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Keywords:

  • antiandrogen;
  • biochemical response;
  • Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE);
  • diethylstilbesterol;
  • luteinizing hormone-releasing hormone;
  • prostate cancer

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Prostate cancer is largely an androgen-sensitive disease. Androgen-deprivation therapy (ADT) generally has been used for patients with advanced disease. However, ADT is used increasingly as monotherapy for patients with clinically localized disease. The objective of the current report was to describe the characteristics of patients who underwent ADT for the management of localized disease.

METHODS

Cancer of the Prostate Strategic Urologic Endeavor (CaPSURE), which is a national disease registry of men with prostate cancer, was screened to identify patients who received treatment with primary ADT (PADT) between 1989 and 2002 for clinically localized disease (T1-T3,Nx/N0,Mx/M0). Clinical data (including Gleason score, prostate-specific antigen [PSA] level, and T classification) and sociodemographic data (including age, race, education, income, and insurance coverage) were analyzed with chi-square statistical tests. Time to failure data were analyzed using log-rank tests, the Kaplan–Meier method, and Cox proportional hazards regression analyses.

RESULTS

Of 7045 men, 993 patients (14.1%) with clinically localized disease received primary ADT. Compared with patients who underwent standard treatment, patients who received PADT had higher risk disease (as defined by PSA level, T classification, and Gleason score) and had more comorbidities. Patients who underwent PADT were older, less educated, had lower income, and were more likely to have Medicare than private insurance. The dominant forms of hormone therapy were luteinizing hormone-releasing hormone (LHRH) monotherapy (48.6%) and combined androgen blockade (LHRH agonist and antiandrogens; 38.8%). At 5 years after the initiation of PADT, 67.3% of patients still were receiving treatment with only androgen deprivation, 103 patients (13.8%) had gone on to receive definitive second treatment (radical prostatectomy, external beam radiotherapy, brachytherapy, or cryotherapy), 27 patients (3.9%) underwent second-line therapy (chemotherapy or alternative hormone-deprivation therapy), 22 patients (4.1%) died of prostate cancer, and 146 patients (19%) died of all causes.

CONCLUSIONS

The use of PADT therapy appeared to control disease in the majority of patients who received it, at least for an intermediate period. However, such patients appeared to be unique based on sociodemographic characteristics, comorbidity status, and risk factors compared with patients who received other forms of therapy. The impact of PADT on quality of life needs to be compared with standard therapy, and its long-term durability should be assessed better in patients with prostate cancer. Cancer 2006. © 2006 American Cancer Society.

Androgen-deprivation therapy (ADT) usually is an effective form of treatment for men with prostate cancer because of the hormone-sensitive nature of the disease. Although it may not be curative, the majority of patients can expect a biochemical and clinical response to such therapy.1 Aside from the proven role in metastatic disease, ADT appears to be useful in an adjuvant setting for patients with intermediate-risk and high-risk prostate cancer who are receiving radiotherapy.2 Conversely, the use of ADT with surgery has been studied in randomized trials and was found to be ineffective in reducing biochemical recurrence.2, 3 The use of hormone therapies for localized disease has become very common and has increased substantially over time.4, 5 However, to our knowledge the effect of such therapy in patients with localized disease has not been well documented.

In the current report, we have described a population of men who received ADT as their primary treatment for localized prostate cancer and compared them with patients who received other treatments, and we have described the types of ADT administered to these patients in the context of an observational data registry of actual urologic practices. In addition, we have described the clinical response and durability of therapy among these men.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE™) is a nationwide longitudinal, observational disease registry of men with biopsy proven adenocarcinoma of the prostate. The CaPSURE data registry contains demographic, clinical, treatment, and outcomes data for >11,000 patients from 40 urology practices, including 34 community-based practices, 3 academic medical centers, and 3 Veterans Administration hospitals. Patients are treated according to the usual practice of their urologist. Random audits of data are performed to ensure data accuracy. Patients are followed until the time of death or withdrawal from the study. Additional details of the project methodology have been reported previously.6 All patients entered into the CaPSURE data registry provide their informed consent.

In August 2004, 11,182 patients were enrolled in the CaPSURE disease registry. When restricted to data for patients who were diagnosed between 1989 and 2002 with clinically localized disease (T1-T3a,Nx/N0,Mx/M0), 7045 patients were eligible for the current study. All patients in this analysis had baseline demographic information (age at diagnosis, race, education, income, relationship status, and type of insurance coverage) and clinical information (prostate-specific antigen [PSA] level at diagnosis, biopsy Gleason score, clinical tumor classification [T classification], number of comorbidities, body mass index, and type of primary ADT [PADT]) available.

PADT was defined as bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonist, antiandrogen, diethylstilbesterol (DES), or finasteride therapy alone or in any combination for ≥9 months without any additional definitive treatment (i.e., surgery, radiotherapy, or cryotherapy) for prostate cancer. The PADT patients were compared with patients who underwent radical prostatectomy, external beam radiotherapy, brachytherapy, or cryotherapy as primary treatment, or patients who were being treated by watchful waiting. Chi-square analysis was performed to compare demographic and clinical data from patients who received PADT with data from patients who received other treatments.

Clinical risk at diagnosis was defined by using modified D'Amico risk criteria. Low-risk patients had a diagnostic PSA level ≤10 ng/mL, a biopsy Gleason total from 2 to 6 with no Gleason 4/5 pattern, and a clinical T classification of T1 or T2a. The intermediate-risk group had a PSA level from 10.1 ng/mL to 20.0 ng/mL, or a Gleason total of 7, or a secondary Gleason score of 4 or 5, or T2b or T2c disease. Patients in the high-risk group had a PSA level >20.0, or a Gleason total from 8 to 10, or a primary Gleason of 4 or 5, or T3a disease.

We investigated several treatment outcome variables for patients on PADT, including 1) the use of a definitive therapy (i.e., radical prostatectomy, external beam radiotherapy, brachytherapy, or cryotherapy) after PADT, 2) second-line therapy (i.e., the use of chemotherapy or medication for hormone-resistant prostate cancer), 3) all cause mortality, and 4) mortality from prostate cancer. Time to failure data were analyzed by using the log-rank test, Kaplan–Meier and life table methods, and Cox proportional hazards regression. Kaplan–Meier curves were created for each of the failure outcomes. Cox proportional hazard models were constructed to determine predictors for failure. Models were adjusted for demographic and baseline clinical covariates. All statistical analyses were performed using SAS for Windows (version 9; SAS Institute, Inc., Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

PADT represented the treatment choice for 14% of patients (n = 993 men) with localized disease. Most patients with localized disease opted for definitive therapy: 50% underwent surgery, 13% received external beam radiotherapy, 13% received brachytherapy, and 4% received cryotherapy. Watchful waiting represented 6% of this cohort. The pretreatment characteristics of patients are displayed in Tables 1 and 2, which compare men who underwent PADT with men who received all other treatments. The mean age of PADT patients was the highest at 73.7 years (standard deviation, 7.84 yrs). PADT patients were older, had less education, had lower incomes, and were more likely to receive Medicare than private insurance compared with patients who received other treatments (P < .01).

Table 1. Patient Demographics
DemographicNo PADTPADTP Value
No. of Patients%No. of Patients%
  1. PADT: primary androgen-deprivation therapy; SD: standard deviation.

Age at diagnosis, y     
 < 5563010192<.01
 55–5983414374 
 60–64119220677 
 65–6914762414915 
 70–7411421921622 
 75–796251028429 
 > 80152322122 
 Mean age (SD), y65.3 (8.04) 73.7 (7.84)  
 Median age, y66.0 75.0  
Race     
 White53628984185<.01
 African American486811011 
 Other2033424 
Education     
 < High school7511620228<.01
 High school graduate12792618826 
 Some college9432013018 
 College graduate18613820328 
Income     
 < $30,00013893334355<.01
 $30,000–50,00011022614223 
 > $50,00017524113522 
Relationship     
 In relationship42859258283<.01
 Single395811817 
Insurance     
 Medicare supplement21683652353<.01
 Medicare8061320921 
 Private26774419019 
 Veterans Administration1533283 
 Other/unknown2474434 
Table 2. Patient Clinical Characteristics
VariableNo PADT (n = 6051)PADT (n = 993)P Value
No. of Patients%No. of Patients%
  1. PADT: primary androgen-deprivation therapy; PSA: prostate-specific antigen; SD: standard deviation.

PSA     
 < 4.0 ng/mL81413768<.01
 4.1–10.0 ng/mL36866141041 
 10.1–20 ng/mL10791821922 
 > 20.0 ng/mL472828829 
 Mean (SD), ng/mL9.8 (12.54) 26.7 (62.79)  
 Median, ng/mL6.6 10.4  
Tumor classification     
 T125154235936<.01
 T233835655456 
 T31533808 
Gleason score     
 2–45559404<.01
 5–637526244745 
 713332230130 
 8–10411720521 
Gleason group     
 4–539307045648<.01
 1–3/4–59611720622 
 4–5/1–57431328230 
Risk group     
 Low24834122723<.01
 Intermediate23053827928 
 High12632148749 
Comorbidities     
 None10272110514<.01
 1–226185332143 
 >313072631342 
Body mass index     
 Normal (< 25.0 kg/m2)13602924335.02
 Overweight(25.0–29.9 kg/m2)23555132947 
 Obese (≥ 30.0 kg/m2)9142012918 

Clinically, 51% of PADT patients had Gleason scores ≥ 7 compared with 29% of patients receiving other therapies (P < .01). The median PSA value was 10.4 ng/mL for patients who received PADT and 6.6 ng/mL for patients who received other treatments (P < .01).

The different modalities used for androgen suppression are shown in Table 3. LHRH agonists, as monotherapy or in combination with antiandrogen medication, represented treatment for 88% of patients who received PADT. In addition, 5% of patients underwent orchiectomy, 2% received antiandrogen monotherapy, 1% received finasteride, and 4% received some other non-LHRH combination. Only 1 patient received DES monotherapy.

Table 3. Different Modalities Used for Androgen Suppression
TreatmentFrequency%
  1. LHRH: luteinizing hormone-releasing hormone; AA: antiandrogen; DES: diethylstilbesterol.

LHRH agonist48349
LHRH and AA38539
Orchiectomy273
Orchiectomy and hormone medication242
AA232
LHRH, AA, and finesteride192
Finasteride131
DES10
Other combination hormone therapy182
Total993100

The time to second definitive treatment is shown in Figure 1. Figure 2 illustrates the time to chemotherapy or other medication for patients with hormone-resistant disease. Kaplan–Meier curves for death from prostate cancer and for all-cause mortality are shown in Figures 3 and 4. Five years after they received PADT, 13.8% of patients went on to receive definitive therapy, 3.9% underwent chemotherapy or received other medication for hormone-resistant prostate cancer, 4.1% died from prostate cancer, and 19% died from all causes.

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Figure 1. This chart illustrates time to second definitive treatment.

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Figure 2. This chart illustrates time to treatment with chemotherapy or other hormone-resistant medication.

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Figure 3. This chart illustrates time to death from prostate cancer.

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Figure 4. This chart illustrates the time to death from any cause.

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A Cox proportional hazards regression analysis of the time to second definitive treatment was adjusted for demographics (age at diagnosis, race, education, income, relationship status, and insurance), clinical risk measures at the time of diagnosis (PSA, Gleason total, and T classification), body mass index at diagnosis, and type of PADT. The model was not adjusted for PSA doubling time or velocity because we did not have PSA values for a sufficient number of participants for the period after hormone therapy and subsequent washout to determine post-ADT PSA changes over time. Predictors for receiving definitive therapy after PADT included age, education, and type of hormone therapy. Men age older than 80 years at diagnosis were less likely to receive second treatment than men age younger than 70 years (hazards ratio [HR], 0.11; 95% confidence interval [95% CI], 0.03-0.39). Men who graduated from high school also were less likely to receive second treatment compared with men who did not finish high school (HR, 0.33; 95% CI, 0.14-0.78). Patients receiving combined androgen blockade (LHRH agonist and antiandrogen) were more than twice as likely as men on LHRH agonist alone to receive definitive therapy (HR, 2.35; 95% CI, 1.37-4.03).

The Cox analysis also was stratified according to risk group to determine whether there was a stronger effect based on putative aggressiveness of disease. For low-risk patients, those who used androgen deprivation other than LHRH agonist or combined androgen blockade were > 5 times as likely to receive definitive treatment (HR, 5.48; 95%CI, 1.06-28.45) compared with patients treated with LHRH monotherapy. In the medium-risk cohort, private insurance (HR, 2.86; 95% CI, 1.07-7.69) and the use of combined androgen therapy rather than LHRH alone (HR, 2.37; 95%CI, 1.03-5.46) were associated with receiving definitive therapy after PADT. In the high-risk group, patients age 80 years and older were much less likely to receive definitive treatment (HR, 0.05; 95%CI, 0.01-0.45) compared with patients age younger than 70 years.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A significant proportion of patients (14% in the current study) received ADT as primary treatment for localized disease, although ADT is indicated for the treatment of advanced disease. Historically, such patients have been treated with focal or curative forms of therapy.7, 8 In addition, many such patients may be candidates for active surveillance or novel therapies, such as cryotherapy.9, 10 However, to our knowledge, there is a paucity of literature assessing the efficacy of PADT in such patients.

The choice of PADT over observation versus other treatments remains controversial. One study examined the use of PADT in patients for whom local treatment was deemed unsuitable. Akaza et al.11 defined failure for PADT patients as increasing PSA level or increase in the size of the lesion on imaging studies. The 2-year progression-free survival rate was 43% for patients with T3 tumors and 62% for patients with T2 tumors who received LHRH monotherapy. Labrie et al.12 studied a cohort of patients on long-term, combined androgen blockade and, for 115 patients who had Stage III disease, the 5-year and 10-year disease-free survival rates were 75% and 54%, respectively. However, both of those studies focused on a selected group of patients and made no comparisons with surveillance or focal, curative treatment.

Chodak et al. examined PADT and found insufficient evidence to support its use in patients with localized disease.13 Loblaw et al.14 published American Society of Clinical Oncology guidelines and based on their exploratory analysis, concluded that treatment with antiandrogen monotherapy was unlikely to lead to a survival benefit in patients with localized disease who are managed with nondefinitive therapy (watchful waiting).

Among CaPSURE patients, men who received PADT appeared to have different characteristics compared with men who had clinically localized disease and received other forms of therapy. Seventy-three percent of PADT patients were age older than 70 years. In contrast, only 32% of patients who received other treatments were age older than 70 years. This population also had a correspondingly lower income and less private insurance than patients who did not receive PADT. Both factors have been associated previously with lower survival rates.15 PADT patients also tended to have more comorbidities than other patients: 42% had ≥3 health conditions compared with 26% among other patients. Comorbidity status has been identified as an independent predictor of nonprostate cancer death, even after adjusting for age and treatment.16 Therefore, physicians may have selected PADT to obviate what they believed was more morbid treatment.

Furthermore, we observed that the tumor characteristics for patients receiving androgen therapy were more aggressive than tumor characteristics for patients who received other treatments. Fifty-one percent of patients had pretreatment PSA values > 10 ng/mL, and 51% had Gleason scores ≥ 7 compared with 26% and 29%, respectively, for patients who did not receive PADT. Although 49% of PADT patients did have high-risk disease, 23% of patients who received ADT had low-risk disease (e.g., PSA ≤ 10 ng/mL, Gleason score ≤ 6, and clinical T classification of ≤ T2a). Active surveillance may be a very good option for the group of patients who have low-risk disease.9, 17

The multivariate analysis that controlled for these covariates demonstrated that advanced age and lower education were associated with less likelihood of receiving definitive therapy after PADT. It has been shown that education has a protective effect from prostate cancer mortality.18 When patients were analyzed by risk group, patients with high-risk cancers appeared to be the group driving the observation that age was protective from receiving another therapy. The observation that older patients with high-risk disease are kept on hormone deprivation intuitively appeared to be appropriate because they were less likely to be eligible for definitive therapies. In the intermediate-risk group, having private insurance indicated 2.8 times the likelihood of undergoing a second treatment. However, the socioeconomic implications of this finding were beyond the scope of the current study.

Furthermore, patients who began on combined androgen blockade (LHRH agonist and antiandrogen) were more than twice as likely to undergo definitive treatment than patients on LHRH monotherapy. The practitioner may be treating more aggressive disease with combined therapy because of evidence that combined androgen blockade prolongs survival compared with monotherapy.19 In addition, combination treatment may be a surrogate for a patient's or physician's desire for more effective therapy.

PADT appears to remain the treatment of choice for the men who start treatment with it. Within 5 years, only 14% of patients in the current study later underwent definitive therapy, and 4% underwent chemotherapy. Only 4% of PADT patients died of prostate cancer, compared with the all-cause mortality rate of 19%.

Unfortunately, because of the manner in which data were collated, it is not possible to ascertain which patients have undergone intermittent versus continuous androgen ablation. However, CaPSURE is a disease registry with nationwide representation and well maintained data. The observational nature of the registry with a preponderance of community urologic practices allows for as accurate a picture of actual practice in the U.S. as currently possible. The current study documents the use of PADT in this population of community-based men with localized prostate cancer, and describes which patients are more likely to receive PADT and their course of additional treatments and mortality after PADT. A randomized trial comparing PADT with active surveillance or local treatment, such as radiation or surgery, will be needed to determine the efficacy of this treatment approach.

The use of PADT for the management of clinically localized disease is increasing. Such therapy appears to be effective in the majority of patients who receive it, at least up to 5 years. However, such patients appear to be unique based on sociodemographics, comorbidity status, and risk factors compared with patients who receive other forms of therapy. The impact of PADT on quality of life and resource use needs to be compared with standard therapy, and its long-term durability should be assessed better. 4

Table 4. Time to and Type of Treatment Failure
Days from PADT initiation toFailure, DaysWithout Failure, DaysMeanMedian
No. of PatientsMeanMedianNo. of Patients
  • PADT: primary androgen-deprivation therapy; SD: standard deviation.

  • *

    Definitive second treatment was defined as radical prostatectomy, external beam radiotherapy, brachytherapy, or cryotherapy.

  • Second-line therapy was defined as chemotherapy or the use of hormone-refractory medications.

Definitive second treatment*1036194158901334990
Second-line therapy2710697939661335991
Death due to prostate cancer221265142797113501009
Death from all causes146135511218471317984
Failure in any form2549936927391266953

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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    Soloway MS, Pareek K, Sharifi R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002; 167: 112116.
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    Cooperberg MR, Grossfeld GD, Lubeck DP, Carroll PR. National practice patterns and time trends in androgen ablation for localized prostate cancer. J Natl Cancer Inst. 2003; 95: 981989.
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    Cooperberg MR, Lubeck DP, Meng MV, Mehta SS, Carroll PR. The changing face of low-risk prostate cancer: trends in clinical presentation and primary management. J Clin Oncol. 2004; 22: 21412149.
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    Labrie F, Candas B, Gomez JL, Cusan L. Can combined androgen blockade provide long-term control or possible cure of localized prostate cancer? Urology. 2002; 60: 115119.
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    Chodak GW, Keane T, Klotz L. Critical evaluation of hormonal therapy for carcinoma of the prostate. Urology. 2002; 60: 201208.
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    Loblaw DA, Mendelson DS, Talcott JA, et al. American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol. 2004; 22: 29272941.
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    Hall SE, Holman CD, Wisniewski ZS, Semmens J. Prostate cancer: socio-economic, geographical and private-health insurance effects on care and survival. BJU Int. 2005; 95: 5158.
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    Fouad MN, Mayo CP, Funkhouser EM, Irene HH, Urban DA, Kiefe CI. Comorbidity independently predicted death in older prostate cancer patients, more of whom died with than from their disease. J Clin Epidemiol. 2004; 57: 721729.
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    Zietman AL, Thakral H, Wilson L, Schellhammer P. Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy. J Urol. 2001; 166: 17021706.
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    Steenland K, Rodriguez C, Mondul A, Calle EE, Thun M. Prostate cancer incidence and survival in relation to education (United States). Cancer Causes Control. 2004; 15: 939945.
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    Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma [review]. Cancer. 2002; 95: 361376.