doi:10.1016/j.ijrobp.2006.05.016
CLINICAL INVESTIGATION Prostate
SECOND MALIGNANCIES AFTER PROSTATE BRACHYTHERAPY:
INCIDENCE OF BLADDER AND COLORECTAL CANCERS IN PATIENTS
WITH 15 YEARS OF POTENTIAL FOLLOW-UP
S
TANLEYL. L
IAUW, M.D.,* J
OHNE. S
YLVESTER, M.D.,
†‡C
HRISTOPHERG. M
ORRIS, M.S.,
§J
OHNC. B
LASKO, M.D.,
† ANDP
ETERD. G
RIMM, 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 (nⴝ11), colorectal cancer (nⴝ3), and prostatic urethra cancer (nⴝ1). The incidence of second malignancy was no different in patients treated with brachytherapy alone (1.6%) vs. those receiving external beam radiotherapy (5.8%, pⴝ0.0623). There were more observed bladder cancers compared with those expected (relative risk, 2.34, 95% confidence interval 0.96 –3.72; 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. © 2006 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 suc-cessful 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 long-term 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 blad-der 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
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 radia-tion therapy.
METHODS AND MATERIALS
This review included 348 patients with biopsy-proven adeno-carcinoma of the prostate who were treated with prostate brachy-therapy at the Seattle Prostate Institute from January 1987 to January 1994. Two subsets of patients included: 125 consecutive patients treated with an Iodine-125 (I-125) implant as mono-therapy 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 Reprint requests to: John E. Sylvester, M.D., Seattle Prostate
Institute, 1101 Madison, Suite 1101, Seattle, WA 98115. Tel: (206) 215-2480; Fax: (206) 215-2481; E-mail: johnsylvester@
seattleprostateinst.com
Received April 4, 2006, and in revised form May 23, 2006. Accepted for publication May 27, 2006.
0360-3016/06/$–see front matter
for each subset are outlined inTable 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 treat-ment including external beam RT and transperineal prostate brachytherapy have been previously described (12, 13). In general, brachytherapy planning was based on transrectal ultrasound vol-umes 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 por-tion of therapy a median 4 weeks before implantapor-tion. 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 ⱖ6-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-sidedp-values; con-fidence 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%) devel-oped a bladder or colorectal malignancy compared with 2 of 125 patients who received brachytherapy alone (1.6%,
p⫽ 0.0623). Details of each potential radiation-associated secondary solid tumor are listed in Table 2. Eleven addi-tional 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 in-volved 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, 0.8 –7.5 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 under-went surgical excision, one after preoperative radiation
ther-Table 1. Patient characteristics
1–125 monotherapy (n⫽125) EBRT⫹seeds (n⫽223)
Median age 70 (range, 47–91) 69 (range, 49–88)
Initial PSA level, median 5.0 (range, 0.2–74.6) 15.2 (range, 0.4–138) T stage T1 11 (18%) 26 (12%) T2a 95 (76%) 55 (25%) T2b 18 (14%) 84 (38%) T2c 1 (1%) 58 (26%) Gleason score 2–6 125 (100%) 145 (65%) 7 55 (25%) 8–10 23 (10%)
Median follow-up 11.4 years (range, 1.2–16.4) 10.2 years (range, 1.4–16.9) Number of survivors with
follow-up longer than:
5 years 102 (82%) 190 (85%)
10 years 70 (56%) 114 (51%)
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 inTable 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 child-hood 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 (ⱖ10 years) (5).
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 90 15 years, 8 months
2 EBRT⫹seeds Bladder 88 13 years, 1 month
3 EBRT⫹seeds Bladder 87 12 years, 10 months
4 EBRT⫹seeds Bladder 85 11 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 67 10 years, 0 months
13 EBRT⫹seeds Sigmoid colon 73 7 years, 11 months
14 Seeds Prostatic urethra 66 11 years, 11 months
15 Seeds Colon 76 6 years, 9 months
Abbreviation:EBRT⫽external beam radiation therapy.
Table 3. Observed and expected rate of bladder cancers
Years after RT Person-years
Observed cases Expected cases* Observed-to-expected ratio (95%CI) 0–1 348.0 0 0.5 0 1.1–5 1298.1 7 2.5 2.80 (0.73–4.87) 5.1–10 1225.3 7 3.0 2.33 (0.60–4.06) 10.1–20 579.2 4 1.7 2.35 (0.05–4.66)
Total all patients 3450.6 18 7.7 2.34 (1.26–3.42)
Total>5 years 1804.5 11 4.7 2.34 (0.95–3.72)
Abbreviation:RT⫽radiation therapy.
* Expected cases were based on SEER incidences per 100,000 men as follows: for year 0 –1, 139.9 (estimated risk for ages 65– 69); for years 1–5, 192.5 (estimated risk for ages 70 –74); for years 5–10, 244.3 (estimated risk for ages 75–79); for years 10 –20, 297.4 (estimated risk for ages 80 – 84) (14).
Institutional reports of second malignancies lack statisti-cal 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) as inTable 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 fash-ion. 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 vig-ilant screening and incidental discovery in the workup of radiation side effects, or baseline elevated risk of develop-ing 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 follow-up 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, pa-tients should be at a lower risk of developing a radiation-associated lung cancer compared with a bladder or colorec-tal 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⫽ 0.0623). 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 malig-nancy (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 be-tween 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 malig-nancies in this series. Regardless, the risk of radiation-related 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 sup-port 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 poten-tial follow-up of 15 years, the results of this study are an important first step toward defining the late risk of devel-oping 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 (abso-lute excess risk 35 bladder cancers per 10,000 patients) than age-matched SEER data indicates. Patients should be fol-lowed 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.
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)
Chrouseret al., 2005 (29) 1743 70.5† 7.1† 24 (1%) NR 1 month
Movsaset al., 1998 (31) 543 70 3.9 4 (1%) 2 (0.3%) 2 months
Johnstoneet al., 1998 (30) 154 66.7† 10.9* 2 (1%) 4 (3%) 1 year
Present series 348 70 10.5 18 (5%) 8 (2%) 1 month
11 (3%) 3 (1%) 5 years
Abbreviations:RT⫽radiation therapy; NR⫽not reported. * Potential follow-up.
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