SECOND MALIGNANCIES AFTER PROSTATE BRACHYTHERAPY: INCIDENCE OF BLADDER AND COLORECTAL CANCERS IN PATIENTS WITH 15 YEARS OF POTENTIAL FOLLOW-UP

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 3, pp , 2006 Copyright 2006 Elsevier Inc. Printed in the USA. All rights reserved /06/$ see front matter CLINICAL INVESTIGATION Prostate SECOND MALIGNANCIES AFTER PROSTATE BRACHYTHERAPY: INCIDENCE OF BLADDER AND COLORECTAL CANCERS IN PATIENTS WITH 15 YEARS OF POTENTIAL FOLLOW-UP STANLEY L. LIAUW, M.D.,* JOHN E. SYLVESTER, M.D., CHRISTOPHER G. MORRIS, M.S., JOHN C. BLASKO, M.D., AND PETER D. GRIMM, D.O. *Department of Radiation and Cellular Oncology, University of Chicago Pritzker School of Medicine, Chicago, IL; Seattle Prostate Institute at Swedish Hospital, Seattle, WA; Swedish Cancer Center at Stevens Hospital, Edmonds, WA; and Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL Purpose: To report the incidence of second bladder and colorectal cancers after prostate brachytherapy. Methods and Materials: This review included 125 patients treated with I-125 brachytherapy alone, and 223 patients who received supplemental external beam radiation therapy. Median follow-up was 10.5 years. Patients were followed for the development of lower genitourinary and colorectal cancers. Second malignancies arising five years after radiation therapy were defined as being potentially associated with treatment; observed rates were then compared with age-matched expected rates according to Surveillance, Epidemiology, and End Results data. Results: Five years out of treatment, there were 15 patients with a second solid tumor, including bladder cancer (n 11), colorectal cancer (n 3), and prostatic urethra cancer (n 1). The incidence of second malignancy was no different in patients treated with brachytherapy alone (1.6%) vs. those receiving external beam radiotherapy (5.8%, p ). There were more observed bladder cancers compared with those expected (relative risk, 2.34, 95% confidence interval ; absolute excess risk 35 cancers per 10,000 patients). Relative risk did not significantly change over increasing follow-up intervals up to 20 years after treatment. Conclusions: There may be an increased but small risk of developing a second malignancy after radiation therapy for prostate cancer. This outcome could be related to radiation carcinogenesis, but more vigilant screening and thorough workup as a result of radiation side effects and predisposing conditions (e.g., genetic and environmental factors) in many of the patients found to have second malignancies likely contributed to the higher number of observed malignancies than expected Elsevier Inc. Prostate cancer, Second malignancy, Brachytherapy. INTRODUCTION Because of a trend toward diagnosing prostate cancer at a younger age and earlier stage (1, 2) and increasingly successful treatment options, (3) the number of prostate cancer survivors is expected to continue to rise. The success of radiation therapy (RT) has been an important factor in increasing rates of survivorship, but one legitimate longterm concern may be radiation-associated malignancies, particularly secondary solid tumors (4). Some estimates of second malignancy after RT for prostate cancer include a small but statistically significant added risk of second bladder cancers (5, 6) and colorectal cancers (5, 7, 8) in patients with long follow-up. One critical factor in the development of secondary cancers appears to be the volume of tissue that is radiated above a threshold dose (9). However, because estimates of the risk of second malignancy after RT are often generated from large datasets that lack the technical Reprint requests to: John E. Sylvester, M.D., Seattle Prostate Institute, 1101 Madison, Suite 1101, Seattle, WA Tel: (206) ; Fax: (206) ; johnsylvester@ details of treatment to obtain sufficient statistical power, risk cannot be easily described according to the volume radiated. The goal of this study is to report the rate of bladder and colorectal cancers in patients with 15 years of potential follow-up who were treated with brachytherapy for prostate cancer, with or without supplemental external beam radiation therapy. METHODS AND MATERIALS This review included 348 patients with biopsy-proven adenocarcinoma of the prostate who were treated with prostate brachytherapy at the Seattle Prostate Institute from January 1987 to January Two subsets of patients included: 125 consecutive patients treated with an Iodine-125 (I-125) implant as monotherapy between 1988 and 1990 (10) and 223 consecutive patients treated with external beam RT followed by an I-125 or Palladium- 103 implant between 1987 and 1994 (11). Patient characteristics seattleprostateinst.com Received April 4, 2006, and in revised form May 23, Accepted for publication May 27,

2 670 I. J. Radiation Oncology Biology Physics Volume 66, Number 3, 2006 for each subset are outlined in Table 1. No patients in this study received neoadjuvant hormonal therapy. Fifteen-year biochemical and survival outcomes will be separately reported for each of these subsets (manuscripts in preparation). Technical aspects of treatment including external beam RT and transperineal prostate brachytherapy have been previously described (12, 13). In general, brachytherapy planning was based on transrectal ultrasound volumes determined a few weeks before implantation. The target treatment volume defined by the radiation oncologist included a 2- to 5-mm margin beyond the prostate. In cases involving an I-125 implant as monotherapy, the prescription dose was 144 Gy (TG- 43). Patients who received external beam RT completed this portion of therapy a median 4 weeks before implantation. The dose prescription for supplemental external beam RT was 45 Gy at 1.8 Gy/fraction once daily for 5 days a week. A four-field technique with customized Cerrobend blocking and 6-MV photons was used to treat a limited pelvic field (typical size 10 cm 10 cm on anteroposterior film), to be followed by a 108-Gy (TG-43) I-125 or 100-Gy (NIST 1999) Pd-103 implant. Median follow-up was 11.4 years for patients treated with I-125 monotherapy, and 10.2 years for patients treated with combined external beam RT and implant. Median potential follow-up, from the time of implant to the time of the study analysis (late 2004), was 15.2 years for all patients. Follow-up included chart review, telephone contact of the patient or referring physician, and/or review of the Surveillance, Epidemiology and End Results (SEER) database when applicable (14). Second malignancies of the lower genitourinary tract (bladder, prostatic urethra) and colorectal tract were recorded. New cancers arising five years after the date of implant were considered to be potentially associated with RT. This time point was chosen based on studies reporting that secondary cancers classically occur after five years (4, 15, 16). Rates of second malignancy after RT were then compared with expected age-adjusted rates according to SEER data from 1989 to 1993 (14). Indices for men with bladder cancer were used for this study; a similar analysis of colorectal cancers was not performed because the low number of cases seen in this series was felt likely to lead to a relatively unreliable statistical result. Statistical comparisons were made using the log-rank test with two-sided p-values; confidence intervals were reported by Poisson distribution. RESULTS Overall, 15 of 348 patients (4.3%) developed a bladder (n 11), colorectal (n 3), or prostatic urethra (n 1) carcinoma five or more years after RT (median time, 9 years 6 months), at a median age of 80 years. Thirteen of 223 patients who received supplemental RT (5.8%) developed a bladder or colorectal malignancy compared with 2 of 125 patients who received brachytherapy alone (1.6%, p ). Details of each potential radiation-associated secondary solid tumor are listed in Table 2. Eleven additional patients were found to have a bladder or colorectal primary less than five years from implant and are not included in this table. Bladder cancers were transitional cell carcinomas (when histologic information was available), and were usually diagnosed at early stages; eight patients had noninvasive disease, one patient had invasion to the lamina propria (stage T1, n 1), and two had unavailable information regarding stage. Of the 10 patients for whom their history of tobacco use was known, at least half had a history of smoking (2 smokers, 4 previous smokers). Treatment involved initial transurethral resection of the bladder tumor (n 11), followed by intravesical therapy of Bacillus Calmette-Guerin and/or mitomycin (n 5), and cystectomy for recurrence (n 3). None of these patients died as a result of bladder cancer, with a median follow-up of 2.4 years after diagnosis (range, years). Of the three colorectal cancers, there were two rectosigmoid primaries, and one primary of the descending colon (out of field). Each patient was at a potentially elevated risk to develop a colorectal primary: one patient had a chronic rectal fistula for several years before diagnosis, another was diagnosed with multiple synchronous colonic polyps and had a family history of colon cancer, and the last had inflammatory bowel disease affecting the entire colonic tract. All patients underwent surgical excision, one after preoperative radiation ther- Table 1. Patient characteristics monotherapy (n 125) EBRT seeds (n 223) Median age 70 (range, 47 91) 69 (range, 49 88) Initial PSA level, median 5.0 (range, ) 15.2 (range, ) T stage T1 11 (18%) 26 (12%) T2a 95 (76%) 55 (25%) T2b 18 (14%) 84 (38%) T2c 1 (1%) 58 (26%) Gleason score (100%) 145 (65%) 7 55 (25%) (10%) Median follow-up 11.4 years (range, ) 10.2 years (range, ) Number of survivors with follow-up longer than: 5 years 102 (82%) 190 (85%) 10 years 70 (56%) 114 (51%) Abbreviations: PSA prostate-specific antigen; EBRT external beam radiation therapy.

3 Secondary malignancies after prostate brachytherapy S. L. LIAUW et al. 671 Table 2. Second malignancies in patients treated with brachytherapy Patient Radiation therapy Site of 2nd malignancy Age at diagnosis of 2nd malignancy Interval after implant 1 EBRT seeds Bladder years, 8 months 2 EBRT seeds Bladder years, 1 month 3 EBRT seeds Bladder years, 10 months 4 EBRT seeds Bladder years, 9 months 5 EBRT seeds Bladder 81 9 years, 8 months 6 EBRT seeds Bladder 80 9 years, 6 months 7 EBRT seeds Bladder 84 8 years, 9 months 8 EBRT seeds Bladder 77 8 years, 9 months 9 EBRT seeds Bladder 86 7 years, 3 months 10 EBRT seeds Bladder 67 6 years, 6 months 11 EBRT seeds Bladder 76 6 years, 0 months 12 EBRT seeds Rectum years, 0 months 13 EBRT seeds Sigmoid colon 73 7 years, 11 months 14 Seeds Prostatic urethra years, 11 months 15 Seeds Colon 76 6 years, 9 months Abbreviation: EBRT external beam radiation therapy. apy of 39.6 Gy at 1.8 Gy/fx once daily with 5-fluorouracil and leucovorin, and two survived with no evidence of disease at a median follow-up of 5.9 years. The single patient with prostatic urethra transitional cell carcinoma was treated with cystoprostatectomy and was lost to follow-up thereafter. In 348 patients, 11 bladder cancers occurred five or more years after RT. SEER data indicated an expected rate of 4.7 bladder cancers over matching years of follow-up, yielding a relative risk of 2.34 (absolute excess risk, 35 per 10,000 patients) for developing bladder cancer with RT. Relative risk is categorized by time intervals after RT in Table 3. DISCUSSION Over the last decade, treatment for prostate cancer has become increasingly successful, in no small part related to earlier diagnosis with PSA screening. RT has led to high rates of curability for all stages of disease (10, 11, 17, 18), with dose, volume treated, and use of hormonal therapy tailored to the risk level of the patient. With control rates and survivorship that approach 100% in some large series (19 21), long-term complications become an increasingly important factor for the clinician and patient to consider in the selection of the best therapy, especially as the newly diagnosed population becomes younger. Patients who receive RT have a known risk of developing second malignancies. Although difficult to quantify, risk appears to be related to the age of the patient, the volume of tissue radiated, and the dose. This relationship has perhaps been best studied in the survivors of the atomic bomb (4), and has also been seen in the follow-up of patients treated with RT, including those with cervical cancer (22), Hodgkin s lymphoma (23), breast cancer (24), and childhood malignancies (25). In patients with prostate cancer, several groups have attempted to estimate the added risk of secondary malignancy when receiving RT (5, 6, 8, 26 28). Using SEER data, RT was found to lead to small but statistically significant increases in the risk of developing bladder (5, 6) and rectal cancer (7), on the order of 1:290 for development of any solid tumor in all patients, and 1:70 for long-term survivors ( 10 years) (5). Table 3. Observed and expected rate of bladder cancers Years after RT Person-years Observed cases Expected cases* Observed-to-expected ratio (95%CI) ( ) ( ) ( ) Total all patients ( ) Total > 5 years ( ) Abbreviation: RT radiation therapy. * Expected cases were based on SEER incidences per 100,000 men as follows: for year 0 1, (estimated risk for ages 65 69); for years 1 5, (estimated risk for ages 70 74); for years 5 10, (estimated risk for ages 75 79); for years 10 20, (estimated risk for ages 80 84) (14).

4 672 I. J. Radiation Oncology Biology Physics Volume 66, Number 3, 2006 Table 4. Institutional reports of second bladder and colorectal cancers diagnosed after radiation therapy Patients Median age Median follow-up (years) Second malignancies: bladder, colorectal Start of evaluation period (after RT) Chrouser et al., 2005 (29) (1%) NR 1 month Movsas et al., 1998 (31) (1%) 2 (0.3%) 2 months Johnstone et al., 1998 (30) * 2 (1%) 4 (3%) 1 year Present series (5%) 8 (2%) 1 month 11 (3%) 3 (1%) 5 years Abbreviations: RT radiation therapy; NR not reported. * Potential follow-up. Mean was reported. Institutional reports of second malignancies lack statistical power to yield strong conclusions, but are important to describe risk as a function of patient factors and treatment techniques. In this study, there were 15 combined lower genitourinary and colorectal malignancies that occurred more than 5 years after RT, which was more than expected according to age-matched incidences for men. These rates are slightly higher than those reported by other institutions (29 31) asintable 4. This may be a function of the longer median follow-up in this set of patients, if not a result of some other patient-related factors (e.g., age, smoking) that cannot be compared across institutions in retrospective fashion. It is also difficult to determine whether the higher number of second malignancies than expected in this series is mostly a function of radiation carcinogenesis, more vigilant screening and incidental discovery in the workup of radiation side effects, or baseline elevated risk of developing another cancer due to genetic or environmental factors (32). We suspect that the workup of radiation-related side effects (e.g., cystitis leading to hematuria, and cystoscopy) increases the rate of diagnosis of second malignancy after RT, whereas control patients would have delayed or missed diagnoses. If radiation carcinogenesis were the central issue behind the higher number of observed cases than expected, we may have expected the relative risk of developing a second malignancy after RT to increase with longer followup times, but this trend was not observed. Moreover, the patients with second malignancies in this study had other major risk factors, including tobacco exposure in half of the observed bladder cancers, and a predisposing inflammatory or genetic condition in each of the observed colorectal cancers. In this report, we chose to focus on the development of bladder or colorectal cancers, but it should be noted that RT could increase the risk of second cancers in more distant sites (e.g., lung (33)) because of machine scatter, as the threshold dose of carcinogenesis may in fact be quite low (9). By eliminating supplemental external beam RT, patients should be at a lower risk of developing a radiationassociated lung cancer compared with a bladder or colorectal primary, given that distant scatter is minimized, and doses to the bladder and colorectal tissue should also be reduced. In this study, patients with brachytherapy alone had a lower incidence of bladder and colorectal cancer (1.6%) than patients with supplemental external beam RT (5.8%, p ). It remains to be seen whether future updates will lead to a statistically significant difference. Although some have estimated that the treatment of a smaller volume of tissue, with less scatter from externally generated radiation, would lower the risk of second malignancy (34), it would take significantly more patients with longer follow-up to make this determination using data from a single institution. Furthermore, as a retrospective analysis, there may be other issues to consider that could affect statistical results, including undetectable imbalances between the two treatment arms, underreporting of important factors and outcomes, and discrepancies between the two arms in the workup of problems leading to the diagnosis of a second solid tumor. Given the retrospective nature of the study and relatively limited numbers, it is difficult to draw strong conclusions about the relation between radiation and secondary malignancies in this series. Regardless, the risk of radiationrelated second malignancies is an important issue to discuss with the patient, and could only be justified by highly effective therapy. With longer follow-up continuing to support the use of brachytherapy for prostate cancer (15-year freedom from failure for this set of patients is approximately 80%), second malignancies in prostate cancer survivors will be an increasingly discussed matter. With a median potential follow-up of 15 years, the results of this study are an important first step toward defining the late risk of developing second malignancies after brachytherapy, with or without supplemental beam RT. CONCLUSIONS The incidence of developing a secondary bladder cancer five or more years after brachytherapy, with or without supplemental external beam RT, was slightly higher (absolute excess risk 35 bladder cancers per 10,000 patients) than age-matched SEER data indicates. Patients should be followed after successful treatment for prostate cancer with the understanding that there may be a small risk of developing a second solid tumor that is radiation-associated, especially in long-term survivors.

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