Long-Term Implications of a Positive Posttreatment Biopsy in Patients Treated with External Beam Radiotherapy for Clinically Localized Prostate Cancer.

PURPOSE: We determined the prognostic importance of a positive posttreatment biopsy after prostate radiotherapy. MATERIALS AND METHODS: A total of 382 patients underwent a posttreatment biopsy after external beam radiotherapy for clinically localized prostate cancer. Posttreatment biopsies were classified as positive (prostatic adenocarcinoma without typical radiation induced changes), negative (no evidence of carcinoma) or adenocarcinoma with a severe treatment effect. Median followup in survivors was 9 years. Competing risks regression was used to assess relationships between prognostic predictors and cause specific mortality, distant metastasis and prostate specific antigen failure. RESULTS: The prevalence of positive biopsy, treatment effect and negative biopsy was 30%, 22% and 48%, respectively. Androgen deprivation therapy omission and high risk disease were associated with a 2.6 and 1.8-fold increase, respectively, in the odds of positive posttreatment biopsy. The 15-year PSA relapse rate associated with negative, severe treatment effect and positive posttreatment biopsies was 34%, 36% and 79%, respectively (p <0.001). After controlling for known predictors the risk of distant metastasis was 2.6-fold higher in patients with a positive biopsy (p <0.001) and cause specific mortality was twice as high in patients with a positive biopsy compared to those with negative and severe treatment effect biopsy outcomes (HR 2.00, p = 0.022). CONCLUSIONS: A positive posttreatment biopsy after external beam radiotherapy was associated with a higher risk of distant metastasis and prostate cancer related death. Patients with severe treatment effect classified biopsies have biological characteristics more like patients with a negative biopsy than a positive biopsy. Posttreatment biopsies were more often positive in the setting of external beam radiotherapy alone without androgen deprivation therapy or in the presence of high risk disease.

Financial toxicity associated with treatment of localized prostate cancer.

Financial toxicity is a broad term to describe the economic consequences and subjective burden resulting from a cancer diagnosis and treatment. As financial toxicity is associated with poor disease outcomes, recognition of this problem and calls for strategies to identify and support those most at risk are increasing. Men with localized prostate cancer face treatment choices including active surveillance, prostatectomy or radiotherapy. The fact that potential patient out-of-pocket costs might influence decision making has rarely been acknowledged and, overall, the risk of financial toxicity for men with localized prostate cancer remains poorly studied. This shortfall requires a work-up in the context of prostate cancer and a multidimensional framework for considering a patient's risk of financial toxicity. The major elements of this framework are direct and indirect costs, patient-specific values, expectations of possible financial burdens, and individual economic circumstances. Current data indicate that total cost patterns probably differ by treatment modality: surgery might have an increased short-term effect, whereas radiotherapy might have an increased long-term risk of financial toxicity. Specific thresholds of patient income levels or out-of-pocket costs that predict risk of financial toxicity are difficult to identify. Compared with other malignancies, prostate cancer might have a lower overall risk of financial toxicity, but persistent post-treatment urinary, bowel or sexual adverse effects are likely to increase this risk.

Low-Dose-Rate Brachytherapy Combined With Ultrahypofractionated Radiation Therapy for Clinically Localized, Intermediate-Risk Prostate Cancer: Results From a Prospective Trial.

PURPOSE: To report early toxicity and tumor control outcomes of Pd-103 brachytherapy with ultrahypofractionated stereotactic radiation therapy (RT) for intermediate-risk prostate cancer. METHODS AND MATERIALS: This prospective trial included 40 patients with intermediate-risk prostate cancer who underwent low-dose-rate (Pd-103) brachytherapy (prescription dose, 100 Gy), followed 1 month later with ultrahypofractionated stereotactic RT (25 Gy in 5 fractions) to the prostate and seminal vesicles. The primary endpoint was the rate of grade 2+ genitourinary toxicity at 12 months using Common Terminology Criteria for Adverse Events v 4.0. Secondary endpoints included patient-reported quality-of-life metrics (International Prostate Scoring System [IPSS], International Index of Erectile Function, and Expanded Prostate Cancer Index Composite-bowel). Biochemical failure was defined as prostate-specific antigen nadir +2 ng/mL. Posttreatment biopsies were performed at between 24 and 36 months; median follow-up was 36 months. RESULTS: The rate of grade 2 urinary toxicity at 12 months was 25% with no grade 3 urinary toxicity noted. Mean IPSS at baseline and 12 and 24 months was 5, 10, and 6.2, respectively. Mean change in IPSS from baseline at 12 months was +5.5 (interquartile range, 1-9.75) and +1.05 (interquartile range, -3 to 3.25) at 24 months. Grade 2 bowel toxicity was 5% at 12 months with no grade 3 bowel toxicity noted. Mean Expanded Prostate Cancer Index Composite-bowel domain scores at baseline and 12 months were 92.8 and 90.3, respectively. Of patients who were potent (International Index of Erectile Function ≥21) at baseline, 75% remained potent at 12 months. Of 40 patients, 28 underwent posttreatment prostate biopsy (PPB), which was negative (n = 20) or demonstrated severe treatment effect (n = 8). No patient had a positive PPB or developed biochemical failure during the follow-up period. One patient without a PPB developed osseous metastases at 18 months posttreatment in the absence of biochemical failure. CONCLUSION: Low-dose-rate brachytherapy in combination with ultrahypofractionated stereotactic RT was safe and effective for intermediate-risk prostate cancer in early results of this trial.

Clinical Outcomes of Combined Prostate- and Metastasis-Directed Radiation Therapy for the Treatment of De Novo Oligometastatic Prostate Cancer.

PURPOSE: The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial reported overall survival benefits for prostate-directed radiation therapy (PDRT) in low-burden metastatic prostate cancer. Oligometastasis-directed radiation therapy (ORT) improves androgen deprivation therapy (ADT)-free and progression-free survivals. Comprehensive PDRT + ORT to all detectable metastases may offer benefit for de novo oligometastatic prostate cancer (DNOPC) and is under prospective study; given few available benchmarks, we reviewed our institutional experience. METHODS AND MATERIALS: Forty-seven patients with DNOPC with predominantly M1b disease received neoadjuvant, concurrent, and adjuvant ADT plus PDRT + ORT to 1 to 6 oligometastases. Gross pelvic (N1) nodes were not considered oligometastases unless focally targeted without broader nodal coverage. Outcomes were analyzed from radiation therapy (RT) start using Kaplan-Meier, competing risks, and Cox regression. Median follow-up was 27 (95% confidence interval, 16-42) months. RESULTS: At 1- and 2-years post-RT, cumulative incidence of distant metastatic progression (DMP) was 21% and 32%, whereas overall survival was 90% and 87%, respectively. Neuroendocrine/intraductal histology, prostate-specific antigen (PSA) < 20, and detectable PSA after PDRT + ORT were associated with increased DMP risk; number and location of oligometastases were not. Local failure was rare, with 3 prostate recurrences and progression of 10 treated oligometastases during follow-up. After neoadjuvant ADT, 9 (19%) patients had undetectable PSA (<0.05 ng/mL), which increased to 32 (68%) after PDRT + ORT. Overall 2-year incidence of biochemical recurrence (BCR) and development of castrate resistance were 23% and 36%, respectively. Undetectable PSA post-RT was associated with lower risk of BCR (hazard ratio, 0.19; P = .004) and DMP (hazard ratio, 0.26; P = .025). Overall, 23 (49%) patients were trialed off ADT; 16 (70%) had testosterone recovery (>150 ng/dL) and, of these, 5 had subsequent PSA rise and restarted ADT 2 to 21 months postrecovery. The remaining 11 were maintained off ADT without BCR. Median noncastrate duration was 8 months; 7 patients had normalized testosterone for >1 year. CONCLUSIONS: A comprehensive, radiotherapeutic-based treatment strategy has favorable clinical outcomes and can produce prolonged noncastrate remissions in a subset with DNOPC.

Early Tolerance and Tumor Control Outcomes with High-dose Ultrahypofractionated Radiation Therapy for Prostate Cancer.

BACKGROUND: Studies using stereotactic body radiotherapy (SBRT) dose escalation in in low- and intermediate-risk prostate cancer patients have indicated favorable outcomes. OBJECTIVE: To evaluate tolerance and tumor control outcomes in low- and intermediate-risk prostate cancer patients treated with high-dose SBRT following our phase 1 trial. DESIGN, SETTING, AND PARTICIPANTS: A total of 551 patients with low- or intermediate-risk prostate cancer were treated with SBRT. INTERVENTION: Treatment with 37.5-40Gy SBRT in five fractions directed to the prostate and seminal vesicles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome measurements included acute toxicities (<3 mo after radiotherapy [RT]) and late toxicities (>3 mo after RT) and tumor control evaluation (prostate-specific antigen [PSA] levels at 3-6-mo intervals and post-treatment prostate biopsy at 2yr). RESULTS AND LIMITATIONS: Acute grade 2 gastrointestinal (GI) toxicities occurred in 1.8% of patients, and late grade 2 and 3 GI toxicities were observed in 3.4% and 0.4% of patients, respectively. Acute grade 2 genitourinary (GU) toxicities occurred in 10% of patients, and grade 3 acute GU toxicities were observed in 0.7% of patients. Late grade 2 and 3 GU toxicities were observed in 21.1% and 2.5% of patients, respectively. The use of a hydrogel rectal spacer was significantly associated with reduced late GI toxicity and lower odds of developing late GU toxicity. The median follow-up was 17 mo, and 53% of those with at least 2yr of follow-up (103/193) had a biopsy performed. The 5-yr cumulative incidence of PSA failure was 2.1%, and the incidence of a positive 2-yr treatment biopsy was 12%. Limitations to this report include its retrospective nature and short follow-up time. CONCLUSIONS: Favorable short-term outcomes were achieved with high-dose SBRT for low- and intermediate-risk disease. Severe late toxicities were observed and favorable tumor control was found. PATIENT SUMMARY: We utilized stereotactic body radiotherapy, a form of external beam radiotherapy that delivers highly targeted high-dose treatment to the prostate, to treat over 500 localized prostate cancer patients in five sessions over 1.5 wk. Treatments were well tolerated without significant urinary or rectal side effects. Nearly 90% of those who underwent biopsies after treatment did not demonstrate residual active disease.

Early biochemical predictors of survival in intermediate and high-risk prostate cancer treated with radiation and androgen deprivation therapy.

BACKGROUND AND PURPOSE: To identify early biochemical predictors of survival in intermediate- and high-risk prostate cancer patients with a pre-treatment PSA <20 ng/mL following definitive radiation therapy (RT) and androgen deprivation therapy (ADT). MATERIALS AND METHODS: A single-institution review of 2566 intermediate and high-risk prostate cancer patients treated with definitive RT and neoadjuvant and concurrent ADT from 1990 to 2012 was performed. The first prostate-specific antigen (PSA) value within three months of ADT initiation (post-ADT PSA) and the first PSA within three months after RT completion (post-RT PSA) were recorded. 1275 had baseline PSA <20 ng/mL and either post-ADT or post-RT PSA available. Median follow-up was 7.6 years. The relationship between post-treatment PSA kinetics and biochemical relapse (BR), distant metastasis (DM), prostate cancer specific death (PCSD) and overall survival (OS) was modeled using Cox regression univariate and multivariate analysis (MVA). RESULTS: MVA demonstrated a strong association between a post-RT PSA ≥0.09 ng/mL and a significantly higher risk of BR (HR: 1.93; 95% CI: 1.45-2.57; p < 0.001), DM (HR: 2.97; 95% CI: 2.01-4.39; p < 0.001), PCSD (HR: 2.99; 95% CI: 1.73-5.15; p < 0.001) and OS (HR: 1.49; 95% CI: 1.18-1.86; p < 0.001). Post-RT PSA reduction of ≥95% relative to the baseline PSA was associated with a significantly lower risk of BR (MVA HR: 0.58; 95% CI: 0.41-0.83; p = 0.003) and DM (MVA HR: 0.47; 95% CI: 0.30-0.76; p = 0.002). CONCLUSION: A PSA value ≥0.09 ng/mL early after RT completion is associated with significantly worse prognosis across all clinical outcomes, and an early PSA reduction of ≥95% is associated with reduced risk of BR and DM. These findings may identify patients who require early aggressive systemic management for high-risk disease.

Early Tolerance Outcomes of Stereotactic Hypofractionated Accelerated Radiation Therapy Concomitant with Pelvic Node Irradiation in High-risk Prostate Cancer.

PURPOSE: This study aimed to evaluate the toxicity of prostate and pelvic lymph node stereotactic body radiation therapy (SBRT) for high-risk prostate cancer. METHODS AND MATERIALS: Twenty-three patients with high-risk or lymph node-positive prostate cancer were treated with SBRT that delivered 37.5 to 40 Gy in 5 fractions to the prostate and seminal vesicles, with concomitant treatment of the pelvic nodes to 25 Gy. In general, patients received neoadjuvant, concurrent, and adjuvant androgen deprivation therapy for a duration of 18 months. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events, version 3.0. The median follow-up was 19 months (range, 3-48 months). RESULTS: Acute grade 1 gastrointestinal (GI) toxicities were noted in 2 patients (9.1%). No patient experienced acute grade ≥2 GI toxicity. Acute genitourinary (GU) grade 1, 2, and 3 toxicities were observed in 7 patients (31.8%), 8 patients (36.4%), and 1 patient (4.5%), respectively. Late grade 2 GI and GU toxicities were observed in 2 patients (9.1%) and 6 patients (27.3%), respectively. No late grade ≥3 GI toxicity was noted. Late grade ≥3 GU (hemorrhagic cystitis) was noted in 1 patient (4.5%), which responded to laser fulguration. CONCLUSIONS: SBRT with pelvic lymph node radiation therapy was feasible and well tolerated. The incidence of grade ≥3 GU and GI toxicities was uncommon. Continued follow-up will be required to determine the long-term safety and efficacy of this approach for high-risk patients.

Five-Year Outcomes of a Phase 1 Dose-Escalation Study Using Stereotactic Body Radiosurgery for Patients With Low-Risk and Intermediate-Risk Prostate Cancer.

PURPOSE: To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5 Gy in 5 fractions, and doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60 cm3. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively. RESULTS: The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013). CONCLUSIONS: SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.