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Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation
Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 5, pp. 1291–1298, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2004.08.034
CLINICAL INVESTIGATION
Prostate
BIOCHEMICAL FAILURE AND THE TEMPORAL KINETICS OF PROSTATESPECIFIC ANTIGEN AFTER RADIATION THERAPY WITH ANDROGEN DEPRIVATION MARK K. BUYYOUNOUSKI, M.D., M.S.,* ALEXANDRA L. HANLON, PH.D.,† ERIC M. HORWITZ, M.D.,* ROBERT G. UZZO, M.D.,‡ AND ALAN POLLACK, M.D., PH.D.* Departments of *Radiation Oncology, †Biostatistics, and ‡Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA Purpose: The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. Methods and Materials: Between December 1, 1991 and April 30, 1998, 688 men with T1c–T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n ⴝ 586) or in combination with either short-term (STAD: 3 to 12 months, n ⴝ 82) or long-term (LTAD: 12 to 36 months, n ⴝ 20) AD. Follow-up, calculated from the end of all treatment, was >48 months. The mean posttreatment PSA was calculated in 3-month intervals. Results: The median posttreatment clinical follow-up period was 76 months (range, 48 –152 months). The posttreatment PSA values from the end of all treatment for the RTⴙSTAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RTⴙSTAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RTⴙSTAD-NBF profile, the RTⴙLTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RTⴙLTAD-BF profile rose continuously but at a slower rate over time. Nine RTⴙSTAD-NBF patients (22%) and 2 RTⴙLTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RTⴙLTAD-BF profile rose constantly and steadily with a doubling time of approximately 16 months, and the RTⴙLAD-NF initially rose to a value of approximately 0.5 ng/mL, then at 36 months began to decline. Conclusions: The temporal kinetics of posttreatment PSA after RTⴙAD and RT alone are different. The American Society of Therapeutic Radiation Oncology definition for biochemical failure overestimates BF in 20 –30% after RTⴙAD compared to 5% after RT alone. © 2005 Elsevier Inc. Prostatic neoplasm, Prostate-specific antigen, Radiotherapy, Treatment failure.
INTRODUCTION
testosterone to castrate levels 3 to 4 weeks after a transient increase. Antiandrogens, either nonsteroidal or steroidal, are commonly used to counteract the initial surge in testosterone from LHRH agonists. Serum prostate-specific antigen (PSA), a glycoprotein serine protease specific to prostatic tissue, responds rapidly and markedly to AD (5). The extent of the drop in PSA does not accurately reflect tumor response. For example, an undetectable PSA does not equate with a complete tumor response, although an undetectable PSA within 9 months is associated with a better prognosis
Several randomized trials (1– 4) have shown a benefit for the combined use of androgen deprivation (AD) and external beam radiation therapy (RT) for the treatment of prostate cancer. As a result, AD and RT are commonly combined for the treatment of intermediate- to high-risk prostate cancer. In this setting, AD is usually achieved by the use of luteinizing hormone releasing hormone (LHRH) agonists acting via suppression of the hypothalamic-pituitary-testicular axis. LHRH agonists reduce luteinizing hormone and
2003, Salt Lake City, UT. Acknowledgment—The authors thank Debra Eisenberg for her assistance with the development of the figures presented herein. Received Jan 20, 2004, and in revised form Aug 13, 2004. Accepted for publication Aug 16, 2004.
Reprint requests to: Alan Pollack, M.D., Ph.D., Fox Chase Cancer Center, Department of Radiation Oncology, 333 Cottman Ave., Philadelphia, PA 19111. Tel: (215) 728-2940; Fax: (215) 214-1629; E-mail: [email protected] Presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 19 –23, 1291
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(6). Upon completion of treatment and withdrawal of AD, androgen levels return, and the PSA rises modestly, usually by 1 to 2 ng/mL. The time course of the post–RT⫹AD PSA kinetics has not been previously described in detail. Biochemical failure (BF), or disease progression evidenced only by an elevated or rising posttreatment PSA, is an early measure of treatment efficacy for prostate cancer (7). What constitutes a BF, however, has been debated greatly since the routine use of PSA (8 –12). In 1997, the American Society of Therapeutic Radiation Oncology (ASTRO) introduced a consensus definition of BF after RT. The definition of 3 consecutive rises in posttreatment PSA was felt to be predictive of a continued rise in PSA and eventual clinical failure (13). Since, the ASTRO consensus definition has been shown to be a robust measure that correlates well with various clinical end points after RT alone (7, 14 –17). The accuracy of the ASTRO definition in patients who have received AD, however, has been questioned (15, 18). The primary objective of this report was to present a descriptive analysis of the PSA kinetics after RT alone, RT⫹STAD (short-term androgen deprivation), and RT⫹LTAD (long-term androgen deprivation) over multiple posttreatment PSA values obtained during an extended follow-up period. The hypothesis was that a graphical representation of the PSA kinetics would do the following: (1) illustrate the differences between the kinetics after RT alone, RT⫹STAD, and RT⫹LTAD; and (2) illustrate the potential for transient rises in PSA after the withdrawal of AD, which may lead to a higher misclassification rate of BF using the ASTRO consensus definition compared to RT alone. The secondary objectives of the report were to determine and compare the accuracy of the ASTRO consensus definition of BF to predict for a steadily rising PSA for RT alone, RT⫹STAD, and RT⫹LTAD.
METHODS AND MATERIALS Between December 1, 1991 and April 30, 1998, 1,051 clinically localized prostate cancer patients were treated definitively with either three-dimensional conformal radiation therapy alone (n ⫽ 808) or with androgen deprivation (n ⫽ 203) in the Department of Radiation Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania. Of those, 586 patients receiving RT and 102 patients receiving RT⫹AD were selected for this analysis based on a minimum clinical follow-up of 48 months’ duration calculated from the completion of all treatment and at least 5 serial “AD-free” posttreatment PSA levels. Androgen deprivation was defined as either short term (STAD, 3 to 12 months) or long term (LTAD, 12 to 36 months). The 2002 American Joint Committee on Cancer system palpation criteria were used to stage all patients (19). No radiographic or pathologic upstaging was allowed. No patient had evidence of metastasis before definitive treatment. All patients had a pretreatment serum PSA level available. Our treatment policy at Fox Chase Cancer Center has been to reserve the use of LTAD for patients with a pretreatment PSA ⬎20, Gleason score ⬎7, or clinical stage T3– 4 disease; the ultimate duration of LTAD varied based on patient tolerance. Fourteen men receiving RT⫹AD (14%) were treated on Radiation
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Therapy Oncology Group 92-02 (20), for which patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT, then were randomly assigned to receive no additional therapy or 24 months of goserelin. Physician-patient preference and prostate size determined the use of STAD. In some cases, STAD was initiated before RT by the referring physician. All men treated with AD received an LHRH agonist, either leuprolide acetate (69%) or goserelin acetate (31%), initiated either before or during external beam radiation. Two-thirds of men received an LHRH agonist in combination with an antiandrogen: flutamide (64 of 68), bicalutamide (3 of 68), or nilandron (1 of 68). Eighty-two patients received RT⫹STAD, and 20 received RT⫹LTAD. The median AD duration for the RT⫹STAD and RT⫹LTAD groups was 3.2 months (range, 2.5–12.0 months) and 19.4 months (range, 12.0 –29.8 months), respectively. Our three-dimensional conformal technique has previously been reported (21). Briefly, patients were treated in the supine position in a custom-made cast for immobilization. In general, T1/T2a– b prostate cancer patients with Gleason score 2– 6 received treatment to the prostate only. Patients with more advanced prostate cancer, T2c/T3 or Gleason score 7–10, received 46 –50 Gy to the prostate and surrounding periprostatic tissues (small pelvis field), followed by a boost to the prostate and seminal vesicles. Radiation dose is reported here as the International Commission on Radiation Units and Measurement (ICRU) reference dose (22). Dose was typically prescribed at the 95% isodose of the beam arrangements and normalized so that the PTV was included within the 95% isodose line. All patients were treated with 10 –18-MV photons. The median total radiation dose for RT, RT⫹STAD, and RT⫹LTAD groups was 73.7 Gy (range, 61.1– 80.0 Gy), 74.7 Gy (range, 62.1– 80.0 Gy), and 74.3 Gy (range, 70.5–75.8 Gy). Biochemical failure was first defined by the ASTRO consensus definition (3 consecutive rises in PSA) (13). No patient in the RT⫹AD group received salvage therapy before 3 consecutive rises. Sixteen patients received salvage therapy before 3 consecutive rises after RT alone and were included in the BF group. A second analysis was performed using the ASTRO definition with the following modification: In the event of a subsequent decline in PSA (without hormone therapy), 2 further consecutive rises in PSA ⬎0.1 ng/dL were required to constitute a failure. In the event that the PSA level immediately after 3 consecutive rises was unchanged but then declined, 2 further consecutive rises were also required. If salvage therapy (i.e., hormone therapy) was initiated before the above criteria for failure were met, a patient was considered a BF. Biochemical control was defined as the absence of BF. Follow-up history and physical examinations were performed every 6 months for the first 5 years, then annually. In general, posttreatment PSA levels were obtained at 3 months post-RT, then every 6 months for 5 years, and then every 6 to 12 months thereafter. Clinical follow-up was defined as the interval from the completion of all treatment to the date of last known patient contact. The mean PSA level was graphically represented as a function of months from the end of all treatment (in 3-month intervals) for both RT⫹STAD and RT⫹LTAD groups subdivided by failure status, BF vs. non-BF (NBF). PSA levels after initiation of salvage therapy were censored. The LOWESS (locally weighted scatter plot smoother) routine was used to calculate a smoothed line relating posttreatment PSA to time (23).
Temporal kinetics of PSA
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Table 1. Clinical, pathologic, and treatment-related patient characteristics by treatment group Treatment group RT alone (n ⫽ 586)
Characteristic Age (yrs) Median (range) T category T1/T2 T3 Gleason sum ⬍7 ⱖ7 Pretreatment PSA (ng/mL) Median ⬍10 10 to 20 ⱖ20 Dose (Gy) Median ⱕ68.4 ⬎68.4
RT⫹STAD (n ⫽ 82)
RT⫹LTAD (n ⫽ 20)
66 (50–82)
68 (60–76)
549 (94%) 37 (6%)
48 (66%) 25 (34%)
15 (79%) 4 (21%)
466 (80%) 120 (20%)
41 (50%) 41 (50%)
10 (50%) 10 (50%)
68 (45–89)
8.8 (0.4–191.0) 342 (59%) 166 (28%) 78 (13%)
17.2 (1.2–170.3) 21 (26%) 26 (32%) 36 (43%)
18.9 (6.0–94.9) 4 (20%) 6 (30%) 10 (50%)
73.7 (61.1–80.0) 20 (3%) 566 (97%)
74.7 (62.1–80.0) 3 (4%) 79 (96%)
74.3 (70.5–75.8) 0 (0%) 20 (100%)
Abbreviations: PSA ⫽ prostate-specific antigen; STAD ⫽ short-term androgen deprivation; LTAD ⫽ long-term androgen deprivation; RT ⫽ radiation therapy.
RESULTS Patient and follow-up characteristics Various clinical, pathologic, and treatment-related characteristics for the study population are summarized by treatment group in Table 1. The median follow-up duration for RT, RT⫹STAD, and RT⫹LTAD groups was 75 months (range, 48 –152 months), 78 months (range, 48 –125 months), and 63 months (range, 48 –91 months), respectively. A total of 7737 posttreatment PSA values from 688 patients (median, 10.5 posttreatment PSA values per patient) were collected at a median interval of 6.2 months (range, ⬍1–95 months). Ninety-two percent of patients had ⱖ7 posttreatment PSA levels, 62% of patients had ⱖ10, and 18% had ⱖ15. Thirty-nine percent (16 of 41) of RT⫹STAD patients and 43% (3 of 7) of RT⫹LTAD patients received salvage therapy after 3 consecutive rises at a median time of 70 and 63 months, respectively, from the completion of all treatment. Patients with 3 consecutive rises had at least 1 PSA before salvage therapy, except 5 men in the RT⫹AD group and 25 men in the RT-alone group. Five men (10%) in the RT⫹AD group and 25 men (14%) in the RT-alone group had salvage therapy initiated either immediately upon 3 consecutive rises or at last follow-up. All of the 5 men in whom salvage therapy was initiated immediately upon BF (after 3 rises) had a PSA doubling time of ⱕ8 months, thus making the likelihood of misclassification unlikely. Ten (40%) of the 25 men in the RT-alone group received salvage therapy immediately upon BF; 6 of these men later developed distant metastasis. ASTRO consensus definition of BF after RT⫹AD Figure 1 shows mean PSA values over time from the end of RT⫹STAD for BF and NBF groups according to the
ASTRO definition. Nonbiochemical failures of STAD had a relatively constant mean PSA over time at a value of approximately 0.5 ng/mL. For the STAD-BF group, initially there was a period of slow rise in which the PSA level accelerated after 12 months, followed by a period of decline. This decline may be explained by 4 factors: (1) the initiation of salvage therapy, (2) declines in PSA level before 3 consecutive rises (i.e., “bouncing”), (3) declines in PSA after 3 consecutive rises with future rises in PSA level, and (4) declines and stabilization in PSA level after 3 consecutive rises. Figure 2 shows mean PSA values over time from the end of RT⫹LTAD for BF and NBF groups, also according to the ASTRO definition. The mean posttreatment PSA profile for the LTAD-NBF group rises continuously to a level approaching 1 ng/mL. The LTAD-BF profile rises initially at a slow rate until approximately 12 months, when the rate of rise accelerates. Then, there appears to be a deceleration. BF analysis with extended clinical follow-up Eleven (23%) RT⫹AD patients who were identified as having achieved 3 consecutive rises in posttreatment PSA level, constituting BF by the ASTRO definition, did not experience clinical failure later and had subsequent stabilization of their posttreatment PSA values. Table 2 shows the posttreatment PSA profiles of these 11 patients. None of these 11 patients had 2 additional consecutive rises after the 3 consecutive rises and decline. All PSA values after 3 consecutive rises and decline were ⱕ2 ng/mL. No patient experienced 3 further consecutive rises after the initial 3 consecutive rises. Inter–PSA level variability was usually 0.1– 0.2 ng/mL but was as high as 0.6 ng/mL. The degree of precision when determining the posttreatment PSA level was also important for the classifica-
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Fig. 1. Mean posttreatment PSA values at 3-month intervals after RT⫹STAD grouped according to the ASTRO consensus definition of biochemical failure. PSA levels after initiation of salvage therapy were censored. PSA ⫽ prostate-specific antigen; STAD ⫽ short-term androgen deprivation (3–12 months.); EOT ⫽ end of all treatment; NBF ⫽ nonbiochemical failure; BF ⫽ biochemical failure; CI ⫽ confidence interval; RT⫽ radiotherapy.
tion of biochemical failure. PSA level determinations with precision ⱕ0.1 ng/mL resulted in the misclassification of biochemical failure in 1 patient. A modification to the ASTRO definition of BF was adopted based on these results. In the event of a decline in PSA level after 3 consecutive rises in posttreatment PSA level (reported with an accuracy of ⬎0.1 ng/mL), 2 additional consecutive rises were required to constitute BF.
Modified ASTRO consensus definition of BF Nine (22%) STAD-BF patients and 2 (29%) LTAD-BF patients were reclassified as NBFs, because 3 consecutive rises were followed by a subsequent decline and stabilization of PSA as deemed by the absence of 2 further consecutive rises. There was no significant difference between the misclassification rate between RT⫹STAD and RT⫹LTAD (p ⫽ 0.6, Fisher’s exact). Figure 3 shows the mean PSA
Fig. 2. Mean posttreatment PSA values at 3-month intervals after RT⫹LTAD grouped according to the ASTRO consensus definition of biochemical failure. PSA levels after initiation of salvage therapy were censored. PSA ⫽ prostate-specific antigen; LTAD ⫽ long-term androgen deprivation (12–36 months.); EOT ⫽ end of all treatment; NBF ⫽ nonbiochemical failure; BF ⫽ biochemical failure; CI ⫽ confidence interval; RT ⫽ radiotherapy.
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Table 2. Posttreatment PSA profiles of patients with a subsequent decline and stabilization of posttreatment PSA level after three consecutive rises (underlined) Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Treatment group RT⫹LTAD RT⫹LTAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT alone RT alone RT alone RT alone RT alone RT alone RT alone RT alone RT alone RT alone
Posttreatment PSA values (ng/mL) 0.10, 0.10, 0.20, 0.10, 0.21, 0.23, 0.25 0.45, 0.40, 0.74, 0.53, 0.62, 0.70, 0.87, 0.58, 0.60 0.2, 0.1, 0.1, 0.1, 0.1, 0.2, 0.3, 0.4, 0.3, 0.2, 0.2, 0.1, 0.2, 0.1, 0.4, 0.6, 0.9, 0.7, 1.3, 0.9, 0.7 0.5, 1.5, 1.8, 1.9, 1.5, 2.0, 1.2, 1.1, 1.1, 1.7, 1.2, 1.4 1.0, 1.0, 0.8, 1.1, 1.3, 1.5, 1.5, 1.5, 1.2, 1.1, 1.1 0.4, 0.7, 0.8, 0.9, 0.8, 0.3, 1.6, 1.2, 0.9, 0.7, 0.8, 0.8 0.5, 0.7, 1.0, 1.5, 1.6, 1.4, 1.4, 0.9, 0.9, 0.9, 0.6 1.6, 1.5, 1.7, 1.5, 1.3, 0.5, 0.7, 1.3, 1.8, 1.1, 0.8, 1.0, 0.4, 0.7, 1.0, 1.2, 0.6, 0.6, 0.7, 0.7, 1.2, 0.7, 0.7, 0.7 0.3, 0.3, 0.4, 0.5, 0.6, 0.6, 0.7, 0.6, 0.8, 0.7, 0.6, 0.2, 1.4, 0.9, 0.7, 0.8, 0.9, 1.5, 0.9, 1.1 3.9, 1.7, 0.9, 0.7, 0.5, 0.6, 1.1, 1.3, 1.0, 1.0, 1.2, 1.0 2.7, 1.4, 1.1, 1.3, 1.5, 2.1, 1.3, 0.8, 0.8, 0.7, 0.9 1.0, 1.1, 2.7, 4.1, 1.7, 0.9, 1.0, 1.0, 1.1, 0.6, 1.0, 0.5 1.4, 1.1, 0.6, 0.8, 1.2, 1.5, 1.4, 1.5, 1.2 3.3, 1.2, 2.7, 0.9, 1.1, 0.6, 1.3, 1.1, 0.8, 1.4, 1.5, 2.3, 4.5, 4.4, 1.9, 0.9, 1.1, 0.9, 0.7, 0.9, 1.3, 2.2, 0.6, 1.6 1.4, 1.1, 0.4, 0.3, 0.1, 0.2, 0.3, 0.4, 0.2, 0.3, 0.3, 0.4, 9.1, 4.0, 3.0, 1.4, 1.2, 0.9, 0.9, 0.8, 0.9, 1.1, 1.2, 1.1 3.7, 1.3, 1.1, 0.9, 0.7, 0.7, 0.9, 1.1, 1.5, 1.1, 1.2
0.1
1.0, 1.0 0.6, 0.5, 0.6
1.7, 2.2, 1.6, 1.4 0.3, 0.2, 0.3, 0.2, 0.3
Abbreviations: PSA ⫽ prostate-specific antigen; RT ⫽ radiation therapy; STAD ⫽ short-term androgen deprivation; LTAD ⫽ long-term androgen deprivation.
values over time using this modified definition of failure for the STAD group and Fig. 4 for the LTAD group. After STAD, Fig. 3 suggests two waves of failure, early and late. Nonbiochemical failures after either STAD have a comparatively constant mean PSA over time valued at approximately 0.5 ng/mL. Biochemical failures after LTAD had a steady rise in the mean posttreatment PSA with a doubling time of approximately 16 months. Nonbiochemical failures after RT⫹LTAD demonstrate an initial rise in PSA level to approximately 0.5 ng/mL followed by a decline at approximately 36 months.
ASTRO consensus definition of BF after RT alone Figure 5A shows the mean posttreatment PSA values after RT alone by the ASTRO consensus definition of BF. The RT-alone–NBF profile declined asymptotically over time to a value ⬍1 ng/mL. For the RT-alone–BF group, there was an initial period of steady decline and a nadir at approximately 18 months. This was followed by a period of rise during which there was a small decline in the mean posttreatment PSA values, which may represent a combination of four factors previously described (See “ASTRO consensus definition of BF after RT⫹AD” [above]). Ten of 196 (5%) patients in this group experienced 3 consecutive rises in PSA followed by a subsequent decline and stabilization in PSA, defined as the absence of two further consecutive rises, compared to 11 of 48 (23%) after RT⫹AD (p ⫽ 0.0003, chi-square). Figure 5B shows the mean posttreatment PSA values for the patients grouped by the modified ASTRO definition. The reclassification of these 10 patients
to the RT-alone–NBF group did not result in appreciable change.
DISCUSSION In the current analysis, we closely examined the posttreatment serum PSA profiles of men treated with RT⫾AD (STAD or LTAD) who had extended follow-up. Patients were required to have a minimum of 5 posttreatment PSA values and at least 48 months of follow-up. The aim was to determine the accuracy of the ASTRO consensus definition in classifying BF through a better understanding of the change in PSA that occurs over time. A large number of PSA values were analyzed, providing an accurate representation of the posttreatment PSA profile. Overall, the ASTRO definition of BF overestimated a steadily rising PSA level over extended follow-up in 5% of patients after RT alone compared to 23% after RT⫹AD (p ⬍ 0.05), 22% after RT⫹STAD, and 29% after RT⫹LTAD (p ⫽ nonsignificant). Concerning the changes in PSA after AD withdrawal, the PSA profiles after RT⫹STAD or RT⫹LTAD for those with ASTRO-defined BF illustrated that at about 30 months after treatment, there is an alteration in the kinetics. PSA levels transiently declined in the STAD⫹RT group, and the rate of rise slowed in the LTAD⫹RT group. One possible factor for these kinetic changes is the misclassification of BF using the ASTRO definition. After withdrawal of AD, approximately one-fourth of men fulfilling ASTRO criteria for BF experienced a subsequent decline and/or stabilization in
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Fig. 3. Mean posttreatment PSA values at 3-month intervals after RT⫹STAD grouped according to the ASTRO definition of biochemical failure corrected for patients with a subsequent decline and stabilization in PSA (modified ASTRO definition). PSA levels after initiation of salvage therapy were censored. Abbreviations as in Fig. 1.
PSA. The modification to the ASTRO definition described herein addressed this misclassification by requiring 2 additional consecutive rises in PSA level in the event of a subsequent nonrising PSA level. This definition better predicted for succeeding rises in PSA that were sustained (true BF). However, this definition does have shortcomings. For example, stabilization in PSA could be delayed, occurring after 4 or more consecutive rises. Additional follow-up may
show that stabilization is also possible despite requiring an additional 2 consecutive rises. Alternatively, some have suggested using cumulative rises rather than consecutive rises as evidence of BF (24). Others have suggested requiring a final PSA in a series of 3 consecutive rises to be ⬎1.5 ng/mL (25), a PSA level ⬎2 ng/mL above the nadir (26), or a rule based on the PSA slope (25, 27) to declare BF. Exponential modeling of posttreatment PSA has been
Fig. 4. Mean posttreatment PSA values at 3-month intervals after RT⫹LTAD grouped according to the ASTRO definition of biochemical failure corrected for patients with a subsequent decline and stabilization in PSA (modified ASTRO definition). PSA levels after initiation of salvage therapy were censored. Abbreviations as in Fig. 2.
Temporal kinetics of PSA
Fig. 5. (A) Mean posttreatment PSA values at 3-month intervals after RT alone by the ASTRO consensus definition of biochemical failure and (B) corrected for patients with a subsequent decline and stabilization in PSA. PSA levels after initiation of salvage therapy were censored. Abbreviations as in Fig. 1.
shown to fit serial values of PSA (28, 29) and provides future estimates of PSA level and velocity that may be used to stratify for risk of subsequent failure. Definitions of BF based on the number of rises in PSA level, consecutive or otherwise, are dependent both on the frequency and precision of PSA determinations. The ASTRO guidelines suggest that PSA determinations be obtained at 3-month or 4-month intervals during the first 2 years after completion of RT, and every 6 months thereafter (13). Our results suggest that PSA levels of NBFs after RT⫹AD can rise steadily, with a small PSA slope, to a time approximately 2 years after LTAD release and approximately 3 years after release of STAD (Fig. 2). Less frequent PSA determinations in the period immediately after the withdrawal of AD and after RT may improve the specificity of the ASTRO definition of BF by lowering the sensitivity
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to transient rises in PSA as serum testosterone recovers. Our results indicate also that the precision to which the PSA level is determined will influence the number of rises. PSA determinations more precise than 0.1 ng/mL may result in a greater chance of BF classification during periods of slow PSA rise. PSA values should be rounded off to the nearest 0.1 ng/mL. Definitions of biochemical failure that incorporate an absolute PSA level have demonstrated greater sensitivity for clinical relapse compared to the ASTRO consensus definition (26). Rounding to the nearest 0.1 ng/mL may not be required for definitions employing an absolute PSA level or absolute PSA level above nadir. Transient rises in PSA level leading to misclassification after RT alone were observed to a lesser degree (5% vs. 23%, p ⫽ 0.0003). A similar rate of BF misclassification using the ASTRO definition has also been reported after brachytherapy alone, 4% (30). This difference in the misclassification rate is likely related to two important contrasts between the PSA profiles of men treated with RT with or without AD: the initial PSA response and level upon completion of therapy. PSA levels were generally undetectable throughout AD and as a consequence rose slightly in the year or so after the release of AD, thereby conferring opportunity for achieving 3 consecutive transient rises. In the case of RT without AD, there was a slow decline and leveling in PSA, and as a result it was less probable there would be 3 subsequent consecutive rises. A greater sensitivity to interassay variability because of lower absolute PSA levels after RT⫹AD may also contribute to the larger misclassification rate in these men. Overall, this difference in the misclassification rate has important implications when the two treatment strategies using the ASTRO definition of BF are compared; the greater misclassification rate after RT⫹AD biases in favor of RT alone. The ASTRO definition of BF is an inappropriate end point when prostate cancer patients treated with RT⫹AD are compared to those treated with RT alone. CONCLUSION Posttreatment PSA values may rise on 3 or more consecutive occasions after RT⫹AD for prostate cancer and subsequently decline and stabilize. The ASTRO definition overestimates BF by approximately 20 –30% after RT⫹AD compared to 5% after RT alone. Less frequent PSA determinations during the initial 2 years after RT⫹AD may improve the positive predictive value of the ASTRO definition for further rises. PSA determinations more precise than 0.1 ng/mL should not be used in the determination of BF after RT⫾AD. The ASTRO definition of biochemical failure should be modified so that one definition is similarly accurate for RT alone or RT⫹AD and is a strong determinant of clinical failure.
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sion adjuvant to radiotherapy in carcinoma of the prostate. Long-term results of phase III RTOG study 85-31. Int J Radiat Oncol Biol Phys 2003;57:S172–173. Bolla M, Collette L, Gonzalez D, et al. Long term results of immediate adjuvant hormonal therapy with goserelin in patients with locally advanced prostate cancer treated with radiotherapy. A phase III EORTC study. Int J Radiat Oncol Biol Phys 1999;45:147. Granfors T, Modig H, Damber J-E, et al. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: A prospective randomized study. J Urol 1998;159:2030 –2034. Ruckle HC, Oesterling JE. Prostate-specific antigen and androgen deprivation therapy. World J Urol 1993;11:227–232. Zagars GK, Sands ME, Pollack A, et al. Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: Prognostic variables and outcome. J Urol 1994;151:1330 –1333. Pollack A, Hanlon AL, Movsas B, et al. Biochemical failure as a determinant of distant metastasis and death in prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:19 –23. Horwitz EM, Vicini FA, Ziaja EL, et al. Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys 1996;36:565–571. Hanks GE, Corn BW, Lee WR, et al. External beam irradiation of prostate cancer. Conformal treatment techniques and outcomes for the 1990s. Cancer 1995;75:1972–1977. Kaplan ID, Cox RS, Bagshaw MA. Prostate specific antigen after external beam radiotherapy for prostatic cancer: Followup. J Urol 1993;149:519 –522. Zietman AL, Coen JJ, Dallow KC, et al. The treatment of prostate cancer by conventional radiation therapy: An analysis of long-term outcome. Int J Radiat Oncol Biol Phys 1995;32: 287–292. Gretzer MB, Trock B, Han M, et al. A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiology and Oncology criteria. J Urol 2002;167:68. 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. Slivjak AM, Pinover WH, Hanlon AL, et al. The ASTRO Consensus Guidelines definition of bNED failure is an inappropriate endpoint for prostate cancer patients receiving conformal radiation therapy and androgen deprivation (CRT ⫹ AD). Int J Radiat Oncol Biol Phys 1998;42:176. Hanlon AL, Hanks GE. Scrutiny of the ASTRO consensus definition of biochemical failure in irradiated prostate cancer patients demonstrates its usefulness and robustness. Int J Radiat Oncol Biol Phys 2000;46:559 –566. Ennis RD, Malyszko BK, Heitjan DF, et al. Changes in biochemical disease-free survival rates as a result of adoption of the Consensus Conference definition in patients with clinically localized prostate cancer treated with external-beam radiotherapy. Int J Radiat Oncol Biol Phys 1998;41:511–517.
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17. Horwitz EM, Vicini FA, Ziaja EL, et al. The correlation between the ASTRO consensus panel definition of biochemical failure and clinical outcome for patients with prostate cancer treated with external beam irradiation. Int J Radiat Oncol Biol Phys 1998;41:267–272. 18. Vicini FA, Kestin LL, Martinez AA. The importance of adequate follow-up in defining treatment success after external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1999;45:553–561. 19. American Joint Committee on Cancer. Prostate. In: Greene FL, Page DL, Fleming ID, et al., editors. AJCC cancer staging manual. Philadelphia: Lippincott Raven Publishers; 2002. p. 309 –316. 20. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003;21:3972–3978. 21. Horwitz EM, Hanlon AL, Pinover WH, Anderson PR, Hanks GE. Defining the optimal radiation dose with three-dimensional conformal radiation therapy for patients with nonmetastatic prostate carcinoma by using recursive partitioning techniques. Cancer 2001;92:1281–1287. 22. Monti AF, Ostinelli A, Frigerio M, et al. An ICRU 50 radiotherapy treatment chart. Radiother Oncol 1995;35:145–150. 23. Cleveland W, Devlin SJ. Locally weighted regression: An approach to regression analysis by local fitting. J Am Stat Assoc 1988;83:596 – 610. 24. Kattan MW, Fearn PA, Leibel S, et al. The definition of biochemical failure in patients treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2000;48:1469 –1474. 25. Taylor JM, Griffith KA, Sandler HM. Definitions of biochemical failure in prostate cancer following radiation therapy. Int J Radiat Oncol Biol Phys 2001;50:1212–1219. 26. Pickles T, Kim-Sing C, Morris WJ, et al. Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time bias. Int J Radiat Oncol Biol Phys 2003;57:11–18. 27. Takamiya R, Weinberg V, Young CD, et al. A zero PSA slope in posttreatment prostate-specific antigen supports cure of patients with long-term follow-up after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2003;56:1073–1078. 28. Vollmer RT, Egawa S, Kuwao S, et al. The dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: A study of 94 Japanese men. Cancer 2002;94: 1692–1698. 29. Zagars GK, Pollack A. The fall and rise of prostate-specific antigen. Kinetics of serum prostate-specific antigen levels after radiation therapy for prostate cancer. Cancer 1993;72: 832– 842. 30. Austen L, Crook J, McLean M, et al. PSA Kinetics following brachytherapy treatment with I-125 seeds in early stage prostate cancer. The annual meeting of the Canadian Association of Radiation Oncologists (CARO-ACRO). Toronto, Canada; 2002.
doi:10.1016/j.ijrobp.2004.08.034
CLINICAL INVESTIGATION
Prostate
BIOCHEMICAL FAILURE AND THE TEMPORAL KINETICS OF PROSTATESPECIFIC ANTIGEN AFTER RADIATION THERAPY WITH ANDROGEN DEPRIVATION MARK K. BUYYOUNOUSKI, M.D., M.S.,* ALEXANDRA L. HANLON, PH.D.,† ERIC M. HORWITZ, M.D.,* ROBERT G. UZZO, M.D.,‡ AND ALAN POLLACK, M.D., PH.D.* Departments of *Radiation Oncology, †Biostatistics, and ‡Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA Purpose: The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. Methods and Materials: Between December 1, 1991 and April 30, 1998, 688 men with T1c–T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n ⴝ 586) or in combination with either short-term (STAD: 3 to 12 months, n ⴝ 82) or long-term (LTAD: 12 to 36 months, n ⴝ 20) AD. Follow-up, calculated from the end of all treatment, was >48 months. The mean posttreatment PSA was calculated in 3-month intervals. Results: The median posttreatment clinical follow-up period was 76 months (range, 48 –152 months). The posttreatment PSA values from the end of all treatment for the RTⴙSTAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RTⴙSTAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RTⴙSTAD-NBF profile, the RTⴙLTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RTⴙLTAD-BF profile rose continuously but at a slower rate over time. Nine RTⴙSTAD-NBF patients (22%) and 2 RTⴙLTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RTⴙLTAD-BF profile rose constantly and steadily with a doubling time of approximately 16 months, and the RTⴙLAD-NF initially rose to a value of approximately 0.5 ng/mL, then at 36 months began to decline. Conclusions: The temporal kinetics of posttreatment PSA after RTⴙAD and RT alone are different. The American Society of Therapeutic Radiation Oncology definition for biochemical failure overestimates BF in 20 –30% after RTⴙAD compared to 5% after RT alone. © 2005 Elsevier Inc. Prostatic neoplasm, Prostate-specific antigen, Radiotherapy, Treatment failure.
INTRODUCTION
testosterone to castrate levels 3 to 4 weeks after a transient increase. Antiandrogens, either nonsteroidal or steroidal, are commonly used to counteract the initial surge in testosterone from LHRH agonists. Serum prostate-specific antigen (PSA), a glycoprotein serine protease specific to prostatic tissue, responds rapidly and markedly to AD (5). The extent of the drop in PSA does not accurately reflect tumor response. For example, an undetectable PSA does not equate with a complete tumor response, although an undetectable PSA within 9 months is associated with a better prognosis
Several randomized trials (1– 4) have shown a benefit for the combined use of androgen deprivation (AD) and external beam radiation therapy (RT) for the treatment of prostate cancer. As a result, AD and RT are commonly combined for the treatment of intermediate- to high-risk prostate cancer. In this setting, AD is usually achieved by the use of luteinizing hormone releasing hormone (LHRH) agonists acting via suppression of the hypothalamic-pituitary-testicular axis. LHRH agonists reduce luteinizing hormone and
2003, Salt Lake City, UT. Acknowledgment—The authors thank Debra Eisenberg for her assistance with the development of the figures presented herein. Received Jan 20, 2004, and in revised form Aug 13, 2004. Accepted for publication Aug 16, 2004.
Reprint requests to: Alan Pollack, M.D., Ph.D., Fox Chase Cancer Center, Department of Radiation Oncology, 333 Cottman Ave., Philadelphia, PA 19111. Tel: (215) 728-2940; Fax: (215) 214-1629; E-mail: [email protected] Presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 19 –23, 1291
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(6). Upon completion of treatment and withdrawal of AD, androgen levels return, and the PSA rises modestly, usually by 1 to 2 ng/mL. The time course of the post–RT⫹AD PSA kinetics has not been previously described in detail. Biochemical failure (BF), or disease progression evidenced only by an elevated or rising posttreatment PSA, is an early measure of treatment efficacy for prostate cancer (7). What constitutes a BF, however, has been debated greatly since the routine use of PSA (8 –12). In 1997, the American Society of Therapeutic Radiation Oncology (ASTRO) introduced a consensus definition of BF after RT. The definition of 3 consecutive rises in posttreatment PSA was felt to be predictive of a continued rise in PSA and eventual clinical failure (13). Since, the ASTRO consensus definition has been shown to be a robust measure that correlates well with various clinical end points after RT alone (7, 14 –17). The accuracy of the ASTRO definition in patients who have received AD, however, has been questioned (15, 18). The primary objective of this report was to present a descriptive analysis of the PSA kinetics after RT alone, RT⫹STAD (short-term androgen deprivation), and RT⫹LTAD (long-term androgen deprivation) over multiple posttreatment PSA values obtained during an extended follow-up period. The hypothesis was that a graphical representation of the PSA kinetics would do the following: (1) illustrate the differences between the kinetics after RT alone, RT⫹STAD, and RT⫹LTAD; and (2) illustrate the potential for transient rises in PSA after the withdrawal of AD, which may lead to a higher misclassification rate of BF using the ASTRO consensus definition compared to RT alone. The secondary objectives of the report were to determine and compare the accuracy of the ASTRO consensus definition of BF to predict for a steadily rising PSA for RT alone, RT⫹STAD, and RT⫹LTAD.
METHODS AND MATERIALS Between December 1, 1991 and April 30, 1998, 1,051 clinically localized prostate cancer patients were treated definitively with either three-dimensional conformal radiation therapy alone (n ⫽ 808) or with androgen deprivation (n ⫽ 203) in the Department of Radiation Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania. Of those, 586 patients receiving RT and 102 patients receiving RT⫹AD were selected for this analysis based on a minimum clinical follow-up of 48 months’ duration calculated from the completion of all treatment and at least 5 serial “AD-free” posttreatment PSA levels. Androgen deprivation was defined as either short term (STAD, 3 to 12 months) or long term (LTAD, 12 to 36 months). The 2002 American Joint Committee on Cancer system palpation criteria were used to stage all patients (19). No radiographic or pathologic upstaging was allowed. No patient had evidence of metastasis before definitive treatment. All patients had a pretreatment serum PSA level available. Our treatment policy at Fox Chase Cancer Center has been to reserve the use of LTAD for patients with a pretreatment PSA ⬎20, Gleason score ⬎7, or clinical stage T3– 4 disease; the ultimate duration of LTAD varied based on patient tolerance. Fourteen men receiving RT⫹AD (14%) were treated on Radiation
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Therapy Oncology Group 92-02 (20), for which patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT, then were randomly assigned to receive no additional therapy or 24 months of goserelin. Physician-patient preference and prostate size determined the use of STAD. In some cases, STAD was initiated before RT by the referring physician. All men treated with AD received an LHRH agonist, either leuprolide acetate (69%) or goserelin acetate (31%), initiated either before or during external beam radiation. Two-thirds of men received an LHRH agonist in combination with an antiandrogen: flutamide (64 of 68), bicalutamide (3 of 68), or nilandron (1 of 68). Eighty-two patients received RT⫹STAD, and 20 received RT⫹LTAD. The median AD duration for the RT⫹STAD and RT⫹LTAD groups was 3.2 months (range, 2.5–12.0 months) and 19.4 months (range, 12.0 –29.8 months), respectively. Our three-dimensional conformal technique has previously been reported (21). Briefly, patients were treated in the supine position in a custom-made cast for immobilization. In general, T1/T2a– b prostate cancer patients with Gleason score 2– 6 received treatment to the prostate only. Patients with more advanced prostate cancer, T2c/T3 or Gleason score 7–10, received 46 –50 Gy to the prostate and surrounding periprostatic tissues (small pelvis field), followed by a boost to the prostate and seminal vesicles. Radiation dose is reported here as the International Commission on Radiation Units and Measurement (ICRU) reference dose (22). Dose was typically prescribed at the 95% isodose of the beam arrangements and normalized so that the PTV was included within the 95% isodose line. All patients were treated with 10 –18-MV photons. The median total radiation dose for RT, RT⫹STAD, and RT⫹LTAD groups was 73.7 Gy (range, 61.1– 80.0 Gy), 74.7 Gy (range, 62.1– 80.0 Gy), and 74.3 Gy (range, 70.5–75.8 Gy). Biochemical failure was first defined by the ASTRO consensus definition (3 consecutive rises in PSA) (13). No patient in the RT⫹AD group received salvage therapy before 3 consecutive rises. Sixteen patients received salvage therapy before 3 consecutive rises after RT alone and were included in the BF group. A second analysis was performed using the ASTRO definition with the following modification: In the event of a subsequent decline in PSA (without hormone therapy), 2 further consecutive rises in PSA ⬎0.1 ng/dL were required to constitute a failure. In the event that the PSA level immediately after 3 consecutive rises was unchanged but then declined, 2 further consecutive rises were also required. If salvage therapy (i.e., hormone therapy) was initiated before the above criteria for failure were met, a patient was considered a BF. Biochemical control was defined as the absence of BF. Follow-up history and physical examinations were performed every 6 months for the first 5 years, then annually. In general, posttreatment PSA levels were obtained at 3 months post-RT, then every 6 months for 5 years, and then every 6 to 12 months thereafter. Clinical follow-up was defined as the interval from the completion of all treatment to the date of last known patient contact. The mean PSA level was graphically represented as a function of months from the end of all treatment (in 3-month intervals) for both RT⫹STAD and RT⫹LTAD groups subdivided by failure status, BF vs. non-BF (NBF). PSA levels after initiation of salvage therapy were censored. The LOWESS (locally weighted scatter plot smoother) routine was used to calculate a smoothed line relating posttreatment PSA to time (23).
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Table 1. Clinical, pathologic, and treatment-related patient characteristics by treatment group Treatment group RT alone (n ⫽ 586)
Characteristic Age (yrs) Median (range) T category T1/T2 T3 Gleason sum ⬍7 ⱖ7 Pretreatment PSA (ng/mL) Median ⬍10 10 to 20 ⱖ20 Dose (Gy) Median ⱕ68.4 ⬎68.4
RT⫹STAD (n ⫽ 82)
RT⫹LTAD (n ⫽ 20)
66 (50–82)
68 (60–76)
549 (94%) 37 (6%)
48 (66%) 25 (34%)
15 (79%) 4 (21%)
466 (80%) 120 (20%)
41 (50%) 41 (50%)
10 (50%) 10 (50%)
68 (45–89)
8.8 (0.4–191.0) 342 (59%) 166 (28%) 78 (13%)
17.2 (1.2–170.3) 21 (26%) 26 (32%) 36 (43%)
18.9 (6.0–94.9) 4 (20%) 6 (30%) 10 (50%)
73.7 (61.1–80.0) 20 (3%) 566 (97%)
74.7 (62.1–80.0) 3 (4%) 79 (96%)
74.3 (70.5–75.8) 0 (0%) 20 (100%)
Abbreviations: PSA ⫽ prostate-specific antigen; STAD ⫽ short-term androgen deprivation; LTAD ⫽ long-term androgen deprivation; RT ⫽ radiation therapy.
RESULTS Patient and follow-up characteristics Various clinical, pathologic, and treatment-related characteristics for the study population are summarized by treatment group in Table 1. The median follow-up duration for RT, RT⫹STAD, and RT⫹LTAD groups was 75 months (range, 48 –152 months), 78 months (range, 48 –125 months), and 63 months (range, 48 –91 months), respectively. A total of 7737 posttreatment PSA values from 688 patients (median, 10.5 posttreatment PSA values per patient) were collected at a median interval of 6.2 months (range, ⬍1–95 months). Ninety-two percent of patients had ⱖ7 posttreatment PSA levels, 62% of patients had ⱖ10, and 18% had ⱖ15. Thirty-nine percent (16 of 41) of RT⫹STAD patients and 43% (3 of 7) of RT⫹LTAD patients received salvage therapy after 3 consecutive rises at a median time of 70 and 63 months, respectively, from the completion of all treatment. Patients with 3 consecutive rises had at least 1 PSA before salvage therapy, except 5 men in the RT⫹AD group and 25 men in the RT-alone group. Five men (10%) in the RT⫹AD group and 25 men (14%) in the RT-alone group had salvage therapy initiated either immediately upon 3 consecutive rises or at last follow-up. All of the 5 men in whom salvage therapy was initiated immediately upon BF (after 3 rises) had a PSA doubling time of ⱕ8 months, thus making the likelihood of misclassification unlikely. Ten (40%) of the 25 men in the RT-alone group received salvage therapy immediately upon BF; 6 of these men later developed distant metastasis. ASTRO consensus definition of BF after RT⫹AD Figure 1 shows mean PSA values over time from the end of RT⫹STAD for BF and NBF groups according to the
ASTRO definition. Nonbiochemical failures of STAD had a relatively constant mean PSA over time at a value of approximately 0.5 ng/mL. For the STAD-BF group, initially there was a period of slow rise in which the PSA level accelerated after 12 months, followed by a period of decline. This decline may be explained by 4 factors: (1) the initiation of salvage therapy, (2) declines in PSA level before 3 consecutive rises (i.e., “bouncing”), (3) declines in PSA after 3 consecutive rises with future rises in PSA level, and (4) declines and stabilization in PSA level after 3 consecutive rises. Figure 2 shows mean PSA values over time from the end of RT⫹LTAD for BF and NBF groups, also according to the ASTRO definition. The mean posttreatment PSA profile for the LTAD-NBF group rises continuously to a level approaching 1 ng/mL. The LTAD-BF profile rises initially at a slow rate until approximately 12 months, when the rate of rise accelerates. Then, there appears to be a deceleration. BF analysis with extended clinical follow-up Eleven (23%) RT⫹AD patients who were identified as having achieved 3 consecutive rises in posttreatment PSA level, constituting BF by the ASTRO definition, did not experience clinical failure later and had subsequent stabilization of their posttreatment PSA values. Table 2 shows the posttreatment PSA profiles of these 11 patients. None of these 11 patients had 2 additional consecutive rises after the 3 consecutive rises and decline. All PSA values after 3 consecutive rises and decline were ⱕ2 ng/mL. No patient experienced 3 further consecutive rises after the initial 3 consecutive rises. Inter–PSA level variability was usually 0.1– 0.2 ng/mL but was as high as 0.6 ng/mL. The degree of precision when determining the posttreatment PSA level was also important for the classifica-
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Fig. 1. Mean posttreatment PSA values at 3-month intervals after RT⫹STAD grouped according to the ASTRO consensus definition of biochemical failure. PSA levels after initiation of salvage therapy were censored. PSA ⫽ prostate-specific antigen; STAD ⫽ short-term androgen deprivation (3–12 months.); EOT ⫽ end of all treatment; NBF ⫽ nonbiochemical failure; BF ⫽ biochemical failure; CI ⫽ confidence interval; RT⫽ radiotherapy.
tion of biochemical failure. PSA level determinations with precision ⱕ0.1 ng/mL resulted in the misclassification of biochemical failure in 1 patient. A modification to the ASTRO definition of BF was adopted based on these results. In the event of a decline in PSA level after 3 consecutive rises in posttreatment PSA level (reported with an accuracy of ⬎0.1 ng/mL), 2 additional consecutive rises were required to constitute BF.
Modified ASTRO consensus definition of BF Nine (22%) STAD-BF patients and 2 (29%) LTAD-BF patients were reclassified as NBFs, because 3 consecutive rises were followed by a subsequent decline and stabilization of PSA as deemed by the absence of 2 further consecutive rises. There was no significant difference between the misclassification rate between RT⫹STAD and RT⫹LTAD (p ⫽ 0.6, Fisher’s exact). Figure 3 shows the mean PSA
Fig. 2. Mean posttreatment PSA values at 3-month intervals after RT⫹LTAD grouped according to the ASTRO consensus definition of biochemical failure. PSA levels after initiation of salvage therapy were censored. PSA ⫽ prostate-specific antigen; LTAD ⫽ long-term androgen deprivation (12–36 months.); EOT ⫽ end of all treatment; NBF ⫽ nonbiochemical failure; BF ⫽ biochemical failure; CI ⫽ confidence interval; RT ⫽ radiotherapy.
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Table 2. Posttreatment PSA profiles of patients with a subsequent decline and stabilization of posttreatment PSA level after three consecutive rises (underlined) Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Treatment group RT⫹LTAD RT⫹LTAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT⫹STAD RT alone RT alone RT alone RT alone RT alone RT alone RT alone RT alone RT alone RT alone
Posttreatment PSA values (ng/mL) 0.10, 0.10, 0.20, 0.10, 0.21, 0.23, 0.25 0.45, 0.40, 0.74, 0.53, 0.62, 0.70, 0.87, 0.58, 0.60 0.2, 0.1, 0.1, 0.1, 0.1, 0.2, 0.3, 0.4, 0.3, 0.2, 0.2, 0.1, 0.2, 0.1, 0.4, 0.6, 0.9, 0.7, 1.3, 0.9, 0.7 0.5, 1.5, 1.8, 1.9, 1.5, 2.0, 1.2, 1.1, 1.1, 1.7, 1.2, 1.4 1.0, 1.0, 0.8, 1.1, 1.3, 1.5, 1.5, 1.5, 1.2, 1.1, 1.1 0.4, 0.7, 0.8, 0.9, 0.8, 0.3, 1.6, 1.2, 0.9, 0.7, 0.8, 0.8 0.5, 0.7, 1.0, 1.5, 1.6, 1.4, 1.4, 0.9, 0.9, 0.9, 0.6 1.6, 1.5, 1.7, 1.5, 1.3, 0.5, 0.7, 1.3, 1.8, 1.1, 0.8, 1.0, 0.4, 0.7, 1.0, 1.2, 0.6, 0.6, 0.7, 0.7, 1.2, 0.7, 0.7, 0.7 0.3, 0.3, 0.4, 0.5, 0.6, 0.6, 0.7, 0.6, 0.8, 0.7, 0.6, 0.2, 1.4, 0.9, 0.7, 0.8, 0.9, 1.5, 0.9, 1.1 3.9, 1.7, 0.9, 0.7, 0.5, 0.6, 1.1, 1.3, 1.0, 1.0, 1.2, 1.0 2.7, 1.4, 1.1, 1.3, 1.5, 2.1, 1.3, 0.8, 0.8, 0.7, 0.9 1.0, 1.1, 2.7, 4.1, 1.7, 0.9, 1.0, 1.0, 1.1, 0.6, 1.0, 0.5 1.4, 1.1, 0.6, 0.8, 1.2, 1.5, 1.4, 1.5, 1.2 3.3, 1.2, 2.7, 0.9, 1.1, 0.6, 1.3, 1.1, 0.8, 1.4, 1.5, 2.3, 4.5, 4.4, 1.9, 0.9, 1.1, 0.9, 0.7, 0.9, 1.3, 2.2, 0.6, 1.6 1.4, 1.1, 0.4, 0.3, 0.1, 0.2, 0.3, 0.4, 0.2, 0.3, 0.3, 0.4, 9.1, 4.0, 3.0, 1.4, 1.2, 0.9, 0.9, 0.8, 0.9, 1.1, 1.2, 1.1 3.7, 1.3, 1.1, 0.9, 0.7, 0.7, 0.9, 1.1, 1.5, 1.1, 1.2
0.1
1.0, 1.0 0.6, 0.5, 0.6
1.7, 2.2, 1.6, 1.4 0.3, 0.2, 0.3, 0.2, 0.3
Abbreviations: PSA ⫽ prostate-specific antigen; RT ⫽ radiation therapy; STAD ⫽ short-term androgen deprivation; LTAD ⫽ long-term androgen deprivation.
values over time using this modified definition of failure for the STAD group and Fig. 4 for the LTAD group. After STAD, Fig. 3 suggests two waves of failure, early and late. Nonbiochemical failures after either STAD have a comparatively constant mean PSA over time valued at approximately 0.5 ng/mL. Biochemical failures after LTAD had a steady rise in the mean posttreatment PSA with a doubling time of approximately 16 months. Nonbiochemical failures after RT⫹LTAD demonstrate an initial rise in PSA level to approximately 0.5 ng/mL followed by a decline at approximately 36 months.
ASTRO consensus definition of BF after RT alone Figure 5A shows the mean posttreatment PSA values after RT alone by the ASTRO consensus definition of BF. The RT-alone–NBF profile declined asymptotically over time to a value ⬍1 ng/mL. For the RT-alone–BF group, there was an initial period of steady decline and a nadir at approximately 18 months. This was followed by a period of rise during which there was a small decline in the mean posttreatment PSA values, which may represent a combination of four factors previously described (See “ASTRO consensus definition of BF after RT⫹AD” [above]). Ten of 196 (5%) patients in this group experienced 3 consecutive rises in PSA followed by a subsequent decline and stabilization in PSA, defined as the absence of two further consecutive rises, compared to 11 of 48 (23%) after RT⫹AD (p ⫽ 0.0003, chi-square). Figure 5B shows the mean posttreatment PSA values for the patients grouped by the modified ASTRO definition. The reclassification of these 10 patients
to the RT-alone–NBF group did not result in appreciable change.
DISCUSSION In the current analysis, we closely examined the posttreatment serum PSA profiles of men treated with RT⫾AD (STAD or LTAD) who had extended follow-up. Patients were required to have a minimum of 5 posttreatment PSA values and at least 48 months of follow-up. The aim was to determine the accuracy of the ASTRO consensus definition in classifying BF through a better understanding of the change in PSA that occurs over time. A large number of PSA values were analyzed, providing an accurate representation of the posttreatment PSA profile. Overall, the ASTRO definition of BF overestimated a steadily rising PSA level over extended follow-up in 5% of patients after RT alone compared to 23% after RT⫹AD (p ⬍ 0.05), 22% after RT⫹STAD, and 29% after RT⫹LTAD (p ⫽ nonsignificant). Concerning the changes in PSA after AD withdrawal, the PSA profiles after RT⫹STAD or RT⫹LTAD for those with ASTRO-defined BF illustrated that at about 30 months after treatment, there is an alteration in the kinetics. PSA levels transiently declined in the STAD⫹RT group, and the rate of rise slowed in the LTAD⫹RT group. One possible factor for these kinetic changes is the misclassification of BF using the ASTRO definition. After withdrawal of AD, approximately one-fourth of men fulfilling ASTRO criteria for BF experienced a subsequent decline and/or stabilization in
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Fig. 3. Mean posttreatment PSA values at 3-month intervals after RT⫹STAD grouped according to the ASTRO definition of biochemical failure corrected for patients with a subsequent decline and stabilization in PSA (modified ASTRO definition). PSA levels after initiation of salvage therapy were censored. Abbreviations as in Fig. 1.
PSA. The modification to the ASTRO definition described herein addressed this misclassification by requiring 2 additional consecutive rises in PSA level in the event of a subsequent nonrising PSA level. This definition better predicted for succeeding rises in PSA that were sustained (true BF). However, this definition does have shortcomings. For example, stabilization in PSA could be delayed, occurring after 4 or more consecutive rises. Additional follow-up may
show that stabilization is also possible despite requiring an additional 2 consecutive rises. Alternatively, some have suggested using cumulative rises rather than consecutive rises as evidence of BF (24). Others have suggested requiring a final PSA in a series of 3 consecutive rises to be ⬎1.5 ng/mL (25), a PSA level ⬎2 ng/mL above the nadir (26), or a rule based on the PSA slope (25, 27) to declare BF. Exponential modeling of posttreatment PSA has been
Fig. 4. Mean posttreatment PSA values at 3-month intervals after RT⫹LTAD grouped according to the ASTRO definition of biochemical failure corrected for patients with a subsequent decline and stabilization in PSA (modified ASTRO definition). PSA levels after initiation of salvage therapy were censored. Abbreviations as in Fig. 2.
Temporal kinetics of PSA
Fig. 5. (A) Mean posttreatment PSA values at 3-month intervals after RT alone by the ASTRO consensus definition of biochemical failure and (B) corrected for patients with a subsequent decline and stabilization in PSA. PSA levels after initiation of salvage therapy were censored. Abbreviations as in Fig. 1.
shown to fit serial values of PSA (28, 29) and provides future estimates of PSA level and velocity that may be used to stratify for risk of subsequent failure. Definitions of BF based on the number of rises in PSA level, consecutive or otherwise, are dependent both on the frequency and precision of PSA determinations. The ASTRO guidelines suggest that PSA determinations be obtained at 3-month or 4-month intervals during the first 2 years after completion of RT, and every 6 months thereafter (13). Our results suggest that PSA levels of NBFs after RT⫹AD can rise steadily, with a small PSA slope, to a time approximately 2 years after LTAD release and approximately 3 years after release of STAD (Fig. 2). Less frequent PSA determinations in the period immediately after the withdrawal of AD and after RT may improve the specificity of the ASTRO definition of BF by lowering the sensitivity
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to transient rises in PSA as serum testosterone recovers. Our results indicate also that the precision to which the PSA level is determined will influence the number of rises. PSA determinations more precise than 0.1 ng/mL may result in a greater chance of BF classification during periods of slow PSA rise. PSA values should be rounded off to the nearest 0.1 ng/mL. Definitions of biochemical failure that incorporate an absolute PSA level have demonstrated greater sensitivity for clinical relapse compared to the ASTRO consensus definition (26). Rounding to the nearest 0.1 ng/mL may not be required for definitions employing an absolute PSA level or absolute PSA level above nadir. Transient rises in PSA level leading to misclassification after RT alone were observed to a lesser degree (5% vs. 23%, p ⫽ 0.0003). A similar rate of BF misclassification using the ASTRO definition has also been reported after brachytherapy alone, 4% (30). This difference in the misclassification rate is likely related to two important contrasts between the PSA profiles of men treated with RT with or without AD: the initial PSA response and level upon completion of therapy. PSA levels were generally undetectable throughout AD and as a consequence rose slightly in the year or so after the release of AD, thereby conferring opportunity for achieving 3 consecutive transient rises. In the case of RT without AD, there was a slow decline and leveling in PSA, and as a result it was less probable there would be 3 subsequent consecutive rises. A greater sensitivity to interassay variability because of lower absolute PSA levels after RT⫹AD may also contribute to the larger misclassification rate in these men. Overall, this difference in the misclassification rate has important implications when the two treatment strategies using the ASTRO definition of BF are compared; the greater misclassification rate after RT⫹AD biases in favor of RT alone. The ASTRO definition of BF is an inappropriate end point when prostate cancer patients treated with RT⫹AD are compared to those treated with RT alone. CONCLUSION Posttreatment PSA values may rise on 3 or more consecutive occasions after RT⫹AD for prostate cancer and subsequently decline and stabilize. The ASTRO definition overestimates BF by approximately 20 –30% after RT⫹AD compared to 5% after RT alone. Less frequent PSA determinations during the initial 2 years after RT⫹AD may improve the positive predictive value of the ASTRO definition for further rises. PSA determinations more precise than 0.1 ng/mL should not be used in the determination of BF after RT⫾AD. The ASTRO definition of biochemical failure should be modified so that one definition is similarly accurate for RT alone or RT⫹AD and is a strong determinant of clinical failure.
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