bNED Rates Research Articles

Durable efficacy of early postoperative radiation therapy for high-risk pT3N0 prostate cancer: the importance of radiation dose

Objectives. To determine the durable efficacy of early postoperative radiation therapy (RT) in patients with pT3N0 prostate cancer who were at an increased risk of biochemical failure. We also evaluated the long-term benefit derived from using higher RT doses. Methods. Seventy-nine patients with pathologic Stage T3N0 prostate cancer and high-risk postoperative features underwent RT within 6 months after surgery. No patient received prior hormonal therapy. Fifty-nine patients had positive surgical margin, 29 had pathologic seminal vesicle invasion, and 27 had persistently elevated postoperative prostate-specific antigen (PSA) levels. Freedom from biochemical relapse (bNED) was defined as an undetectable (less than 0.2 ng/mL) PSA level. Median follow-up time was 39 months, and the median radiation dose was 64.8 Gy. All patients were followed for at least 2 years to be considered biochemically controlled. Results. Patients receiving adjuvant RT for an undetectable pre-RT PSA level had a 3-year bNED rate of 90%, compared with 44% for those receiving salvage RT for a detectable level ( P < 0.0001). In the group of adjuvant patients, RT doses more than 61.2 Gy resulted in a 3-year bNED rate of 90% compared with 64% for those receiving a lower dose ( P = 0.015). The salvage patients irradiated with a dose of 64.8 Gy or greater had a 3-year bNED rate of 52% compared with 18% for those irradiated with lower doses ( P = 0.048). Severe late RT-related complications were infrequent and did not correlate with dose. Conclusions. In patients with high-risk pT3N0 prostate cancer, an RT dose response may exist. Although some studies suggest limited durable efficacy for early postoperative RT, our data suggest that RT doses of 64.8 Gy or more appear superior to prevent future biochemical failures. A prospective randomized study evaluating a postoperative RT dose response is warranted.

Effect of higher radiation dose on biochemical control after radical prostatectomy for pT3N0 prostate cancer

Purpose: The appropriate radiation dose has not been determined for postoperative radiation therapy (RT) of prostate cancer. Postoperative PSA level is a useful marker of local residual disease, and may allow evaluation of RT dose–response after radical prostatectomy. Methods and Materials: Between 1989 and 1996, 86 consecutive patients with pT3N0 prostate cancer who did not receive prior hormonal therapy or chemotherapy were irradiated postoperatively. All patients received 55.8 to 70.2 Gy (median = 64.8 Gy) to the prostatic/seminal vesicle bed. Patients were judged to be free of biochemical failure (bNED) if their PSA remained undetectable or decreased to undetectable level (< 0.2 ng/ml). The median follow-up time was 32 months from time of irradiation. Results: Univariate and multivariate analyses of variables showed that the preRT PSA level was the most significant predictor of improved bNED survival ( p < 0.001). Actuarial analyses of radiation dose grouped with preRT PSA levels found higher radiation dose to be significant ( p < 0.05). For the 52 patients with an undetectable preRT PSA level, the 3-year bNED rate was 91% for patients irradiated to 61.5 Gy or more and 57% for those irradiated to lower doses ( p = 0.01). For the 21 patients with preRT PSA level > 0.2 and ≤ 2.0 ng/ml, the 3-year bNED rate was 79% for patients irradiated to 64.8 Gy or more and 33% for those irradiated to a lower dose ( p = 0.02). No other preRT PSA interval or radiation dose level was associated with a dose–response function. Conclusion: In patients with pT3N0 prostate cancer after radical prostatectomy, a radiation dose–response function may be present and depends on the preRT PSA value. Patients with high postoperative PSA levels (> 2.0 ng/ml) may be less likely to benefit from higher doses of RT, and should be considered a group for which systemic therapy should be tested.

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.

Endorectal coil magnetic resonance imaging identifies locally advanced prostate cancer in select patients with clinically localized disease

Objectives. Endorectal coil magnetic resonance imaging (erMRI) has been reported to improve the prediction of pathologic Stage T3 disease in patients with clinical Stage T1,2 disease, prostate-specific antigen (PSA) of 10 to 20 ng/mL, biopsy Gleason score of 7 or less, and at least 50% of the biopsy specimens positive from a sextant sampling. This study examines the performance characteristics of the erMRI to predict established extracapsular extension (ECE), seminal vesicle invasion (SVI), and PSA failure-free survival (bNED) in this subgroup. Methods. The sensitivity, specificity, positive and negative predictive value, and accuracy of the erMRI to predict established ECE and SVI were calculated in the proposed subgroup. PSA failure-free survival stratified by the erMRI-defined stage was estimated by using the method of Kaplan and Meier. Results. The sensitivity, specificity, positive and negative predictive value, and accuracy to predict established ECE and SVI in clinical Stage T1, 2 patients was 65%, 100%, 100%, 79%, and 84%, respectively. No patient would have been excluded from surgery on the basis of a false-positive study. Moreover, the percent of patients with pathologic organ-confined disease would have increased from 32% to 61%, and the 3-year bNED rate would have increased from 12% to 45% ( P = 0.07) if only patients with erMRI Stage T2 disease were selected for surgery. Conclusions. The erMRI may significantly improve the identification of established ECE and SVI in select patients with prostate cancer preoperatively. Further study of the erMRI in these select patients is warranted and ongoing.

Equivalent 5-year bNED in select prostate cancer patients managed with surgery or radiation therapy despite exclusion of the seminal vesicles from the CTV

Prostate Specific Antigen (PSA) failure free survival was determined for select prostate cancer patients managed definitively with external beam radiation therapy to the prostate only or radical retropubic prostatectomy. A logistic regression multivariable analysis evaluating the variables of PSA, biopsy Gleason score, and clinical stage was used to evaluate the endpoint of pathologic seminal vesicle invasion (SVI) in 749 consecutive prostate cancer patients managed with a radical retropubic prostatectomy. In a subgroup of 332 surgically and 197 radiation managed patients who did not have the clinical predictors of SVI, PSA failure free survival (bNED) was determined. Comparisons were made using the log rank test between surgically and radiation managed patients in this subgroup. In this subgroup, radiation managed patients were treated to a median dose of 66 Gy (66-70 Gy) to the prostate only. The pretreatment PSA (> 10 ng/ml), biopsy Gleason score (> or = 7), and clinical stage (T2b, 2c, or 3) were found to be significant independent predictors (p < 0.001) of SVI. Only 2% of patients without any of these factors had SVI and 17% had extracapsular extension (15% microscopic; 2% macroscopic). In this subgroup the 5-year bNED rates were equivalent [84 vs. 89% (p = 0.67)] for surgically and radiation managed patients, respectively. Conventional dose external beam radiation therapy directed at the prostate alone resulted in 5-year bNED rates equivalent to surgery on retrospective comparison in patients with clinical stage T1,2a, PSA < or = 10 ng/ml, and biopsy Gleason < or = 6 prostate cancer.

Conformai external beam treatment of prostate cancer

Objectives This study reports the 5-year outcomes of treatment for patients with prostate cancer treated largely with conformal three-dimensional radiation therapy. Methods Results are presented for 456 consecutive patients treated prior to December 31, 1993 whose pretreatment prostate-specific antigen (PSA) levels are known. Biochemical failure was defined as two consecutive rises in the PSA that equals or exceeds 1.5 ng/mL. Kaplan-Meier product limit methods, the logrank test, and Cox regression models were used in evaluating the data. No patient was lost to follow-up. Results The 5-year biochemically free of failure (bNED) rate for all patients was 61% and 57% at 7 years. In the group with pretreatment PSA less than 10 ng/mL, the 5-year bNED rate for patients with localized disease (T1,2AB disease, Gleason sum of 6 or less) was 85% and for those with locally advanced disease (T2C,3), 70%. In the group with pretreatment PSA of 10 to 19.9 ng/mL, the 5-year bNED rate for patients with localized disease was 66% and for those with locally advanced disease, 44%. In the group with pretreatment PSA of 20 ng/mL or above, the patients with localized or locally advanced disease had 5-year bNED rates of 31% and 21%, respectively. Conclusions The results of largely conformal three-dimensional external beam treatment of localized prostate cancer produced 5-year bNED results that are comparable to recent reports of nerve-sparing prostatectomy. Preliminary 7-year bNED results in all patients and in patients with localized tumors indicated a modest decrease in the cancer-free rate from that observed at 5 years, suggesting the results are durable.

Results of 3D conformal radiotherapy in the treatment of localized prostate cancer

Purpose : 3D conformal radiotherapy (3D CRT) has been shown to decrease acute morbidity in the treatment of prostate cancer. Therapeutic outcome and late morbidity data have been accumulating. To evaluate the resutls of 3D CRT for the treatment of prostate cancer, we analyzed the outcome of a large series of patients treated with conformal techniques. Methods and Materials : From January 1987 through June 1994, 707 patients with localized prostate cancer were trreated with 3D CRT. Patients with pathologically-confirmed pelvic lymph node metastasis, treated with pre-irradiation (preRT) androgen ablation, or treated post-prostatectomy were excluded. All had CT obtained specifically for treatment planning, multiple structures contoured on the axial images, and beam's s-eye view conformal beams edited to provide 3D dose coverage. Median follow-up is 36 mos; 70 patients have been followed longer than 5.5 years. Six hundred three had T1-–T2 tumors. PreRT prostate specific antigen (PSA) was available for 649 patients: median preRT PSA was 12.9 ng/ml, 209 patients had preRT PSA > 20 ng/ml. The median dose of radiation was 69 Gy; 102 patients received ≥ 69 Gy. Biochemical failure was defined as: 1) two consecutive PSA rises over 2.0 ng/ml if nadir PSA ⩽ 2.0 ng/ml, 2) two consecutive PSA rises over nadir if nadir PSA > 2.0 ng/ml, or 3) initiation of hormonal therapy after RT. Complications were graded using the RTOG system. Results : PreRT PSA and Gleason score emerged as independent indicators of biochemical control (bNED). Patients with preRT PSA > 10 had a significantly worse bNED at 5 years than patients with preRT PSA ⩽ 10. Five-year bNED was determined according to preRT PSA: PSA ⩽4, 88%; PSA > 4 ⩽ 10, 72%; PSA > 10 ⩽ 20, 43% and PSA > 20, 30%. Patients with Gleason score ≥ 7 also had a significantly worse bNED than patients with Gleason score ≥ 7. Patients were divided into two prognostic groups: a favorable group with PSA ⩽ 10, Gleason score < 7, and T1–T2 tumors, and an unfavorable group with PSA > 10, Gleason score ≥ 7 or T3–T4 tumors and studied for the effect of dose on bNED status. The bNED at 5 years was 75% for the favorable group and 37% for the unfavorable group. In addition, a group that might be considered a surgical subset was reviewed: patients with PSA ⩽ 10, Gleason score ⩽ 7, and T1–T2 tumors who were < 70 years old. This subset had an 84% 5-year bNED rate and 98% 5-year overall survival. Complications with the techniques used here are very low: 3% risk at 7 years of Grade 3–4 complications and 1% risk at 7 years of Grade 3 bladder complications (no Grade 4). Conclusion : 3D CRT allows for treatment of prostate cancers with a very low risk of complications. Patients with relatively early disease as defined by preRT PSA, Gleason score < 7, and T1–2 tumors and patients who are candidates for radical prostatectomy have excellent 5-year bNED rates. Patients with adverse prognostic factors have a high risk of biochemical recurrence and are candidates for innovative therapy.