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Isotope selection for patients undergoing prostate brachytherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 2, pp. 391–395, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
PII S0360-3016(99)00187-X
CLINICAL INVESTIGATION
Prostate
ISOTOPE SELECTION FOR PATIENTS UNDERGOING PROSTATE BRACHYTHERAPY CHRISTINE M. CHA, M.D.,* LOUIS POTTERS, M.D.,* RICHARD ASHLEY, M.D.,† KATHERINE FREEMAN, DR. P.H.,‡ XIAO-HONG WANG, PH.D.,* ROBERT WALDBAUM, M.D.,§ AND STEVEN LEIBEL, M.D.* *Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center at Mercy Medical Center, Rockville Center, NY; Department of Urology, Mercy Medical Center, Rockville Center, NY; ‡Department of Biostatistics, Montefiore Medical Center, Bronx, NY; and §Division of Urology, North Shore University Hospital, Manhasset, NY
†
Purpose: Ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) is generally performed with either 103Pd or 125I. The use of 125I for low Gleason score tumors and 103Pd for higher Gleason scores has been suggested based on isotope dose rate and cell doubling time observed in in vitro studies. While many centers follow these isotope selection criteria, other centers have elected to use only a single isotope, regardless of Gleason score. No clinical data have been published comparing these isotopes. This study was undertaken to compare outcomes between 125I and 103Pd in a matched pair analysis for patients undergoing prostate brachytherapy. Methods and Materials: Six hundred forty-eight consecutively treated patients with clinically confined prostate cancer underwent TIPPB between June 1992 and February 1997. Five hundred thirty-two patients underwent TIPPB alone, whereas 116 received pelvic external beam irradiation and TIPPB. Ninety-three patients received androgen deprivation therapy prior to TIPPB. The prescribed doses for TIPPB were 160 Gy for 125I (pre-TG43) and 120 Gy for 103Pd. Patients treated with combination therapy received 41.4 or 45 Gy (1.8 Gy/fraction) external beam irradiation followed by a 3- to 5-week break and then received either a 120-Gy 125I or a 90-Gy 103Pd implant. Until November 1994, all patients underwent an 125I implant after which the isotope selection was based on either Gleason score (Gleason score 2–5:125I; Gleason 5– 8:103Pd) or isotope availability. A matched pair analysis was performed to assess any difference between isotopes. Two hundred twenty-two patients were matched according to Gleason score, prostate-specific antigen (PSA), and stage. PSA relapse-free survival (PSA-RFS) was calculated based on the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Group definition of failure. Kaplan-Meier actuarial survival curves were compared to assess differences in pretreatment PSA and Gleason score. Results: Univariate analysis of the 648 patients identified Gleason score, pretreatment PSA value, and stage as significant factors to predict PSA-RFS, but failed to identify isotope selection as significant. To address the significance of isotope selection further, the matched pair groupings were performed. The minimum follow-up for all 222 matched patients is 24 months with a median follow-up of 42 months (24 – 82). The actuarial PSA-RFS at 5 years for all 222 patients is 86.5%. One hundred eleven of the 222 matched patients received a 103Pd implant with an 87.1% 5-year PSA-RFS. The remaining 111 patients underwent a 125I implant with an 85.9% 5-year PSA-RFS (p ⴝ n.s.). Analysis of Gleason score subgroups 2– 4, 5– 6, and 7–9 failed to show any significant difference in PSA-RFS comparing isotopes. Pretreatment PSA subgroups of < 10 or > 10 ng/ml also failed to show any significant difference in PSA-RFS survival comparing isotopes. Analysis of postimplant dosimetry using dose delivered to 90% of the prostate volume (D90) did not identify any difference between the isotope groups. Conclusions: This matched pair analysis failed to demonstrate a difference for 125I and 103Pd in PSA-RFS for patients undergoing TIPPB. In addition, there were no observed advantages for either 125I or 103Pd in either the low or high Gleason score groups. This data indicates that the role of isotope selection for patients undergoing TIPPB requires further clarification. © 1999 Elsevier Science Inc. Prostate cancer, Brachytherapy, Iodine-125, Palladium-103.
Over the past several years, ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) has
become increasingly popular for the treatment of early stage prostate cancer. Outcome data with 5- to 10-year results has been reported on several hundred patients (1–3). The predominance of the data is reported for 125I implants, but
Presented at the 40th annual meeting of the American Society for Therapeutic Radiology and Oncology in Phoenix, AZ, October 25–29, 1998. Reprint requests to: Louis Potters, M.D., Department of Radi-
ation Oncology, Memorial Sloan-Kettering Cancer Center at Mercy Medical Center, 1000 N. Village Avenue, Rockville Center, NY 11570. Accepted for publication 10 May 1999.
INTRODUCTION
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excellent results are available for 103Pd as well (4 – 6). Despite the lack of clinical data, many practitioners have been utilizing 103Pd for patients with higher Gleason scores as set forth by the protocol established by Blasko and colleagues (7). The rationale for this protocol is based on in vitro radiobiologic data by Ling comparing isotope dose rate and cell doubling time for 125I, 103Pd, and 198Au (8). That work identified a benefit for 103Pd as opposed to 125I for tumors with a cell doubling time of 10 days. While this data has influenced the modern practice of TIPPB, this rationale has yet to be confirmed by clinical data. Manufacturer availability and cost have also complicated isotope selection. Due to the increase in TIPPB over the last several years (9), the availability of either 103Pd or 125I has caused some physicians to use one isotope exclusively. To date, there has been no published data comparing 103Pd and 125 I to assess clinical outcomes in patients undergoing TIPPB. This study is a retrospective, matched pair analysis to assess 125I and 103Pd for prostate-specific antigen relapsefree survival (PSA-RFS) selected from a large cohort of TIPPB patients.
METHODS AND MATERIALS Six hundred forty-eight consecutively treated patients with clinically confined prostate cancer underwent TIPPB between June 1992 and February 1997. All patients had biopsy-proven adenocarcinoma with central pathology review performed on all specimens. Patients were staged with history and physical examination, according to American Joint Cancer Commission standards (10). Patients underwent both bone scan and abdominal–pelvic CT scans. All patients underwent transrectal ultrasound to assess prostate size and those with glands greater than 60 cc were treated with 3– 4 months of antiandrogen therapy (n ⫽ 93). Patients were stratified into risk groups based on PSA and Gleason score in accordance with Blasko and colleagues (7, 11). Patients who had a PSA ⬍ 10, Gleason score 2– 6 and were clinical stage T1 or T2a were considered low-risk and treated with TIPPB alone. The dose used for 125I implants was 160 Gy (pre-TG43) and 120 Gy for 103Pd (TheraSeed) (12). High-risk patients with PSA ⬎ 10, Gleason score 7–10, or clinical stage T2b generally underwent external beam irradiation and TIPPB. This consisted of external beam irradiation to doses of 41.4 or 45 Gy (1.8 Gy/fraction) on a linear accelerator with 4 MV or more, followed in 3–5 weeks by TIPPB. When external beam irradiation was used the dose used for 125I implant was 120 Gy (pre-TG43) and for 103Pd, 90 Gy. Preplanning for TIPPB was performed using the prostate dimensions as measured on transrectal ultrasound. The isotope activity nomogram developed by Anderson (13) was modified to account for underdosing and used to determine the total activity required for 103Pd or 125I (5, 14). Intraoperatively, patients underwent spinal anesthesia and were placed in an exaggerated lithotomy position. The implant
Volume 45, Number 2, 1999
was performed using a biplane ultrasound probe (B&K, Marlborough, MA) with needles placed using weighted peripheral loading with urethral sparing. Micro-aerosolized jelly was instilled into the urethra to enhance urethral imaging. The mean activity for 125I was 0.52 mCi (0.36 – 0.72 mCi) and for 103Pd was 1.48 mCi (1.11–1.62 mCi). Implants with 125I used a mean number of needles and seeds of 12 (8 –24) and 64 (22–106), respectively. For those implanted with 103Pd, the mean number of needles and seeds was 15 (8 –26) and 82 (22–106), respectively. Individual seeds were placed in the prostate with an interstitial gun applicator without fluoroscopy (Mick Nuclear, Bronx, NY). All patients were given intraoperative antibiotics. After seed implantation, the urologist performed cystoscopy and patients were discharged with a Foley catheter in place for 24 – 48 hours. Postimplant dosimetry originally consisted of stereo-shift films and two-dimensional reconstruction within 48 hours of the implant. As of 1995, patients underwent CT scans 2-3 weeks postimplant with calculations performed to assess the volume of the prostate receiving 100% of the prescribed dose (V100), the volume receiving 150% of the prescribed dose (V150), and the minimum dose received by 90% of the prostate (D90) (n ⫽ 251). Follow-up was at 5 weeks, then every 3 months for 2-3 years, and then every 6 months thereafter. At each follow-up visit a serum PSA level was drawn. The American Urologic Association urine scoring questionnaire was completed by the patient and assessment of morbidity using a modified Radiation Therapy Oncology Group (RTOG) toxicity score was obtained at each follow-up. The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus defined PSA failure as 3 consecutive rising PSA values defined PSA-RFS in this study (15). The time of failure was calculated as the midpoint between the PSA value nadir and the first rise. If there was a detectable rise in the serum PSA at follow-up, the PSA was repeated every 8 weeks. If a patient had 3 or more PSA value rises, an abdominal–pelvic CT scan and a bone scan were obtained. Generally, antiandrogen deprivation therapy was administered to patients who failed TIPPB, with several patients continuing on observation. To create the matched groups, the dataset was divided according to isotope used. For each Gleason grouping (2– 4, 5– 6, 7–9), patients were matched according to PSA (ⱕ 10 or ⬎ 10) and clinical stage. Two hundred forty-three patients were matched to compare outcome based on isotope use. Kaplan-Meier curves were constructed to demonstrate survival distributions. Log-rank test was used to compare PSA-RFS between patients for each isotope. Univariate and multivariate analysis was performed by Cox proportional square hazards model testing (16, 17). RESULTS The median follow-up for all 648 patients was 41 months (8 – 82). Twenty-eight patients are excluded from this study
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Table 1. Univariate analysis and multivariate analysis of factors affecting PSA RFS for 648 patients undergoing TIPPB Univariate analysis p value
Multivariate analysis p value
0.0001 0.0001 0.023 0.101 0.530 0.505
0.0001 0.0025 n.s.
Pretreatment PSA Gleason score Stage Isotope selection Addition of external beam Use of antiandrogen therapy
having less than 24 months follow-up. Six died of illnesses other than prostate cancer and 22 are lost to follow-up. Univariate analysis identified Gleason score, pretreatment PSA value, and stage as significant for PSA-RFS, and multivariate analysis identified Gleason score and PSA as significant for PSA-RFS (Table 1). Isotope selection for TIPPB was not found to be significant in this analysis. The significant factors on univariate analysis were then used for the selection of the randomly matched pairs of patients receiving either a 103Pd or 125I implant. The characteristics of each matched group are shown in Table 2. There was no statistically significant difference between the matched groups for Gleason score, PSA, stage, the addition of external beam irradiation, or the use of androgen deprivation therapy. The median follow-up of the matched group is 42 months (24 – 82). Of the 222 matched patients, 2 patients are lost to follow-up. Ten patients have died with 3 of the 10 dying with metastatic prostate cancer. All three had been treated with 103Pd. The overall survival for this group is 95% with a disease-specific survival of 99%. The actuarial PSA-RFS at 5 years was 86.5% for all 222 patients (Fig. 1). As shown in Fig. 2, the 5-year PSA-RFS for patients undergoing 103Pd was 87.1% and for those undergoing 125I was 86.9% (p ⫽
Fig. 1. Actuarial PSA-RFS for all 222 matched patients.
0.625). Subgroup analysis comparing PSA-RFS for Gleason score groupings and pretreatment PSA values did not show any significant difference in outcome (Table 3, Figs. 2–5). To examine the possibility of poor dose conformity confounding the observed results, an analysis of implant quality was performed on 251 patients having had CT-based postimplant dosimetry using the D90 (the minimum dose that covers 90% of the prostate volume). To quantify the D90 relative to the prescribed dose, which varies depending on the addition of external beam irradiation, we used the D90%, defined as the percent of the D90 dose relative to the prescribed implant dose. No significant difference was identified between 125I or 103Pd for the D90%, even when stratified by Gleason score (Table 4). DISCUSSION In this retrospective matched pair study comparing outcomes for patients who underwent TIPPB with either 103Pd
Table 2. Patient characteristics in the matched pair analysis (n ⫽ 222) 103
Gleason score 2–4 5–6 7–9 Stage T1c T2a T2b PSA ⱕ 10 ⬎ 10 Treatment variation Implant alone XRT and implant Androgen deprivation
125
Pd (n ⫽ 111)
I (n ⫽ 111)
8 91 12
9 90 12
61 26 24
49 38 24
70 41
71 42
92 19 12
96 15 14
p Value 0.991
0.091
0.998 0.523 0.846
Fig. 2. Actuarial PSA-RFS comparing patients matched for implant with 125I and those implanted with 103Pd.
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Table 3. Actuarial 5-year PSA-RFS for Gleason score and pretreatment PSA comparing 103Pd and 125I 103
125
p Value
88.6% 80.5%
87.3% 78.6%
0.408 0.817
100.0% 86.4% 75.0%
88% 85.5% 81.3%
0.832 0.991 0.184
Pd
Pretreatment PSA ⱕ 10 ⬎ 10 Gleason score 2–4 5–6 7–9
I
or 125I, there was no significant difference in PSA-RFS between isotopes used. Subset analysis of either high or low Gleason score also did not demonstrate any difference in PSA-RFS based on isotope use. This is the first clinical analysis comparing isotopes for localized prostate cancer treated with TIPPB. The lack of a significant difference in PSA-RFS fails to justify the use of Pd-103 as advantageous for higher Gleason score tumors or conversely, the use of 125 I for low Gleason score tumors. The rationale for distinguishing isotope on Gleason score is based on in vitro studies comparing isotope dose rate and cell doubling time for 125I, 103Pd, and 198Au (8). The radiobiologic data presented by Ling suggests an advantage for 103 Pd for tumors with a Tpot (potential cell doubling time assuming no cell loss) (18) of 10 days. However, Helpap et al. observed that prostate tumor cells actually had a much larger Tpot (19). For highly differentiated tumors, the calculated Tpot ranges between 25–75 days. For poorly differentiated adenocarcinoma the Tpot is calculated to be 18 –33 days. These data would seem to contradict the Ling data as supporting the use of Pd-103 implants for higher Gleason score tumors. In addition, for cells with a Tpot greater than 10, it is implied by the projection of the cell survival curves
Fig. 3. Actuarial PSA-RFS comparing with Gleason score 5– 6 tumors.
125
I and
103
Pd for patients
Fig. 4. Actuarial PSA-RFS comparing with Gleason score 7–9 tumors.
125
I and
103
Pd for patients
in the Ling data that 125I implants would be more effective than 103Pd, not less. While data is not available to report the individual Tpot for different Gleason scores, the lack of a difference in the clinical outcomes identified in this study including a wide range of Gleason scores, would suggest that there is no significant radiobiologic difference between isotopes. As the caseload of TIPPB has risen in the last several years, seed availability has been in short supply (20). Many radiation departments have elected to use only one isotope; others have attempted to match Gleason score to either 125I or 103Pd. The similarity of both isotopes in energy and physical construct allows for individualized selection on a case-by-case basis. The half-life difference, however, may be pertinent with regard to radiation safety issues and exposure in the home to young children, as we instruct patients to avoid physical contact with infants for 3 half-lives of
Fig. 5. Actuarial 4-year PSA-RFS comparing patients with pretreatment PSA ⬎ 10 ng/ml.
125
I and
103
Pd for
Isotope selection and prostate brachytherapy
Table 4. Implant analysis of the mean D90% for 251 patients
Isotope 103 Pd 125 I Gleason score 2–4 103 Pd 125 I Gleason score 5–6 103 Pd 125 I Gleason score 7–9 103 Pd 125 I
D90%
Range
96.6 101.7
65–136 52–153
91.5 112.0
60–124 91–122
97.7 99.4
56–154 65–124
97.6 108.8
52–153 84–136
p Value 0.122 0.251 0.150 0.096
* The D90% is defined as the percent of the prescribed dose covering 90% of the prostate volume. No significant difference was noted between 125I and 103103Pd implants. There was no difference between Gleason score and isotope when comparing D90%.
theisotope. In addition, the energy differences between 125I and 103Pd are significant for dose penetration and the num-
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ber of seeds required. Generally, for an equivalent sized prostate, more 103Pd seeds are required compared with 125I. Prestidge demonstrated better dosimetry when more seeds are used (9). Nonetheless, we were unable to distinguish any difference in the D90% for implants with 103Pd or 125I, despite the difference in median number of seeds between isotopes (Table 4). Since prostate cancer is a slowly progressive disease with long survival, longer follow-up will be required to confirm the outcomes reported by this study. The consistency afforded by the practice of the single practitioner (L.P.) was advantageous in limiting bias due to operator performance. As has been observed by Prestidge, there is considerable variability in the delineation of tumor volume and implant quality between practitioners (9). The lack of a difference in clinical effectiveness between isotopes in this matched pair analysis would best be confirmed by a randomized, prospective study. However, the clinical experience reported with either isotope corroborates the results in this matched pair analysis showing excellent 5-year PSA-RFS, regardless of the isotope used.
REFERENCES 1. Ragde H, Elgamal AA, Snow PB, et al. Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer 1998;83:989 –1001. 2. Beyer DC, Priestley JB Jr. Biochemical disease-free survival following 125I prostate implantation. Int J Radiat Oncol Biol Phys 1997;37:559 –563. 3. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996;14:449 – 453. 4. Stock RG, Stone NN, DeWyngaert JK, Lavagnini P, Unger PD. Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer 1996;77:2386 –2392. 5. Dattoli M, Wallner K, Sorace R, et al. 103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma [see comments]. Int J Radiat Oncol Biol Phys 1996;35:875– 879. 6. Nag S, Scaperoth DD, Badalament R, Hall SA, Burgers J. Transperineal palladium 103 prostate brachytherapy: Analysis of morbidity and seed migration. Urology 1995;45:87–92. 7. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasoundguided implantation of the prostate: Morbidity and complications. Scand J Urol Nephrol Suppl 1991;137:113–118. 8. Ling CC. Permanent implants using Au-198, Pd-103 and I-125: Radiobiological considerations based on the linear quadratic model. Int J Radiat Oncol Biol Phys 1992;23:81– 87. 9. Prestidge BR. Radioisotopic implantation for carcinoma of the prostate: Does it work better than it used to? Semin Radiat Oncol 1998;8:124 –131. 10. Fleming ID, Cooper JS, Henson DE, et al. AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott-Raven; 1997.
11. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep 1966;50:125–128. 12. 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. 13. Anderson LL, Moni JV, Harrison LB. A nomograph for permanent implants of palladium-103 seeds. Int J Radiat Oncol Biol Phys 1993;27:129 –135. 14. Unger PD, Hoon V, Stone N, et al. Computerized interactive morphometry in the differential diagnosis of irradiated prostates. Anal Quant Cytol Histol 1995;17:100 –108. 15. Consensus statement: Guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997;37:1035–1041. 16. Cox DR, Abadir R. Regression models and life tables. J Roy Statist Soc 1972;34:187–220. 17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Cancer Res Clin Oncol 1958;53:447– 457. 18. Hall EJ. Radiobiology for the radiologist. 3rd ed. Philadelphia: J.B. Lippincott; 1988. 19. Helpap B, Stiens R, Bruhl P. The proliferative pattern of the prostatic carcinoma before and under hormonal treatment. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1976;87:311– 320. 20. Prestidge BR, Prete JJ, Buchholz TA, et al. A survey of current clinical practice of permanent prostate brachytherapy in the United States. Int J Radiat Oncol Biol Phys 1998;40: 461– 465.
PII S0360-3016(99)00187-X
CLINICAL INVESTIGATION
Prostate
ISOTOPE SELECTION FOR PATIENTS UNDERGOING PROSTATE BRACHYTHERAPY CHRISTINE M. CHA, M.D.,* LOUIS POTTERS, M.D.,* RICHARD ASHLEY, M.D.,† KATHERINE FREEMAN, DR. P.H.,‡ XIAO-HONG WANG, PH.D.,* ROBERT WALDBAUM, M.D.,§ AND STEVEN LEIBEL, M.D.* *Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center at Mercy Medical Center, Rockville Center, NY; Department of Urology, Mercy Medical Center, Rockville Center, NY; ‡Department of Biostatistics, Montefiore Medical Center, Bronx, NY; and §Division of Urology, North Shore University Hospital, Manhasset, NY
†
Purpose: Ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) is generally performed with either 103Pd or 125I. The use of 125I for low Gleason score tumors and 103Pd for higher Gleason scores has been suggested based on isotope dose rate and cell doubling time observed in in vitro studies. While many centers follow these isotope selection criteria, other centers have elected to use only a single isotope, regardless of Gleason score. No clinical data have been published comparing these isotopes. This study was undertaken to compare outcomes between 125I and 103Pd in a matched pair analysis for patients undergoing prostate brachytherapy. Methods and Materials: Six hundred forty-eight consecutively treated patients with clinically confined prostate cancer underwent TIPPB between June 1992 and February 1997. Five hundred thirty-two patients underwent TIPPB alone, whereas 116 received pelvic external beam irradiation and TIPPB. Ninety-three patients received androgen deprivation therapy prior to TIPPB. The prescribed doses for TIPPB were 160 Gy for 125I (pre-TG43) and 120 Gy for 103Pd. Patients treated with combination therapy received 41.4 or 45 Gy (1.8 Gy/fraction) external beam irradiation followed by a 3- to 5-week break and then received either a 120-Gy 125I or a 90-Gy 103Pd implant. Until November 1994, all patients underwent an 125I implant after which the isotope selection was based on either Gleason score (Gleason score 2–5:125I; Gleason 5– 8:103Pd) or isotope availability. A matched pair analysis was performed to assess any difference between isotopes. Two hundred twenty-two patients were matched according to Gleason score, prostate-specific antigen (PSA), and stage. PSA relapse-free survival (PSA-RFS) was calculated based on the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Group definition of failure. Kaplan-Meier actuarial survival curves were compared to assess differences in pretreatment PSA and Gleason score. Results: Univariate analysis of the 648 patients identified Gleason score, pretreatment PSA value, and stage as significant factors to predict PSA-RFS, but failed to identify isotope selection as significant. To address the significance of isotope selection further, the matched pair groupings were performed. The minimum follow-up for all 222 matched patients is 24 months with a median follow-up of 42 months (24 – 82). The actuarial PSA-RFS at 5 years for all 222 patients is 86.5%. One hundred eleven of the 222 matched patients received a 103Pd implant with an 87.1% 5-year PSA-RFS. The remaining 111 patients underwent a 125I implant with an 85.9% 5-year PSA-RFS (p ⴝ n.s.). Analysis of Gleason score subgroups 2– 4, 5– 6, and 7–9 failed to show any significant difference in PSA-RFS comparing isotopes. Pretreatment PSA subgroups of < 10 or > 10 ng/ml also failed to show any significant difference in PSA-RFS survival comparing isotopes. Analysis of postimplant dosimetry using dose delivered to 90% of the prostate volume (D90) did not identify any difference between the isotope groups. Conclusions: This matched pair analysis failed to demonstrate a difference for 125I and 103Pd in PSA-RFS for patients undergoing TIPPB. In addition, there were no observed advantages for either 125I or 103Pd in either the low or high Gleason score groups. This data indicates that the role of isotope selection for patients undergoing TIPPB requires further clarification. © 1999 Elsevier Science Inc. Prostate cancer, Brachytherapy, Iodine-125, Palladium-103.
Over the past several years, ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) has
become increasingly popular for the treatment of early stage prostate cancer. Outcome data with 5- to 10-year results has been reported on several hundred patients (1–3). The predominance of the data is reported for 125I implants, but
Presented at the 40th annual meeting of the American Society for Therapeutic Radiology and Oncology in Phoenix, AZ, October 25–29, 1998. Reprint requests to: Louis Potters, M.D., Department of Radi-
ation Oncology, Memorial Sloan-Kettering Cancer Center at Mercy Medical Center, 1000 N. Village Avenue, Rockville Center, NY 11570. Accepted for publication 10 May 1999.
INTRODUCTION
391
392
I. J. Radiation Oncology
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Biology
●
Physics
excellent results are available for 103Pd as well (4 – 6). Despite the lack of clinical data, many practitioners have been utilizing 103Pd for patients with higher Gleason scores as set forth by the protocol established by Blasko and colleagues (7). The rationale for this protocol is based on in vitro radiobiologic data by Ling comparing isotope dose rate and cell doubling time for 125I, 103Pd, and 198Au (8). That work identified a benefit for 103Pd as opposed to 125I for tumors with a cell doubling time of 10 days. While this data has influenced the modern practice of TIPPB, this rationale has yet to be confirmed by clinical data. Manufacturer availability and cost have also complicated isotope selection. Due to the increase in TIPPB over the last several years (9), the availability of either 103Pd or 125I has caused some physicians to use one isotope exclusively. To date, there has been no published data comparing 103Pd and 125 I to assess clinical outcomes in patients undergoing TIPPB. This study is a retrospective, matched pair analysis to assess 125I and 103Pd for prostate-specific antigen relapsefree survival (PSA-RFS) selected from a large cohort of TIPPB patients.
METHODS AND MATERIALS Six hundred forty-eight consecutively treated patients with clinically confined prostate cancer underwent TIPPB between June 1992 and February 1997. All patients had biopsy-proven adenocarcinoma with central pathology review performed on all specimens. Patients were staged with history and physical examination, according to American Joint Cancer Commission standards (10). Patients underwent both bone scan and abdominal–pelvic CT scans. All patients underwent transrectal ultrasound to assess prostate size and those with glands greater than 60 cc were treated with 3– 4 months of antiandrogen therapy (n ⫽ 93). Patients were stratified into risk groups based on PSA and Gleason score in accordance with Blasko and colleagues (7, 11). Patients who had a PSA ⬍ 10, Gleason score 2– 6 and were clinical stage T1 or T2a were considered low-risk and treated with TIPPB alone. The dose used for 125I implants was 160 Gy (pre-TG43) and 120 Gy for 103Pd (TheraSeed) (12). High-risk patients with PSA ⬎ 10, Gleason score 7–10, or clinical stage T2b generally underwent external beam irradiation and TIPPB. This consisted of external beam irradiation to doses of 41.4 or 45 Gy (1.8 Gy/fraction) on a linear accelerator with 4 MV or more, followed in 3–5 weeks by TIPPB. When external beam irradiation was used the dose used for 125I implant was 120 Gy (pre-TG43) and for 103Pd, 90 Gy. Preplanning for TIPPB was performed using the prostate dimensions as measured on transrectal ultrasound. The isotope activity nomogram developed by Anderson (13) was modified to account for underdosing and used to determine the total activity required for 103Pd or 125I (5, 14). Intraoperatively, patients underwent spinal anesthesia and were placed in an exaggerated lithotomy position. The implant
Volume 45, Number 2, 1999
was performed using a biplane ultrasound probe (B&K, Marlborough, MA) with needles placed using weighted peripheral loading with urethral sparing. Micro-aerosolized jelly was instilled into the urethra to enhance urethral imaging. The mean activity for 125I was 0.52 mCi (0.36 – 0.72 mCi) and for 103Pd was 1.48 mCi (1.11–1.62 mCi). Implants with 125I used a mean number of needles and seeds of 12 (8 –24) and 64 (22–106), respectively. For those implanted with 103Pd, the mean number of needles and seeds was 15 (8 –26) and 82 (22–106), respectively. Individual seeds were placed in the prostate with an interstitial gun applicator without fluoroscopy (Mick Nuclear, Bronx, NY). All patients were given intraoperative antibiotics. After seed implantation, the urologist performed cystoscopy and patients were discharged with a Foley catheter in place for 24 – 48 hours. Postimplant dosimetry originally consisted of stereo-shift films and two-dimensional reconstruction within 48 hours of the implant. As of 1995, patients underwent CT scans 2-3 weeks postimplant with calculations performed to assess the volume of the prostate receiving 100% of the prescribed dose (V100), the volume receiving 150% of the prescribed dose (V150), and the minimum dose received by 90% of the prostate (D90) (n ⫽ 251). Follow-up was at 5 weeks, then every 3 months for 2-3 years, and then every 6 months thereafter. At each follow-up visit a serum PSA level was drawn. The American Urologic Association urine scoring questionnaire was completed by the patient and assessment of morbidity using a modified Radiation Therapy Oncology Group (RTOG) toxicity score was obtained at each follow-up. The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus defined PSA failure as 3 consecutive rising PSA values defined PSA-RFS in this study (15). The time of failure was calculated as the midpoint between the PSA value nadir and the first rise. If there was a detectable rise in the serum PSA at follow-up, the PSA was repeated every 8 weeks. If a patient had 3 or more PSA value rises, an abdominal–pelvic CT scan and a bone scan were obtained. Generally, antiandrogen deprivation therapy was administered to patients who failed TIPPB, with several patients continuing on observation. To create the matched groups, the dataset was divided according to isotope used. For each Gleason grouping (2– 4, 5– 6, 7–9), patients were matched according to PSA (ⱕ 10 or ⬎ 10) and clinical stage. Two hundred forty-three patients were matched to compare outcome based on isotope use. Kaplan-Meier curves were constructed to demonstrate survival distributions. Log-rank test was used to compare PSA-RFS between patients for each isotope. Univariate and multivariate analysis was performed by Cox proportional square hazards model testing (16, 17). RESULTS The median follow-up for all 648 patients was 41 months (8 – 82). Twenty-eight patients are excluded from this study
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Table 1. Univariate analysis and multivariate analysis of factors affecting PSA RFS for 648 patients undergoing TIPPB Univariate analysis p value
Multivariate analysis p value
0.0001 0.0001 0.023 0.101 0.530 0.505
0.0001 0.0025 n.s.
Pretreatment PSA Gleason score Stage Isotope selection Addition of external beam Use of antiandrogen therapy
having less than 24 months follow-up. Six died of illnesses other than prostate cancer and 22 are lost to follow-up. Univariate analysis identified Gleason score, pretreatment PSA value, and stage as significant for PSA-RFS, and multivariate analysis identified Gleason score and PSA as significant for PSA-RFS (Table 1). Isotope selection for TIPPB was not found to be significant in this analysis. The significant factors on univariate analysis were then used for the selection of the randomly matched pairs of patients receiving either a 103Pd or 125I implant. The characteristics of each matched group are shown in Table 2. There was no statistically significant difference between the matched groups for Gleason score, PSA, stage, the addition of external beam irradiation, or the use of androgen deprivation therapy. The median follow-up of the matched group is 42 months (24 – 82). Of the 222 matched patients, 2 patients are lost to follow-up. Ten patients have died with 3 of the 10 dying with metastatic prostate cancer. All three had been treated with 103Pd. The overall survival for this group is 95% with a disease-specific survival of 99%. The actuarial PSA-RFS at 5 years was 86.5% for all 222 patients (Fig. 1). As shown in Fig. 2, the 5-year PSA-RFS for patients undergoing 103Pd was 87.1% and for those undergoing 125I was 86.9% (p ⫽
Fig. 1. Actuarial PSA-RFS for all 222 matched patients.
0.625). Subgroup analysis comparing PSA-RFS for Gleason score groupings and pretreatment PSA values did not show any significant difference in outcome (Table 3, Figs. 2–5). To examine the possibility of poor dose conformity confounding the observed results, an analysis of implant quality was performed on 251 patients having had CT-based postimplant dosimetry using the D90 (the minimum dose that covers 90% of the prostate volume). To quantify the D90 relative to the prescribed dose, which varies depending on the addition of external beam irradiation, we used the D90%, defined as the percent of the D90 dose relative to the prescribed implant dose. No significant difference was identified between 125I or 103Pd for the D90%, even when stratified by Gleason score (Table 4). DISCUSSION In this retrospective matched pair study comparing outcomes for patients who underwent TIPPB with either 103Pd
Table 2. Patient characteristics in the matched pair analysis (n ⫽ 222) 103
Gleason score 2–4 5–6 7–9 Stage T1c T2a T2b PSA ⱕ 10 ⬎ 10 Treatment variation Implant alone XRT and implant Androgen deprivation
125
Pd (n ⫽ 111)
I (n ⫽ 111)
8 91 12
9 90 12
61 26 24
49 38 24
70 41
71 42
92 19 12
96 15 14
p Value 0.991
0.091
0.998 0.523 0.846
Fig. 2. Actuarial PSA-RFS comparing patients matched for implant with 125I and those implanted with 103Pd.
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Table 3. Actuarial 5-year PSA-RFS for Gleason score and pretreatment PSA comparing 103Pd and 125I 103
125
p Value
88.6% 80.5%
87.3% 78.6%
0.408 0.817
100.0% 86.4% 75.0%
88% 85.5% 81.3%
0.832 0.991 0.184
Pd
Pretreatment PSA ⱕ 10 ⬎ 10 Gleason score 2–4 5–6 7–9
I
or 125I, there was no significant difference in PSA-RFS between isotopes used. Subset analysis of either high or low Gleason score also did not demonstrate any difference in PSA-RFS based on isotope use. This is the first clinical analysis comparing isotopes for localized prostate cancer treated with TIPPB. The lack of a significant difference in PSA-RFS fails to justify the use of Pd-103 as advantageous for higher Gleason score tumors or conversely, the use of 125 I for low Gleason score tumors. The rationale for distinguishing isotope on Gleason score is based on in vitro studies comparing isotope dose rate and cell doubling time for 125I, 103Pd, and 198Au (8). The radiobiologic data presented by Ling suggests an advantage for 103 Pd for tumors with a Tpot (potential cell doubling time assuming no cell loss) (18) of 10 days. However, Helpap et al. observed that prostate tumor cells actually had a much larger Tpot (19). For highly differentiated tumors, the calculated Tpot ranges between 25–75 days. For poorly differentiated adenocarcinoma the Tpot is calculated to be 18 –33 days. These data would seem to contradict the Ling data as supporting the use of Pd-103 implants for higher Gleason score tumors. In addition, for cells with a Tpot greater than 10, it is implied by the projection of the cell survival curves
Fig. 3. Actuarial PSA-RFS comparing with Gleason score 5– 6 tumors.
125
I and
103
Pd for patients
Fig. 4. Actuarial PSA-RFS comparing with Gleason score 7–9 tumors.
125
I and
103
Pd for patients
in the Ling data that 125I implants would be more effective than 103Pd, not less. While data is not available to report the individual Tpot for different Gleason scores, the lack of a difference in the clinical outcomes identified in this study including a wide range of Gleason scores, would suggest that there is no significant radiobiologic difference between isotopes. As the caseload of TIPPB has risen in the last several years, seed availability has been in short supply (20). Many radiation departments have elected to use only one isotope; others have attempted to match Gleason score to either 125I or 103Pd. The similarity of both isotopes in energy and physical construct allows for individualized selection on a case-by-case basis. The half-life difference, however, may be pertinent with regard to radiation safety issues and exposure in the home to young children, as we instruct patients to avoid physical contact with infants for 3 half-lives of
Fig. 5. Actuarial 4-year PSA-RFS comparing patients with pretreatment PSA ⬎ 10 ng/ml.
125
I and
103
Pd for
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Table 4. Implant analysis of the mean D90% for 251 patients
Isotope 103 Pd 125 I Gleason score 2–4 103 Pd 125 I Gleason score 5–6 103 Pd 125 I Gleason score 7–9 103 Pd 125 I
D90%
Range
96.6 101.7
65–136 52–153
91.5 112.0
60–124 91–122
97.7 99.4
56–154 65–124
97.6 108.8
52–153 84–136
p Value 0.122 0.251 0.150 0.096
* The D90% is defined as the percent of the prescribed dose covering 90% of the prostate volume. No significant difference was noted between 125I and 103103Pd implants. There was no difference between Gleason score and isotope when comparing D90%.
theisotope. In addition, the energy differences between 125I and 103Pd are significant for dose penetration and the num-
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ber of seeds required. Generally, for an equivalent sized prostate, more 103Pd seeds are required compared with 125I. Prestidge demonstrated better dosimetry when more seeds are used (9). Nonetheless, we were unable to distinguish any difference in the D90% for implants with 103Pd or 125I, despite the difference in median number of seeds between isotopes (Table 4). Since prostate cancer is a slowly progressive disease with long survival, longer follow-up will be required to confirm the outcomes reported by this study. The consistency afforded by the practice of the single practitioner (L.P.) was advantageous in limiting bias due to operator performance. As has been observed by Prestidge, there is considerable variability in the delineation of tumor volume and implant quality between practitioners (9). The lack of a difference in clinical effectiveness between isotopes in this matched pair analysis would best be confirmed by a randomized, prospective study. However, the clinical experience reported with either isotope corroborates the results in this matched pair analysis showing excellent 5-year PSA-RFS, regardless of the isotope used.
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