Changing prostate-specific antigen outcome after surgery or radiotherapy for localized prostate cancer during the prostate-specific antigen era

PURPOSE: To evaluate the change in prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) or external beam radiotherapy (EBRT), controlling for follow-up during the PSA era. METHODS AND MATERIALS: The study cohort consisted of 1440 patients with clinically localized prostate cancer managed with RP (n = 1059) or EBRT (n = 381) between 1989 and 2000. A single genitourinary pathologist reviewed all pathology specimens. For patients with a 2-year minimal follow-up, the 2-year actual PSA outcome stratified by risk group (low vs. high) was calculated for three periods (January 1, 1989 to December 31, 1992; January 1, 1993 to December 31, 1996; and January 1, 1997 to December 31, 2000) and compared for each treatment modality. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition for all patients, and comparisons were made using a chi-square metric. RESULTS: During the study period, the proportion of patients treated with RP and EBRT with low-risk disease increased significantly (p <0.0001) from 60% to 89% and from 26% to 76%, respectively. In addition, the 2-year actual PSA outcome also improved from 60% to 82% (RP: p < 0.0001) and from 67% to 91% (RT: p = 0.0008). The 2-year actual PSA outcome was not significantly different in the low-risk patients but improved during the three periods in the high-risk patients treated with RP (from 20% to 39% to 75%, p = 0.0004) or EBRT (from 50% to 59% to 83%, p = 0.01). This improvement in PSA outcome could be explained by a shift toward a more favorable PSA level (RP: p = 0.0002; RT: p = 0.006) and clinical T stage (RP: p = 0.0008, RT: p < 0.0001) distribution for patients with biopsy Gleason score >or=7 disease. CONCLUSION: Improved PSA outcome during the PSA era after RP or EBRT has resulted from a shift in presentation toward low-risk disease and earlier detection of high-grade disease.     

Evaluation and management of prostate-specific antigen recurrence after radical prostatectomy for localized prostate cancer

A radical prostatectomy has been established as one of the standardmanagement options for localized prostate cancer. However, asubstantial proportion of patients who undergo a radical prostatectomydevelop prostate-specific antigen (PSA) recurrence which iscommonly defined as a PSA cut-off point value of 0.2 ng/ml.Although the management of PSA recurrence after radical prostatectomymay depend on the site of recurrence, it is quite difficultto identify the recurrent lesion accurately based on the currentlyavailable imaging technology. Patients who have surgical margininvolvement or a Gleason score 7 based on the radical prostatectomyspecimens, who do not have nodal or seminal vesicle involvement,and who develop a PSA recurrence >1–2 years after surgerywith a doubling time of >1 year, and whose pre-treatmentPSA is <1.0–1.5 ng/ml are considered to benefit fromlocal treatment with at least 64 Gy of salvage radiotherapy.Patients with different characteristics are considered to havedistant metastases or both local lesions and distant metastases,and thus may be candidates for hormonal manipulation ratherthan radiotherapy. Since local recurrent lesions are consideredto be quite small at the early stage of PSA recurrence, hormonalmanipulation may be sufficient to prevent disease progressioninstead of radiotherapy. However, the optimal type and timingof hormonal manipulation remain to be elucidated. As a result,no consensus regarding the treatment for PSA recurrence afterradical prostatectomy has yet been reached.     

Algorithms for prostate-specific antigen recurrence after treatment of localized prostate cancer

Nomograms are devices that predict outcome probabilities for the individual patient. Herein we discuss their strengths and limitations, focusing on responses to several frequently asked questions about nomograms. We believe these tools are useful and necessary for patient counseling, follow-up scheduling, and clinical trial design and analysis.     

Predictors of mortality after androgen-deprivation therapy in patients with rapidly rising prostate-specific antigen levels after local therapy for prostate cancer

BACKGROUND: The authors identified biochemical and pathologic factors that were associated significantly with prostate cancer-specific mortality (PCSM) after androgen deprivation therapy (ADT) in men who had rapidly rising prostate-specific antigen (PSA) levels after they received local treatment. METHODS: The study population consisted of 67 patients who had a PSA doubling time (DT) < or =6 months after radical prostatectomy (n = 50 patients) or external beam radiation therapy (n = 17 patients) for localized prostate cancer. Multivariate Cox proportional hazards regression analysis was used to evaluate whether the interval to PSA failure, pre-ADT PSA DT, PSA level at the time of ADT initiation, time to PSA nadir, PSA nadir after 8 months on ADT, and Gleason score were associated significantly with the time to PCSM 8 months after the initiation of ADT. RESULTS.: A PSA nadir >0.2 ng/mL (adjusted hazard ratio [HR], 8.0; 95% confidence interval [95% CI], 1.7-38.7; P = 0.009) and a Gleason score > or =8 (adjusted HR, 5.2; 95% CI, 1.3-20.6; P = 0.02) were associated significantly with a short time to PCSM. The cumulative incidence estimates of 3-year PCSM were 5.8% versus 50.9% for patients with a PSA nadir < or =0.2 ng/mL versus >0.2 ng/mL, respectively, and 10.8% versus 35.8% for patients who had tumors with a Gleason score < or =7 versus > or =8, respectively. CONCLUSIONS.: Among men with a PSA DT < or =6 months, both a PSA nadir >0.2 ng/mL after ADT and a Gleason score > or =8 cancer identified men who were at high risk for PCSM. These men would be ideal candidates for Phase III studies that evaluate the impact on survival of new systemic therapies for prostate cancer.     

Decision analyses in consideration of treatment strategies for patients with biochemical failure after curative therapy on clinically localized prostate cancer in the prostate-specific antigen era

BACKGROUND: The introduction of prostate-specific antigen (PSA) testing has not only shortened the time required to make diagnosis but changed the treatment strategies of localized prostate cancer. We conducted the decision analysis on its treatment focusing on patients with biochemical failure. METHODS: We developed a Markov model to calculate life expectancy (LE) and quality-adjusted life expectancy (QALE) stratified by age, comorbidity and tumor characteristics in patients with newly diagnosed prostate cancer or biochemical failure after curative therapy. For newly diagnosed patients, three treatment strategies were considered as primary managements: radial prostatectomy (RP), external beam radiotherapy (EBRT) and watchful waiting (WW). Managements considered for biochemical failure were: after RP, salvage radiotherapy (SRT), salvage hormonal therapy (SHT) and WW; and after EBRT, SHT and WW. Transition probabilities in the Markov model were derived from published studies. Quality of life (QOL) data to estimate QALE score were derived from 323 patients with prostate cancer. RESULTS: For patients with Gleason 2-6 cancer at diagnosis, WW yielded the greatest number of QALE. For patients with Gleason 7 cancer, it was controversial whether curative therapy was the preferred strategy. For patients with Gleason 8-10 cancer, curative therapy yielded the greatest number of QALE in younger patients without severe comorbidity. Patients' benefit from salvage therapy for biochemical failure after curative therapy depended on age, comorbidities, tumor characteristics and QOL effect. CONCLUSIONS: Our findings support the need for various treatment options, taking into consideration the patient's age, comorbidity and the QOL effect in the aging society.     

Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era.

PURPOSE: To determine whether pretreatment risk groups shown to predict time to prostate cancer-specific mortality (PCSM) after treatment at a single institution retained that ability in a multi-institutional setting. PATIENTS AND METHODS: From 1988 to 2002, 7,316 patients treated in the United States at 44 institutions with either surgery (n = 4,946) or radiation (n = 2,370) for clinical stage T1c-2, N0 or NX, M0 prostate cancer made up the study cohort. A Cox regression analysis was performed to determine the ability of pretreatment risk groups to predict time to PCSM after treatment. The relative risk (RR) of PCSM and 95% confidence intervals (CIs) were calculated for the intermediate- and high-risk groups relative to the low-risk group. RESULTS: Estimates of non-PCSM 8 years after prostate-specific antigen (PSA) failure were 4% v 15% (surgery versus radiation; Plog rank =.002) compared with 13% v 18% (surgery versus radiation; Plog rank =.35) for patients whose age at the time of PSA failure was less than 70 as compared with >or= 70 years, respectively. The RR of PCSM after treatment for surgery-managed patients with high- or intermediate-risk disease was 14.2 (95% CI, 5.0 to 23.4; PCox <.0001) and 4.9 (95% CI, 1.7 to 8.1; PCox =.0037), respectively. These values were 14.3 (95% CI, 5.2 to 24.0; PCox <.0001) and 5.6 (95% CI, 2.0 to 9.3; PCox =.0012) for radiation-managed patients. CONCLUSION: This study provided evidence to support the prediction of time to PCSM after surgery or radiation on the basis of pretreatment risk groups for patients with clinically localized prostate cancer managed during the PSA era.     

Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure-free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT. RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality. CONCLUSION: Men at high risk (> 50%) for early (< or = 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.     

Influence of body mass index on prostate-specific antigen failure after androgen suppression and radiation therapy for localized prostate cancer

BACKGROUND: Increasing body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure after radical prostatectomy. Whether BMI is associated with time to PSA failure was investigated in men treated with androgen suppression therapy (AST) and radiation therapy (RT) for clinically localized prostate cancer. METHODS: The observational prospective cohort study consisted of 102 men with clinically localized prostate cancer who received 70 Gy RT with 6 months of AST on a single arm of a randomized trial between December 1995 and April 2001. Height and weight data were available at baseline for 99 (97%) of the men, from which BMI was calculated. Adjusting for age (continuous) and known prognostic factors including PSA level (continuous), Gleason score, and T-category, Cox regression analyses were performed to analyze whether BMI (continuous) was associated with time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits). RESULTS: Median age and median BMI (interquartile range [IQR]) at baseline was 72 (69.1-74.7) years and 27.4 (24.8-30.7) kg/m,(2) respectively. In addition to an increasing PSA level (P = .006) and Gleason 8-10 cancer (P = .024), after a median follow-up (IQR) of 6.9 (5.6-8.5) years, an increasing BMI was also significantly associated with a shorter time to PSA failure (adjusted hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.01-1.19; P = .026) after RT and AST. CONCLUSIONS: After adjusting for known prognostic factors, baseline BMI is significantly associated with time to PSA failure after RT and AST for men with clinically localized prostate cancer. Further study is warranted to assess the impact of an increasing BMI after AST administration on PSA failure, prostate cancer-specific, and all-cause mortality.     

The dynamics of prostate-specific antigen after definitive radiation therapy for prostate cancer.

We report the use of an exponential model for capturing the dynamics of serial measurements of prostate-specific antigen (PSA) made just before and after definitive radiation therapy of localized prostate cancer. Our study patients consisted of 164 men treated at a community hospital and without use of adjuvant hormonal therapy, and we had a mean of 5 years follow-up. We found that the model fits allowed us to condense PSA dynamic information into four parameters, including the initial pretreatment value of PSA, and three of these related significantly to subsequent outcome. The model also provided greater understanding of the prognosis of men with rising PSA after radiation therapy. Specifically, two of the model's parameters allowed us to compare the PSA status of these men to those with hormone-refractory disease, and we discovered that at the time of "biochemical relapse," there is a broad spectrum in expected probability of imminent death as well as in time to an adverse outcome. Thus, the model provides information that allows one to stratify men with rising PSA into a continuous spectrum from low to high risk for an adverse outcome. We believe these results show that exponential models have the potential for providing useful clinical information about men with rising PSA after definitive radiation therapy and that they could help us decide when further therapy is needed. Therefore, we recommend further study and development of these models as part of clinical research protocols involving radiation therapy of localized prostate cancer.     

Significance of prostate-specific antigen kinetics after three-dimensional conformal radiotherapy with androgen deprivation therapy in patients with localized prostate cancer

Background

To evaluate the relationship between biochemical recurrence and post-radiation prostate-specific antigen (PSA) kinetics in patients with localized prostate cancer treated by radiotherapy with various durations of androgen deprivation therapy (ADT).

Methods

We reviewed our single-institution, retrospectively maintained data of 144 patients with T1c-T3N0M0 prostate cancer who underwent three-dimensional conformal radiotherapy (3D-CRT) between December 2005 and December 2015 and 113 patients were fulfilled the inclusion criteria. In this cohort, 3D-CRT was delivered with a dose in the range from 70.0 to 72.0 Gy with ADT. All patients received ADT as concurrent regimens. Biochemical recurrence was defined on the basis of the following: “PSA nadir + 2.0 ng/ml or the clinical judgement of attending physicians”. Kaplan–Meier, log-rank, and Cox regression analyses were carried out.

Results

The median follow-up period was 54.0 months. The median duration of ADT was 17 months (interquartile range, 10–24 months). There was a trend toward statistical significant correlation between post-radiation PSA decline rate of ≥ 90% and PSA recurrence (p = 0.056). The same correlation could be observed in D’Amico high-risk patients (p = 0.036). However, it was not observed between PSA nadir and PSA recurrence (p = 0.40) in univariate analysis. Furthermore, multivariate analysis showed that post-radiation PSA decline rate of ≥ 90% was a significant predictor of biochemical recurrence in patients who received radiotherapy with various durations of ADT (p = 0.044).

Conclusions

Post-radiation PSA decline rate of ≥ 90% was a prognostic factor for biochemical recurrence in localized prostate cancer patients received 3D-CRT with various durations of ADT.

     

Temporarily deferred therapy (watchful waiting) for men younger than 70 years and with low-risk localized prostate cancer in the prostate-specific antigen era.

PURPOSE: Watchful waiting (WW) is an acceptable strategy for managing prostate cancer (PC) in older men. Prostate-specific antigen (PSA) testing has resulted in a stage migration, with diagnoses made in younger men. An analysis of the Department of Defense Center for Prostate Disease Research Database was undertaken to document younger men with low- or intermediate-grade PC who initially chose WW. PATIENTS AND METHODS: We identified men choosing WW who were diagnosed between January 1991 and January 2002, were 70 years or younger, had a Gleason score < or = 6 with no Gleason pattern 4, had no more than three positive cores on biopsy, and whose clinical stage was < or = T2 and PSA level was < or = 20. We analyzed their likelihood of remaining on WW, the factors associated with secondary treatment, and the influence of comorbidities. RESULTS: Three hundred thirteen men were identified. Median follow-up time was 3.8 years. Median age was 65.4 years (range, 41 to 70 years). Ninety-eight patients remained on WW; 215 proceeded to treatment. A total of 57.3% and 73.2% chose treatment within the first 2 and 4 years, respectively. Median PSA doubling time (DT) was 2.5 years for those who underwent therapy; those remaining on WW had a median DT of 25.8 years. The type of secondary treatment was associated with the number of patient's comorbidities (P =.012). CONCLUSION: Younger patients who choose WW seemed more likely to receive secondary treatment than older patients. PSA DTs often predict the use of secondary treatment. The number of comorbidities a patient has influences the type of secondary therapy chosen. The WW strategy may better be termed temporarily deferred therapy.     

Cancer incidence after localized therapy for prostate cancer

BACKGROUND: Second cancers may occur in patients who have undergone radiation therapy. The risk for these adverse events after therapy is uncertain. In this study, the authors examined the size and significance of the observed association between occurrences of secondary cancers 5 years after radiotherapy in a large population of men with incident prostate cancer. METHODS: Men with incident prostate cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) registry and were distinguished by the type of treatment received, tumor stage, tumor grade, and age at diagnosis. SEER data also were used to identify occurrences of secondary cancer beginning 5 years after the date patients were diagnosed with prostate cancer. Multivariate logistic regression analysis was used to estimate the adjusted odds of the subsequent occurrence of other cancers associated with types of radiation therapy received and was adjusted for the type of surgery, tumor grade, stage, and patient age. RESULTS: Compared with men who received no prostate cancer-directed radiation, men who received external beam radiation therapy (EBRT) as their only form of radiation therapy had statistically significant increased odds of developing secondary cancers at several sites potentially related to radiation therapy, including the bladder (odds ratio [OR], 1.63; 95% confidence interval [95% CI], 1.44-1.84) and rectum (OR, 1.60; 95% CI, 1.29-1.99). Men who received EBRT also had statistically significant higher odds of developing secondary cancers at sites in the upper body and other areas not potentially related to radiation therapy, including the cecum (OR, 1.63; 95% CI, 1.10-1.70), transverse colon (OR, 1.85; 95% CI, 1.30-2.63), brain (OR, 1.83; 95% CI, 1.22-2.75), stomach (OR, 1.38; 95% CI, 1.09-1.75), melanoma (OR, 1.29; 95% CI, 1.09-1.53), and lung and bronchus (OR, 1.25; 95% CI, 1.13-1.37) compared with the odds among men who received no radiation therapy. Men who received radiation therapy in the form of radioactive implants or isotopes, either in isolation or combined with beam radiation, did not have significantly different odds of secondary cancer occurring at any of the 20 most common sites. CONCLUSIONS: Patients who received with EBRT had significantly higher odds of developing second cancers both overall and in the areas that were exposed to radiation. It is noteworthy that, to the authors' knowledge, this report shows for the first time that, despite the higher doses of radiation delivered, patients who received radioactive implants had the lowest odds of developing second cancers.     

Predictors of mortality after prostate-specific antigen failure

PURPOSE: We identified factors associated with the length of survival after prostate-specific antigen (PSA) failure. METHODS AND MATERIALS: The study cohort comprised 81 of 206 men enrolled on a randomized trial evaluating external-beam radiation therapy (RT) with or without androgen suppression therapy (AST) and who experienced PSA failure. Salvage AST was administered at a PSA level of approximately 10 ng/mL as per protocol. Cox regression was used to determine factors associated with length of survival after PSA failure. RESULTS: A PSA DT (doubling time) <6 months (p = 0.04) and age at the time of PSA failure (p = 0.009) were significantly associated with length of survival. By 5 years, 35% and 65% of all-cause mortality was from prostate cancer in men whose age at PSA failure was 75 or higher vs. <75, respectively. Across all ages, 0%, 4%, as compared with 63% of men, were estimated to die of prostate cancer within 5 years after PSA failure if their PSA DT was >12, 6-12, or <6 months, respectively. CONCLUSIONS: Advanced age and a PSA DT <6 months at the time of PSA failure are associated with a significantly shorter survival.     

Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer.

PURPOSE: To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy. PATIENTS AND METHODS: Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity. RESULTS: Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by > or = 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12). CONCLUSION: This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.