Prostate cancer is the most common nonskin cancer in men. Estimates in 2001 suggest that about 198,100 men in the United States will be diagnosed with adenocarcinoma of the prostate annually and approximately 31,500 men will die from this disease . Treatment options for men with organ-confined disease include observation, cryotherapy, external beam radiation therapy, radical prostatectomy, prostate brachytherapy, as well as a combination of external beam radiation therapy and prostate brachytherapy. Although the active treatment options may have similar biochemical responses, they can have different toxicities, including urinary, bowel, and/or sexual dysfunction.
A popular treatment for early-stage/favorable-risk adenocarcinoma of the prostate is transperineal interstitial permanent prostate brachytherapy (TIPPB) [2–5]. This procedure is often chosen over external beam radiation treatment and radical prostatectomy because of the perception that there are fewer “side effects.” The sharp falloff in dose rate associated with prostate brachytherapy offers a potential advantage for reducing dose to normal structures; i.e., urethra, bladder, and rectum. A combination of external beam radiation therapy (EBRT) and TIPPB is often employed in patients with intermediate-risk disease to take advantage of the benefits of both modalities [6–8]. However, little is known about the side effects from such a treatment combination, although much has been reported on the side effects of EBRT or interstitial implant alone [9–12].
Permanent implants are typically performed using either 103palladium (103Pd) or 125iodine (125I). Fundamentally, there are significant differences between the two radionuclides . 103Pd has a shorter half-life than 125I and, therefore, a higher dose rate, which might be more effective for rapidly proliferating tumors [14,15]. 103Pd also has a lower energy (21 KeV) compared to 125I (28 KeV). Furthermore, controversy exists over the toxicity profile of the two isotopes, specifically with respect to urinary and rectal morbidity [6,10,12,16].
The purpose of this analysis was to correlate isotope use with the urinary symptoms of patients who received a combination of EBRT and TIPPB boost with either a 103Pd or 125I radioisotope. Findings from this study suggest that 125I may be associated with greater urinary morbidity than 103Pd. This necessitated studying the postimplant dosimetry on all patients to evaluate both urethral dose and implant quality.
MATERIALS AND METHODS
Twenty-seven patients received EBRT (50.4 Gy/28 fractions) using a 1-cm uniform margin surrounding the gross tumor volume (GTV). Implants were performed 2–4 weeks after completion of EBRT. Between 1996–1998, 14 patients received a 103Pd boost of 70 Gy. For logistic reasons, we switched the isotope to 125I and 13 of the 27 patients received a boost dose of 100 Gy with this isotope following EBRT. Implants were initially preplanned CT-based but later were performed using transrectal ultrasound guidance. The implants were characterized by peripheral loading and the use of relatively high-strength seeds (125I, NIST-99, 0.4–0.6 mCi/seed or 103Pd, 1.0–1.5 mCi/seed). The implants were planned such that the prescribed isodose line was typically 3–5 mm beyond the prostatic capsule. The postimplant dosimetry was based on a CT scan obtained at 44 ± 31 days postimplant in the 125I group and 23 ± 19 days in the 103Pd group [16,17]. During the period of study, the preplanned D5 urethral dose was limited to 220–250 Gy. A dose-volume histogram (DVH) of the urethra was generated for each patient.
American Urologic Association (AUA) symptom scores  were obtained pretreatment and at 1 month follow-up, then every 3 months. Statistical analysis was carried out using Student's t-test . We obtained IRB approval for this retrospective analysis.
The preimplant characteristics of both groups of patients are listed in Table 1. In order to downsize the prostate volume to decrease pubic arch interference, five of the 125I and three of the 103Pd boost patients received preimplant hormonal therapy utilizing a luteinizing hormone releasing hormone agonist alone or in combination with a nonsteroidal antiandrogen. Alpha blocker usage was similar between the two groups. Ten of 13 (77%) 125I and 10 of 14 (71%) 103Pd patients received an alpha-blocker.
Table 1. Preimplant Characteristics of the Patients Receiving Both External Beam Radiation Therapy and Prostate Brachytherapy Boost
The mean AUA symptom scores for the 125I and 103Pd patients at 1, 3, 6, and 12 months of follow-up are shown in Figure 1 and listed in Table 2. The mean pretreatment AUA scores for the 125I and 103Pd boost implant patients were not significantly different (9 ± 4 and 6 ± 5, respectively; P = 0.3). The mean AUA score of the patients who received the 125I implants were significantly higher (P < 0.01) at each follow-up. There was no significant difference between obstructive or irritative symptoms either before or after implant. A postimplant dosimetric analysis was carried out to investigate whether there was a dosimetric basis for the difference in symptoms.
Table 2. American Urologic Association Scores Pre- and Postimplant
9 ± 4
18 ± 6
17 ± 7
10 ± 3
14 ± 8
6 ± 5
11 ± 9
11 ± 7
9 ± 4
7 ± 5
Postimplant Dosimetry and Evaluation of Implant Quality
The average urethral pre- and postimplant DVHs for the 125I and 103Pd implants are plotted in Figure 2. The difference in the shapes of the curves was revealing. The postimplant dose at the lower levels of coverage (D10–D50) was significantly higher than the preimplant dose for both 125I and 103Pd. This was attributed to source placement errors in which some of the seeds were implanted closer to the urethra than intended. At the higher levels of coverage (D50–D90) the dose achieved was less than planned. This was particularly true for the 103Pd implants and suggests that implant quality may have been a factor in the doses delivered. The 103Pd implants were performed much earlier in our experience and the dose coverage was generally lower.
To adjust for the differing relative biological effectiveness (RBE) of both isotopes , we multiplied the 103Pd doses by 1.4, as shown in Figure 3 (dashed line). The highest urethral doses are represented by D10 and D25, which appear to be equivalent. These data are listed in Table 3. Among the four levels of coverage shown, the only significant difference occurred at D90, where the 125I dose was significantly higher (P < 0.01). This finding suggests that differences in AUA score may have been due to the minimum dose delivered to a large percentage of the urethra instead of the maximum dose delivered to a small percentage of the urethra. Therefore, we next attempted to correlate the symptoms with dose.
Table 3. Doses Delivered to Various Percentages of Urethra Based on Postimplant Dosimetric Calculations
103Pd RBE Adjusted
RBE, relative biological effectiveness.
144 ± 34
83 ± 28
195 ± 41
180 ± 29
223 ± 47
199 ± 39
233 ± 47
238 ± 50
Correlation of Symptoms with Dose
The D90 urethral doses delivered by the 125I implants are plotted vs. the corresponding change in the AUA score at 1 month postimplant in Figure 4. This was undertaken to determine whether or not changes in AUA score were merely a result of increased urethral dose. The solid line represents a linear least-squares-fit to the data, which indicates that the change in the AUA score was proportional to the urethral D90 dose; however, the correlation coefficient, R2 = 0.20, suggests a weak correlation. The same parameters are plotted in Figure 5 for the 103Pd implants but the change in the AUA score did not correlate with the D90 dose (R2 = 0.00). Hence, this suggests that the higher AUA score of the 125I patients was not necessarily the result of the higher D90 dose.
There are several studies addressing the efficacy and symptoms of patients receiving 103Pd or 125I seed monotherapy for treatment of prostate cancer [21–23]. Data from pilot studies have demonstrated promising results with combined EBRT and implant and have led to the development of a Phase II Radiation Therapy Oncology Group trial [24–27]. Peschel et al. , in a retrospective analysis, reported that 103Pd monotherapy had fewer side effects than 125I monotherapy. We hypothesized that this might also be the case with combined EBRT and implant.
It has been suggested that the urinary symptoms postimplant might be related to the dose delivered to the urethra [11,12]. Parameters studied by Wallner et al.  for an implant as monotherapy included the maximum dose delivered to the prostate, length of urethra that received greater than 400 Gy, and large prostate size. Patients whose implants possessed these characteristics exhibited greater long-term morbidity than those who did not. Likewise, Desai et al.  reported that urinary frequency correlated with dose to both the prostate and urethra. However, in a recent study, Coakley et al.  reported a lack of association between voiding symptoms and seed placement near the urethra. To date, there are no data in the literature comparing the urinary symptoms between 103Pd and 125I in combination with EBRT. It is therefore difficult to compare these monotherapy parameters to our data. Furthermore, postimplant dosimetry and analysis of implant quality were not uniformly incorporated in all of the aforementioned studies. This article evaluates the differences in urinary morbidity between the two isotopes in combination with EBRT, with emphasis on postimplant dosimetry. In our series, the postimplant AUA symptom scores of the 125I patients were significantly higher. Additionally, we were unable to find a correlation between dose delivered to the urethra and urinary morbidity. Isotope selection is a potential explanation for the difference in symptoms.
Comparing two isotopes can be challenging. A portion of the difference between the postimplant DVHs in Figure 2 can be accounted for by the difference in prostate doses prescribed for 125I (100 Gy) and 103Pd (70 Gy). That is, it is assumed that 1 Gy delivered by 103Pd is equivalent to 1.4 Gy delivered by 125I . Hence, if the prostate doses delivered by the 125I and 103Pd were equivalent, the DVHs should be superimposable when the 103Pd doses are multiplied by 1.4.
The minimum dose delivered to 90% of the urethra (D90) was significantly higher in the 125I group, whereas the doses at other levels of coverage were similar. The question remains as to why the 125I D90 dose was higher. This difference could have been due to the properties of 125I and 103Pd or to differences in the quality of the implants. The latter was possible because most of the 103Pd implants were performed much earlier in our learning curve, although some of the difference may have been due to the properties of the radioisotopes. If the higher urethral D90 dose in the 125I implants is correlated with increased urinary symptoms, then one would expect the increase in the AUA score to correlate with dose. A weak correlation was observed for 125I, but not for 103Pd. Hence, we are unable to show that the increase in AUA score was necessarily dose-related.
Two weakness of this study are that the sample size was small and the 125I and 103Pd implants were not equivalent in terms of implant quality. However, we are the first to report a dosimetric analysis comparing urinary symptoms of patients receiving combined EBRT and implant based on isotope selection. To better address this question, a much larger prospective study in which the quality of the 125I and 103Pd implants are equivalent would be required. Such a study may affirm whether the difference in urinary morbidity is related to purely isotope selection, urethral dose, or a combination of factors.
Patients who received combined EBRT and TIPPB using 125I had significantly more urinary morbidity than the 103Pd patients, as measured by AUA score. Postimplant dosimetric evaluation suggests that the higher AUA score of the 125I patients was not necessarily the result of the higher D90 dose. We recommend further validating our findings in a larger prospective study in which the quality of the 125I and 103Pd implants can be evaluated.