Prostate-specific Antigen Bounce After Intensity-modulated Radiotherapy for Prostate Cancer

Prostate Cancer Prostate-specific Antigen Bounce After Intensity-modulated Radiotherapy for Prostate Cancer Courtney Sheinbein, Bin S. Teh, Wei Y. Mai, Walter Grant, Arnold Paulino, and E. Brian Butler OBJECTIVES

METHODS

RESULTS

CONCLUSIONS

To report prostate-specific antigen (PSA) bounce in patients treated with intensity-modulated radiotherapy (IMRT) alone. Previous studies have reported PSA bounce in prostate cancer patients treated with conventional radiotherapy, 3D conformal radiotherapy, and permanent seed brachytherapy. From January 1997 to July 2002, 102 patients with clinically localized prostate cancer were treated with IMRT alone. No patients received androgen ablation. PSA bounce was defined as a PSA increase of at least 0.4 ng/mL, followed by any PSA decrease. Biochemical failure was defined by both the American Society for Therapeutic Radiology and Oncology 1996 and 2006 consensus definitions. The median follow-up was 76 months. The median length of time until the first PSA bounce was 13.6 months. Thirty-three patients (32.4%) had at least 1 PSA bounce, with 25 (24.5%) having 1 bounce; 6 (5.9%), 2 bounces; and 2 (2.0%), 4 bounces. PSA bounce was not significantly associated with biochemical no evidence of disease survival, clinical stage, pretreatment PSA, Gleason combined score, prostate planning target volume, PSA nadir, or mean dose to the prostate. The rate of PSA bounce in patients aged ⱕ 70 and ⬎ 70 years was 44.4% and 22.8%, respectively (P ⫽ .032). Our patient series is the first report on PSA bounce in patients treated with IMRT. Our study confirms that the majority of patients with a bouncing PSA remain biochemically and clinically free of disease with extended follow-up. UROLOGY 76: 728 –733, 2010. © 2010 Elsevier Inc.

O

ver the last decade, intensity-modulated radiotherapy (IMRT) has become an invaluable tool in delivering radiotherapy.1,2 IMRT is a technology in radiation therapy that delivers radiation more precisely to the target while relatively sparing the surrounding normal tissues from high doses of radiation. By delivering radiation with greater precision, IMRT has allowed the radiation oncologist to deliver a higher dose to the prostate, as well as minimize acute and chronic treatment-related morbidity. Dose escalation is desired as there is evidence to suggest dose response.3 At our institution, IMRT has been used in the treatment of prostate cancer since 1997. Previous studies have analyzed the association of prostate-specific antigen (PSA) bounce to biochemical disease control in patients treated with conventional external beam radiotherapy,

From the Department of Radiology/Radiation Oncology, Baylor College of Medicine, Houston, Texas; Department of Radiation Oncology, The Methodist Hospital, Houston, Texas; and The Methodist Hospital Research Institute, Houston, Texas Reprint Requests: Bin S. Teh, M.D., Department of Radiation Oncology, The Methodist Hospital, 6565 Fannin, DB1-077, Houston, TX 77030. E-mail: bteh@ tmhs.org Submitted: January 26, 2009, accepted (with revisions): April 29, 2009

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3-D conformal radiotherapy (3D-CRT), and permanent seed brachytherapy. To our knowledge, there are no published data regarding the phenomenon of PSA bounce in patients treated with IMRT alone, which is the main external beam radiation technique used today for the treatment of localized prostate cancers. We, therefore, retrospectively reviewed the hospital and radiotherapy records of patients treated at our institution, to study the occurrence and significance of PSA bounces in patients treated with IMRT alone.

MATERIAL AND METHODS Patient Characteristics From January 1997 to July 2002, 102 patients with clinically localized prostate cancer were treated with IMRT alone using the Peacock system (NOMOS Corporation, Sewickley, PA). The patient characteristics are described in Table 1. All patients had biopsy-proven adenocarcinoma, and all biopsies were reviewed at our institution. The patients were staged clinically with a digital rectal examination and all patients had a pretreatment PSA. Computer-assisted tomography scans of the pelvis and bone scans (conventional radiographs or magnetic resonance imaging [MRI] if indicated) were performed for pa0090-4295/10/$34.00 doi:10.1016/j.urology.2009.04.074

cles, bladder, and rectum. The treatment plan was verified using a phantom and film dosimetry.

Table 1. Patient characteristics Age (y) Mean Median ⱕ 70 ⬎ 70 Clinical T stage T1 T2 Gleason combined score 5 6 7 Pretreatment PSA 0-4 4-10 ⬎ 10 Prostate PTV (mL) ⱕ 100 ⬎ 100

71 72 45 57

44.1% 55.9%

57 45

55.9% 44.1%

6 68 28

5.9% 66.7% 27.5%

12 85 5

11.8% 83.3% 4.9%

53 49

52.0% 48.0%

PTV ⫽ planning target volume; PSA ⫽ prostate-specific antigen.

tients at high risk for metastatic disease. Metastatic work-up was negative in all patients. Patients’ ages ranged from 50 to 85 years, with a mean of 71. Clinical palpation stage ranged from T1 to T2 (55.9% with T1 and 44.1% with T2). The mean and median pretreatment PSA was 6.3 and 6.1, respectively, with a range of 0.8-16.0. Gleason combined scores (GCS) ranged from 5 to 7 (5.9% with GCS of 5, 66.7% with GCS of 6%, and 27.5% with GCS of 7). None of these patients received androgen blockade before, during, or after radiotherapy. None of the patients had any previous definitive treatment for their prostate cancer such as radical prostatectomy, cryotherapy, or brachytherapy. A review of potential toxicities of therapy was conducted, and informed consent was obtained before treatments.

Assessment of Disease Outcome Outcome was assessed with regard to PSA bounce, biochemical no evidence of disease survival (bNED), and overall survival. All patients were examined weekly during treatment for assessment and management of treatment-related toxicity. After completion of IMRT, the patients were examined and assessed in follow-up clinics at 6 weeks and every 6 months thereafter. Digital rectal examination and PSA were performed during follow-up visits. In the event of a PSA increase, patients received a repeat PSA examination at 3 months. With further increase, patients were treated for possible subclinical prostatitis with antibiotic and anti-inflammatory therapy. They then received additional PSA testing 3 months later. With a PSA decrease, patients were returned to the regular 6-month schedule. Tumor recurrence was assessed during follow-up with physical examination, laboratory studies (PSA), and radiographic studies (CT or MRI). PSA bounce was defined as a rate of PSA increase corresponding to a minimum 0.4 ng/mL increase, followed by any PSA decrease. PSA nadir was the lowest posttreatment PSA value. Biochemical failure was defined by both the American Society for Therapeutic Radiology and Oncology (ASTRO) 1996 consensus criteria of 3 consecutive increases in post-treatment PSA after reaching a nadir8 and the 2006 criteria of a 2 ng/mL increase in PSA above the nadir level.9 Statistical analysis (␹2 tests) was used to correlate PSA bounce with age, clinical palpation stage, pretreatment PSA, GCS, pretreatment prostate planning target volume, and PSA nadir. The occurrence of PSA bounce was compared with the mean dose to the prostate by analysis of variance. Kaplan Meier curves were generated to evaluate bNED survival and overall survival. Finally, multivariate analysis was used to evaluate the effect of PSA bounce, age, clinical palpation stage, pretreatment PSA, GCS, pretreatment prostate planning target volume, and PSA nadir on bNED survival.

Intensity-Modulated Radiotherapy Detailed descriptions of the Peacock IMRT system have been previously published.1,2 All patients received IMRT throughout the course of radiotherapy. IMRT as a boost is not part of the treatment strategy. The patients were immobilized using a VacLok bag (Med-TEC, Orange City, IA) and carrier box system. Patient setup and immobilization has previously been described in detail.4 During simulation, a cystourethrogram was performed. A rectal catheter was then inserted, followed by filling the inflatable balloon with 100 mL of air. The rectal catheter/ balloon was used daily to minimize prostate movement.4-7 A planning CT scan (3-mm cuts, 3-mm thick) was acquired with the patient in the prone treatment position. Prostate, seminal vesicles, and the critical normal structures (eg, bladder, rectum) were then outlined on each axial image on the treatment computer. A 5-mm margin was planned around the prostate gland and seminal vesicles in a 3D fashion, using the 5-mm expansion function of the system. Megavoltage linear accelerators and 15-MV photons were used. The average mean dose was approximately 76 Gy (range 73-79 Gy) over 35 fractions. The dose distributions were examined carefully on every axial image. Percent and volume of treatment targets below goal as well as percent and volume of normal structures above limit were evaluated. Dose-volume histogram analyses were performed for prostate, seminal vesiUROLOGY 76 (3), 2010

RESULTS Patient Outcome The mean and median follow-up for the 102 patients evaluated was 74 and 76 months, with a range of 32-110 months. Thirty-three patients (32.4%) had at least 1 PSA bounce, with 25 (24.5%) having 1 bounce; 6 (5.9%), 2 bounces, and 2 (2.0%), 4 bounces. The mean and median length of time until the first PSA bounce was 18.9 and 13.6 months. The time to first bounce was 3.5-87.4 months. The mean PSA nadir value was 0.21. The median time to the PSA nadir was 40.2 months (range 4.0-107.9 months). On multivariate analysis, only PSA nadir had a significant association with bNED survival. Values ⱕ 0.5 and ⬎ 0.5 were associated with a 5-year bNED survival rate of 97.7% and 75.0%, respectively (P ⫽ .000) (Fig. 1). Using the ASTRO 1996 definition, the 5-year bNED rate was found to be 96% and 95.7% in bouncers and nonbouncers, respectively (P ⫽ .912). With the ASTRO 2006 definition, the 5-year bNED rate was 94.0% in bouncers and 97.0% in nonbouncers (P ⫽ .190). The 729

in patients with a GCS of 5, 6, and 7 (P ⫽ .266). Among patients with a prostate planning target volume (PTV) ⱕ 100 mL, 28.3% experienced a bounce, compared with 36.7% of patients with a PTV ⬎ 100 mL (P ⫽ .402). A PSA bounce was experienced by 30.9% of patients with a PSA nadir of ⱕ 0.5. A bounce was experienced by 50% of patients with a PSA nadir ⬎ 0.5 (P ⫽ .269). Mean dose to the prostate was not significantly associated with the occurrence of PSA bounce or with the level of the PSA nadir.

DISCUSSION

Figure 1. Cox Regression analysis of biochemical no evidence of disease survival and prostate-specific antigen nadir level (P ⫽ .000). Table 2. PSA bounce and associated factors Patients With Patients Without Bounce Bounce Age (y) ⱕ 70 ⬎ 70 PSA nadir ⱕ 0.5 ⬎ 0.5 Clinical stage T1 T2 Pretreatment PSA 0-4 4-10 ⬎ 10 Gleason combined score 5 6 7 Prostate PTV (mL) ⬍ 100 ⬎ 100

P

20 (44.4%) 13 (22.8%)

25 (55.6%) 44 (77.2%)

.032

29 (30.9%) 4 (50.0%)

65 (69.1%) 4 (50.0%)

.269

21 (36.8%) 12 (26.7%)

36 (63.2%) 33 (73.3%)

.295

4 (33.3%) 27 (31.8%) 2 (40.0%)

8 (66.7%) 58 (68.2%) 3 (60.0%)

.927

3 (50.0%) 24 (35.3%) 6 (21.4%)

3 (50.0%) 44 (64.7%) 22 (78.6%)

.266

15 (28.3%) 18 (36.7%)

38 (71.7%) 31 (63.3%)

.402

PTV ⫽ planning target volume; PSA ⫽ prostate-specific antigen.

5-year overall survival rate in patients with a PSA bounce was 97.0%, and in nonbouncers it was 93.9%. This difference was not significant (P ⫽ .178). The rate of PSA bounce in patients aged ⱕ 70 years was 44.4% (20 patients) and the rate in patients aged ⬎ 70 years was 22.8% (13 patients) (P ⫽ .032). Table 2 describes the various factors evaluated with regard to PSA bounce. The rate of PSA bounce in patients with a clinical stage of T1 was 36.8% and the rate in patients with clinical T2 disease was 26.7% (P ⫽ .295). The rate of PSA bounce was 33.3% in patients with an initial PSA of 0-4, whereas it was 31.2% and 40% in those with a PSA of 4-10 and ⬎ 10, respectively (P ⫽ .927). The PSA bounce rate was 50.0%, 35.3%, and 21.4%, respectively, 730

The phenomenon of PSA bounce has been described in patients treated with conventional external beam radiotherapy (EBRT), 3D CRT, and permanent seed brachytherapy. To our knowledge, there is no published data in patients treated with IMRT. Multiple definitions of PSA bounce have been described (Table 3). PSA bounce has been defined as a minimum increase of 0.1-0.5 ng/mL.10-16 As would be expected, the bounce rate decreases as the definition is made more stringent. Several authors have analyzed their data pool using multiple definitions to establish the optimal method, but no consensus has been reached. Stock et al17 reported a bounce rate of 31% when a 0.1 ng/mL minimum increase is used and 17% when the definition is changed to a 0.4 ng/mL increase.18 In addition, previous authors have shown that PSA can vary as much as 20%-25% between readings due to inherent limitations of the PSA assay as well as individual physiological variation.19,20 Das et al21 defined PSA bounce as a 15% increase over previous values in an attempt to account for the inherent variability in the PSA assay. We defined PSA bounce as an increase of at least 0.4 ng/mL followed by any decrease to filter out PSA fluctuations that could be due to physiological variance in each patient as well as due to the limitations of the PSA assay. This is similar to that used in a recent multi-institutional pooled analysis by Horwitz et al.22 The occurrence of PSA bounce has been described to occur at a median of 13-35 months. When limited to trials using EBRT without brachytherapy, the median time to first bounce occurred with a range of 14-35 months. Trials evaluating implant patients with or without EBRT, the median times ranged from 13 to 20.5 months. When evaluating all previous published series, no definite trend seems to exist regarding the time to bounce and the modality of therapy. Pickles et al23 compared the time to bounce in patients given EBRT or brachytherapy. Patients treated with EBRT alone had a median time to bounce of 15 months, whereas the patients given brachytherapy alone bounced at a median of 13 months. The addition of hormonal therapy delayed the time to bounce in all patients. In our patients treated with IMRT alone, the median time to the first bounce was 13.6 months, which is comparable to previous data in patients given EBRT, both conventional and 3D-conforUROLOGY 76 (3), 2010

UROLOGY 76 (3), 2010

Table 3. Comparison of PSA bounce studies

Reference

Type of Therapy

Critz et al Cavanagh et al Critz et al Hanlon et al Das et al Merrick et al Rosser et al Sengoz et al Stock et al

125-I implant then EBRT 125-I or 103-Pd ⫾ EBRT 125-I implant then EBRT 3D-CRT alone 125-I ⫾ EBRT 125-I or 103-Pd ⫾ EBRT EBRT EBRT ⫾ ADT 125-I or 103-Pd alone

Critz et al Patel et al Morita et al Akyol et al

125-I implant then EBRT 125-I implant alone 125-I or 103-Pd ⫾ EBRT 3D-CRT ⫹ ADT

Ciezki et al Zietman et al Pickles et al

125-I implant alone EBRT ⫹ ADT EBRT alone EBRT ⫹ ADT Brachytherapy alone Brachytherapy ⫹ ADT EBRT alone IMRT alone

Horwitz et al Present series

PSA Bounce Definition Increase ⱖ 0.1 ng/mL followed by a decrease to prebounce Increase ⱖ 0.2 ng/mL followed by any decrease Increase ⱖ 0.1 ng/mL followed by a decrease to prebounce Increase ⱖ 0.4 ng/mL over 6 mo followed by any decrease Increase ⱖ 15% followed by a decrease to prebounce level Increase ⱖ 0.2 ng/mL followed by a durable decrease Increase ⱖ 0.5 ng/mL followed by a decrease to prebounce Increase ⱖ 0.4 ng/mL over 6 mo followed by any decrease Increase ⱖ 0.1 ng/mL followed by any decrease Increase ⱖ 0.4 ng/mL followed by any decrease Increase ⱖ 35% followed by any decrease Increase ⱖ 0.1 ng/mL followed by a decrease to prebounce Increase ⱖ 0.2 ng/mL followed by a decrease below nadir Increase ⱖ 0.1 ng/mL followed by a decrease to prebounce Increase ⱖ 0.1 ng/mL followed by a decrease to prebounce Increase ⱖ 0.2 ng/mL followed by any decrease Increase ⱖ 0.4 ng/mL over 6 mo followed by any decrease Increase ⱖ 0.5 ng/mL followed by a decrease to prebounce Increase ⱖ 0.2 ng/mL followed by a decrease below nadir Increase ⱖ 0.2 ng/mL followed by a decrease ⱖ 0.2 ng/ml Any increase followed by any decrease Any increase followed by any decrease Any increase followed by any decrease Any increase followed by any decrease Increase ⱖ 0.4 ng/mL over 6 mo followed by any decrease Increase ⱖ 0.4 ng/mL, followed by any decrease

level level

level

level level level level

Total Patients

Patients With PSA Bounce

Association of Bounce With bNED

Median Time to Start of Bounce (Mo)

779 595 539 306 186 218 964 72 373 373 373 1011 295 200 83 83 83 83 162 190 877 704 134 315 4839 102

273 (35%) 191 (36%) 185 (34%) 95 (31%) 115 (62%) 52 (23.9%) 119 (12%) 17 (24%) 97 (31%) 55 (17%) 62 (20%) 414 (41%) 82 (28%) 80 (40%) 33 (40%) 21 (25%) 11 (13%) 7 (8%) 75 (46%) 59 (31%) 582 (66.4%) 389 (55.3%) 96 (71.4%) 280 (88.9%) 978 (20%) 33 (32.4%)

NS NS N/A More likely to fail N/A N/A Less likely to fail NS NS NS NS NS Less likely to fail N/A NS NS NS NS Less likely to fail N/A N/A N/A N/A N/A More likely to fail NS

18 24.8* NS 35 26.4-31.2 16.3 9* 14 19.5 20.5 20.5 19-25* 19.4 13 NS NS NS NS 15.1 26.4-27.6 22 15 18 13 NS 13.6

PSA ⫽ prostate-specific antigen; EBRT ⫽ external beam radiation therapy; IMRT ⫽ intensity-modulated radiotherapy; ADT ⫽ androgen deprivation therapy; CRT ⫽ conformal radiotherapy. NS—not significantly associated. N/A—not applicable (ie, not specifically mentioned in source article). * Mean (median not given).

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mal. PSA bounce occurred as long as 87.4 months after the completion of radiotherapy. Because of the variety of definitions used as well as the broad range of times until the first PSA bounce, it is difficult to predict whether a PSA increase in the first several years after therapy is related to a PSA bounce or a biochemical failure based solely on the time of the event. Several series have evaluated the longevity of the PSA bounce. Critz et al described most bounces as lasting ⬍ 6 months, with one-third lasting longer than 12 months. Hanlon et al24 noted bounces lasting for 3-40 months (median 12 months). Both series correlate well to our data, with most bounces lasting ⬍ 12 months. This is of interest because it is unclear how many short-lived bounces occur in between the routine 6-month follow-up interval. Without more frequent evaluations, this question cannot be adequately answered. Despite this uncertainty, we recommend following the PSA every 6 months for the first 5 years, and then annually. Our justification for this recommendation is that PSA bounce was not associated with failure in our dataset, so an increased frequency of tests is unnecessary. In the event of a PSA bounce, more frequent PSA follow-up is justified to rule out the possibility of a biochemical failure. In our series, we elected to perform studies every 3 months until the bounce resolved. Most brachytherapy series report a higher bounce rate than do series describing EBRT patients. Some have theorized that this may be due to increased dose inhomogeneity of brachytherapy as compared to the conventional EBRT. This report of patients treated with IMRT finds a bounce rate of 32.4%, which is in line with other publications on 3D CRT. We did not find a higher rate of bounce when compared to conventional EBRT methods despite the increased dose inhomogeneity of IMRT. Of the reported previous series on PSA bounce, 4 have found a correlation between PSA bounce and improved bNED rates.25-28 One series by Hanlon et al24 described an association with decreased biochemical control and the occurrence of PSA bounce. In the previously mentioned multi-institutional analysis, 30% of the patients were treated with conformal techniques and many patients were treated to doses ⬍ 70 Gy. With a bounce rate of 20%, they found that the bNED rate using the ASTRO 1996 criteria was 58% in bouncers vs 72% in nonbouncers. This negative association of bounce with bNED is in contradiction with all published brachytherapy series, as well as the majority of other series of PSA bounce with conventional EBRT and 3D CRT. In our series we associated a PSA nadir ⬎ 0.5 with decreased bNED survival, though bounce rates were not associated with this variable. It is possible that with a larger sample size of IMRT patients, similar to the pooled analysis, that elevated PSA nadir and PSA bounce would become statistically associated. Zeitman et al,29 in their study, evaluated bounce patients for false-positive biochemical failures based on several definitions of biochemical failure. The 732

ASTRO 1996 consensus definition, the ASTRO 2006 consensus definition (nadir ⫹ 2), and the nadir ⫹ 3 definitions were evaluated. The ASTRO 1996 and 2006 definitions scored a similar number of bounce patients as false positives; nadir ⫹ 3 scored the fewest. All of our patients were treated with an average mean dose to the prostate of 76 Gy. In our series, biochemical failure and overall survival— using the ASTRO 1996 and 2006 definitions—were not associated with the occurrence of a PSA bounce. Interestingly, no bounce patients were falsely scored as failures using the 1996 criteria, but there were 2 false positives using the 2006 definition. Although many factors have been evaluated for a consistent association with the phenomenon, no consistent prognostic indicators have been found. The evaluated factors include age of the patient, clinical stage, pretreatment PSA, GCS, prostate PTV, PSA nadir, the use of androgen ablation, isotope of brachytherapy implant, and mean dose to the prostate. Horwitz et al, in their pooled dataset, found that age ⱕ 70 and pretreatment PSA could predict for the occurrence of bounce. As previously mentioned, Stock17,18 et al analyzed their data using multiple definitions to determine the optimal description of PSA bounce. Using each rendering of the data, different factors were found to correlate with PSA. Although age, prostate PTV, and pretreatment PSA were significant using several of the definitions, no one factor was consistently correlative with the occurrence of a bounce. In our series, age ⬍ 70 is associated with the occurrence of a bounce, but interpretation of this fact is difficult given that this occurs in only a portion of the available published data. Increased likelihood for sexual function in younger men has been implicated as a possible source of the age disparity. Das et al21 noted a median increase in PSA of 1.4 ng/mL with ejaculation. This would satisfy the constraints of most bounce definitions as a PSA bounce event and could therefore be a possible explanation of the increased incidence in younger men. In our group of 102 patients, rates of bNED and overall survival were acceptable and comparable to previously published data. Our patient series is the first report on PSA bounce in patients treated with IMRT. Others have reported their experience with the conventional EBRT, 3D CRT, and permanent seed brachytherapy. The occurrence of a PSA bounce was seen during routine follow-up and was not a predictor of disease failure. PSA bounce was significantly associated with patient age. A PSA nadir ⱕ 0.5 was associated with improved bNED survival. Although routine follow-up consists of PSA studies every 6 months during the first 5 years after therapy, we recommend more frequent follow-up and PSA testing in all patients with increasing or bouncing PSA. Our study reaffirms that the majority of patients with a PSA bounce do, in fact, remain biochemically and clinically free of disease with extended follow-up. With the ASTRO 1996 and 2006 definitions of PSA failure, there is no association between PSA bounce and biochemical failure. HowUROLOGY 76 (3), 2010

ever, stricter definitions of PSA failure were not analyzed in the present study. Future areas of interest could include a larger cohort of patients treated with IMRT, longer follow-up, addition of patients treated with hormonal therapy, and analysis of bounce with additional definitions of PSA failure. References 1. Teh BS, Woo SY, Butler EB. Intensity modulated radiation therapy (IMRT): a new promising technology in radiation oncology. Oncologist. 1999;4:433-442. 2. Teh BS, Mai WY, Grant WH III, et al. Intensity modulated radiotherapy (IMRT) decreases treatment-related morbidity and potentially enhances tumor control. Cancer Invest. 2002;20:437451. 3. 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. 4. McGary JE, Teh BS, Butler EB, et al. Prostate immobilization using a rectal balloon. J Appl Clin Med Phys. 2002;3:6-11. 5. Teh BS, Mai WY, Uhl BM, et al. Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose-volume analysis. Int J Radiat Oncol Biol Phys. 2001;49:705-712. 6. Teh BS, Woo SY, Mai WY, et al. Clinical experience with intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of rectal balloon for prostate immobilization. Med Dosim. 2002;27:105-113. 7. Teh BS, Dong L, McGary JE, et al. Rectal wall sparing by dosimetric effect of rectal balloon used during intensity-modulated radiation therapy (IMRT) for prostate cancer. Med Dosim. 2005; 30:25-30. 8. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys. 1997;37:1035-1041. 9. Roach M III, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65:965-974. 10. Critz FA, Williams WH, Benton JB, et al. Prostate specific antigen bounce after radioactive seed implantation followed by external beam radiation for prostate cancer. J Urol. 2000;163:1085-1089. 11. Critz FA. Time to achieve a prostate specific antigen nadir of 0.2 ng/ml after simultaneous irradiation for prostate cancer. J Urol. 2002;168:2434-2438. 12. Critz FA, Williams WH, Levinson AK, et al. Prostate specific antigen bounce after simultaneous irradiation for prostate cancer: the relationship to patient age. J Urol. 2003;170:1864-1867. 13. Cavanagh W, Blasko JC, Grimm PD, et al. Transient elevation of serum prostate-specific antigen following (125)I/(103)Pd brachytherapy for localized prostate cancer. Semin Urol Oncol. 2000;18: 160-165. 14. Merrick GS, Butler WM, Wallner KE, et al. Prostate-specific antigen spikes after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2002;54:450-456.

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15. Sengoz M, Abacioglu U, Cetin I, et al. PSA bouncing after external beam radiation for prostate cancer with or without hormonal treatment. Eur Urol. 2003;43:473-477. 16. Morita M, Lederer JL, Fukagai T, et al. [PSA bounce phenomenon after transperineal interstitial permanent prostate brachytherapy for localized prostate cancer]. Nippon Hinyokika Gakkai Zasshi. 2004;95:609-615. 17. Stock RG, Stone NN, Cesaretti JA. Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: descriptions and implications. Int J Radiat Oncol Biol Phys. 2003;56:448-453. 18. Akyol F, Ozyigit G, Selek U, et al. PSA bouncing after short term androgen deprivation and 3D-conformal radiotherapy for localized prostate adenocarcinoma and the relationship with the kinetics of testosterone. Eur Urol. 2005;48:40-45. 19. Prestigiacomo AF, Stamey TA. Physiological variation of serum prostate specific antigen in the 4.0 –to 10.0 ng/ml range in male volunteers. J Urol. 1996;155:1977-1980. 20. Komatsu K, Wehner N, Prestigiacomo AF, et al. Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology. 1996;47:343-346. 21. Das P, Chen MH, Valentine K, et al. Using the magnitude of PSA bounce after MRI-guided prostate brachytherapy to distinguish recurrence, benign precipitating factors, and idiopathic bounce. Int J Radiat Oncol Biol Phys. 2002;54:698-702. 22. Horwitz EM, Levy LB, Thames HD, et al. Biochemical and clinical significance of the posttreatment prostate-specific antigen bounce for prostate cancer patients treated with external beam radiation therapy alone: a multiinstitutional pooled analysis. Cancer. 2006; 107:1496-1502. 23. Pickles T. Prostate-specific antigen (PSA) bounce and other fluctuations: which biochemical relapse definition is least prone to PSA false calls? An analysis of 2030 men treated for prostate cancer with external beam or brachytherapy with or without adjuvant androgen deprivation therapy. Int J Radiat Oncol Biol Phys. 2006; 64:1355-1359. 24. Hanlon AL, Pinover WH, Horwitz EM, et al. Patterns and fate of PSA bouncing following 3D-CRT. Int J Radiat Oncol Biol Phys. 2001;50:845-849. 25. Ciezki JP, Reddy CA, Garcia J, et al. PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time. Int J Radiat Oncol Biol Phys. 2006;64:512-517. 26. Patel C, Elshaikh MA, Angermeier K, et al. PSA bounce predicts early success in patients with permanent iodine-125 prostate implant. Urology. 2004;63:110-113. 27. Rosser CJ, Kuban DA, Levy LB, et al. Prostate specific antigen bounce phenomenon after external beam radiation for clinically localized prostate cancer. J Urol. 2002;168:2001-2005. 28. Rosser CJ, Kamat AM, Wang X, et al. Is patient age a factor in the occurrence of prostate-specific antigen bounce phenomenon after external beam radiotherapy for prostate cancer? Urology. 2005;66: 327-331. 29. Zietman AL, Christodouleas JP, Shipley WU. PSA bounces after neoadjuvant androgen deprivation and external beam radiation: impact on definitions of failure. Int J Radiat Oncol Biol Phys. 2005;62:714-718.

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