- Email: [email protected]
Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 1, pp. 119 –124, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter
PII S0360-3016(00)00632-5
CLINICAL INVESTIGATION
Prostate
RECTAL COMPLICATIONS ASSOCIATED WITH TRANSPERINEAL INTERSTITIAL BRACHYTHERAPY FOR PROSTATE CANCER DAPHNA Y. GELBLUM, M.D.,
AND
LOUIS POTTERS, M.D.
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center at Mercy Medical Center, Rockville Center, New York, NY Purpose: As transperineal interstitial permanent prostate brachytherapy (TIPPB) grows in acceptance as an option in the treatment of organ-confined prostate cancer, its associated toxicities are being defined. This clinical report documents rectal toxicity from a large cohort of men treated by a single practitioner for adenocarcinoma of the prostate. Methods and Materials: Eight hundred twenty-five men were treated from September 1992 to September 1998 with TIPPB. One hundred-forty were treated in conjunction with external beam irradiation (EBRT) and 685 with TIPPB alone. All patients were implanted under real-time ultrasound guidance. No dose–volume histogram analysis was performed for this study. All patients were followed at 5 weeks after the procedure, then every 3– 6 months thereafter. Rectal morbidity was graded by a modified RTOG toxicity scale. Therapy to control symptoms was recommended on an individual basis. Results: The median follow-up for the cohort is 48 months. A total of 77 patients (9.4%) reported Grade 1 toxicity at some time following an implant whereas 54 patients (6.6%) reported Grade 2 toxicity. The peak post-TIPPB time for experiencing rectal toxicity was 8 months at which time Grade 1 and 2 rectal toxicity was reported in 9.5% of the patients. This improved over the subsequent months and resolved in all patients by 31⁄2 years. Four patients (0.5%) reported Grade 3 rectal toxicity with rectal ulceration identified on colonoscopy at 1 year from implant. Two of the four patients had colonic manipulation in the radiated portion of the colon which subsequently caused it to bleed. None of the patients required blood product transfusion. In 3 of the 4 patients the Grade 3 rectal toxicity has resolved spontaneously and 1 patient continues to heal at the time of this report. No patient required hospitalization or surgical intervention. Conclusion: TIPPB is a tolerable and acceptable treatment option when used alone in early-stage, organ-confined adenocarcinoma of the prostate and in conjunction with EBRT in more advanced disease. This clinical report adds to the growing literature regarding the potential morbidity associated with this procedure and indicates that serious rectal injury is rare. © 2000 Elsevier Science Inc. Prostate cancer, Brachytherapy, Rectal injury, Iodine, Palladium.
rectal toxicity reported from a large cohort of men treated with TIPPB by the same practitioner (L.P.).
INTRODUCTION Ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) alone or in conjunction with external beam irradiation (EBRT) for adenocarcinoma of the prostate is quickly growing in popularity as a treatment option for patients with early-stage, localized cancers. As experience with this technique has grown over the last several years, reports in the literature have presented the urinary morbidity from several centers (1–3). The rectal morbidity associated with TIPPB has been less well investigated and documented (4, 5). As patients are asked to participate in the treatment decisions for early-stage, localized prostate cancer, the morbidity of each treatment method plays an important role in the selection process for each patient. This clinical study was undertaken to assess
METHODS AND MATERIALS Between September 1992 and September 1998, 825 consecutive patients with biopsy-proven adenocarcinoma of the prostate were treated with TIPPB (Table 1). One hundredforty men were treated in combination with EBRT and 685 had an implant alone. One hundred seventy-three patients were started on antiandrogen therapy prior to treatment while 652 were not. Patients were staged clinically by a single practitioner according to the American Joint Committee on Cancer (AJCC) standards (6). Patients with T1N0M0 and T2N0M0 disease were considered eligible for
Reprint requests to: Daphna Y. Gelblum, M.D., Dept. of Radiation Oncology, Memorial Sloan-Kettering Cancer Center @ Mercy Medical Center, 1000 North Village Ave., Rockville Center, NY 11570. E-mail: [email protected]
Accepted for publication 10 April 2000.
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Table 1. Patient characteristics Variable Number of patients implanted Age (median) Median preimplant PSA PSA ⬍ 10 ng/mL PSA 10–20 ng/mL PSA ⬎ 20 ng/mL Gleason Score 2–4 5–6 7 8–9 Stage (1998 AJC) T1c T2a T2b Prostate size (median) Isotope 125 I 103 Pd Neoadjuvant antiandrogen therapy Preimplant XRT Total activity (median) 103 Pd 125 I
Volume 48, Number 1, 2000
Table 2. Modified RTOG rectal toxicity scale used in the current study
No. (%) 825 67 yr (range 52–89) 9.49 ng/ml (range 0.6–56 ng/mL) 393 378 54 99 471 206 49 380 379 66 34.6 cc 240 685 173 140 116 mCi 38.2 mCi
TIPPB. The treatment method for these patients has been previously reported (7). TIPPB was performed using real-time intraoperative transrectal ultrasound guidance with needles placed using the peripheral spacing technique. The individual seeds were inserted with the assistance of a Mick interstitial gun (Mick Nuclear Associates, Bronx, NY). No needles were placed closer than 5 mm from the posterior prostate capsule. Both the sagittal and axial images on the transrectal ultrasound were used to confirm the proximity of needle placement to the posterior prostate margin. Patients who received TIPPB alone were treated to a minimum peripheral dose (MPD) of 120 Gy with palladium-103, and 144 Gy with iodine-125 (post TG43 formalized) (8). When EBRT preceded TIPPB, a median dose of 43 Gy (41.4 – 45 Gy) at 180 cGy/fraction was prescribed and delivered via four-field technique. Anterior and lateral fields measured on average 12 ⫻ 12 cm and 11 ⫻ 12 cm, respectively. The MPD for Pd-103 was 90 Gy and for I-125 was 100 Gy (post TG-43 formalized) in combined modality treatment. Five hundred eighty-five patients were implanted with Pd-103 and 240 were implanted with I-125 seeds. Patients were seen for follow-up at 6 weeks post-TIPPB, then every 4 months for 2 years, and every 6 months thereafter. One hundred-seventy six patients (21%) did not return for their scheduled clinic follow-up as requested. Eighty-nine percent of these patients were more than 2.5 years out from their implants and they were tracked by a computer database. Follow-up forms were sent to assess prostate-specific antigen (PSA) outcome and toxicity in this
Grade 1 Grade 2 Grade 3 Grade 4
Tenesmus, clear mucous discharge Intermittent rectal bleeding, erythema of rectal lining on proctoscopy Rectal ulceration Bowel obstruction, fistula formation, blood transfusion required
subgroup. Fifteen of these patients returned for follow-up while 161 patients returned completed toxicity forms. At each follow-up appointment, patients were interviewed with respect to their bowel function. Bowel and rectal complaints were documented using a modified Radiation Therapy Oncology Group (RTOG) rectal symptom scoring scale (Table 2). Patients who complained of rectal irritation were treated with hydrocortisone acetate hemorrhoidal suppositories three times a day for a minimum of 3 weeks and advised to use sitz baths. Patients with persistent irritation or complaints were treated with hydrocortisone retention enemas twice a day for 2 to 4 weeks. Crude and actuarial analysis for the incidence of rectal morbidity was evaluated. Log-rank and Cox square testing was performed to evaluate any differences in rectal toxicity dependent upon which isotope was used, the addition of EBRT, and the addition of hormone therapy (9). CT-based post-TIPPB dosimetry was initiated in 1994 – 95. The method of rectal dose calculation has varied considerably since this time (rectal point dose vs. rectal volume) and thus meaningful data from the dose–volume histogram are not available to be included in this study. RESULTS The median follow-up for this cohort of 825 men is 48 months (range 24 – 85 months). The actuarial incidence of rectal toxicity in this patient cohort is shown in Fig. 1. A total of 77 patients (9.4%) reported Grade 1 toxicity at some time following implant whereas 54 patients (6.6%) reported Grade 2 toxicity or rectal bleeding. The actuarial incidence of rectal toxicity for patients who underwent TIPPB alone versus TIPPB and EBRT is shown in Table 3. The addition of EBRT did not impact the incidence of rectal morbidity. Additionally there was no difference in the incidence of Grade 1 or 2 rectal toxicity for the selection of isotope, the addition of hormone therapy, or case order (Table 4). The incidence of comorbid medical conditions in this population and its impact on morbidity is not available. The peak incidence of Grade 1 and 2 rectal toxicity was reported at 8 months after TIPPB (Fig. 2). At that time, 79 patients (9.5%) were experiencing either Grade 1 or 2 rectal irritation. Fifty-eight patients (7%) had Grade 1 complaints whereas 21 (2.5%) reported Grade 2 complaints at 8 months post-TIPPB. By 31⁄2 years, no patients reported rectal complaints. Rectal ulceration reported as a Grade 3 complication was
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Table 4. Univariate analysis of contributing factors for Grade 1 and 2 rectal toxicity Characteristic
Grade 1 and 2 (p-value)
Isotope Neoadjuvant hormones External beam irradiation Case order
0.634 0.962 0.086 0.178
DISCUSSION
Fig. 1. The actuarial incidence of rectal toxicity experienced by the 825 prostate patients in this cohort.
not reported until 12 months after TIPPB (Table 5). Four cases of the 825 patients in this study (0.5%) reported a Grade 3 rectal complication. Colonoscopy or proctoscopy documented all 4 patients with Grade 3 toxicity. Two patients reported problems with rectal ulceration at 12 months post-TIPPB and one each at 18 and 23 months after the implant. Three of the four patients were implanted with I-125, and one patient was implanted with Pd-103. One of the three patients treated with I-125 received EBRT in combination with TIPPB and only one of these patients received neoadjuvant antiandrogen therapy as part of his treatment. Two of the 4 patients with rectal ulcers were biopsied at the time of routine colonoscopy for “anterior rectal proctitis,” with bleeding and ulceration subsequent to the biopsy. Both pathology reports identified inflammatory proctitis. The ulcerated regions were described as ranging in size from 2 to 4 cm in greatest dimension. Three of the four ulcers resolved with conservative management, and the fourth is slowly healing at the time of this report 8 months after diagnosis. No patient has had a significant drop in hematocrit or required a blood transfusion. No Grade 4 toxicities were reported.
Table 3. Actuarial incidence of rectal toxicity for patients receiving combined external beam irradiation and TIPPB verses TIPPB alone
Grade 1 Grade 2 Grade 3
TIPPB ⫹ EBRT (n ⫽ 140)
TIPPB alone (n ⫽ 685)
10.5% 7.1% 0.7%
8.9% 6.5% 0.4%
TIPPB ⫽ Transperineal interstitial permanent prostate brachytherapy; EBRT ⫽ external beam irradiation.
Modern series demonstrate compatible survival for men with early-stage, localized prostate cancer treated with radical prostatectomy, three-dimensional conformal radiation therapy (3D-CRT), or prostate brachytherapy (10 –14). TIPPB is an attractive option due to its ability to deliver high-dose radiation to the prostate with a sharp dose gradient thus minimizing the radiation exposure to surrounding normal tissues. Often the selection of treatment for localized adenocarcinoma of the prostate is based on the intensity and duration of the treatment-related side effects associated with a therapeutic modality. This clinical study demonstrates tolerable rectal morbidity associated with modern TIPPB techniques in a large cohort of patients. The mechanism of radiation proctitis appears related to edema and fibrosis of arterioles in the luminal crypts of the colonic mucosa (15, 16). As fibrosis increases, the mucosal lining becomes more friable and is clinically associated with bleeding. The gastrointestinal literature has reported an increased risk of developing radiation proctitis in patients with underlying vascular changes associated with diabetes, hypertension, and chronic inflammatory bowel diseases. Grann and Wallner have demonstrated that patients with inflammatory bowel diseases may not be at an increased risk of rectal injury when treated with TIPPB (17). Several medical interventions have been reviewed in the literature, including sucralfate enemas, systemic and per-rectum steroids, and argon laser coagulation for large ulcers (18 –25); however, the optimal medical treatment for radiation proctitis has not been identified. Nonetheless, it is accepted that if areas of proctitis are identified in a previously irradiated field, surgical interventions such as biopsies may precipitate further erosion of the mucosa with the subsequent formation of an ulcer or fistula (15). This is illustrated in our series where 50% of the patients who experienced Grade 3 rectal toxicity had been biopsied prior to the development of the ulcer. These patients also appear to require a longer time to heal from their ulcers (8 –9 months vs. 3– 4 months for patients not biopsied). No fistulas were reported in this series. Merrick et al. report similar results of rectal toxicity in their small, retrospective series of patients treated with TIPPB alone (26). They report a rate of self-limited proctitis of 9% from a cohort of 45 patients. They calculate anterior rectal wall doses based on postimplant CT scans done with a rectal obturator in place on the fifth postoperative day with
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Fig. 2. The line of crude incidence of rectal toxicity in all 825 patients who received TIPPB.
the total isotope activity implanted, the MPD, or individual seed strength. An update of this series by Hu and Wallner (28) reports a median time to rectal bleeding of 8 months post-TIPPB. Thirteen patients from that study underwent sigmoidoscopy and 7 were found to have rectal ulceration whereas the remaining 6 had radiation proctitis. Rectal bleeding resolved spontaneously in that study as well. An earlier report from Blasko and colleagues (29) reports a 2.6% incidence of proctitis following TIPPB with 71% resolving spontaneously. They suggested an increased risk of late proctitis after combined modality treatment (6%) versus TIPPB alone (1%). Recent series reporting on three-dimensional conformal EBRT of the prostate present much higher rates of rectal bleeding and discomfort (30 –32). A report from the Fox Chase Cancer Center (33) describes late rectal bleeding to be an expected complication of high-dose treatment of prostate cancer. The cumulative incidence of Grade 2 and Grade 3 rectal toxicity at 12 months was approximately 40% and 25%, respectively. The median rectal dose delivered to the prostate gland in that study was 72 Gy, with a
a mean estimated dose exposure to the anterior portion of the rectum of 82.5% of the prescription dose from the implant. No correlation was found between the average rectal dose and prostatic volume. They also found no relationship to the isotope used for TIPPB and the incidence of proctitis. The addition of EBRT to TIPPB was also not a contributing factor for the development of rectal toxicity. They conclude from their dosimetric calculations that permitting doses ⱕ85% of the prescribed dose to the anterior rectal wall, independent of isotope used is associated with a 9% incidence of proctitis. This is identical to the 9% quoted in the current study. A second study evaluating rectal dosimetry in patients treated with TIPPB by Wallner et al. (27) reviewed 65 patients treated with T1/T2 prostate cancers treated with CT-planned prostate implants alone. They report a 10% incidence of proctitis. Further, a correlation was noted with reported Grade 1 (rectal bleeding) and Grade 2 (rectal ulceration) toxicity and a rectal surface dose greater than or less than 100 Gy for patients treated with I-125. There was no significant relationship for the onset of rectal toxicity for
Table 5. Grade 3 rectal toxicities
Patient
Isotope
EBRT
Hormones
1 2 3 4
I-125 I-125 I-125 Pd-103
No Yes No No
No No Yes No
EBRT ⫽ external beam radiation.
Implant dose 144 100 144 120
Gy Gy Gy Gy
Time for ulcer formation (months)
Time to resolution (months)
12 12 23 18
9 8 7 Still healing at 8 months
Rectal biopsy Yes Yes No No
Rectal toxicity and prostate brachytherapy
range of 62.11 to 80.74 Gy. Most rectal bleeding developed between 6 and 12 months after the treatment for a median duration of 3 months. The central dose to the prostate gland was the only treatment-related factor found to be significant on Cox multivariate analysis. Treatment planning in that study required a 1 cm margin around the clinical tumor volume (CTV) in all directions. A comparison of 3D-CRT technique and CT-guided prostate brachytherapy was recently reported by Zelefsky et al. (34). They report a combined rate of acute Grade 1 and 2 rectal toxicity of 14% in patients undergoing 3D-CRT with the majority of the patients receiving 70.2 or 75.6 Gy to the prostate, while no patients undergoing an implant had any reported acute toxicity. Late toxicity defined as that occurring or persisting more than 90 days post-treatment was 6% and 4% for the 3D-CRT patients and TIPPB patients, respectively. Treatment planning from this study defined the PTV as a 1-cm margin taken around the anterior surface of the prostate
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gland and a 0.6-cm margin posteriorly along the rectal interface. CONCLUSION TIPPB is a now a standard option for most men seeking treatment of early-stage, localized prostate cancer. A review of the literature shows a lack of information regarding the development of gastrointestinal toxicity after TIPPB. In fact, the recently reported guidelines by the American Brachytherapy Society fail to consider rectal morbidity at this time (35). This clinical study on rectal morbidity from a large cohort of patients after TIPPB identifies an acceptable risk of rectal injury from this procedure. More importantly, these cases are almost always self-limited and rectal biopsies after TIPPB for limited erythema or edema of the anterior rectal wall should be avoided.
REFERENCES 1. Gelblum DY, Potters L, Ashley R, Waldbaum R, Wang XH, Leibel S. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999;45:59 – 67. 2. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998;160: 1379 –1382. 3. Nag S, Scaperoth DD, Badalament R, Hall SA, Burgers J. Transperineal palladium 103 prostate brachytherapy: Analysis of morbidity and seed migration. Urology1995;45:87–92. 4. Vicini FA, Kini VR, Edmundson G, Gustafson GS, Stromberg J, Martinez A. A comprehensive review of prostate cancer brachytherapy: Defining an optimal technique. Int J Radiat Oncol Biol Phys 1999;44:483– 491. 5. Kleinberg L, Wallner K, Roy J, et al.Treatment-related symptoms during the first year following transperineal 125I prostate implantation. Int J Radiat Oncol Biol Phys 1994;28:985–990. 6. Fleming ID, Cooper JS, Henson DE, et al.AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott-Raven; 1997. 7. Cha CM, Potters L, Ashley R, et al.Isotope selection for patients undergoing prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999;45:391–395. 8. Nath R, Anderson LL, Meli JA, Olch AJ, Stitt JA, Williamson JF. Code of practice for brachytherapy physics: Report of the AAPM Radiation Therapy Committee Task Group No. 56. American Association of Physicists in Medicine. Med Phys 1997;24:1557–1598. 9. Cox DR, Abadir R. Regression models and life tables. J Roy Statist Soc 1972;34:187–220. 10. Zelefsky MJ, Leibel SA, Gaudin PB, et al.Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. 11. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: A multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997;37:1043–1052. 12. Beyer DC, Priestley JB Jr. Biochemical disease-free survival following 125I prostate implantation. Int J Radiat Oncol Biol Phys 1997;37:559 –563. 13. Ragde H, Elgamal AA, Snow PB, et al. Ten-year disease free survival after transperineal sonography-guided iodine-125
14. 15. 16. 17. 18. 19.
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brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer1998;83: 989 –1001. Eastham JA, Kattan MW, Groshen S, et al. Fifteen-year survival and recurrence rates after radiotherapy for localized prostate cancer. J Clin Oncol 1997;15:3214 –3222. Rubin P, Cassarett GW. Clinical radiation pathology. Philadelphia: W.B. Saunders; 1968. p. 207–240. Donner CS. Pathophysiology and therapy of chronic radiationinduced injury to the colon. Dig Dis 1998;16:253–261. Grann A, Wallner K. Prostate brachytherapy in patients with inflammatory bowel disease. Int J Radiat Oncol Biol Phys 1998;40:135–138. Babb RR. Radiation proctitis: A review. Am J Gastroenterol 1996;91:1309 –1311. Sasai T, Hiraishi H, Suzuki Y, Masuyama H, Ishida M, Terano A. Treatment of chronic post-radiation proctitis with oral administration of sucralfate. Am J Gastroenterol 1998;93: 1593–1595. Grigsby PW, Pilepich MV, Parsons C. L. Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis. Am J Clin Oncol 1990;13:28 –31. Fantin AC, Binek J, Suter WR, Meyenberger C. Argon beam coagulation for treatment of symptomatic radiation-induced proctitis. Gastrointest Endosc 1999;49:515–518. Kochhar R, Sharma SC, Gupta BB, Mehta SK. Rectal sucralfate in radiation proctitis. Lancet 1988;2:400. Charneau J, Bouachour G, Person B, Burtin P, Ronceray J, Boyer J. Severe hemorrhagic radiation proctitis advancing to gradual cessation with hyperbaric oxygen. Dig Dis Sci 1991; 36:373–375. Baum CA, Biddle WL, Miner PB Jr. Failure of 5-aminosalicylic acid enemas to improve chronic radiation proctitis. Dig Dis Sci 1989;34:758 –760. Counter SF, Froese DP, Hart MJ. Prospective evaluation of formalin therapy for radiation proctitis. Am J Surg 1999;177: 396 –398. Merrick GS, Butler WM, Dorsey AT, Lief JH, Walbert HL, Blatt HJ. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999;43:1021– 1027.
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27. 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. 28. Hu K, Wallner K. Clinical course of rectal bleeding following I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998;41:263–265. 29. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasoundguided implantation of the prostate: Morbidity and complications. Scand J Urol Nephrol Suppl 1991;137:113–118. 30. Shipley WU, Zietman AL, Hanks GE, et al. Treatment related sequelae following external beam radiation for prostate cancer: A review with an update in patients with stages T1 and T2 tumor. J Urol 1994;152:1799 –1805. 31. Schultheiss TE, Lee WR, Hunt MA, Hanlon AL, Peter RS, Hanks GE. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:3–11.
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32. Zelefsky MJ, Leibel SA, Kutcher GJ, Kelson S, Ling CC, Fuks Z. The feasibility of dose escalation with three-dimensional conformal radiotherapy in patients with prostatic carcinoma. Cancer J Sci Am 1995;1:142. 33. Teshima T, Hanks GE, Hanlon AL, Peter RS, Schultheiss TE. Rectal bleeding after conformal 3D treatment of prostate cancer: Time to occurrence, response to treatment and duration of morbidity. Int J Radiat Oncol Biol Phys 1997;39:77– 83. 34. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer. J Clin Oncol 1999; 17:517–522. 35. Nag S, Beyer D, Friedland J, Grimm P, Nath R. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789 –799.
PII S0360-3016(00)00632-5
CLINICAL INVESTIGATION
Prostate
RECTAL COMPLICATIONS ASSOCIATED WITH TRANSPERINEAL INTERSTITIAL BRACHYTHERAPY FOR PROSTATE CANCER DAPHNA Y. GELBLUM, M.D.,
AND
LOUIS POTTERS, M.D.
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center at Mercy Medical Center, Rockville Center, New York, NY Purpose: As transperineal interstitial permanent prostate brachytherapy (TIPPB) grows in acceptance as an option in the treatment of organ-confined prostate cancer, its associated toxicities are being defined. This clinical report documents rectal toxicity from a large cohort of men treated by a single practitioner for adenocarcinoma of the prostate. Methods and Materials: Eight hundred twenty-five men were treated from September 1992 to September 1998 with TIPPB. One hundred-forty were treated in conjunction with external beam irradiation (EBRT) and 685 with TIPPB alone. All patients were implanted under real-time ultrasound guidance. No dose–volume histogram analysis was performed for this study. All patients were followed at 5 weeks after the procedure, then every 3– 6 months thereafter. Rectal morbidity was graded by a modified RTOG toxicity scale. Therapy to control symptoms was recommended on an individual basis. Results: The median follow-up for the cohort is 48 months. A total of 77 patients (9.4%) reported Grade 1 toxicity at some time following an implant whereas 54 patients (6.6%) reported Grade 2 toxicity. The peak post-TIPPB time for experiencing rectal toxicity was 8 months at which time Grade 1 and 2 rectal toxicity was reported in 9.5% of the patients. This improved over the subsequent months and resolved in all patients by 31⁄2 years. Four patients (0.5%) reported Grade 3 rectal toxicity with rectal ulceration identified on colonoscopy at 1 year from implant. Two of the four patients had colonic manipulation in the radiated portion of the colon which subsequently caused it to bleed. None of the patients required blood product transfusion. In 3 of the 4 patients the Grade 3 rectal toxicity has resolved spontaneously and 1 patient continues to heal at the time of this report. No patient required hospitalization or surgical intervention. Conclusion: TIPPB is a tolerable and acceptable treatment option when used alone in early-stage, organ-confined adenocarcinoma of the prostate and in conjunction with EBRT in more advanced disease. This clinical report adds to the growing literature regarding the potential morbidity associated with this procedure and indicates that serious rectal injury is rare. © 2000 Elsevier Science Inc. Prostate cancer, Brachytherapy, Rectal injury, Iodine, Palladium.
rectal toxicity reported from a large cohort of men treated with TIPPB by the same practitioner (L.P.).
INTRODUCTION Ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) alone or in conjunction with external beam irradiation (EBRT) for adenocarcinoma of the prostate is quickly growing in popularity as a treatment option for patients with early-stage, localized cancers. As experience with this technique has grown over the last several years, reports in the literature have presented the urinary morbidity from several centers (1–3). The rectal morbidity associated with TIPPB has been less well investigated and documented (4, 5). As patients are asked to participate in the treatment decisions for early-stage, localized prostate cancer, the morbidity of each treatment method plays an important role in the selection process for each patient. This clinical study was undertaken to assess
METHODS AND MATERIALS Between September 1992 and September 1998, 825 consecutive patients with biopsy-proven adenocarcinoma of the prostate were treated with TIPPB (Table 1). One hundredforty men were treated in combination with EBRT and 685 had an implant alone. One hundred seventy-three patients were started on antiandrogen therapy prior to treatment while 652 were not. Patients were staged clinically by a single practitioner according to the American Joint Committee on Cancer (AJCC) standards (6). Patients with T1N0M0 and T2N0M0 disease were considered eligible for
Reprint requests to: Daphna Y. Gelblum, M.D., Dept. of Radiation Oncology, Memorial Sloan-Kettering Cancer Center @ Mercy Medical Center, 1000 North Village Ave., Rockville Center, NY 11570. E-mail: [email protected]
Accepted for publication 10 April 2000.
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Table 1. Patient characteristics Variable Number of patients implanted Age (median) Median preimplant PSA PSA ⬍ 10 ng/mL PSA 10–20 ng/mL PSA ⬎ 20 ng/mL Gleason Score 2–4 5–6 7 8–9 Stage (1998 AJC) T1c T2a T2b Prostate size (median) Isotope 125 I 103 Pd Neoadjuvant antiandrogen therapy Preimplant XRT Total activity (median) 103 Pd 125 I
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Table 2. Modified RTOG rectal toxicity scale used in the current study
No. (%) 825 67 yr (range 52–89) 9.49 ng/ml (range 0.6–56 ng/mL) 393 378 54 99 471 206 49 380 379 66 34.6 cc 240 685 173 140 116 mCi 38.2 mCi
TIPPB. The treatment method for these patients has been previously reported (7). TIPPB was performed using real-time intraoperative transrectal ultrasound guidance with needles placed using the peripheral spacing technique. The individual seeds were inserted with the assistance of a Mick interstitial gun (Mick Nuclear Associates, Bronx, NY). No needles were placed closer than 5 mm from the posterior prostate capsule. Both the sagittal and axial images on the transrectal ultrasound were used to confirm the proximity of needle placement to the posterior prostate margin. Patients who received TIPPB alone were treated to a minimum peripheral dose (MPD) of 120 Gy with palladium-103, and 144 Gy with iodine-125 (post TG43 formalized) (8). When EBRT preceded TIPPB, a median dose of 43 Gy (41.4 – 45 Gy) at 180 cGy/fraction was prescribed and delivered via four-field technique. Anterior and lateral fields measured on average 12 ⫻ 12 cm and 11 ⫻ 12 cm, respectively. The MPD for Pd-103 was 90 Gy and for I-125 was 100 Gy (post TG-43 formalized) in combined modality treatment. Five hundred eighty-five patients were implanted with Pd-103 and 240 were implanted with I-125 seeds. Patients were seen for follow-up at 6 weeks post-TIPPB, then every 4 months for 2 years, and every 6 months thereafter. One hundred-seventy six patients (21%) did not return for their scheduled clinic follow-up as requested. Eighty-nine percent of these patients were more than 2.5 years out from their implants and they were tracked by a computer database. Follow-up forms were sent to assess prostate-specific antigen (PSA) outcome and toxicity in this
Grade 1 Grade 2 Grade 3 Grade 4
Tenesmus, clear mucous discharge Intermittent rectal bleeding, erythema of rectal lining on proctoscopy Rectal ulceration Bowel obstruction, fistula formation, blood transfusion required
subgroup. Fifteen of these patients returned for follow-up while 161 patients returned completed toxicity forms. At each follow-up appointment, patients were interviewed with respect to their bowel function. Bowel and rectal complaints were documented using a modified Radiation Therapy Oncology Group (RTOG) rectal symptom scoring scale (Table 2). Patients who complained of rectal irritation were treated with hydrocortisone acetate hemorrhoidal suppositories three times a day for a minimum of 3 weeks and advised to use sitz baths. Patients with persistent irritation or complaints were treated with hydrocortisone retention enemas twice a day for 2 to 4 weeks. Crude and actuarial analysis for the incidence of rectal morbidity was evaluated. Log-rank and Cox square testing was performed to evaluate any differences in rectal toxicity dependent upon which isotope was used, the addition of EBRT, and the addition of hormone therapy (9). CT-based post-TIPPB dosimetry was initiated in 1994 – 95. The method of rectal dose calculation has varied considerably since this time (rectal point dose vs. rectal volume) and thus meaningful data from the dose–volume histogram are not available to be included in this study. RESULTS The median follow-up for this cohort of 825 men is 48 months (range 24 – 85 months). The actuarial incidence of rectal toxicity in this patient cohort is shown in Fig. 1. A total of 77 patients (9.4%) reported Grade 1 toxicity at some time following implant whereas 54 patients (6.6%) reported Grade 2 toxicity or rectal bleeding. The actuarial incidence of rectal toxicity for patients who underwent TIPPB alone versus TIPPB and EBRT is shown in Table 3. The addition of EBRT did not impact the incidence of rectal morbidity. Additionally there was no difference in the incidence of Grade 1 or 2 rectal toxicity for the selection of isotope, the addition of hormone therapy, or case order (Table 4). The incidence of comorbid medical conditions in this population and its impact on morbidity is not available. The peak incidence of Grade 1 and 2 rectal toxicity was reported at 8 months after TIPPB (Fig. 2). At that time, 79 patients (9.5%) were experiencing either Grade 1 or 2 rectal irritation. Fifty-eight patients (7%) had Grade 1 complaints whereas 21 (2.5%) reported Grade 2 complaints at 8 months post-TIPPB. By 31⁄2 years, no patients reported rectal complaints. Rectal ulceration reported as a Grade 3 complication was
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Table 4. Univariate analysis of contributing factors for Grade 1 and 2 rectal toxicity Characteristic
Grade 1 and 2 (p-value)
Isotope Neoadjuvant hormones External beam irradiation Case order
0.634 0.962 0.086 0.178
DISCUSSION
Fig. 1. The actuarial incidence of rectal toxicity experienced by the 825 prostate patients in this cohort.
not reported until 12 months after TIPPB (Table 5). Four cases of the 825 patients in this study (0.5%) reported a Grade 3 rectal complication. Colonoscopy or proctoscopy documented all 4 patients with Grade 3 toxicity. Two patients reported problems with rectal ulceration at 12 months post-TIPPB and one each at 18 and 23 months after the implant. Three of the four patients were implanted with I-125, and one patient was implanted with Pd-103. One of the three patients treated with I-125 received EBRT in combination with TIPPB and only one of these patients received neoadjuvant antiandrogen therapy as part of his treatment. Two of the 4 patients with rectal ulcers were biopsied at the time of routine colonoscopy for “anterior rectal proctitis,” with bleeding and ulceration subsequent to the biopsy. Both pathology reports identified inflammatory proctitis. The ulcerated regions were described as ranging in size from 2 to 4 cm in greatest dimension. Three of the four ulcers resolved with conservative management, and the fourth is slowly healing at the time of this report 8 months after diagnosis. No patient has had a significant drop in hematocrit or required a blood transfusion. No Grade 4 toxicities were reported.
Table 3. Actuarial incidence of rectal toxicity for patients receiving combined external beam irradiation and TIPPB verses TIPPB alone
Grade 1 Grade 2 Grade 3
TIPPB ⫹ EBRT (n ⫽ 140)
TIPPB alone (n ⫽ 685)
10.5% 7.1% 0.7%
8.9% 6.5% 0.4%
TIPPB ⫽ Transperineal interstitial permanent prostate brachytherapy; EBRT ⫽ external beam irradiation.
Modern series demonstrate compatible survival for men with early-stage, localized prostate cancer treated with radical prostatectomy, three-dimensional conformal radiation therapy (3D-CRT), or prostate brachytherapy (10 –14). TIPPB is an attractive option due to its ability to deliver high-dose radiation to the prostate with a sharp dose gradient thus minimizing the radiation exposure to surrounding normal tissues. Often the selection of treatment for localized adenocarcinoma of the prostate is based on the intensity and duration of the treatment-related side effects associated with a therapeutic modality. This clinical study demonstrates tolerable rectal morbidity associated with modern TIPPB techniques in a large cohort of patients. The mechanism of radiation proctitis appears related to edema and fibrosis of arterioles in the luminal crypts of the colonic mucosa (15, 16). As fibrosis increases, the mucosal lining becomes more friable and is clinically associated with bleeding. The gastrointestinal literature has reported an increased risk of developing radiation proctitis in patients with underlying vascular changes associated with diabetes, hypertension, and chronic inflammatory bowel diseases. Grann and Wallner have demonstrated that patients with inflammatory bowel diseases may not be at an increased risk of rectal injury when treated with TIPPB (17). Several medical interventions have been reviewed in the literature, including sucralfate enemas, systemic and per-rectum steroids, and argon laser coagulation for large ulcers (18 –25); however, the optimal medical treatment for radiation proctitis has not been identified. Nonetheless, it is accepted that if areas of proctitis are identified in a previously irradiated field, surgical interventions such as biopsies may precipitate further erosion of the mucosa with the subsequent formation of an ulcer or fistula (15). This is illustrated in our series where 50% of the patients who experienced Grade 3 rectal toxicity had been biopsied prior to the development of the ulcer. These patients also appear to require a longer time to heal from their ulcers (8 –9 months vs. 3– 4 months for patients not biopsied). No fistulas were reported in this series. Merrick et al. report similar results of rectal toxicity in their small, retrospective series of patients treated with TIPPB alone (26). They report a rate of self-limited proctitis of 9% from a cohort of 45 patients. They calculate anterior rectal wall doses based on postimplant CT scans done with a rectal obturator in place on the fifth postoperative day with
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Fig. 2. The line of crude incidence of rectal toxicity in all 825 patients who received TIPPB.
the total isotope activity implanted, the MPD, or individual seed strength. An update of this series by Hu and Wallner (28) reports a median time to rectal bleeding of 8 months post-TIPPB. Thirteen patients from that study underwent sigmoidoscopy and 7 were found to have rectal ulceration whereas the remaining 6 had radiation proctitis. Rectal bleeding resolved spontaneously in that study as well. An earlier report from Blasko and colleagues (29) reports a 2.6% incidence of proctitis following TIPPB with 71% resolving spontaneously. They suggested an increased risk of late proctitis after combined modality treatment (6%) versus TIPPB alone (1%). Recent series reporting on three-dimensional conformal EBRT of the prostate present much higher rates of rectal bleeding and discomfort (30 –32). A report from the Fox Chase Cancer Center (33) describes late rectal bleeding to be an expected complication of high-dose treatment of prostate cancer. The cumulative incidence of Grade 2 and Grade 3 rectal toxicity at 12 months was approximately 40% and 25%, respectively. The median rectal dose delivered to the prostate gland in that study was 72 Gy, with a
a mean estimated dose exposure to the anterior portion of the rectum of 82.5% of the prescription dose from the implant. No correlation was found between the average rectal dose and prostatic volume. They also found no relationship to the isotope used for TIPPB and the incidence of proctitis. The addition of EBRT to TIPPB was also not a contributing factor for the development of rectal toxicity. They conclude from their dosimetric calculations that permitting doses ⱕ85% of the prescribed dose to the anterior rectal wall, independent of isotope used is associated with a 9% incidence of proctitis. This is identical to the 9% quoted in the current study. A second study evaluating rectal dosimetry in patients treated with TIPPB by Wallner et al. (27) reviewed 65 patients treated with T1/T2 prostate cancers treated with CT-planned prostate implants alone. They report a 10% incidence of proctitis. Further, a correlation was noted with reported Grade 1 (rectal bleeding) and Grade 2 (rectal ulceration) toxicity and a rectal surface dose greater than or less than 100 Gy for patients treated with I-125. There was no significant relationship for the onset of rectal toxicity for
Table 5. Grade 3 rectal toxicities
Patient
Isotope
EBRT
Hormones
1 2 3 4
I-125 I-125 I-125 Pd-103
No Yes No No
No No Yes No
EBRT ⫽ external beam radiation.
Implant dose 144 100 144 120
Gy Gy Gy Gy
Time for ulcer formation (months)
Time to resolution (months)
12 12 23 18
9 8 7 Still healing at 8 months
Rectal biopsy Yes Yes No No
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range of 62.11 to 80.74 Gy. Most rectal bleeding developed between 6 and 12 months after the treatment for a median duration of 3 months. The central dose to the prostate gland was the only treatment-related factor found to be significant on Cox multivariate analysis. Treatment planning in that study required a 1 cm margin around the clinical tumor volume (CTV) in all directions. A comparison of 3D-CRT technique and CT-guided prostate brachytherapy was recently reported by Zelefsky et al. (34). They report a combined rate of acute Grade 1 and 2 rectal toxicity of 14% in patients undergoing 3D-CRT with the majority of the patients receiving 70.2 or 75.6 Gy to the prostate, while no patients undergoing an implant had any reported acute toxicity. Late toxicity defined as that occurring or persisting more than 90 days post-treatment was 6% and 4% for the 3D-CRT patients and TIPPB patients, respectively. Treatment planning from this study defined the PTV as a 1-cm margin taken around the anterior surface of the prostate
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gland and a 0.6-cm margin posteriorly along the rectal interface. CONCLUSION TIPPB is a now a standard option for most men seeking treatment of early-stage, localized prostate cancer. A review of the literature shows a lack of information regarding the development of gastrointestinal toxicity after TIPPB. In fact, the recently reported guidelines by the American Brachytherapy Society fail to consider rectal morbidity at this time (35). This clinical study on rectal morbidity from a large cohort of patients after TIPPB identifies an acceptable risk of rectal injury from this procedure. More importantly, these cases are almost always self-limited and rectal biopsies after TIPPB for limited erythema or edema of the anterior rectal wall should be avoided.
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