Perineural invasion and Gleason 7-10 tumors predict increased failure in prostate cancer patients with pretreatment PSA <10 ng/ml treated with conformal external beam radiation therapy

Purpose: It has been well established that prostate cancer patients with pretreatment PSA<10 ng/ml enjoy excellent bNED control when treated with definitive external beam radiation therapy. This report identifies predictors of failure for patients with pretreatment PSA <10 ng/ml. These predictors are then used to define favorable and unfavorable prognostic subgroups of patients for which bNED control is compared.

Methods and Materials: Between 3/87 and 11/94, 266 patients with T1-T3NXM0 prostate cancer and pretreatment PSA values <10 ng/ml were treated with definitive external beam radiation therapy. Median central axis dose and median follow-up for the entire group was 72 Gy (63–79 Gy) and 48 months (2–120 months). Predictors of bNED control were evaluated univariately using Kaplan-Meier methodology and the log-rank test and multivariately using Cox proportional hazards modeling. Covariates considered were pretreatment PSA, palpation stage, Gleason score, presence of perineual invasion (PNI) and central axis dose. Independent predictors based on multivariate results were then used to stratify the patients into two prognostic groups for which bNED control was compared. bNED failure is defined as PSA ≥ 1.5 ng/ml and rising on two consecutive determinations.

Results: Univariate analysis according to pretreatment and treatment factors for bNED control demonstrates a statistically significant improvement in 5-year bNED control for patients with Gleason score 2–6 vs. 7–10, patients without evidence of perineural invasion (PNI) vs. those with PNI, and patients with palpation stage T1/T2AB vs. T2C/T3. Multivariate analysis demonstrates that Gleason score (p = 0.0496), PNI (p = 0.0008) and palpation stage (p = 0.0153) are significant independent predictors of bNED control. Based on these factors, patients are stratified into a more favorable prognosis group (Gleason 2–6, no PNI, and stage T1/T2AB, n = 172) and a less favorable prognosis group (Gleason 7–10 or PNI or T2C/T3, n = 94). A comparison of the two groups reveals that bNED control is significantly lower in the less favorable prognosis group (74% vs. 91% at 5 years, p = 0.0024).

Conclusions: (1) This report identifies Gleason 7–10 and the presence of PNI as well as palpation stage T2C/T3 as factors that predict worse bNED outcome for patients with pretreatment PSA < 10 ng/ml who are treated with radiation therapy alone. (2) Patients with these pretreatment prognostic factors may benefit from adjuvant therapies or altered treatment programs. (3) In order to make fair comparisons between radiation therapy and prostatectomy series, the distribution of perineual invasion and Gleason 7–10 must be taken into account.     

Defining the appropriate radiation dose for pretreatment PSA < or = 10 ng/mL prostate cancer

PURPOSE: To investigate whether a dose response exists for biochemical no evidence of disease (bNED) control in prostate cancer patients with pretreatment prostate-specific antigen (PSA) < or = 10 ng/mL and to identify the patient subgroups affected. METHODS AND MATERIALS: Between 5/89 and 10/97, 488 T1-T3 NX-0 M0 prostate cancer patients with PSA < or = 10 ng/mL were treated with three-dimensional conformal radiation therapy (3D-CRT) alone. Median and mean pretreatment PSA values were 6.3 and 6.2, respectively. Gleason scores of 2-6 and 7-10 were noted in 386 and 102 men, respectively. AJCC 1992 palpation T1-T2AB tumors were noted in 415 patients. Perineural invasion (PNI) was noted in 60 men. Mean and median age was 67 and 68 years, respectively. Dose to the center of the prostate ranged from 6260 cGy to 8409 cGy with a mean and median of 7423 cGy and 7278 cGy, respectively. Patients were stratified into three groups according to dose: <7250 cGy, 7250-7599 cGy, and > or =7600 cGy. Median dose in these three groups was 7067 cGy, 7278 cGy, and 7734 cGy, respectively. Univariate analysis was performed to determine differences in bNED control (American Society for Therapeutic Radiology and Oncology [ASTRO] Consensus Guidelines definition of failure) by dose group for the entire cohort, for 310 good prognosis patients (T1-T2A, Gleason score 2-6, absence of PNI), and for 178 poor prognosis patients (T2B-T3 or Gleason score 7-10 or presence of PNI) (1). Multivariate analysis (MVA) was performed to determine if dose was an independent predictor of bNED control. Median follow-up was 36 months. RESULTS: A dose response was not demonstrated for the entire group of patients with pretreatment PSA < or =10 ng/mL. Doses of <7250 cGy, 7250-7599 cGy, and > or =7600 cGy were associated with 5-year bNED control rates of 73%, 86%, and 89%, respectively (p = 0.12). MVA demonstrated prognosis group (p = 0. 038) to be the only independent predictor of bNED control. Good prognosis patients had a 5-year bNED of 85% and no dose response was seen. The subgroup of poor prognosis patients demonstrated a 5-year bNED control rate of 81% and a dose response was seen for those receiving > or =7600 cGy, compared to the two lower dose groups (94% vs. 75% vs. 70%; p = 0.0062). MVA for the poor prognosis subset demonstrated dose (p = 0.01) to be the only independent predictor for improved bNED control. CONCLUSIONS: The poor prognosis subset of PSA < or =10 ng/mL prostate cancer patients benefit from dose escalation. A dose response is not demonstrated for prostate cancer patients with pretreatment PSA < or =10 ng/mL and other favorable features.     

Association of percent positive prostate biopsies and perineural invasion with biochemical outcome after external beam radiotherapy for localized prostate cancer

PURPOSE: Few studies have evaluated the significance of the percentage of positive biopsies (PPB) and perineural invasion (PNI) for patients treated with external beam radiotherapy (EBRT) for localized prostate cancer. Our goal was to investigate the value of these factors in predicting biochemical control (bNED) after EBRT. METHODS AND MATERIALS: The study cohort consisted of 331 patients who received EBRT between 1993 and 1999 for clinically localized prostate cancer. The median follow-up was 4.4 years (range, 3 months to 9.6 years). The distribution by clinical T stage was as follows: T1 in 55 (17%), T2a in 94 (28%), T2b in 76 (23%), T2c in 74 (22%), T3a in 27 (8%), and T3b in 5 (2%). The pretreatment prostate-specific antigen (iPSA) level was < or =10 ng/mL in 224 patients, 10.1-20 ng/mL in 72 patients, and >20 ng/mL in 35 patients. The biopsy Gleason score was < or =6 in 216 patients and > or =7 in 115 patients. On the basis of the pathology report, the PPB was calculated for 239 patients and was < or =33% in 109, 34-66% in 72, and > or =67% in 58 patients. PNI was present in 30 patients. The median dose of EBRT was 68.4 Gy (range, 64-71 Gy). Patients were categorized into three risk groups: 142 patients were low risk (T1-T2, iPSA < or =10 ng/mL, and Gleason score < or =6), 137 were intermediate risk (increase in the value of one of the risk factors); and 52 patients were high risk (increase in value of two or more of the risk factors). Biochemical failure was defined as three consecutive rises in the PSA level. RESULTS: The 5-year bNED rate for the entire cohort was 62%. The 5-year bNED rate for the low-, intermediate, and high-risk group was 79%, 51%, and 47%, respectively (p <0.0001). On univariate analysis (log-rank test), clinical stage (p = 0.0073), grade (p <0.0001), iPSA (p = 0.0043), risk group (p <0.0001), PPB (p = 0.0193), and presence of PNI (p = 0.0137) correlated with bNED. For T1-T2a, T2b-T2c, and T3 patients, the 5-year bNED rate was 71%, 59%, and 40%, respectively. The 5-year bNED rate was 68% for those with an iPSA level of < or =10 ng/mL and 49% for those with an iPSA level of >10 ng/mL. For patients with PPB < or =33%, 34-66%, and > or =67%, the 5-year bNED rate was 75%, 67%, and 51%, respectively. Within the intermediate-risk group, the PPB was significantly associated with the bNED rate: 67%, 52%, and 30% for those with PPB < or =33%, 34-66%, and > or =67%, respectively (p = 0.0046). This association was not seen in the low- or high-risk group. The 5-year bNED rate was 64% for patients without PNI and 48% for those with PNI. On multivariate analysis (Cox proportional hazards model), the statistically significant predictive factors for bNED were risk group (p = 0.0032) and PPB (p = 0.044). Using the chi-square test, statistically significant associations between T stage, PSA level, Gleason score, and risk group with PPB were found; PNI was significantly associated with T stage and PSA level only. CONCLUSION: Our results showed that PPB and PNI have a statistically significant impact on the bNED rate in patients treated with conventional dose of EBRT (< or =71 Gy). Within the intermediate-risk group, the PPB was predictive of bNED, suggesting that patients with < or =33% PPB had a statistically significant better treatment outcome compared with those with a greater PPB. PNI was not significant for bNED in multivariate analysis. The effects of these two prognostic factors in patients who have been treated with higher doses of RT (> or =75.6 Gy) should be studied.     

Dose response in prostate cancer with 8-12 years' follow-up

PURPOSE: This communication reports the long-term results of the original group of prostate cancer patients who participated in the first prospective Fox Chase Cancer Center radiation dose escalation study for which 8-12 years of follow-up is now available. METHODS AND MATERIALS: Between March 1, 1989 and October 31, 1992, 232 patients with clinically localized prostate cancer received three-dimensional conformal radiotherapy only at Fox Chase Cancer Center in a prospective dose-escalation study. Of these patients, 229 were assessable. The 8-, 10-, and 12-year actuarial rates of biochemical control (biochemically no evidence of disease [bNED]), freedom from distant metastasis (FDM), and morbidity were calculated. The Cox proportional hazards model was used to assess multivariately the predictors of bNED control and FDM, including pretreatment prostate-specific antigen (PSA) level (continuous), tumor stage (T1/T2a vs. T2b/T3), Gleason score (2-6 vs. 7-10), and radiation dose (continuous). The median total dose for all patients was 74 Gy (range 67-81). The median follow-up for living patients was 110 months (range 89-147). bNED control was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. RESULTS: The actuarial bNED control for all patients included in this series was 55% at 5 years, 48% at 10 years, and 48% at 12 years. Patients with pretreatment PSA levels of 10-20 ng/mL had statistically significant differences (19% vs. 31% vs. 84%, p = 0.0003) in bNED control when stratified by dose (<71.5, 71.5-75.6, and > 75.6 Gy, respectively) on univariate analysis. For the 229 patients with follow-up, 124 (54%) were clinically and biochemically without evidence of disease. Sixty-nine patients were alive at the time of last follow-up, and 55 patients were dead of intercurrent disease. On multivariate analysis, radiation dose was a statistically significant predictor of bNED control for all patients and for unfavorable patients with a pretreatment PSA <10 ng/mL. For the patients with a pretreatment PSA level of 10-20 ng/mL, the radiation dose was a statistically significant predictor across all groups. No radiation dose response was seen for those patients with a pretreatment PSA level >20 ng/mL, although large numbers of patients are required to demonstrate a difference. The radiation dose, Gleason score, and palpation T stage were significant predictors for the entire patient set, as well as for those with pretreatment PSA levels between 10 and 20 ng/mL. The FDM rate for all patients included in this series was 89%, 83%, and 83% at 5, 10, and 12 years, respectively. For patients with pretreatment PSA levels <10 ng/mL, all four covariates (radiation dose, Gleason score, pretreatment PSA, and palpation T stage) were significant predictors of distance metastasis. Using the Radiation Therapy Oncology Group morbidity scale, no difference was noted in the frequency of Grade 2 and 3 genitourinary and Grade 3 gastrointestinal morbidity when patients in this data set were stratified by radiation dose. However, a significant increase occurred in Grade 2 gastrointestinal complications as the radiation dose increased. CONCLUSION: The long-term results of the original Fox Chase radiation dose escalation study with >9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure.     

Outcome and predictive factors for patients with Gleason score 7 prostate carcinoma treated with three-dimensional conformal external beam radiation therapy

BACKGROUND: The purpose of this study was to determine the biochemical outcome and factors predictive of outcome in prostate carcinoma patients with Gleason score 7 tumors who were treated with three-dimensional conformal radiation therapy (3DCRT). METHODS: Between August 1990 and October 1997, 163 T1-T3NXM0 prostate carcinoma patients with Gleason score 7 were treated with definitive 3DCRT alone. The median follow-up, International Commission on Radiological Units dose, and pretreatment prostate specific antigen (PSA) for the entire group were 50 months, 76 grays (Gy), and 11.4 ng/mL, respectively. Independent predictors based on multivariate results were used to stratify the patients into prognostic groups for which biochemical no evidence of disease (bNED) control was reported. Biochemical NED failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS: The 5-year bNED control for all patients was 66%. Stratified by pretreatment PSA, 5-year bNED control rates were 83%, 65%, and 21% for 0-9.9 ng/mL, 10-19.9 ng/mL, and > or =20 ng/mL, respectively. Dose to the central axis was found to be a significant treatment factor, with patients receiving > or =76 Gy experiencing 76% 5-year bNED control versus 54% when treated with <76 Gy to isocenter. Pretreatment PSA, dose, and palpation stage were significant independent predictors for bNED control upon multivariate analysis. Patients with a PSA <10 ng/mL who received a dose of > or =76 Gy had excellent 5-year bNED control of 100% compared with 50% bNED if patients had PSA >10 ng/mL or received radiation therapy doses of <76 Gy. CONCLUSIONS: Patients with Gleason score 7 adenocarcinoma who had a pretreatment PSA <10 ng/mL and received doses of > or =76 Gy had excellent 5-year bNED control, emphasizing the importance of higher central axis doses in treating Gleason 7 tumors. Patients with intermediate PSA (10-19.9 ng/mL) also required doses > or =76 Gy. Pretreatment PSA > or = 20 ng/mL portends a very poor bNED outcome for Gleason 7 patients treated with radiation therapy alone, and thus efforts should be directed toward multimodal or long term hormonal treatment strategies.     

Clinical utility of endorectal MRI in determining PSA outcome for patients with biopsy Gleason score 7, PSA <or=10, and clinically localized prostate cancer

PURPOSE: Although the optimal management for patients with high-grade clinically localized prostate cancer is undefined, radical prostatectomy (RP) or external beam radiotherapy (EBRT) is performed. The clinical utility of the pretreatment prostrate-specific antigen (PSA) level (10 ng/mL) and endorectal MRI (erMRI) stage (T3 vs. T2) to stratify PSA outcome after RP in these patients was evaluated. METHODS AND MATERIALS: erMRI was performed in 147 men with biopsy Gleason score >or=7 and 1992 AJCC clinical Stage T1c or T2a disease before RP. Enumerations of the biopsy and prostatectomy Gleason scores, pathologic stage, and margin status were performed for each pretreatment group on the basis of erMRI findings and PSA level. Comparisons were made using a chi-square metric. The median follow-up was 4.5 years (range 1-10 years). Comparisons of the actuarial freedom from PSA failure (bNED) were made using the log-rank test. RESULTS: erMRI Stage T2 and T3 disease was found in 132 and 15 patients, respectively. On stratification by PSA level, patients with erMRI T3 disease had similar bNED outcomes (p = 0.46), regardless of the PSA level. The 3-year bNED rate was 82%, 64%, and 25% (p <0.0001) for Group 1 (erMRI T2 and PSA 10 ng/mL), and Group 3 (erMRI T3 with any PSA level), respectively. The rates of prostatectomy T3 disease, biopsy and prostatectomy Gleason score 8-10, and positive surgical margins were significantly higher (p or=7, PSA 相似文献   

Dose escalation with 3D conformal treatment: five year outcomes,treatment optimization,and future directions

Purpose: To report the 5-year outcomes of dose escalation with 3D conformal treatment (3DCRT) of prostate cancer.Methods and Materials: Two hundred thirty-two consecutive patients were treated with 3DCRT alone between 6/89 and 10/92 with ICRU reporting point dose that increased from 63 to 79 Gy. The median follow-up was 60 months, and any patient free of clinical or biochemical evidence of disease was termed bNED. Biochemical failure was defined as prostate-specific antigen (PSA) rising on two consecutive recordings and exceeding 1.5 ng/ml. Morbidity was reported by the Radiation Therapy Oncology Group (RTOG) scale, the Late Effects Normal Tissue (LENT) scale, and a Fox Chase modification of the latter (FC-LENT). All patients were treated with a four-field technique with a 1 cm clinical target volume (CTV) to planning target volume (PTV) margin to the prostate or prostate boost; the CTV and gross tumor volume (GTV) were the same. Actuarial rates of outcome were calculated by Kaplan-Meier and cumulative incidence methods and compared using the log rank and Gray’s test statistic, respectively. Cox regression models were used to establish prognostic factors predictive of the various measures of outcome. Five-year Kaplan-Meier bNED rates were utilized by dose group to estimate logit response models for bNED and late morbidity.Results: PSA <10 ng/ml: No dose response was demonstrated using estimated bNED rates or by analysis of PSA nadir vs. dose. PSA 10–19.9 ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model showed 5-year bNED rates of 35% at 70 Gy and 75% at 76 Gy (p = 0.0049) and illustrated the relative ineffectiveness of conventional dose treatment. PSA 20+ ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model indicated a 5-year bNED rate of 10% at 70 Gy and 32% at 76 Gy (p = 0.10). Morbidity: Dose response was demonstrated for FC-LENT grade 2 and grade 3,4 GI morbidity and for LENT grade 2 GU sequelae. RTOG grade 3,4 GI morbidity at 5 years was <1%. Factors associated with bNED, cause-specific survival, and metastasis were studied using Cox multivariate analysis. Pretreatment PSA (p = 0.0001), Gleason score 7–10 (p = 0.0001), and dose (p = 0.017) were significantly predictive of bNED. For each 1 Gy increase in dose, the hazard of bNED failure decreased by 8%. Palpation stage was associated with cause-specific survival (p = 0.002) and distant metastasis (p = 0.0004). Gleason score was also predictive of distant metastasis (p = 0.02).Conclusions: A dose response was observed for patients with pretreatment PSA >10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA <10 ng/ml. Dose response was observed for FC-LENT grade 2 and grade 3,4 GI sequelae and for LENT grade 2 GU sequelae. Optimization of treatment was made possible by the results in this report. The improvement in 5-year bNED rates for patients with PSA levels >10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76–80 Gy.     

Is there a subset of patients with PSA > or = 20 ng/ml who do well after conformal beam radiotherapy?

To determine if there is a subgroup of patients with pretreatment PSA > or = 20 ng/ml with a favorable outcome after external beam radiation therapy. We analyzed retrospectively treatment outcomes of 129 patients with pretreatment PSA > or = 20 ng/ml treated in our department from 2/88-8/94. Median patient age was 70 years (range 51-89 years). Tumor stage was T1/T2ab in 68, T2c/T3 in 61 patients. Initial Gleason grade was < 7 in 82 and > or = 7 in 47 patients. Median PSA was 35 ng/ml (mean 45 ng/ml, range 20-191 ng/ml). Ninety-seven patients received four-field conformal external beam radiation therapy. No patient received surgery or hormonal therapy prior to treatment. Median central axis dose was 73 Gy (range 68-79 Gy). Covariates considered in univariate and multivariate analyses included central axis dose, pretreatment PSA, presence of perineural invasion, Gleason score, palpable tumor stage and patient age. bNED failure was defined as a PSA > or = 1.5 and rising on two consecutive determinations. Median follow up was 50 months (range 3-100 months). Overall bNED control for the entire patient population was 22% at five years. Of the covariates analyzed, dose (P < 0.01), stage (P < 0.01), Gleason Score (P < 0.01), and the presence of PNI (P = 0.01) were significant on multivariate analysis. Based on these results, patients could be stratified into two distinct groups. Group I consisted of 19 patients with favorable features including T1/T2ab disease, Gleason Score 2-6, no perineural invasion treated to a dose > 73 Gy to the central axis. Patients in Group II had at least one of the above poor prognostic features or were treated to central axis doses < 73 Gy. The bNED control was significantly higher for patients in Group I than those in Group II (58% vs. 23%, P = 0.0027). There appears to be a favorable subgroup of patients with PSA > or = 20 ng/ml where treating to doses over 73 Gy to the central axis is warranted (four-year bNED rate of 58%). However, because of the small patient numbers, these results will need to be validated with longer follow up.     

External beam radiotherapy dose response characteristics of 1127 men with prostate cancer treated in the PSA era

PURPOSE: To characterize the relationship of radiotherapy dose to prostate cancer patient outcome, with an emphasis on the influence of pretreatment prognostic variables. METHODS AND MATERIALS: The 1127 Stage T1-T4 prostate cancer patients examined were treated consecutively with definitive external beam radiotherapy at the University of Texas-M.D. Anderson Cancer Center from 1987 to 1997. All had a pretreatment prostate-specific antigen (PSA) level. Treatment failure was defined as two consecutive PSA elevations on follow-up. There were 994 patients treated with a four-field box throughout to 60-70 Gy after a small reduction at 46 Gy and 161 treated with a six-field conformal boost after 46 Gy to 74-78 Gy. No patient received neoadjuvant or adjuvant androgen ablation. Median follow-up was 51.8 months. RESULTS: Patients were divided into three radiotherapy dose groups consisting of 67-77 Gy (n = 495), and >77 Gy (n = 132). Relative to other prognostic factors, there were fewer patients treated to the highest dose level with a pretreatment PSA (PSAB) 20 ng/ml, Stage T3/T4 disease, or a Gleason score of 2-6. Actuarial 4-year freedom from biochemical failure (bNED) rates for the entire cohort were 54%, 71%, and 77% (p < 0.0001) for the low-, intermediate-, and high-dose groups. PSAB, palpable stage, and Gleason score were also highly significant. In Cox proportional hazards regression, dose (p < 0. 0001 as a continuous or categorical variable) was an independent predictor of bNED, as were the other prognostic factors. Pairwise univariate comparisons showed that an increase in dose from 67-77 Gy was associated with improved bNED rates for all PSAB (10), stage (T1/T2 and T3/T4), and Gleason score (2-6 and 7-10) subgroups tested. In contrast, the only prognostic group that benefited from raising dose from >67-77 Gy to >77 Gy was patients with a PSAB >10 ng/ml; although trends were noted for Stage T1/T2 and Gleason 2-6 patients. Patients with the combined features of a PSAB >10 ng/ml and Stage T1/T2 disease had 4-year bNED rates of 61% and 93% at the intermediate- and high-dose levels. A strongly significant linear association between dose (60-78 Gy) and 4-year actuarial bNED was demonstrated for patients with these intermediate-risk features. CONCLUSION: Prostate cancer dose response to external beam radiotherapy should be considered in the context of pretreatment prognostic factors. Our data indicate that, for favorable patients with a PSAB of 67-77 Gy provide the same rate of control as higher doses. However, longer follow-up may reveal a benefit to dose escalation >77 Gy, even in this favorable subset. Substantial and clinically relevant enhancements in bNED were seen at all dose levels for moderate-risk patients, such as those having a PSAB >10 ng/ml and Stage T1/T2 disease. Sustained bNED was not realized for high-risk patients, even using 78 Gy; these patients may be best treated with higher doses, whole pelvic irradiation, and/or androgen ablation plus radiation.     

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer

PURPOSE: To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS: The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION: A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.     

Is there a role for short-term hormone use in the treatment of nonmetastatic prostate cancer?

We reviewed our institution's experience treating patients with prostate cancer with 3-dimensional conformal radiation therapy (3DCRT) and short-term adjuvant hormonal therapy to determine biochemical no evidence of disease (bNED) and clinical outcome compared with patients treated with 3DCRT alone. Between 4/1/89 and 11/30/94, 558 patients with clinically localized prostate cancer received treatment at Fox Chase Cancer Center (Philadelphia, Pa.); 484 patients were treated with 3DCRT alone (Group I); 74 patients were treated with 3DCRT and hormones (Group II). Five-year actuarial rates of bNED control, distant metastasis-free survival (DMFS), cause-specific survival (CSS), and overall survival (OS) were calculated for pretreatment PSA, Gleason score, T stage, use of hormones, treatment field size, age, and dose. A matched case/control analysis was performed to further evaluate the effect of hormones on treatment with 3DCRT. Median follow-up was 47 months (range: 2-97 months). The 5-year actuarial rates of bNED control, DMFS, CSS, and OS were 66%, 93%, 98%, and 86%, respectively, for Group I patients and 68%, 93%, 98%, and 89%, respectively, for Group II patients. Multivariate analysis demonstrated that hormone use was an independent predictor of bNED control only. A significant difference in bNED control was observed between Group I and II (43% vs. 71%) using the matched case/control analysis (P = 0.02). A trend towards significance was observed for different rates of DMFS between Group I and II (79% vs. 94%, P = 0.09). Patients with clinically localized prostate cancer with poor prognostic features (pretreatment PSA > or = 10 ng/ml, Gleason score > or = 7, and/or T2c or greater palpation stage) show improved rates of bNED control and a trend towards improved DMFS when treated with 3DCRT and short-term adjuvant hormones compared with 3DCRT alone. Long-term observation will be necessary to see if improvements in bNED control will translate into improvements in overall survival.     

Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis

PURPOSE: Recent publications have indicated that the alpha/beta ratios for carcinoma of the prostate are much lower than had originally been thought, suggesting that prostate cancer may be highly sensitive to fraction size. We have reviewed our unique experience of the use of 3.13 Gy fractions in a large cohort of men treated homogeneously in a single institute. MATERIALS AND METHODS: The outcome for 705 men with T1-T4, N0, M0 prostate cancer who received conformal radiotherapy between 1995 and 1998 at this center was analyzed. No patient received hormonal manipulation. Mean age was 68 years (range: 49-84 years). Median pretreatment PSA was 13 ng/mL (range: 0.6-270 ng/mL). Disease characteristics were as follows: Stage T1, 125 (18%); T2, 365 (52%); T3/4, 215 (30%); Gleason 2-6, 463 (66%); Gleason 7-10, 242 (34%); pretreatment PSA < or =10 ng/mL, 291 (41%); 10 to < or =20, 228 (32%); >20, 186 (27%). Median follow-up was 48 months (range: 1-82 months). Biochemical-free survival (bNED) was defined by the American Society for Therapeutic Radiology and Oncology consensus definition. Radiotherapy was delivered to a planning target volume (prostate plus all/base of the seminal vesicles dependent on risk criteria with a 1-cm margin) with a 4-field conformal technique to a dose of 50 Gy in 16 daily fractions over 22 days. RESULTS: The 5-year bNED survival was significantly associated (p < 0.001) with pretreatment PSA, stage, and Gleason score. Five-year bNED rates with respect to pretreatment characteristics were as follows: 73% (PSA < or =10), 52% (>10-20), 35% (>20), 64% (Stage T1/2), 38% (T3/4), 61% (Gleason score 2-6), and 46% (Gleason > or =7). When patients were grouped into good (Stage T1/2, PSA < or =10 ng/mL, and Gleason score <7) (n = 181), intermediate (1 raised value) (n = 247), or poor (2 or more raised values) (n = 277) prognostic groups, the bNED was, respectively, 82%, 56%, and 39%. Radiation Therapy Oncology Group Grade > or =2 bowel toxicity was 5% and bladder 9%. CONCLUSIONS: These data indicate that the delivery of a relatively low total dose using a hypofractionated regime results in similar tumor control and normal-tissue toxicity to 65-70 Gy delivered in 1.8-2 Gy fractions. These data suggest that this is an acceptable regime for good-prognosis patients. However, because of the evidence for a dose effect at doses above 70 Gy with "conventional fractionation," we are now treating intermediate- and poor-risk patients within a hypofractionated dose escalation trial to 60 Gy in 20 fractions using intensity- modulated radiotherapy.     

Defining the optimal radiation dose with three-dimensional conformal radiation therapy for patients with nonmetastatic prostate carcinoma by using recursive partitioning techniques

BACKGROUND: The objective of this study was to determine the effect of dose and its interaction with known prognostic variables, including pretreatment prostate specific antigen (PSA), Gleason score (GS), and T classification, on patients with nonmetastatic prostate carcinoma treated with three-dimensional conformal radiation therapy (3DCRT) alone using recursive partitioning analysis. METHODS: Between November 1987 and November 1997, 939 patients with nonmetastatic prostate carcinoma were treated with 3DCRT alone at Fox Chase Cancer Center. Biochemical no evidence of disease (bNED) control was defined using the American Society of Therapeutic Radiology and Oncology Consensus definition. Recursive partitioning analysis was used to identify subgroups with similar risks of bNED failure. Prognostic factors used in the model included pretreatment PSA, GS, T classification, and radiation dose. The median follow-up was 47 months (range, 2-133 months). RESULTS: Twelve terminal nodes of the decision tree were merged to form four prognostic groups with similar bNED control rates. The 5-year actuarial rates of bNED control rates for Groups I, II, III, and IV were 84%, 41%, 16%, and 67%, respectively (P < 0.0001). Increasing the dose to greater than 7235 centigray (cGy) improved bNED control rates for patients with PSA levels of 10-19.9 ng/mL and T1/2a classification disease. Increasing the dose to greater than 7629 cGy improved bNED control rates for patients with T2b/3 classification disease with PSA levels less than 20 ng/mL. Patients with PSA levels greater than or equal to 20 ng/mL need high-dose 3DCRT. For those patients with GS 2-6 and T1/2a classification disease, treatment with greater than 7400 cGy resulted in 67% bNED control rate versus 16% at 5 years for treatment with less than 7400 cGy. High radiation dose (> 7700 cGy) improved bNED control rate from 16% to 41% for patients with high-risk disease (PSA > or = 20 ng/mL and GS 7-10) at 5 years. CONCLUSIONS: The authors showed that with recursive partitioning techniques radiation dose continues to be an important predictor of bNED control rate and that a radiation dose response for patients with clinically localized prostate carcinoma exists. Patients with one or more prognostic feature (PSA > 10 ng/mL, classification T2b/T3, GS 7-10, or the presence of perineural invasion) achieve similar rates of bNED control compared with those patients with lower volume disease when radiation dose is increased.     

Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation

PURPOSE: To assess long-term prostate-specific antigen (PSA) outcome after permanent prostate brachytherapy (BT) and identify predictors of improved disease-free survival. METHODS AND MATERIALS: Eleven institutions combined data on 2,693 patients treated with permanent interstitial BT monotherapy for T1-T2 prostate cancer. Of these patients, 1,831 (68%) were treated with I-125 (median dose, 144 Gy) and 862 (32%) were treated with Pd-103 (median dose, 130 Gy). Criteria for inclusion were: available pre-BT PSA, BT > or =5 years before data submission, BT between 1988-1998, and no androgen deprivation before failure. The median follow-up was 63 months. RESULTS: Among patients where the I-125 dose to 90% of the prostate (D90) was > or =130 Gy, the 8-year PSA relapse-free survival (PRFS) was 93% compared with 76% for those with lower D90 dose levels (p < 0.001). A multivariable analysis identified tumor stage (p = 0.002), Gleason score (p < 0.001), pretreatment PSA level (p < 0.001), treatment year (p = 0.001), and the isotope used (p = 0.004) as pretreatment and treatment variables associated with PRFS. When restricted to patients with available postimplantation dosimetric information, D90 emerged as a significant predictor of biochemical outcome (p = 0.01), and isotope was not significant. The 8-year PRFS was 92%, 86%, 79%, and 67%, respectively, for patients with PSA nadir values of 0-0.49, 0.5-0.99, 1.0-1.99, and >2.0 ng/mL (p < 0.001). Among patients free of biochemical relapse at 8 years, the median nadir level was 0.1 ng/mL, and 90% of these patients achieved a nadir PSA level <0.6 ng/mL. CONCLUSIONS: Outcome after permanent BT for prostatic cancer relates to tumor stage, Gleason score, pretreatment PSA, BT year, and post-BT dosimetric quality. PSA nadir < or =0.5 ng/mL was particularly associated with durable long-term PSA disease-free survival. The only controllable factor to impact on long-term outcome was the D90 which is a reflection of implant quality.     

Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer

PURPOSE: To link posttreatment biochemical profiles to distant failure and cause-specific survival by assessing the relationship between posttreatment prostate-specific antigen (PSA) nadir and PSA doubling time (PSADT) with these outcome measures. METHODS AND MATERIALS: A total of 615 men were treated at the Fox Chase Cancer Center between April 1989 and December 1995 with three-dimensional conformal radiotherapy alone (median dose 73 Gy). The median follow-up was 64 months (range 2-135). Kaplan-Meier methods were used to estimate the rates of biochemical control, freedom from distant metastasis (FDM), and cause-specific survival. Multivariate predictors of outcome were assessed using stepwise Cox regression analysis. RESULTS: Multivariate analyses demonstrated that the predictors of improved biochemical control were a lower PSA nadir (p <0.0001), lower pretreatment PSA level (p <0.0001), Gleason score of 2-6 (p = 0.001), Stage T1-T2a tumors (p = 0.03), and higher RT dose (p = 0.02). The predictors of improved FDM were a lower PSA nadir (p <0.0001), longer interval to nadir from start of treatment (p = 0.0002), Gleason score of 2-6 (p = 0.005), androgen deprivation for biochemical failure (p = 0.001), and Stage T1-T2a tumors (p = 0.01). The predictors of improved cause-specific survival were a lower PSA nadir (p = 0.006) and longer interval to nadir from the start of treatment (p = 0.03). The 8-year FDM rate was 96%, 89%, and 61% for PSA nadir values of 2.0 ng/mL (p <0.0001), respectively. The 8-year cause-specific survival rate was 97%, 96%, and 78% for posttreatment PSA nadir values of 2.0 ng/mL (p <0.0001), respectively. For patients with sufficient PSA follow-up for PSADT calculations (n = 136), multivariate analysis of FDM from the time of biochemical failure demonstrated that androgen deprivation (p = 0.001), longer PSADT (p = 0.003), lower PSA nadir (p = 0.02), and longer interval to nadir from start of treatment (p = 0.04) were independent predictors of improved FDM. CONCLUSION: This is the first study, to our knowledge, to demonstrate the overwhelming predictive power of posttreatment PSA nadir for distant failure and death from prostate cancer. It is also the first study, to our knowledge, to demonstrate a strong association between posttreatment PSADT and distant failure. The results provide new information regarding disease progression as a function of posttreatment PSA profiles (time to achieve nadir from start of treatment, nadir, and PSADT) and the timing of androgen deprivation for biochemical relapse. This study may be used for the early identification of patients at high risk of distant metastasis and who may be directed to applicable systemic treatment clinical trials.     

Using PSA,biopsy Gleason score,clinical stage,and the percentage of positive biopsies to identify optimal candidates for prostate-only radiation therapy

PURPOSE: An identification of prostate cancer patients most likely to benefit from prostate-only radiation was made based upon the pretreatment prostate-specific antigen (PSA), biopsy Gleason score, clinical stage, percentage of positive biopsies, and the 5-year postoperative PSA outcome. METHODS: Between 1989 and 2000, 2099 patients underwent radical prostatectomy for clinically localized prostate cancer. The primary end points were pathologic evidence of seminal vesicle invasion 2(SVI), extracapsular extension (ECE) with or without positive surgical margins, and the 5-year postoperative PSA outcome. RESULTS: Pretreatment PSA, biopsy Gleason score, and clinical stage were used to assign patients to low-, intermediate-, and high-risk groups. These risk groups were stratified by the percentage of positive biopsies and the primary pathologic and biochemical outcomes examined. The rates of SVI, ECE with positive margin, and no biochemical evidence of disease (bNED) for low-risk patients with < or =50% positive biopsies were 2%, 7%, and 93%, respectively. Patients with >50% positive biopsies had higher rates of SVI and ECE (5% and 11%, respectively) and 52% bNED (p < 0.0001). For intermediate-risk patients with < or =17% positive biopsies, the rates of SVI, ECE with positive margin, and bNED were 3%, 9%, and 90%, respectively. As the percentage of positive biopsies increased above 17% in intermediate-risk patients, there was a statistically significant increase in SVI and ECE and a significant decrease in bNED. CONCLUSIONS: Low-risk patients with < or =50% positive biopsies and intermediate-risk patients with < or =17% positive biopsies had a very low risk of SVI and ECE with positive surgical margins. Given that the presence of SVI and ECE with positive surgical margins was uncommon (<10%) with a > or =90% PSA failure-free survival after radical prostatectomy, these patients may be optimal candidates for radiation therapy directed at the prostate only (prostate gland + 1.5-cm margin).     

Does short-term androgen deprivation substitute for radiation dose in the treatment of high-risk prostate cancer?

PURPOSE: Randomized trials have corroborated the clinical benefit of adding androgen deprivation (AD) to radiotherapy (RT) in the treatment of high-risk prostate cancer. Another competing strategy is to escalate the RT dose using three-dimensional conformal RT (3D-CRT). In this analysis, we asked whether the addition of short-term AD (STAD) (20 ng/mL, Gleason score 8-10, or T3-4) prostate cancer is an effective substitute for dose escalation. METHODS AND MATERIALS: Between March 1, 1990 and November 30, 1998, 296 high-risk prostate cancer patients were treated with 3D-CRT alone (n = 206) or in combination with STAD (n = 90). The patient characteristics were median age 68 years, median follow-up 58 months, pretreatment initial prostate-specific antigen 21.8 ng/mL, RT dose 75 Gy, STAD duration 3 months, and time off STAD 64 months. The impact of STAD with respect to dose was examined using univariate analysis for dose ranges of <75 Gy and >or=75 Gy. Stepwise Cox proportional hazards regression multivariate analysis was performed to determine independent correlates of freedom from biochemical failure (bNED), freedom from distant metastasis (FDM), and overall survival. In a separate matched-pair analysis (n = 44 per group), those treated to <75 Gy + STAD (Group A) were compared with those who received >or=75 Gy alone (Group B). RESULTS: On univariate analysis, the addition of STAD had no impact on bNED, FDM, or overall survival in either dose group. On multivariate analysis, initial prostate-specific antigen level, palpation T stage, and RT dose were significant correlates of bNED. For FDM and overall survival, the significant covariates were palpation T stage and Gleason score, respectively. Finally, in matched-pair analysis, the higher RT dose group had a significantly greater bNED rate at 5 years (Group A 35% vs. Group B 57%, p = 0.0190). CONCLUSION: Our data suggest that STAD, as used here (median 3 months), is not a substitute for RT dose in the treatment of high-risk prostate cancer. RT dose is an essential element in the treatment of high-risk prostate cancer.     

Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage

Purpose: Ideal candidates for 3D dose escalation conformal radiation or external beam + implant therapy are identified on the basis of the prostate-specific antigen (PSA) level, biopsy Gleason score, and the 1992 American Joint Commission Cancer (AJCC) clinical T-stage.

Methods and Materials: The pathologic findings of 1742 men with clinical stage T1c,2 prostate cancer managed with a radical prostatectomy (RP) between 1990 and 1998 were subjected to a logistic regression multivariable analysis. The endpoints examined included pathologic organ–confined (OC), specimen-confined (SC), and margin (M) or seminal vesicle (SV) positive disease. SC disease was defined as extracapsular extension (ECE) with a negative surgical margin. The clinical factors tested included PSA level, biopsy Gleason score, and the 1992 AJCC clinical T-stage. PSA failure–free (bNED) survival was calculated according to the method of Kaplan and Meier.

Results: Significant negative predictors of pathologic OC–disease or positive predictors of M⁺ or SV⁺ disease included a PSA > 10 ng/ml (p < 0.0001), biopsy Gleason score ≥7 (p ≤ 0.0004), and ≥ T2b disease (p ≤ 0.03). Only biopsy Gleason score 7 (p = 0.0006) and PSA 10–15 ng/ml (p = 0.04) were significant predictors of SC disease. The estimates of 5-year bNED survival were 80%, 62%, and 35% (p < 0.0001) for patients having a low, intermediate, or high likelihood of having M⁺ or SV⁺ disease respectively.

Conclusions: Patients most likely to derive a survival benefit from the improved local control possible using dose escalation techniques were those who had both a low risk of having occult micrometastatic disease (<25% M⁺ or SV⁺) and a reasonable likelihood of remaining disease-free after RP (>50% 5-year bNED). These patients included those having T1c, 2a, PSA > 10–15 ng/ml, and biopsy Gleason ≤6 or T1c, 2a, 2b, PSA ≤ 10 ng/ml, and biopsy Gleason ≤ 7 prostate cancer.     

Outcome evaluation of the 1997 American Joint Committee on Cancer staging system for prostate carcinoma treated by radiation therapy

BACKGROUND: The 1997 American Joint Committee on Cancer (AJCC) staging system condensed unilobular tumors into one entity and continues the use of both imaging and biopsy to alter classification status in T2 and T3 carcinomas. This study analyzes the biochemical freedom from disease recurrence (bNED) outcome in a large database to determine whether these changes reflect outcome differences. METHODS: Five hundred and thirty-seven patients with adenocarcinoma of the prostate were treated with radiation therapy to a median dose of 7180 centigrays (cGy) (range, 6316-8074 cGy) between November 1987 and November 1994. The median age of the patients was 70 years and the median follow-up was 51 months. The median pretreatment prostate specific antigen (PSA) was 11.0 ng/mL. Patients were analyzed using 1992 AJCC stage comparing bNED outcome after radiation therapy for T2a versus T2b versus T2c tumors using Kaplan-Meier estimation and the log rank test. Patients then were analyzed multivariately using Cox regression with the known prognostic variables of dose, pretreatment PSA, palpation stage, and grade in addition to palpation plus imaging stage and palpation plus biopsy stage. The prognostic endpoint was bNED with failure as defined by the 1997 American Society for Therapeutic Radiology and Oncology Consensus Panel. RESULTS: The 1992 AJCC palpation classifications T2a versus T2b versus T2c have a significantly different (P = 0.02) bNED outcome. Prognostic significance is lost by pooling these three classifications in the 1997 AJCC staging system. Adding imaging information to palpation did not improve the ability of palpation alone to assess bNED status (P = 0.33). However, the addition of biopsy information to palpation significantly (P = 0.02) increased the accuracy of palpation stage alone to predict for bNED outcome for T2 and T3 tumors. CONCLUSIONS: The subdivision of T2 tumors in the 1992 AJCC classification (T2a, T2b, and T2c) should be used in the next revision of the 1997 AJCC staging system. The addition of imaging data does not discriminate bNED outcome any better than palpation stage alone in T2 and T3 tumors and should not be used. The addition of biopsy information to palpation stage did significantly improve the predicted outcome compared with palpation alone and should continue to be used.     

Risk group stratification in patients undergoing permanent (125)I prostate brachytherapy as monotherapy

PURPOSE: Patients undergoing prostate brachytherapy (PB) as monotherapy are often selected on the basis of favorable pretreatment factors. However, intermediate and high-risk prostate cancer patients are commonly offered PB as monotherapy without the addition of external beam radiotherapy (EBRT) or hormonal therapy. This series reports the outcome of patients undergoing PB as monotherapy who were stratified into low, intermediate, and high-risk groups with extended follow-up. METHODS AND MATERIALS: A total of 102 patients with clinically localized prostate cancer underwent PB alone as monotherapy. EBRT or hormonal therapy was not part of their initial treatment. Prostate-specific antigen (PSA) relapse-free survival (PRFS) was determined in accordance with the American Society for Therapeutic Radiology and Oncology consensus statement. Patients were stratified as at favorable risk (Stage T1-2a, pretreatment PSA < or =10.0 ng/mL, and Gleason score < or =6), intermediate risk (one prognostic indicator with a higher value), or unfavorable risk (> or =2 indicators with higher values). The median follow-up period for patients in this series was 7 years (range 2.1-9.7). The median age at treatment was 71 years (range 54-80), and the median prescribed dose of (125)I was 145 Gy. RESULTS: Forty patients experienced a biochemical relapse at a median of 1.9 years (range 0.4-4.2). The 5-year actuarial PRFS rate for patients with favorable, intermediate, and unfavorable risk was 85%, 63%, and 24%, respectively (p <0.0001). All but 1 patient had the relapse within the first 5 years of treatment. When stratifying patients on the basis of their pretreatment PSA level, the 5-year PRFS rate for men with a PSA < or =10 ng/mL vs. >10 ng/mL was 78% vs. 35%, respectively (p = 0.0005). Furthermore, the 5-year PRFS rate for men with a Gleason score of < or =6 vs. > or =7 was 74% vs. 33%, respectively (p = 0.0001). No difference was found between Stage T1-T2a and Stage T2b or higher (64% vs. 54%, respectively; p = 0.353). CONCLUSION: On the basis of risk stratification, PB as monotherapy produces comparable PRFS to EBRT and surgery at 7 years of follow-up. PB as monotherapy is particularly ineffective in patients with unfavorable risk factors, and additional therapy is warranted.