During the past 20 years of treatment of prostate cancer, significant changes in the detection, workup, and management of this disease have taken place. With the advent of prostate-specific antigen (PSA) screening that became routine in the late 1980s, a gradual shift in the clinical features of prostate cancer at diagnosis occurred, leading to increased rates of detecting organ-confined disease.1–5 Advances in imaging technology including transrectal ultrasound (TRUS), computerized tomography (CT), magnetic resonance imaging (MRI), and technetium Tc 99 bone scans permitted more accurate staging of patients with localized, locally advanced, and metastatic disease, resulting in better selection of stage-appropriate treatments.6 During this same period, significant changes in the definitive management of prostate cancer with external beam radiation therapy (RT) also occurred. The evolution from conventional to 3-dimensional conformal to intensity modulated RT (IMRT) techniques allowed the delivery of progressively higher doses of radiation, leading to improved rates of biochemical control.7–12 Concomitant with dose escalation, increasing use of androgen deprivation therapy (ADT) in patients with high-risk and locally advanced disease occurred,13–17 with 74% of patients treated with neoadjuvant ADT before RT in the modern treatment era.18
Given these significant changes in prostate cancer detection and treatment during the past 2 decades, the aims of this study were to analyze the impact of these changes on the clinical outcomes of prostate cancer after RT by treatment era and to identify the factors most highly associated with these observed changes.
The study group was selected from a cohort of 2838 men with localized prostate adenocarcinoma who were sequentially treated at MD Anderson between 1987 and 2007 with definitive external beam RT with or without ADT. This study was approved by the institutional review board, and waiver of consent was obtained in this retrospective analysis. Pathology and Gleason score for all patients were reviewed at the treating institution by a pathologist with expertise in genitourinary oncology. In total, 2675 men comprised the study cohort and met inclusion criteria including a pretreatment PSA of less than 100 ng/mL, a radiation dose of 60 Gy or higher, and a documented T stage. Patients were categorized into 3 treatment eras: 1987 to 1993 (n = 722), 1994 to 1999 (n = 828), and 2000 to 2007 (n = 1125) corresponding to the early PSA screening era, a transition period when ADT and higher-dose RT became more routinely incorporated into treatment, and a recent era when all patients received standard higher-dose RT and high-risk patients received ADT, respectively. Radiation treatment technique had evolved during this period, allowing the delivery of progressively higher doses of RT. In the first era, a simple 2-dimensional technique had largely been used in treatment of the pelvis. Between 1994 and 1999, a progression to a 3D technique occurred with the use of CT-based treatment planning. As of 2000, all patients were treated with IMRT with daily prostate localization.
Patients were stratified according to low-, intermediate-, and high-risk groups as defined by the National Comprehensive Cancer Network to help adjust for stage migration over time.19 Risk groups were defined as follows: low risk, stage T1a-T2a and Gleason score of 6 or lower and PSA less than 10 ng/mL; high risk, stage T3-4 or Gleason score of 8 or higher or PSA greater than 20 ng/mL; intermediate risk, all others. Patients were routinely followed up every 3 months for the first 2 years after treatment, every 6 months between 2 and 5 years after treatment, and then annually with serial digital rectal examinations (DREs) and PSA levels. The Phoenix definition of nadir PSA + 2 ng/mL was used to define biochemical recurrence.20 Any local, nodal, or distant recurrence or the institution of salvage therapy before a documented PSA rise was also included in the definition of biochemical recurrence. Local failure (LF) was defined as a rise in serum PSA leading to a positive needle biopsy or palpable disease recurrence on DRE. Nodal and distant recurrences were confirmed by abdominopelvic CT, MRI, or bone scan imaging. Clinical failure (CF) was defined as any LF, nodal failure, or distant failure (DF). The cause of death was determined by death certificate as recorded in the National Death Index database or in the patient’s electronic medical record from the institutional tumor registry, which routinely contacts patients regarding disease and vital status. Men with progressive, castrate-resistant metastatic disease at last follow-up were classified as having a death due to prostate cancer.
All statistical analyses were performed using Stata, release 11 (Stata Corp, College Station, TX) and SAS version 9.2 (SAS Institute, Inc, Cary, NC). Clinical outcomes of biochemical failure (BF), LF, DF, any CF, prostate cancer–specific survival (PCSS), and overall survival (OS) were calculated from end of RT and analyzed according to the Kaplan-Meier method. Follow-up for individual patients was censored at the last date of contact or death. Descriptive statistics were used to define the study cohort. Differences between prognostic patient characteristics including age, T stage, Gleason sum, pretreatment PSA, and National Comprehensive Cancer Network risk group as well as treatment-related factors of dose and ADT were analyzed using the Pearson χ2 test, and all tests were 2-sided. For the multivariate analysis, a Cox proportional hazards model was used applying backward elimination and a cut point of P = 0.05.
The median age was 68.5 years, and the median follow-up was 6.4 years (interquartile range, 6.5 years). Baseline patient-, disease-, and treatment-related characteristics for each treatment era are listed in Table 1. A total of 551 patients (21%) had low-risk, 1081 patients (40%) had intermediate-risk, and 1043 patients (39%) had high-risk disease. Overall, fewer patients treated in the most recent era presented with high-risk disease than patients treated in earlier eras. Although the median age at treatment did not change significantly over time, the percentage of patients presenting with earlier T stages (T1a-T2a) nearly doubled, whereas patients presenting with locally advanced disease decreased by two-thirds (P < 0.001). Most patients presented with PSA less than 10 ng/mL in the most recent era. Gleason 7 histology also increased with time. This likely contributed to the finding that nearly half of the patients treated in the most recent era were characterized as having intermediate-risk disease (P < 0.001).
Significant changes in treatment occurred with each successive era. The evolution of radiation technique from 2-dimensional to 3D to IMRT permitted the escalation of deliverable dose over time (P < 0.001). Only 4% of patients treated before 1994 received 72 Gy or higher, whereas 99% of patients treated from 2000 to 2007 received 72 Gy and higher. Patients were also increasingly treated with ADT, with men in the most recent era having a 10-fold greater likelihood of receiving some form of ADT compared with those treated in the earliest era (P < 0.001).
Kaplan-Meier estimates of BF-free survival (BFFS) across the 3 treatment eras are shown in Figure 1 for all patients and for each risk group (all Kaplan-Meier curves truncated when 10 or fewer patients at-risk remained). For low-risk men treated after the year 2000, 99% (95% confidence interval [CI], 95.7%–99.7%) remained free of BF 5 years after treatment. Intermediate- and high-risk patients had even greater absolute improvements with each treatment era (P < 0.001). Consequently, CF-free survival (CFFS) for all risk groups improved with time, especially in men with high-risk disease (Table 2). This was largely driven by improved rates of local control in high-risk men, where 10-year LF-free survival (LFFS) was 68% (95% CI, 62.0%–72.6%) in treatment era 1 versus 93% (95% CI, 88.6%–95.5%) in treatment era 2 (P < 0.001). Intermediate-risk patients also had fewer local relapses with each era, and there was even a trend toward improved local control in the low-risk group (P < 0.001 and P = 0.054, respectively). Rates of DF, less common than local recurrence, were significantly improved only in high-risk patients (Table 2). Of the 123 high-risk patients who developed distant metastases at last follow-up, 61% had been treated before 1993, 26% between 1994 and 1999, and 13% after the year 2000.
These improvements in disease control by era translated into improved PCSS in the highest-risk patients (P = 0.028; Fig. 2). Although not seen in men with low-risk disease (P = 0.663), a trend toward improved PCSS was evident in men with intermediate-risk disease, with only 8 (1%) of 860 patients dying of prostate cancer in the 2 most recent treatment eras combined (P = 0.078). Still, death due to prostate cancer was uncommon even in patients with high-risk disease. Ten years after treatment in the earliest era, 17% of high-risk patients died of prostate cancer, although the doses of RT were comparatively low (median, 66 Gy) and only 6% of all patients received ADT. Deaths from prostate cancer continued to occur more than 15 years after treatment, however. To date, only 10 (3%) of 339 high-risk patients treated in the most recent era have died of disease. Overall survival also improved during the last 20 years (Fig. 3). When stratified by risk group, this trend was largely due to improvements seen in high-risk patients, although a trend toward improved OS was also seen in patients with intermediate-risk disease (P = 0.067).
Multiple disease- and treatment-related factors predicted for LF on multivariable analysis. Patients with T3-4 tumors were 2.5 times more likely to develop local disease recurrence, whereas a pretreatment PSA of 10 ng/mL or less reduced the risk of LF to a similar magnitude as treatment with RT dose of 72 Gy and higher compared to patients with PSA greater than 10 ng/mL or those treated with a lower RT dose (adjusted hazard ratio [HR], 0.59; 95% CI, 0.42–0.79, P < 0.001; and adjusted HR, 0.51; 95% CI, 0.31–0.83, P = 0.007, respectively). Patients treated between 1994 and 1999 had significantly fewer LFs than patients treated in the early PSA era (adjusted HR, 0.63; 95% CI, 0.44–0.90, P = 0.012), and those treated in the modern era had the highest local disease control. The adjusted proportional hazards models for BF and CF as well as disease-specific and all-cause mortality are described in Tables 3 and 4. Compared to men with low pretreatment PSA less than 10 ng/mL or Gleason score of 6 or lower, men with a pretreatment PSA greater than 20 ng/mL or a Gleason of 8 to 10 pathology were 2.5 to 3.3 times more likely to develop BF or DF in this series. Men with PSA greater than 20 ng/mL or Gleason 8 to 10 had an increased risk of death from prostate cancer (PCSM) 3 to 4 times greater than men with low-risk disease (P < 0.001). Era of treatment was highly associated with radiation dose of 72 Gy or higher as well as treatment with ADT and predicted for improved PCSM after the early PSA era (1987–1993). After 2000, treatment era did not predict for PCSM because only 12 patients from this era had died of their disease at the last follow-up. Compared with men who did not receive ADT, men who were treated with ADT had a greater than one-third relative risk reduction in PCSM, and PCSM in men treated with RT dose of 72 Gy or higher was reduced by half compared with men treated with lower dose during earlier eras.
In this study looking at disease control and survival outcomes in men with localized prostate cancer treated with external beam RT during a 20-year period at a single institution, treatment during the modern era predicted for improved biochemical, local, and distant disease control in men of all risk groups. In men with low- and intermediate-risk disease, improvements in biochemical control with each successive treatment era have led to improved rates of CFFS. For high-risk men, improvements in biochemical and clinical disease control in the modern era have translated into improved PCSS compared with high-risk men treated in earlier periods. Moreover, treatment during the recent era predicted for improved OS in men with high-risk disease. Without a doubt, advances in cardiac and general medical care during the last 20 years have significantly influenced competing causes of mortality in this population of older patients. Consequently, patients treated in the modern era who are at highest risk of disease recurrence and death due to prostate cancer can expect to survive their disease and live longer than patients treated in the early PSA era. Indeed, a recent report from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) program demonstrates consistent improvement in PCSS between 1973 and 1995 for men with localized disease.21 In this study, an improvement in disease-specific survival and OS by treatment era was not seen in patients with low-risk disease. This is likely due to the paucity of prostate cancer–related deaths in this group of patients, with no patients dying of disease in the modern era. Even for men with low-risk disease treated in the early PSA era, most deaths from prostate cancer (6 total) occurred more than 10 years after treatment. With longer follow-up, this difference in prostate cancer–related deaths by treatment era may become more pronounced.
Multiple factors account for the differences in clinical outcome seen over time. Improvements in staging accuracy, stage migration due to the introduction of PSA screening, as well as treatment-related advances likely underlie these observed trends. The largest absolute improvements in BFFS and clinical disease control occurred between the earliest (1987–1993) and middle (1994–1999) treatment eras for patients of all risk groups. This corresponds to the early PSA screening era that preceded the era when PSA testing was in routine use, and the effects of stage migration were beginning to manifest. Indeed, multiple clinical and pathological series describe the rise in the number of organ-confined tumors at this time in patients who underwent PSA screening compared with evaluation based on abnormal DRE alone.22 In 1 report, the frequency of extracapsular extension after radical prostatectomy declined from 81% to 36% between 1987 and 1997 independent of preoperative PSA level, tumor stage, or Gleason score.23 Methods of detection also changed during this period. Advances in transrectal ultrasound, CT, and MRI have allowed the detection of smaller-volume cancers independent of PSA and Gleason grade24 and permitted better selection of stage-appropriate treatments. We found that the rate of organ-confined disease and a pretreatment PSA of 10 ng/mL or less rose significantly with each successive era of treatment, which contributed to high rates of local control in patients of all risk groups treated after 1994. Improvement in outcomes after the early PSA era reflect a more favorable subset of patients with earlier T-stage and lower pretreatment PSA who were increasingly treated with modern doses of RT >72 Gy and with ADT when appropriate. This is particularly evident in the high-risk cohort treated after the year 2000, when the incidence of locally advanced disease was as uncommon as a presenting PSA greater than 20 ng/mL, contributing to rates of local, regional, and distant disease control that exceeded 90%. Failure rates of PSA were slightly higher than CF rates in this cohort owing to the limited follow-up after the year 2000.
Beyond improvements in imaging and the gradual shift toward more favorable disease presentations, advances in treatment also explain the observed changes seen by treatment era. In this series, patients with high-risk disease had the greatest advances in biochemical and clinical disease control. Likely, the increasing use of ADT in the 1990s in patients with advanced or high-risk disease contributed to the significant improvement in outcomes seen between the first 2 eras. In high-risk patients, this translated into decreased rates of distant metastases and improved PCSS, and likely contributed to the improvement in OS seen only in this group of patients. Moreover, during the middle treatment era (1994–1999), higher doses of RT were beginning to be used at our institution based on retrospective work showing benefit in biochemical disease control.25 It was during this era that the MD Anderson randomized trial evaluated the benefit of dose-escalation to the prostate to 78 Gy. Beginning in 2000, the routine use of IMRT at our institution permitted the delivery of this higher dose to the planning target volume (prostate ± seminal vesicles) with minimal toxicity. Other studies showing the benefit of higher delivered doses on biochemical control altered practice patterns during this period.7,26–28 Even with limited follow-up, significant improvements in BFFS were seen in all risk groups treated in the late 1990s versus after the year 2000, including those with low-risk disease. Similar improvements in CF and prostate cancer-specific mortality were not seen after the late 1990s likely due to the few events occurring during the shorter period of follow-up.
Given the coevolution of disease- and treatment-related factors during this extended period, the relative significance of any individual factor is impossible to disentangle. The era of treatment examined in this study is likely a surrogate for a group of complex, interrelated factors that have changed the presentation and management of prostate cancer during the last 2 decades. The relatively long natural history of localized prostate cancer is influenced by a number of prognostic factors whose individual effects are difficult to define in a retrospective analysis. In addition, lead-time bias may affect the outcomes observed in patients treated across eras of variable PSA screening. Treatment-related factors of higher radiation dose, more sophisticated RT techniques, and the use of ADT are closely interrelated and evolved together during this period. Finally, as with any period analysis, limited follow-up in patients treated most recently may overestimate recent improvements in clinical outcomes, as not enough time has elapsed to see a significant number of events, particularly in low- and intermediate-risk patients.
In conclusion, in this study looking at outcomes of men in the PSA era treated at a single institution with definitive RT for localized prostate cancer, significant improvements in disease control and survival outcomes were seen with each successive treatment era. Without a doubt, earlier detection and disease presentation as well as advancements in therapy have contributed to the observed improvements in cancer control. Although all patients have benefited, men with high-risk disease have experienced the greatest improvement in freedom from PSA failure, clinical disease progression, PCSS, and OS during the last 2 decades. Longer follow-up is needed to determine whether similar disease-specific survival benefits are seen in patients with low- and intermediate-risk disease.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
Prostate; cancer; improvement; survival