PSA After Radiation for Prostate Cancer

Transcription

1 Review Article [1] May 01, 2004 By Deborah A. Kuban, MD [2], Howard D. Thames, PhD [3], and Larry B. Levy, MS [4] The introduction of prostate-specific antigen (PSA) as a reliable tumor marker for prostate cancer brought significant changes in the end points used for outcome reporting after therapy. With regard to a definition of failure after radiation, a consensus was reached in 1996 that took into account the particular issues of an intact prostate after therapy. Over the next several years, the consensus definition issued by the American Society for Therapeutic Radiology and Oncology (ASTRO) was used and studied. Concerns and criticisms were raised. The sensitivity and specificity of this definition vs other proposals has been investigated, and differences in outcome analyzed and compared. Although the ASTRO definition came from analysis of datasets on external- beam radiation and most of the work on this topic has been with this modality, failure definitions for brachytherapy must be explored as well. The concept of a universal definition of failure that might be applied to multiple modalities, including surgery, should also be investigated, at least for comparative study and research purposes. Although we are lucky enough to have a marker in the treatment of prostate cancer to predict prognosis before therapy and outcome afterwards, it has taken over 15 years to determine how to best use it, and recent long-term outcome studies have raised several issues along with options for improvement. While little controversy surrounds the prognostic use of this marker in choosing therapy, we are still exploring treatment failure definitions, their application across unlike therapeutic modalities, and the utility of early documentation of recurrence and associated salvage therapy. History When prostate-specific antigen (PSA) first came into clinical use in the mid- to late 1980s, there was great enthusiasm for its use in screening and in the follow-up of prostate cancer after therapy. As studies were conducted, PSA was also found to be a surrogate for tumor burden and proved its value in pretreatment prognosis and therapeutic decision-making. A normal postsurgery PSA level was soon agreed upon, given that with nearly all prostate tissue removed, it had to be very close to zero. Such was not the case with radiation, however, because PSA-secreting prostate was left intact. Thus, the dilemma and debate began. Some of the first publications using PSA as a measure of outcome defined successful radiation as a posttreatment PSA level 4 ng/ml[1]; it was soon discovered, however, that this level might be normal before therapy but too high for an irradiated prostate with a markedly changed secretory capacity.[2-4] Much discussion ensued as to what the appropriate level should be.[5] We saw a rapid transition to using this marker as an indicator of treatment efficacy as opposed to waiting long periods for local or distant disease to become clinically evident. Outcome studies were reported with a variety of PSA end points, however. Of note were the differences between the clinical outcome measures previously used- local, regional, and distant failure- and the PSA results that appeared to document treatment failure earlier and in higher proportion.[1,6] Consensus Guidelines In an effort to standardize study reporting using this objective PSA parameter, the American Society for Therapeutic Radiology and Oncology (ASTRO) assembled an expert panel in 1996 and charged the members with reaching a consensus on "the significance of the depth of the PSA nadir, the definition of a rising PSA, the optimal PSA surrogate end point for total eradication of tumor or for relapse after irradiation, and guidelines for using PSA end points for reporting (publishing) success or failure after irradiation."[7] Data on patient outcomes with various PSA characteristics and trends after external-beam radiation along with illustration of various failure definitions were supplied by investigators from seven institutions, who had made significant contributions to the literature in the PSA era. Following presentations by these individuals and additional information obtained from recursive partitioning techniques, the ASTRO panel agreed on four guidelines: Biochemical failure is not justification per se to initiate additional treatment. It is not equivalent to clinical failure. It is, however, an appropriate early end point for clinical trials. Three consecutive rises in PSA is a reasonable definition of biochemical failure after radiation therapy. For clinical trials, the date of failure should be the midpoint between the Page 1 of 13

2 postirradiation nadir PSA and the first of the three consecutive rises. No definition of PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival; and Nadir PSA is a strong prognostic factor, but no absolute level is a valid cutoff point for separating successful and unsuccessful treatments. Nadir PSA is similar in prognostic value to pretreatment prognostic variables. In addition, the following guidelines were suggested for studies submitted for publication: (1) series should have a minimum observation period of 24 months; (2) PSA determinations should be obtained at 3- or 4-month intervals during the first 2 years after the completion of radiation therapy, and every 6 months thereafter; and (3) patients reported in a series who have had one or two consecutive rises in PSA but not the three consecutive rises necessary for failure should be reported separately in the results.[7] In the 6 years following the consensus conference, the ASTRO definition has been the most frequently used PSA definition of failure after radiotherapy, providing a consistent standard by which studies can be evaluated and compared. Shortly after the conference, six of the participating investigators pooled data on stage T1/2 prostate cancer patients who had a pretreatment PSA and received external- beam radiation at least 2 years prior to analysis. They reported outcome for 1,765 patients with a median follow-up of 4.1 years using the ASTRO definition of failure.[8] The efficacy and durability of irradiation were established and prognostic factors confirmed. Subsequently, singleinstitution studies added to the body of outcome data using a consistent end point for reporting. Deficiencies in the ASTRO Definition As is not uncommon in any situation where attention is focused on one primary recommendation, the less salient, seemingly minor points that arose from the consensus conference, such as requiring a minimum of 24 months follow-up before reporting a study and in some way indicating patients who had two but not three rises in PSA, were largely overlooked. Additionally, as frequently occurs in piloting a new procedure, more experience with the proposed definition and mature follow-up in the PSA era led to the emergence of deficiencies and interpretative issues. Major criticisms of the ASTRO definition included the lack of consideration of laboratory variation and standard error, the extensive period of time (which was follow-up interval- dependent) required to document three PSA rises, the bias associated with backdating the failure date, the potential for greater sensitivity and specificity of other definitions in predicting clinical failure, and the substantial difference between this and surgical definitions of failure. Several methods have been proposed to deal with the areas of concern. To accommodate the variation in laboratory testing of PSA levels, to reduce the problems associated with PSA values near the lower limit of detection appearing to change by large percentages when increases occurred, and to discount minor fluctuations in PSA production in normal prostate tissue, a definition that quantified the minimum amount of each rise in PSA was proposed-for example, three PSA rises of at least 0.5 ng/ml each.[9] Another method recommended as a way to compensate for small but consecutive increases in PSA level, which also reportedly enhanced the predictive power of the ASTRO definition, was to stipulate a required minimum total PSA level (eg, 1.5 ng/ml) in addition to the requirement of three consecutive rises in PSA.[10] Proposals to decrease the amount of time necessary to document three PSA rises, especially with follow-up intervals of 6 months or more, included defining failure as fewer rises, such as two but of a certain value each, or any elevation above an absolute nadir value, such as 0.2 ng/ml.[9,11] Some authors suggested that the bias introduced by backdating could be remedied by allowing for adequate length of follow-up, perhaps an additional 3 years beyond the point chosen for analysis.[12] The bias stems from reporting failure at the backdated date, when it actually takes considerably longer (ie, time for three PSA rises) to declare a treatment failure. If there is not enough follow-up time available to allow for three rises in PSA, the failure rate may be significantly underestimated at the backdated date. This bias could also be dealt with by moving the reported failure date to the date when the failure was actually determined-in the case of the ASTRO definition, to the date of the third PSA rise.[13] This, of course, would remove the backdating aspect of the definition. Finally, the backdating bias could be handled by a more complicated option that would involve backdating the censor date for patients with one or two PSA rises for whom no additional information was available.[14] To address the lack of uniformity between the definitions of failure used for differing treatment modalities, a single, surgically oriented definition using a solitary cutoff point was proposed.[ 11,15] As might be expected, without appropriate sensitivity and specificity testing, enthusiasm was decidedly lacking. Comparing Failure Definitions External-Beam Page 2 of 13

3 Irradiation To expand the work of Shipley et al and the first multi-institutional outcome study,[8] nine institutions recently contributed 4,839 T1/2 prostate cancer patients to a single, combined database.[16] All patients were treated in the PSA era and, therefore, had both pretreatment and a series of posttreatment PSA measurements. These men were treated with definitive external- beam irradiation alone no more recently than 1995, to provide potential follow-up of at least 5 years. Median follow-up was calculated at 6.3 years with 2,049 patients still available for analysis at 5 years, 616 at 8 years, and 179 at 10 years posttreatment. Not only did this database provide the most robust outcome report on external-beam radiation to date, but it also provided a valuable resource with which to test and compare definitions of failure. Although multiple failure definitions have been suggested for various reasons, this large body of data provided a sound basis for the testing and objective comparison of definitions. Page 3 of 13

4 Sensitivity and Specificity-After examining the work on this subject, Thames et al tested 101 definitions of PSA failure with regard to their sensitivity and specificity in predicting Page 4 of 13

5 clinical failure using the 4,839 patient multi-institution database.[17] A selection of these findings is listed in Table 1. The investigators defined current nadir as the lowest PSA measurement prior to the current measurement. Thus, current nadir will change during follow-up. Absolute nadir is the lowest PSA value during the entire follow-up period as assessed retrospectively. (The absolute nadir is the minimum of all the current nadirs measured during follow-up.) Failure definitions based on two, three, or four PSA rises are dated either at the time of the last rise ("call date"), or are "backdated" to the date halfway between the first PSA rise and the previous PSA. Clinical failure was defined as local disease recurrence, distant metastasis, PSA > 25 ng/ml, or the administration of hormone therapy. Although the last two of these factors are subject to debate, this definition took into account reasonable criterion and opinion to date. The last issue-the administration of hormone therapy before clinical failure-is especially problematic. While the reality of the situation found in any dataset is that hormone therapy is at times administered prior to clinical failure, altering the natural progression of disease, it is not certain that these patients would indeed have developed clinical failure if treatment had not been administered. One must assume, however, that they would be the very ones with the most suspicion of failure such that this circumstance cannot be ignored and the patients simply censored. Therefore, each of these four criteria was included in the definition of clinical failure. To calculate the sensitivity and specificity of each definition of failure, each patient was scored as either true-negative (no biochemical failure and no clinical failure), true-positive (biochemical failure followed by clinical failure), false-negative (clinical failure without a preceding biochemical failure or biochemical failure occurring after clinical failure), or falsepositive (biochemical failure not followed by clinical failure). Then: Sensitivity = true-positive/ true-positive + false-negative Specificity = true-negative/ true-negative + false-positive Thus, the sensitivity of a definition is the proportion of patients with a clinical Page 5 of 13

6 recurrence who have had a prior biochemical failure, and the specificity is the proportion of patients without clinical failure who have not had a biochemical failure. As seen in Table 1, only four definitions of biochemical failure were both more sensitive and specific than the ASTRO definition. In retrospect, the ASTRO definition appears to have been a remarkably good choice. Page 6 of 13

7 Predictive Value- A different way to quantify the usefulness of PSA failure definitions is to ask what proportion of patients with biochemical failure go on to have a clinical failure (called the positive predictive value) and, alternatively, what proportion of patients without biochemical failure do not go on to have a clinical failure (called the negative predictive value): Positive predictive value =true-positive/ true-positive + false-negative Negative predictive value =true-negative/ true-negative + false-positive Although the sensitivity and specificity are clearly useful at the time of data analysis, after all follow-up information has been collected, it is clear that positive predictive value and negative predictive value will be more valuable to the patient during the period of ongoing follow-up, when PSA measurements are actively being evaluated, especially if the patient's status changes. For this reason, this information could prove useful in counseling patients. Figure 1 shows patients at low, intermediate, and high risk for failure when the failure definition "current nadir + 2 ng/ml" is applied. A patient in the low-risk group (Figure Page 7 of 13

8 1A) who has been followed for 4 years without biochemical failure has an 89% chance of surviving another 4 years without clinical failure-ie, to 8 years after treatment (point X in Figure 1A). For patients in the intermediate- (Figure 1B) and high-risk (Figure 1C) groups, the corresponding percentages are 83% and 71%, respectively (point X in Figures 1B and C). For patients in the low-risk group who have had a biochemical failure 3 years after treatment, their chance of experiencing a clinical failure 2 years later-ie, 5 years from the end of treatment-is about 47% (point Y in Figure 1A). For patients in the intermediate- and highrisk groups, the corresponding percentages are 47% and 59%, respectively (point Y in Figures 1B and 1C). On the other hand, a patient in the low-risk group who experienced a biochemical failure 1 year after treatment has a 27% chance of clinical failure (point Z in Figure 1A) by 2 years later (3 years after the end of treatment). For patients in the intermediate- and high-risk groups, the corresponding percentages are 55% and 78%, respectively (point Z in Figures 1B and C). Follow-up Issues-Once PSA was introduced as a tool for assessing outcome, it was assumed that it would provide an early surrogate for treatment success or failure. Although it does provide information sooner than clinical recurrence declares itself, it has become evident that a significant period of time is still necessary to formulate a reliable estimate of disease-free status, especially if the ASTRO definition of failure is used. The median time to nadir in patients treated with external- beam therapy is 17 to 32 months.[18,19] Given that failure is signaled by a rising PSA level following nadir, surely any study without ample follow-up time for patients to nadir may report premature results. Additionally, with the ASTRO definition, three PSA rises must be documented, which also requires an extended period of time. For example, if posttreatment PSA measurements are obtained every 3 months, 9 months is necessary to observe three consecutive PSA rises. For follow-up periods of 4 and 6 months, 12 and 18 months, respectively, would be required to establish a PSA failure. Although yearly hazard rates show that when using the ASTRO definition, the greatest risk of failure is at 1.5 to 3.5 years after radiotherapy,[16] one must bear in mind that this is the backdated failure date (halfway between the nadir and the first PSA rise) and that the failure would have been established or called 7.5 to 15 months after the backdated point, depending on the follow-up interval. Data from the 4,839-patient study showed that 38% of PSA failures were called by 3 years posttherapy, 73% by 5 years, 95% by 8 years, and 99% by 10 years, illustrating further the significant amount of time necessary to document three PSA rises and declare a PSA failure by a definition dependent on this criterion.[16] The effect of follow-up time on outcome reporting has been illustrated by other authors as well. Vicini and colleagues, in applying the ASTRO definition to patients treated with external-beam radiation, showed that the rate of biochemical failure differed markedly depending on the amount of follow-up information used.[12] If only 3 years of follow-up information was allowed, the 3-year biochemical disease-free survival rate was 71% vs 44% when 6 years of follow-up data was used. This phenomenon was confirmed with the nineinstitution, 4,839-patient dataset.[17] Using the intermediate-risk subgroup, follow-up information was truncated to produce median followup times of 3, 4, 5, and 6.3 years for the same group of patients. PSA disease-free survival was recalculated four times, each time using one of these median follow-up times (Figure 2A). As for any PSA-based definition, the greater the length of follow-up, the more failures are documented, so that outcome assessment, even if statistically accurate, may be overly optimistic after a short follow- up. The situation after short follow- up times is even worse when one uses a backdated definition; however, the statistical bias in outcome assessment using backdating becomes more and more apparent the shorter the follow-up time. Thus, although reporting study results prematurely may provide outcome estimates that are too optimistic- especially when evaluating new treatment methods and technology- backdating introduces an additional factor that statistically alters the survival curves. Caution must be taken when comparing groups of patients in whom the median survival is significantly different. The bias related to follow-up time, which results from backdating the failure date, can be avoided by including in outcome analyses only patients with enough follow-up time to allow for nearly all failures to be counted or by using a failure definition that scores the failure at the call Page 8 of 13

9 date, without backdating. Alternatively, a more complicated calculation can be performed that particularly addresses patients with one or two PSA rises who are at considerable risk for failure. In these patients, the censor date (when there is no additional follow-up information available) would be backdated to halfway between the nadir date and the first PSA rise, similar to backdating the PSA failure date. This compensates for the effect of follow-up time when using a backdated failure definition (Figure 2B).[17] Failure Definition-Based Outcome- Since multiple definitions of failure are available, the question arises as to how this would affect outcome reporting for external-beam radiation therapy. Would PSA diseasefree survival differ significantly depending on the particular definition used? Several authors have compared various definitions. Horwitz and colleagues tested PSA nadir levels of 1 ng/ml, 1.5 ng/ml, and 4 ng/ml as the definition of failure.[2] Hanlon et al compared the ASTRO definition of failure to the Fox Chase definition, ie, two consecutive PSA rises to a level exceeding 1.5 ng/ml.[20] Jani et al compared the ASTRO definition, Zagars definition (two consecutive PSA rises), and a definition using a quadratic curve fitted to the log of the posttreatment PSA profile.[21] Differences in PSA disease-free survival of up to 30%, depending Horwitz andon colleagues the risk group recently analyzed illustrated and the the failure difference criteria in outcome applied, results were seen. related to backdating the failure date to various points in time vs calculating failure from the time it is declared, at the third PSA rise (Figure 3A).[13] This group showed that distortion of the Kaplan-Meier curves would be minimized by moving the failure date closer to the point at which it is declared (Figure 3B). They felt that this would provide a more realistic assessment of an actuarial- based estimate of outcome. Using the 4,839-patient, multi-institutional dataset, outcome was plotted for three definitions found to be more sensitive and specific than the ASTRO definition: (1) two PSA rises of at least 0.5 ng/ml each, backdated, (2) PSA current nadir PSA + 2 ng/ml, and (3) PSA current nadir PSA + 3 ng/ml. Differences in PSA disease-free survival are shown graphically (Figures 4A and 4B). It appears that a backdated failure definition clusters the failures within the first 5 years after treatment, when the first PSA rise occurs, and therefore, PSA disease-free survival is lower in the earlier years of reporting for the ASTRO definition than for the two definitions that use a call date to denote the time of failure, definitions 2 and 3. To illustrate this further, a failure definition defined as three PSA rises backdated can be compared to three PSA rises recorded at the call date (Figure 4C). Biochemical failure rates are greater in the earlier years after therapy when the backdated definition is used. The curves cross at 6 years where there are then fewer failures for the backdated definition, having moved the failures from the time of the third PSA rise back to the earlier years when PSA first starts to rise. In comparing the definition based on two PSA rises of at least 0.5 ng/ml, backdated, to the ASTRO definition, Page 9 of 13

10 the curves are parallel and separated by only a few percentage points (Figure 4A). These analyses show that outcome results could vary widely and be difficult to compare if the same definition of failure is not consistently applied. Additionally, it has been suggested that to fairly compare outcomes between treatment modalities, similar definitions of failure must be used.[15,22] Using surgical patients, Amling et al[22] and Gretzer et al[15] demonstrated outcome differences comparing the ASTRO definition, either backdating or at call date, to a typical surgical definition of 0.2 ng/ml (Gretzer) or 0.4 ng/ml (Amling). As seen in Figure 5A, outcome estimates for the backdated ASTRO definition are lower within the first 4 years after treatment but higher than the surgical definition in later years.[22] One must bear in mind, however, that with radiation therapy the prostate remains intact and still produces at least a small amount of PSA, which can vary with conditions such as prostatitis, the "bounce" phenomenon, gland size, and length of time from treatment. When the ASTRO definition was compared to the surgical definition of failure (PSA > 0.2 ng/ml) for the 4,839 irradiated patients in the multiinstitutional study, great disparity in outcome was seen; however, the sensitivity and specificity of the surgical definition were 91% and only 9%, respectively (Figure 5B). This indicates that although the majority of true failures are expeditiously detected, unfortunately, so are all other nonmalignant conditions, indiscriminately. Of note, the multi-institutional study did show that while one PSA nadir level could not predict failure for every patient, the median and mode nadir PSA levels for patients who were disease-free at 8 to 10 years followup were very low-0.5 and 0.1 ng/ml, respectively.[16] Brachytherapy The ASTRO failure definition was developed using externally irradiated patients, and subsequent testing of other proposed definitions was performed on this population as well. Whether PSA characteristics and failure criteria are the same for brachytherapy patients remains to be determined. From the work of Critz, it appears that patients treated with a combination of implant and external-beam irradiation show a correlation between PSA nadir values and subsequent disease progression that is very different from that seen in patients treated with external irradiation alone.[11] Critz maintains that a PSA nadir of 0.2 ng/ml is necessary to retain disease- free status as defined by a nonrising PSA. According to his analysis, 99% of patients with this nadir level do so, and he, therefore, proposes that this nadir level be used as the definition of biochemically disease-free. Further strengthening this position is his finding that only 16% of his patients with a PSA nadir level of 0.3 to 1.0 ng/ml remain disease-free at 7 years posttreatment.[11] Page 10 of 13

11 The multi-institutional analysis of patients treated by external-beam radiation alone shows a very different association between PSA nadir level and subsequent PSA failure as determined by the ASTRO definition.[16] These data showed that while fewer and fewer patients were disease-free with progressively higher PSA nadir levels, choosing one nadir level, such as 0.2 ng/ml, would label a significant number of patients as failures when, in fact, their PSA level remained stable. The percentages of externally irradiated patients who were disease-free 8 years posttreatment by the ASTRO definition with nadir levels of 0 to 0.49, 0.50 to 0.99, 1.0 to 1.99, 2.0 to 3.99, and 4.0 ng/ml were 70%, 53%, 42%, 23%, and 12%, respectively. As previously noted, the sensitivity of the 0.2-ng/mL failure definition for this group of patients was 91%, but the specificity was only 9%,[17] as would be expected from the correlation of nadir level and failure presented above. Perhaps the effect of the combination of external-beam radiation and radioisotopic implant on the prostate is different from externalbeam radiation alone in terms of the amount of normal PSA-producing prostate that remains after treatment. This may account for the nonrising but higher PSA levels. To address some of the previous criticisms related to the ASTRO failure definition, Kattan and colleagues used data from 1,213 brachytherapy patients, some of whom also received external-beam irradiation. The investigators compared the ASTRO definition to four definitions of failure that modified it as follows: (1) early censoring of nonrecurrent patients with rising PSA levels, (2) cumulative rather than consecutive rises (without a decrease) as evidence of recurrence, (3) both of the above, and (4) waiting 2 years before performing an analysis of data.[14] The first definition dealt with the bias introduced by backdating, the second with the potentially Page 11 of 13

12 lengthy period of time necessary for three consecutive rises, and the fourth with the effect of short follow-up on outcome. As Figure 6 shows, only minimal differences in outcome were seen as compared to the reports of Thames and Vicini, which showed greater differences with externally irradiated patients.[12,17] These findings point to the need for proper analysis of failure definitions using sensitivity and specificity testing in brachytherapytreated patients, as has been conducted in externally irradiated patients. Universal Failure Definition Although we have learned a great deal about the use of PSA as an early surrogate for treatment failure and disease recurrence in prostate cancer patients, distinctly different parameters have been used to define surgical, external radiation, and brachytherapy failure. In the case of surgery, the prostate is totally removed, while with both external radiation and radioisotopic implant, the gland remains intact although the functional- and PSAproducing capabilities after each respective treatment may differ. This may mean that a definition of failure must be established for each modality, but treatment comparisons would surely be simplified if the use of a universal definition of failure were possible. To date, definitions of failure have been tested and compared most thoroughly for external-beam radiotherapy, and to a lesser extent for brachytherapy and prostatectomy. Only through more extensive comparative testing of failure definitions for the various treatment modalities will the potential for the use of one encompassing definition be learned. Collaborative studies similar to the multi-institutional analysis discussed above[16-17] are in progress. Disclosures: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. References: 1. Kuban DA, El-Mahdi AM, Schellhammer PF: Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 32: , Horwitz EM, Vicini FA, Ziaja E, 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 36: , Kuban DA, el-mahdi AM, Schellhammer PF: PSA for outcome prediction and posttreatment evaluation following radiation for prostate cancer: Do we know how to use it? Semin Radiat Oncol 8:72-80, Wilett CG, Zietman AL, Shipley WU, et al: The effect of pelvic radiation therapy on serum levels of prostate specific antigen. J Urol 151: , McLaughlin PW, Sandler HN, Jiroutek MR: Prostate-specific antigen following prostate radiotherapy: How low can you go? J Clin Oncol 14: , Zietman AL, Tibbs MK, Dallow KC, et al: Use of PSA nadir to predict subsequent biochemical outcome following external beam radiation therapy for T1-2 adenocarcinoma of the prostate. Radiother Oncol 40: , American Society for Therapeutic Radiology and Oncology Consensus Panel Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37: , Shipley WU, Thames HW, Sandler HM, et al: Radiation therapy for clinically localized prostate cancer: A multi-institutional pooled analysis. JAMA 281: , Taylor JMG, Griffith KA, Sandler HM: Definitions of biochemical failure in prostate cancer following radiation therapy. Int J Radiat Oncol Biol Phys 50: , Pickles T, Duncan GG, Kim-Sing C, et al: PSA relapse definitions: The Vancouver rules show superior predictive power. Int J Radiat Oncol Biol Phys 43: , Critz FA: A standard definition of disease freedom is needed for prostate cancer: Undetectable prostate specific antigen compared with the American Society of Therapeutic Radiology and Oncology Consensus Definition. J Urol 167: , 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 45: , Horwitz EM, Uzzo RG, Hanlon AL, et al: Modifying the American Society for Therapeutic Radiology and Oncology definition of biochemical failure to minimize the influence of backdating in patients with prostate cancer treated with 3-dimenional conformal radiation therapy alone. J Urol 169: , Page 12 of 13

13 14. 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 48: , Gretzer MB, Trock BJ, Han M, et al: A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria. J Urol 168: , Kuban DA, Thames HD, Levy LB, et al: Long-term multi-institutional analysis of stage T1 T2 prostate cancer treated with radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys 57: , Thames H, Kuban D, Levy L, et al: Comparison of alternative biochemical failure definitions based on clinical outcome in 4,839 prostate cancer patients treated by external-beam radiotherapy between 1986 and Int J Radiat Oncol Biol Phys 57: , Aref I, Eapen L, Agboola O, et al: The relationship between biochemical failure and time to nadir in patients treated with externalbeam therapy for T1-T3 prostate carcinoma. Radiother Oncol 48: , Hanlon AL, Diratzouian H, Hanks GE: Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer. Int J Radiat Oncol Biol Phys 53: , 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 46: , Jani AB, Chen MH, Vaida F, et al: PSAbased outcome analysis after radiation therapy for prostate cancer: A new definition of biochemical failure after intervention. Urology 54: , Amling CL, Bergstralh EJ, Blute ML, et al: Defining prostate specific antigen progression after radical prostatectomy: What is the most appropriate cut point? J Urol 165: , Source URL: Links: [1] [2] [3] [4] Page 13 of 13