitis was found to be significantly volume dependent for a given dose. The prescription dose (160 Gy) delivered to <1.3 cc of rectal tissue resulted in a 5% rate of proctitis at 5 years vs. 18% for volumes >1.3 cc (p ⴝ 0.001). Similar results were found for all doses examined. As the rectal volume receiving the prescription dose (160 Gy) increased, so did the proctitis rate: 0% for <0.8 cc, 7% for >0.8 –1.3 cc, 8% for >1.3–1.8 cc, 24% for >1.8 –2.3 cc, and 25.5% for >2.3cc (p ⴝ 0.002). Conclusions: Rectal dose–volume histogram analysis is a practical and predictive method of assessing the risk of developing Grade 2 proctitis after 125I prostate implantation. Delivered dose should be kept below defined rectal volume thresholds to minimize this risk. This information can allow one to decrease rectal morbidity by modifying prostate implant technique. © 2001 Elsevier Science Inc. Prostate brachytherapy, Rectal dosimetry, Proctitis.
INTRODUCTION
intermittent painless rectal bleeding to more severe cases of ulceration and fistula formation. Initial reports in the literature reveal proctitis rates ranging from 1.0% to 5.0% with implant alone (2– 4). Although these rates are low, one might expect rates to increase with longer follow-up and improved implant technique. Our initial experience revealed a Grade 2 proctitis rate of 1.0% (5). We began to observe an increased rate of rectal bleeding as our implants became more accurate and prostate doses increased. Due to this observation, we undertook this study to better define the risk of developing proctitis and to develop a practical and easily reproducible tool for assessing this risk. The goal of this analysis was to provide guidelines that would enable physicians to modify planning
As prostate brachytherapy has evolved, the ability to more precisely place seeds has improved. Postimplant dosimetry analysis has also helped physicians perfect the technique. These factors have resulted in increased dose delivered to the prostate (1). Whereas this increased dose has been shown to improve biochemical control, it also has the potential to increase morbidity. One potential late complication of prostate brachytherapy is radiation proctitis. This complication results from the difficulty inherent in sparing the anterior rectal wall from high radiation dose due to its close proximity to the prostate. Radiation proctitis is variable in its presentation and can range in severity from Reprint requests to: Richard G. Stock, M.D., Department of Radiation Oncology, Box 1236, Mount Sinai Hospital, 1184 Fifth Avenue, New York, NY 10029. Tel: (212) 241-7502; Fax: (212)
410-7194; E-mail: [email protected] Accepted for publication 20 December 2000. 335
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Biology
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Physics
and implantation technique to decrease this treatment-related side effect.
METHODS AND MATERIALS A total of 229 patients underwent 125I (Nycomed Amersham Model 6711) permanent radioactive seed implants for T1–T2 prostate cancer and had postimplant CT-based dosimetry. Seed activities ranged from 0.264 mCi to 0.556 mCi, with the median being 0.405 mCi. The study period was from 1/95 to 6/98. This time frame was selected so that all dosimetric analyses could be performed on the same planning system. Implants done before this time could not be converted over to the new system to allow for a uniform method of defining rectal volumes. Of these patients, 223 had a minimum follow-up of one year and did not receive adjuvant external beam irradiation. An additional 11 patients were eliminated from the study for the following reasons: bilateral hip prosthesis, movement during the CT scan making seed identification difficult, or unattainable or unusable CT scan. The remaining 212 patients were analyzed for the study. Patients were followed from 12 to 61 months (median: 28 months) after implantation by the urologist or radiation oncologist. Those patients who had not been seen in the past 6 months, approximately 10%, were contacted via phone and asked detailed questions concerning rectal bleeding by the author (R.S.). Patients with rectal bleeding were sent to a gastroenterologist for endoscopic evaluation of the proctitis. Patients who developed rectal bleeding were treated with Metamucil and corticosteroid suppositories or foams. A typical regimen involved daily medication for 3 to 4 weeks. Treatment All patients were implanted using the real time interactive ultrasound-guided transperineal technique. Details of this technique have been previously reported (6). The basic plan involved a two-phased peripheral loaded implant. The prostate volume was measured using ultrasound planemetry. The total amount of activity to implant was determined from an activity-per-volume table to achieve a prostate prescription dose of 160 Gy. Needle and seed deposition were guided by transrectal ultrasound. The first phase was peripheral implantation. This involved placing needles (average 13–17) 0.75 to 1 cm apart in the periphery of the largest transverse diameter of the prostate. These needles were used to implant 75% of the total activity using longitudinal ultrasound guidance. The second phase involved interior needles that were inserted into the prostate so that they covered the periphery of the apex and base and were no closer than 0.5 cm from the urethra. Twenty-five percent of the remaining activity was inserted into the prostate via these needles (average 6 – 8). Seeds were inserted using a Mick applicator. Most of this activity was deposited near the apex and base, keeping the interior of the gland relatively free of seeds.
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Postimplant dosimetry One month after implantation, in the absence of a pre-CT bowel prep or GI contrast, a CT scan of the implanted area was performed using 3-mm abutting slices. This time period was selected to allow for the acute swelling of the prostate after implantation to subside. Studies have demonstrated that this time for analysis provides the most accurate assessment of actual delivered doses (7, 8). Dosimetry was performed using the ADAC Pinnacle system, and all doses were defined using TG43 formulism (9). To provide a consistency in defining rectal volumes, all rectal outlining was redone by one person (K.S.). Volumes were outlined from 9 mm above the seminal vesicles to 9 mm below the prostate apex. Both inner and outer walls were drawn to define the volume. The inner wall of the rectum was defined by the edge of the lumen, taking care to exclude any feces. If the lumen was absent, the inner wall was approximated based on the diameter of the outer rectal wall and the thickness of the rectal wall in abutting slices. A dose– volume histogram (DVH) of the rectum was generated for each patient. Study parameters and analysis Grade 2 proctitis was defined as rectal bleeding occurring at least once a week for a minimum period of one month. Grade 3– 4 toxicity was defined using the Radiation Therapy and Oncology Group (RTOG) scale (10). Proctitis rates were calculated using the methods of Kaplan and Meier (11). The log-rank test was used to compare rates (12, 13). Dose levels examined were 80 Gy, 100 Gy, 120 Gy, 140 Gy, 160 Gy, 180 Gy, 200 Gy, 220 Gy, and 240 Gy. For each dose level, the risk of proctitis was calculated for patients in whom the given dose covered above or below a given amount of rectal tissue. By examining different rectal volume cutpoints for a given dose, patients were separated into two groups (less than or equal to or above the volume threshold). This volume threshold was determined based on two goals: minimizing the p value in a univariate comparison and finding a ⱕ5% risk of proctitis in the low-volume group. RESULTS Twenty-two patients developed Grade 2 proctitis: 14% within the first year, 72% between the first and second year, and 14% during the third year after the implant date. After the third year postimplantation, no cases of proctitis were reported. No patient developed Grade 3– 4 toxicity. The risks of developing Grade 2 proctitis at 5 years using volume cutpoints for the above dose levels are listed in Table 1. Actuarial risk curves for doses 80 Gy (50% of prescription dose), 160 Gy (prescription dose), and 240 Gy (150% of prescription dose) can be found in Figs. 1–3. Figure 4 shows graphically the volume cutpoints by dose that demonstrate a ⱕ5% risk of proctitis at 5 years. The development of proctitis was found to be significantly volume dependent for a given dose. The prescription
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Table 1. Relationship between volume of rectal wall receiving a given dose and 5-year risk of developing Grade 2 radiation proctitis 5-Year actuarial Grade 2 proctitis rate (%) Dose (Gy)
Rectal volume cutpoint (cc)
ⱕVolume cutpoint
⬎Volume cutpoint
p value
80 100 120 140 160 180 200 220 240
4.0 3.0 2.5 2.0 1.3 1.2 0.8 0.5 0.4
5 4 5 5 5 5 6 5 5
21.0 20.0 21.0 23.6 18.0 22.0 20.0 18.0 20.0
0.0007 0.0006 0.0002 0.0001 0.0010 0.0002 0.0009 0.0040 0.0009
dose (160 Gy) delivered to ⱕ1.3 cc of rectal tissue resulted in a 5% rate of proctitis at 5 years vs. 18% for volumes ⬎1.3 cc (p ⫽ 0.001). As the rectal volume receiving the prescription dose (160 Gy) increased, so did the proctitis rate: 0% for ⱕ0.8 cc, 7% for ⬎0.8 –1.3 cc, 8% for ⬎1.3–1.8 cc, 24% for ⬎1.8 –2.3 cc, and 25.5% for ⬎2.3 cc. There also appeared to be a strong correlation between dose levels and volume of rectum irradiated. For example, the dose cutpoint for 240 Gy was 0.4 cc and increased to 4 cc for 80 Gy. In addition, the following factors were analyzed using univariate analyses for their effects on proctitis: diabetes, age, ultrasound prostate volume, and dose delivered to 90% of the prostate (D90) (Table 2). Of these factors, only
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prostate volume significantly affected the development of proctitis. The 5-year freedom from proctitis rate was 94% for prostate volumes ⱕ40 cc vs. 73% for volumes ⬎40 cc (p ⫽ 0.001). Prostate volumes as well as dose levels were tested using multivariate analysis (Table 3). Only the amount of rectum receiving 80 Gy was significant in multivariate analysis. This finding is probably due to the larger amount of rectal tissue receiving this dose as opposed to higher doses. The large volume allows for greater variation among patients and can better separate out hot vs. cold rectums. DISCUSSION A common side effect of radiation therapy in the treatment of prostate carcinoma is the development of radiation proctitis. This late morbidity is a result of the close proximity of the anterior rectal wall to the prostate. As greater doses of radiation are being delivered to the prostate to improve biochemical control, the risk of rectal morbidity increases. Hanks et al. conducted the first study examining the relationship between escalating prostate prescription doses and radiation proctitis (14). In comparing the dose response curves for biochemical freedom of disease and Grade 2 proctitis in patients with an initial PSA ⬎10, they found that the slope of the dose response curve for Grade 2 proctitis became steeper than the curve for cancer control after a prescription dose of 72–75 Gy. They recommended reducing the area of rectum treated above 72 Gy during treatment planning to reduce the risk of developing this morbidity.
Fig. 1. Effect of rectal volume receiving 80 Gy on Grade 2 proctitis.
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Fig. 2. Effect of rectal volume receiving 160 Gy on Grade 2 proctitis.
A dose response for developing radiation proctitis was confirmed by Zelefsky et al. (15) in a multivariate analysis of 743 patients examining predictors of rectal morbidity after external beam radiation treatment for prostate carcinoma. In this study, they found that the following factors
were independent predictors for developing Grade ⱖ2 proctitis: prostate doses ⱖ75.6 Gy, a history of diabetes, and presence of acute gastrointestinal symptoms during treatment. A more extensive study carried out on the same patients by Skwarchuk et al. (16) found the following fac-
Fig. 3. Effect of rectal volume receiving 240 Gy on Grade 2 proctitis.
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Fig. 4. Rectal volume thresholds associated with ⱕ5% risk of Grade 2 proctitis at 5 years.
tors to be significant for developing Grade ⱖ2 proctitis after a prostate dose of ⱖ75.6 Gy: smaller anatomically defined rectal wall volume, higher rectal Dmax (maximum dose to the rectal wall), enclosure of the outer rectal wall by the 50% isodose line on the central CT slice, patient age, history of diabetes mellitus, and acute rectal toxicity. Although several of these parameters are fixed (age, diabetes, rectal wall volume), modification of dose factors (rectal Dmax, enclosure of the outer rectal wall by the 50% isodose line, higher treatment doses) offers the possibility of decreasing radiation proctitis. Although these studies did not specifically address DVH analysis, Skwarchuk et al. (16) reported that DVH parameters were highly correlated with late rectal bleeding in univariate analysis. Other studies have specifically examined the relationship between the rectal dose–volume histogram and late rectal Table 2. The effect of diabetes, age, prostate ultrasound volume, and D90 on developing Grade 2 proctitis
Factor Diabetes Yes No Age ⱕ65 ⬎65 Prostate ultrasound volume ⱕ40 cc ⬎40 cc D90 ⱕ160 Gy ⬎160 Gy
Number of patients
5-Year freedom from Grade 2 proctitis (%)
14 198
85 88
0.660
105 107
89 86
0.780
139 73
94 73
0.001
75 137
94 84
0.070
p value
toxicity. Boersma et al. looked at 130 patients who underwent conformal radiation therapy and failed to observe any correlation between Grade 2 radiation proctitis and any of the examined DVH parameters (17). However, the study found an association between the percentage of rectal volume receiving a given dose and severe rectal bleeding (defined as requiring a blood transfusion or laser therapy). There was an association between several consecutive DVH cutoff levels and the percentage of rectal volume receiving a particular dose. Similarly, Hartford et al. found a statistical correlation between the percentage of anterior rectal volume receiving various doses and Grade 1 radiation proctitis (18). These studies confirm a correlation between dose delivered to the rectum and proctitis. Whereas there are multiple reports examining radiation proctitis after external beam radiation treatment, only two studies have addressed rectal toxicity after prostate brachytherapy. Wallner et al. looked at 45 patients who underwent 125 I implantation without supplemental external beam radiation therapy (19). Patients with rectal complications had, on average, 17 mm2 of rectal wall irradiated to doses greater than 100 Gy vs. 11 mm2 in those without rectal morbidity. There was no relationship seen between radiation proctitis and matched peripheral dose, mCi/source, or total mCi implanted. This study validated the notion that there is a Table 3. Multivariate analysis of factors affecting proctitis Factor Prostate volume Volume (cc) of rectum receiving 80 Gy 140 Gy 160 Gy 240 Gy
p value 0.8 ⬍0.0001 0.6 0.5 0.08
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dose effect involved with proctitis. However, there are several limitations to this study. First, the number of patients involved in the study was small (45), and there were only 6 patients with rectal complications. Second, the guideline to limit radiation proctitis was to decrease the surface area of the anterior rectal wall receiving 100 Gy (preTG43). The data generated for a dose–surface relationship cannot be converted into the more widely used dose–volume relationship to predict complications. A second study by Merrick et al. took an alternative approach to calculating rectal dose by examining the relationship between point doses on the anterior rectal wall and radiation proctitis (20). This study set parameters involving the average rectal mucosa point dose and the length of the rectum receiving percentages of the prescribed dose in which the incidence of serious rectal complications would be rare. However, due to a lack of significant rectal complications in the study, no conclusions were made regarding rectal tolerance. The findings of this study are difficult to apply to general practice as well. First, the study was small in number, and the treatment regimens were not consistent. Patients were treated with either 125I or 103Pd alone or as a boost after 45 Gy of external beam radiotherapy. Radiobiologic differences in dose rate and fractionation among the different therapies make extrapolation of the data difficult. In addition, a rectal obturator was inserted before the CT scan to identify the anterior rectal mucosa on each CT slice. The obturator is not practical for large groups of patients, and it can be argued that it distorts the rectum. In our study, we attempted to correct for some of these limitations and develop an accurate and practical method for ascertaining the risk of developing proctitis. To analyze patients undergoing the same treatment, only patients treated with 125I monotherapy were selected. We utilized the rectal dose–volume histogram in our analysis, since it is
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available on all major brachytherapy-planning systems. Absolute volume was used as opposed to the percentage volume for two reasons. One, it was hypothesized that proctitis depends only on the absolute amount of rectal tissue receiving a given dose rather than the percentage of entire rectal tissue receiving that same dose. Second, it reduces the possible error in underestimating or overestimating the total rectal volume when deciding where the rectum begins and ends or in outlining the inner wall of the rectum. This approach is less dependent on the total rectal volume. Through this analysis, we were able to define a volume threshold for a range of doses that can be found in a tabular DVH for the rectum that would limit Grade 2 proctitis to a rate less than or equal to 5% at 5 years (Table 1). The information provided by this analysis can be used to help modify implant technique. This type of rectal DVH data can be used in both preplanning as well as postimplant dosimetry analysis. Reviewing rectal DVH data from postimplant dosimetry can allow physicians to learn from their implants and hopefully use this information to improve future prostate brachytherapy procedures. In addition, we have begun to develop an intraoperative dosimetry system to optimize dose distributions (21). We plan to use this rectal DVH data in the intraoperative setting to help minimize rectal morbidity as well as achieve the planned prostate dose. CONCLUSION Rectal dose–volume histogram analysis is a practical and predictive method for assessing the risk of developing Grade 2 proctitis after 125I prostate implantation. Delivered dose should be kept below defined rectal volume thresholds to minimize the risk. This information can allow one to decrease rectal morbidity by modifying prostate implant technique.
REFERENCES 1. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41:101–108. 2. Beyer DC, Priestley JB Jr. Biochemical disease-free survival following 125I prostate implantation. Int J Radiat Oncol Biol Phys 1997;37:559 –563. 3. Blasko JC, Ragde H, Luse RW, et al. Should brachytherapy be considered a therapeutic option in localized prostate cancer? Urol Clin North Am 1996;23:633– 650. 4. 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. 5. Stock RG, Stone NN, DeWyngaert JK. Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer 1996;77:2386 –2392. 6. Stock RG, Stone NN, Wesson MF, et al. A modified technique allowing interactive ultrasound-guided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995;32:219 –225. 7. Prestidge BR, Bice WS, Kiefer EJ, et al. Timing of computed
8.
9.
10. 11. 12. 13.
14.
tomography-based postimplant assessment following permanent transperineal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998;40:1111–1115. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46:221–230. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995;22:209 –234. Winchester DP, Cox JD. Standards for breast conservation treatment. Ca Center J Clin 1992;2:134 –162. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. Cox DR, Oakes D. Analysis of survival data. Chapman and Hall. 1984. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–170. Hanks GE, Schultheiss TE, Hanlon AL, et al. Optimization of
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conformal radiation treatment of prostate cancer: Report of a dose escalation study. Int J Radiat Oncol Biol Phys 1997;37:543–550. 15. Zelefsky MJ, Cowen DM, Fuks Z, et al. Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate cancer. Cancer 1999;85: 2460 –2468. 16. 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;47:103–113. 17. Boersma LJ, van den Brink M, Bruce AM, et al. Estimation of the incidence of late bladder and rectum complications after high-dose (70 –78 Gy) conformal radiotherapy for prostate cancer, using dose-volume histograms. Int J Radiat Oncol Biol Phys 1998;41:83–92.
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18. Hartford AC, Niemierko A, Adams JA, et al. Conformal irradiation of the prostate: Estimating long-term rectal bleeding risk using dose-volume histograms. Int J Radiat Oncol Biol Phys 1996;36:721–730. 19. 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. 20. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999;43:1021–1027. 21. Stock RG, Stone NN, Lo YC. Intraoperative dosimetric representation of the real-time ultrasound-guided prostate implant. Techniques in Urology 2000;6:95–98.