International Journal of Radiation Oncology * Biology * Physics
Volume 71, Issue 5 , Pages 1295-1301, 1 August 2008

In Patients Experiencing Biochemical Failure After Radiotherapy, Pretreatment Risk Group and PSA Velocity Predict Differences in Overall Survival and Biochemical Failure-Free Interval

  • Daniel E. Soto, M.D., M.S.

      Affiliations

    • Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
    • Corresponding Author InformationReprint requests to: Daniel E. Soto, M.D., M.S., Department of Radiation Oncology, University of Michigan, 1500 E. Medical Center Dr., B2 C490, Box 0010, Ann Arbor, MI 48109-0010. Tel: (734) 936-4288; Fax (734) 763-7370
    • ,
  • Rebecca R. Andridge, M.S.

      Affiliations

    • Department of Biostatistics, University of Michigan, Ann Arbor, MI
    • ,
  • Charlie C. Pan, M.D.

      Affiliations

    • Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
    • ,
  • Scott G. Williams, F.R.A.N.Z.C.R.

      Affiliations

    • Division of Radiation Oncology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VC, Australia
    • ,
  • Jeremy M.G. Taylor, Ph.D.

      Affiliations

    • Department of Biostatistics, University of Michigan, Ann Arbor, MI
    • ,
  • Howard M. Sandler, M.D., M.S.

      Affiliations

    • Department of Radiation Oncology, University of Michigan, Ann Arbor, MI

Received 12 January 2008; received in revised form 27 February 2008; accepted 29 February 2008. published online 09 May 2008.

Article Outline

Purpose

To characterize the demographics and survival outcomes of localized prostate cancer patients who developed biochemical failure (BF) according to a prostate-specific antigen (PSA) nadir plus 2 ng/mL.

Methods and Materials

We identified 375 prostate cancer patients who had undergone external beam radiotherapy without androgen deprivation therapy but with sufficient PSA data to study PSA kinetics. Of these patients, we identified 82 with BF. The pretreatment PSA velocity was calculated for each patient.

Results

For the BF cohort, 26% were low-risk and 74% were intermediate- or high-risk patients. Of the 82 BF patients, 16 (20%) were noted to have both low-risk disease and a pretreatment low PSA velocity of ≤2 ng/mL/y (termed “low-risk low-velocity” [LRLV]). The remaining BF patients had either intermediate- or high-risk features or a high PSA velocity >2 ng/mL/y (termed “higher risk” [HR]). For patients who had BF, the LRLV group had a delayed median time to BF of 55 months compared with 33 months for the HR patients (p = 0.04). With a median clinical follow-up of 112 months, the 5-year overall survival rate was 100% for the LRLV BF patients vs. 84% for the HR patients (p = 0.02).

Conclusions

We observed that LRLV BF patients represent a sizeable proportion of all patients with treatment failure. However, when comparing LRLV BF with HR BF patients, the former had significantly better overall survival and a longer interval to BF. This suggests that not all BF events are equivalent and emphasizes the challenges associated with using BF alone as a surrogate for a survival endpoint.

Prostatic neoplasms, Prostate-specific antigen, Radiotherapy, Kinetics, Statistics

 

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Introduction 

A critical process in the evaluation of prostate cancer patients is pretreatment risk stratification. The goal of stratification is to help characterize a patient's risk of extraprostatic and nodal spread, as well as the response to therapy. This information can guide the physician and patient through the therapeutic decision-making process. A variety of risk stratification schemes 1, 2, 3, 4, 5, 6 and tools 6, 7, 8 have been described. These have been based on the observation that the pretreatment initial prostate-specific antigen PSA (iPSA), T stage, and Gleason score are independent predictors of biochemical failure (BF) 4, 5, 6, 9, 10. However, the superiority of one scheme over the others has not been demonstrated (11).

In clinical settings, patients are typically divided into low-, intermediate-, and high-risk groups. Although the exact dividing cutpoints for these can vary, the overall prognostic meaning is the same. For example, patients within the low-risk group have significantly better outcomes compared with the other risk group patients 1, 2. However, 8–20% of low-risk patients will still develop BF by 5 years 5, 12, 13, 14, 15. This occurs despite the use of dose-escalated radiotherapy (RT) 2, 12, 13 or the use of androgen deprivation therapy (ADT) 14, 15. Thus, a need has been demonstrated to further refine these stratification schemes to help identify these relatively unfavorable low-risk patients. If this can be achieved, the next goal would be to improve future therapeutic approaches for this subgroup.

One factor that appears to warrant widespread clinical application is the pretreatment PSA kinetics, such as the PSA doubling time or PSA velocity (PSAV). Several studies have shown that this information can help predict for BF 16, 17, survival 16, 17, 18, 19, 20, 21, and adverse pathologic features (22). This has even been demonstrated in low-risk patients (17). After 7 years of follow-up in an otherwise low-risk patient cohort with a median PSAV of 1.5 ng/mL/y, the BF rate was 51% (23).

Given the utility of PSA kinetics before treatment in predicting prostate cancer outcomes, we set out to characterize patients who had BF according to the definition of PSA nadir plus 2 ng/mL (24). We hypothesized that low-risk patients with favorable pretreatment PSAVs might still be developing BF. This question could have a significant effect on future risk stratification schemes and therapeutic approaches.

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Methods and Materials 

Patient selection 

With institutional review board approval, we retrospectively reviewed the medical records of patients treated for localized prostate cancer with three-dimensional conformal RT or intensity-modulated RT with curative intent at the University of Michigan Cancer Center and the Peter MacCallum Cancer Centre (Melbourne, VC, Australia). Patients were treated between January 1988 through December 2005 and January 1997 through December 2003 at the University of Michigan and the Peter MacCallum Cancer Center, respectively. Required data for the inclusion in this study included documentation of T stage, iPSA, and Gleason score. In addition, patients were required to have at least two recorded PSA measurements before RT, adequately spaced as a pair of consecutive values ≥90 days apart, or at least two pairs of consecutive values ≥60 days apart. The exclusion criteria included the presence of known lymphatic metastases, nonpelvic metastatic disease, the use of neoadjuvant or concurrent ADT or chemotherapy, and a history of prostatectomy, cryosurgery, or brachytherapy. We identified 375 patients who met our criteria.

All patients had undergone a pretreatment evaluation that included history and physical examination, pretreatment PSA measurement, prostate biopsy, as well as bone scan and diagnostic computed tomography, if clinically indicated. The pretreatment risk groups were defined as follows: low risk, Stage T2a or less, Gleason score <7, and PSA <10 ng/mL; high risk, Stage T2c or greater and/or Gleason score >7 and/or PSA level >20 ng/mL. All other patients were considered to have intermediate-risk disease.

Patient treatment 

All patients were treated with computed tomography-based three-dimensional conformal RT or intensity-modulated RT. Depending on their pretreatment risk group, the pelvic lymph nodes and/or seminal vesicles were treated. The median prostate dose to the International Commission on Radiation Units and Measurements point was 70.6 Gy.

Follow-up and endpoints 

The patients were seen at regular intervals, every 3–6 months for physical examination, digital rectal examination, and serial PSA measurement. Radiologic evaluation was performed if clinically indicated. The median PSA follow-up after RT for all patients was 39 months (interquartile range, 20–65). We used a BF definition based on the Phoenix definition of the current PSA nadir plus 2 ng/mL (24). In this study, we found 1 patient who had started ADT as a part of their salvage treatment before developing BF according to a PSA nadir plus 2 ng/mL and who was thus excluded from this analysis. The BF-free survival (BFFS) was measured starting from the end of RT and entailed censoring patients who had not developed BF at death. Overall survival (OS) was measured from the end of RT and included death from any cause.

Statistical analysis 

The median number of pre- and post-RT PSA values was 3 and 8, respectively. Any PSA level after salvage surgery, ADT, or chemotherapy was excluded, leaving a median of seven post-RT values per subject. We choose a PSAV cutpoint of 2 ng/mL/y because the D'Amico series demonstrated an effect on OS 17, 19. The PSAV was calculated from the regression of PSA in months. The post-RT PSA doubling time was calculated from the regression of log(PSA+1) in months for PSA values recorded after nadir for BF subjects. The regression was determined to be the best fit across multiple PSA values. PSA values taken after the start of ADT were excluded. One was added to each PSA value to avoid errors associated with logarithms of values approximating 0. The data were analyzed using the Statistical Analysis Systems, version 9.1, software (SAS Institute, Cary, NC).

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Results 

Patient characteristics 

Of the 375 patients identified, 82 (22%) met the BF definition of a PSA nadir plus 2 ng/mL. The mean age of this BF subgroup was 70 years. Of the 82 patients, 63% were white, 1% were African American, and 35% were “race unknown.” Patients were treated with a median radiation dose of 70.6 Gy. The median iPSA level was 9.4 ng/mL. Overall, 26%, 41%, and 33% of patients considered to have low, intermediate, and high risk, respectively (Table 1).

Table 1. Clinical and treatment characteristics∗
CharacteristicOverallLRLVHRp†
Patients (n)821666
Age at start of RT (y) 0.69
Mean70.169.770.3
SD5.65.05.7
Pretreatment PSA (ng/mL) <0.001
Median9.47.110.9
IQR7.1–14.05.6–8.87.8–15.3
Treatment year 0.45
Median199719971998
IQR1993–20001996–20001992–2000
Total dose 0.21
Median70.673.870
IQR68.4–74.069.9–74.967.8–74.0
Post-RT PSA values (n) 0.36
Median121511
IQR8–209–228–18
T stage (n) 0.02
T118 (22)7 (44)11 (17)
T250 (61)9 (56)41 (63)
T3-T414 (17)0 (0)13 (20)
Gleason score (n) <0.001
2–639 (48)16 (100)23 (35)
735 (43)0 (0)35 (53)
8–108 (10)0 (0)8 (12)
Pretreatment PSA (n) <0.001
<10 ng/mL45 (55)16 (100)29 (44)
10–20 ng/mL27 (33)0 (0)27 (41)
>20 ng/mL10 (12)0 (0)10 (15)
Risk group (n) <0.001
Low21 (26)16 (100)5 (8)
Intermediate34 (41)0 (0)34 (52)
High27 (33)0 (0)27 (41)
PSA failure82 (100)16 (100)66 (100)
Death17 (21)0 (0)17 (26)
Median OS follow-up (mo)‡90.1102.986.7
5-y Survival (%)
BFFS245018
OS8710084

Abbreviations: LRLV = low risk low velocity; HR = higher risk; RT = radiotherapy; SD = standard deviation; PSA = prostate-specific antigen; IQR = interquartile range; OS = overall survival; BFFS = biochemical failure-free survival.

∗All patients had BF using definition of PSA nadir plus 2 ng/mL.

†Comparisons between groups done using chi-square tests for frequencies, t tests for means, Wilcoxon rank sum tests for medians, and log–rank tests for survival analyses.

‡Median follow-up calculated using reverse Kaplan-Meier estimator.

Of the BF cohort, 16 (20%) were both low risk and had a low PSAV of ≤2 ng/mL/y (LRLV). The remaining 66 had either intermediate- or high-risk features or a PSAV >2 ng/mL/y (termed “high risk” [HR]). Comparing the LRLV and HR groups revealed a similar mean age (p = 0.69) and a median radiation dose (p = 0.21). In addition, both groups were treated in a similar treatment era, with a median year of 1997–1998 (p = 0.45). However, as expected, the LRLV group, by definition, had a more favorable T stage, Gleason score, and iPSA. The patient characteristics are listed in Table 1. For the full set of both BF and non-BF patients, the 5-year BF rate for those with LRLV was 11% vs. 31% for HR patients.

BF and post-RT, postnadir PSA kinetics 

Limiting the analysis to patients who had developed BF according to a PSA nadir plus 2 ng/mL, the LRLV group had a median BFFS of 55.1 months compared with 32.5 months for the HR group (p = 0.04). The 5-year BFFS rate was 50% and 18% for the LRLV and HR groups, respectively (Fig. 1).

  • View full-size image.
  • Fig. 1. 

    Biochemical failure-free interval. All patients had eventual biochemical failure using prostate-specific antigen nadir plus 2 ng/mL. Patients grouped by low risk and pretreatment prostate-specific antigen velocity of ≤2 ng/mL vs. patients with either prostate-specific antigen velocity >2 ng/mL or high/intermediate-risk features (p = 0.04).

The LRLV and HR groups also differed in their median PSA nadir (0.7 ng/mL vs. 1.2 ng/mL, respectively; p = 0.02). In addition, the median post-RT PSAVs were slower for the LRLV group at 0.9 ng/mL/y vs. 1.9 ng/mL/y for the HR group (p = 0.01). This was further supported by the longer median post-RT PSA doubling time of 33 months vs. 17 months for the LRLV and HR groups, respectively (p = 0.02). The post-treatment kinetics are listed in Table 2.

Table 2. Post-treatment PSA kinetics for patients with BF
Post-RT, post-PSA nadir kineticsOverallLRLVHRp
Patients∗ (n)781662
Nadir PSA (ng/mL) 0.02
Median1.00.71.2
IQR0.6–1.70.5–1.00.7–2.1
Interval to PSA nadir (mo) 0.40
Median131513
IQR9.7–2011–209.4–19
PSAV (ng/mL/y) 0.01
Median1.40.91.9
IQR0.86–4.10.49–1.41.0–4.7
PSADT (mo) 0.02
Median183117
IQR10–3318–4710–26
First to last PSA interval (mo) 0.06
Median243322
IQR12–4025–5510–37
PSA measurements (n) 0.05
Median554
IQR3–64–103–5
PSAV (n) 0.02
0–1 ng/mL/y24 (31)10 (63)14 (23)
1–2 ng/mL/y22 (28)4 (25)18 (29)
2–3 ng/mL/y8 (10)0 (0)8 (13)
>3 ng/mL/y24 (31)2 (13)22 (35)
PSADT (n) 0.05
24 mo51 (65)7 (44)44 (71)
24–48 mo19 (24)5 (31)14 (23)
48–72 mo5 (6)2 (13)3 (5)
>72 mo3 (4)2 (13)1 (2)

Abbreviations: BF = biochemical failure; PSAV = prostate-specific antigen velocity; PSADT = PSA doubling time; other abbreviations as in Table 1.

∗At least one pair of consecutive values ≥90 days apart or at least two pairs of consecutive values ≥60 days apart after PSA nadir.

Overall survival 

For patients with BF, we noted a median OS follow-up of 103 and 87 months for the LRLV and HR groups, respectively. The 5-year OS rate was 100% and 84% for the LRLV and HR groups, respectively (p = 0.04). Kaplan-Meier curves are displayed in Fig. 2.

  • View full-size image.
  • Fig. 2. 

    Overall survival. All patients had eventual biochemical failure using prostate-specific antigen nadir plus 2 ng/mL. Patients grouped by low risk and prostate-specific antigen velocity of ≤2 ng/mL vs. patients with either prostate-specific antigen velocity >2 ng/mL or high/intermediate-risk features (p = 0.02).

Comparison of LRLV-BF patients with non–BF-LRLV patients 

Of our complete 375 patient cohort, we found 97 LRLV patients with a PSAV of ≤2 ng/mL/y without BF. These patients had a median age (p = 0.10) and median iPSA level (p = 0.07) similar to those of the LRLV patients with BF. In addition, their median PSA nadirs were similar (p = 0.80). However, the non-BF patients had been treated more recently and thus had a shorter follow-up (p = 0.006). In addition, they had been treated with a greater median dose (p = 0.009). The characteristics are listed in Table 3.

Table 3. Comparison of BF and non-BF LRLV patients
LRLV∗ characteristicWith BFWithout BFp∗
Patients (n)1697
Age at start of RT (y)
Mean69.767.20.10
SD5.07.4
Median68680.26
IQR65–7461–73
Pretreatment PSA (ng/mL) 0.07
Median7.16.0
IQR5.6–8.84.2–7.6
Treatment year
Median199720010.006
IQR1996–20001999–2003
Total dose (Gy) 0.009
Median73.875.8
IQR69.9–74.974.0–75.8
Post-RT PSA measurements (n) <0.001
Median158
IQR9–224–11
Nadir PSA (ng/mL) 0.80
Median0.70.7
IQR0.5–1.00.4–1.3
T stage (%) 0.09
T17 (44)66 (68)
T29 (56)31 (32)

Abbreviations: BF = biochemical failure; other abbreviations as in Table 1.

∗All patients in both groups were low risk and, thus, by definition had Stage T2a or less, Gleason score 2-6, and PSA <10 ng/mL.

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Discussion 

A number of reports have failed to demonstrate a relationship between BF and OS 25, 26, 27, 28. However, two different series recently demonstrated that BF can predict OS 29, 30. On the basis of these conflicting reports, a consensus on the ability of BF to act as a surrogate endpoint for OS has not yet been reached. Thus, an interest in analyzing the PSA kinetics has been generated to help refine the ability to predict for inferior prostate treatment outcomes, including survival.

One factor that has gained significant attention is the use of pretreatment PSA kinetics, such as PSAV. Several studies have shown that this information can help predict BF 16, 17 and survival 16, 17, 18, 19, 20, 21. The source of PSA failure in patients with an unfavorable PSAV is either locally persistent disease or extraprostatic disease that was not addressed by the local therapy. In support of this, the pretreatment PSAV has been noted to predict for adverse pathologic features such as extraprostatic extension, positive surgical margins, higher Gleason score, larger tumor burden (22), and metastatic disease (31).

Although not formally incorporated into pretreatment risk stratification schemes or tools, pretreatment kinetics such as the PSAV seem to add a greater level of discrimination in identifying patients at risk of inferior outcomes 16, 17, 19, 20, 23, 32, 33. Thus, some have proposed that patients with unfavorable pretreatment PSAVs might warrant additional therapy to improve the treatment outcomes 34, 35.

Traditional stratification schemes, by definition, have demonstrated that low-risk patients have significantly better outcomes compared with the other risk groups 1, 2, 5. However, a significant number (8–20%) of low-risk patients still develop BF within the first 5 years. These BFs occur despite the use of RT dose escalation 2, 12 or ADT 14, 15. This demonstrates the need to further refine the low-risk stratification subgroup to help identify who these unfavorable low-risk patients are. One factor that has been shown to improve low-risk stratification is the pretreatment PSAV 17, 19.

D'Amico et al. (17) reported on an external beam RT monotherapy series of 125 low-risk and 223 intermediate-risk patients in which a pretreatment PSAV of >2 ng/mL/y was independently associated with inferior OS (p = 0.005). This significant difference was maintained in the low-risk subgroup analysis (p = 0.003). This translated to a 7-year OS rate of 86% vs. 47% in favor of those with a PSAV of ≤2 ng/mL/y. The corresponding 7-year estimates of BF were high at 54% vs. 78%. In this series, low-risk patients were defined as those with Stage T2a or less, PSA level ≤10 ng/mL, and Gleason score ≤6. The median radiation dose was 70.4 Gy, and the median follow-up was 4 years (17). Consistent with these findings, a recent report of a low-risk cohort with a median PSAV of 1.5 ng/mL/y noted that by 7 years, BF had developed in 51% of patients (23). However, only a small portion of BF patients develop a serious clinical event (36).

A closer look at the series of D'Amico et al. (17) revealed that 160 of the 358 patients met the American Society for Therapeutic Radiology and Oncology consensus definition of BF. Of all patients with BF, only 31 (19%) of 160 were low risk and had a pretreatment PSAV of ≤2 ng/mL/y. The remainder had intermediate/high-risk features or an unfavorable PSAV. When examining all low-risk patients with a PSAV ≤2 ng/mL/y, 31 (32%) of 96 had BF (17). This suggests that despite adding PSAV to the pretreatment risk stratification scheme, a significant number of favorable low-risk patients will still develop BF. The reason LRLV patients could experience BF is unclear. However, one possibility is understaging of the true Gleason score or T stage 22, 37, 38.

Given the observation that low-risk patients with favorable pretreatment PSAVs might still develop BF, we set out to characterize patients who had developed BF using the definition of a PSA nadir plus 2 ng/mL (24) in our patient series. If such a group could be identified, we wanted determine whether they differed from other BF patients, as well as from low-risk patients without BF.

In our series, a number of findings were observed. First, of the 82 patient BF cohort, 16 (20%) were both low risk and had a pretreatment PSAV of ≤2 ng/mL/y (LRLV). The remaining 66 had either intermediate/high-risk features or an unfavorable PSAV of >2 ng/mL/y (HR). We observed a superior median BFFS for the LRLV group (p = 0.04), indicating that BF, when it occurs, is a later event if patients initially have low-risk disease and favorable PSA kinetics. Consistent with these findings, the median post-RT PSAVs were slower for the LRLV group at 0.9 ng/mL/y than for the HR group at 1.9 ng/mL/y (p = 0.02). However, the 5-year OS was significantly superior for the LRLV BF group than for the unfavorable BF patients (p = 0.02). This suggests that not all BFs have an equivalent effect on OS, indicating some of the challenges with using BF alone as a surrogate for a survival endpoint.

We thus set out to compare LRLV BF patients and no-BF LRLV patients. We did not observe differences in age (p = 0.26), median iPSA (p = 0.07), or median PSA nadir (p = 0.80). However, the no-BF patients had been treated more recently (p = 0.006) and with a greater median dose (p = 0.009).

These findings suggest that other factors need to be incorporated to improve low-risk group stratification. Two potential candidates include perineural invasion (PNI) status and the percentage of positive cores. Both of these have been shown to predict BF and prostate cancer-specific mortality 38, 39, 40, 41, 42, 43. However, at this time, validated predictive tools using these factors have not been described. Once such validated tools become available, we should be able to predict which patients with low-risk disease and favorable pretreatment PSAVs will still develop BF. This group could then be the focus of future studies aimed at improving the therapeutic approaches.

At present, we do not know whether LRLV BF patients would go on to develop clinical significant events with longer follow-up. However, should these patients be found to have inferior clinical outcomes, they might potentially benefit from augmented therapy. One potential method of augmenting therapy would be the use of systemic therapies such as ADT. For example, a retrospective series reported by D'Amico et al. (35) of 241 men with a pretreatment PSAV >2 ng/mL/y reported that adding 6 months of ADT to RT improved the biochemical, prostate cancer mortality, and OS endpoints. However, most of these patients had intermediate- and high-risk features. Subgroup analysis using pretreatment risk groups was not presented. This emphasizes the need for prospective studies examining this issue.

No consensus has yet been reached on the optimal method of calculating the PSAV. Some groups use only the most recent PSA values within 12–18 months before the start of treatment 17, 19, 35, and others use all available pretreatment PSA values within 24 months or even longer before treatment 16, 33. However, it does appear that using PSA values within the 18 months before treatment, compared with all available PSA levels, yields slightly better predictive values for BF, prostate cancer-specific mortality, and OS (44). This could be the reason some series failed to demonstrate PSAV's predictive power on OS (33). In our own series, we choose to use all available pre-RT PSA values.

Our study did have several limitations. First our sample size was modest. Thus, these findings should be considered preliminary and in need of validation in a larger patient group. Second, it might be impractical in a clinical setting to have patients routinely present with a sufficient number and adequately spaced pretreatment PSA values to calculate the pre-RT PSAV. Third, our LRLV BF group had received a greater median radiation dose and had a shorter follow-up. These factors could have favored the BFFS and OS endpoints in these patients. Finally, these results cannot be extrapolated to patients undergoing brachytherapy or neodjuvant or adjuvant ADT as a part of their treatment. Patients undergoing ADT were excluded, because their PSA kinetics can be dramatically altered by androgen suppression 45, 46.

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Conclusions 

We observed that LRLV BF patients constitute a significant proportion of all patients with treatment failure and all LRLV patients. However, when comparing LRLV BF patients with HR patients, the former had significantly better OS and a longer BF-free interval. This emphasizes the idea that not all BF events are equivalent in terms of survival, as well as the challenges of using BF alone as a surrogate for a survival endpoint. In addition, these data emphasize the need to determine whether LRLV BFs are clinically significant and whether they warrant additional therapy.

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Acknowledgments 

We are indebted to Steven Kronenberg for assistance in generating the figures.

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 Note—An online CME test for this article can be taken at http://asro.astro.org under Continuing Education.

 Conflict of interest: none.

PII: S0360-3016(08)00503-8

doi:10.1016/j.ijrobp.2008.02.069

International Journal of Radiation Oncology * Biology * Physics
Volume 71, Issue 5 , Pages 1295-1301, 1 August 2008

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