Xin Pei

Long-term survival and toxicity in patients treated with high-dose intensity modulated radiation therapy for localized prostate cancer.

PURPOSE To report long-term survival and toxicity outcomes with the use of high-dose intensity modulated radiation therapy (IMRT) to 86.4 Gy for patients with localized prostate cancer. METHODS AND MATERIALS Between August 1997 and December 2008, 1002 patients were treated to a dose of 86.4 Gy using a 5-7 field IMRT technique. Patients were stratified by prognostic risk group based on National Comprehensive Cancer Network risk classification criteria. A total of 587 patients (59%) were treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range, 1-14 years). RESULTS For low-, intermediate-, and high-risk groups, 7-year biochemical relapse-free survival outcomes were 98.8%, 85.6%, and 67.9%, respectively (P<.001), and distant metastasis-free survival rates were 99.4%, 94.1%, and 82.0% (P<.001), respectively. On multivariate analysis, T stage (P<.001), Gleason score (P<.001), and >50% of initial biopsy positive core (P=.001) were predictive for distant mestastases. No prostate cancer-related deaths were observed in the low-risk group. The 7-year prostate cancer-specific mortality (PCSM) rates, using competing risk analysis for intermediate- and high-risk groups, were 3.3% and 8.1%, respectively (P=.008). On multivariate analysis, Gleason score (P=.004), percentage of biopsy core positivity (P=.003), and T-stage (P=.033) were predictive for PCSM. Actuarial 7-year grade 2 or higher late gastrointestinal and genitourinary toxicities were 4.4% and 21.1%, respectively. Late grade 3 gastrointestinal and genitourinary toxicity was experienced by 7 patients (0.7%) and 22 patients (2.2%), respectively. Of the 427 men with full potency at baseline, 317 men (74%) retained sexual function at time of last follow-up. CONCLUSIONS This study represents the largest cohort of patients treated with high-dose radiation to 86.4 Gy, using IMRT for localized prostate cancer, with the longest follow-up to date. Our findings indicate that this treatment results in excellent clinical outcomes with acceptable toxicity.

Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer

The authors investigated long‐term tumor control and toxicity outcomes after high‐dose, intensity‐modulated radiation therapy (IMRT) in patients who had clinically localized prostate cancer.

Dose Escalation for Prostate Cancer Radiotherapy: Predictors of Long-Term Biochemical Tumor Control and Distant Metastases–Free Survival Outcomes

BACKGROUND Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. OBJECTIVE Identify predictors of biochemical tumor control and distant metastases-free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. DESIGN, SETTING, AND PARTICIPANTS This retrospective analysis comprised 2551 patients with clinical stages T1-T3 PCa. Median follow-up was 8 yr, extending >20 yr. INTERVENTION Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. MEASUREMENTS A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. RESULTS AND LIMITATIONS Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels < 70.2 Gy and 70.2-79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse-free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. CONCLUSIONS Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.

Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality.

BACKGROUND In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC). OBJECTIVE To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC. DESIGN, SETTING, AND PARTICIPANTS Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States. INTERVENTION Use of metformin in localized prostate cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality (PCSM), overall survival (OS), and development of CRPC. RESULTS AND LIMITATIONS With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24-3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78-7.62]; p<0.001), and PCSM (HR: 5.15 [1.53-17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01). The retrospective study design was the primary limitation of the study. CONCLUSIONS To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformins potential benefits is warranted.

Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma.

PURPOSE To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. PATIENTS AND METHODS Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). RESULTS The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a high single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). CONCLUSION High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.

Improved Toxicity Profile Following High-Dose Postprostatectomy Salvage Radiation Therapy With Intensity-Modulated Radiation Therapy

BACKGROUND With salvage radiation therapy (SRT) in the postprostatectomy setting, the need to deliver sufficient radiation doses to achieve a high probability of tumor control is balanced with the risk of increased toxicity. Intensity-modulated radiation therapy (IMRT) in the postprostatectomy salvage setting is gaining interest as a treatment strategy. OBJECTIVE Compare acute and late toxicities in patients treated with IMRT and three-dimensional conformal radiation therapy (3D-CRT) in the postprostatectomy salvage setting. DESIGN, SETTING, AND PARTICIPANTS A total of 285 patients who were treated at our institution between 1988 and 2007 with SRT after radical prostatectomy for biochemical recurrence were identified. All medical records were reviewed and toxicity recorded. Median follow-up was 60 mo. INTERVENTION All patients were treated with SRT with either 3D-CRT (n=109) or IMRT (n=176). A total of 205 patients (72%) were treated with doses ≥70Gy. MEASUREMENTS Late gastrointestinal (GI) and genitourinary (GU) toxicities were recorded using the Common Terminology Criteria for Adverse Events v. 3.0 definition. RESULTS AND LIMITATIONS The 5-yr actuarial rates of late grade ≥2 GI and GU toxicity were 5.2% and 17.0%, respectively. IMRT was independently associated with a reduction in grade ≥2 GI toxicity compared with 3D-CRT (5-yr IMRT, 1.9%; 5-yr 3D-CRT, 10.2%; p=0.02). IMRT was not associated with a reduction in risk of grade ≥2 GU toxicity (5-yr IMRT, 16.8%; 5-yr 3D-CRT, 15.8%; p=0.86), urinary incontinence (5-yr IMRT, 13.6%; 5-yr 3D-CRT, 7.9%; p=0.25), or grade 3 erectile dysfunction (5-yr IMRT, 26%; 5-yr 3D-CRT, 30%; p=0.82). Of patients who developed late grade ≥2 GI or GU toxicity, 38% and 44%, respectively, experienced resolution of their symptoms prior to the last follow-up. CONCLUSIONS Our experience with high-dose IMRT in the postprostatectomy salvage setting demonstrates that the treatment can be delivered safely with an associated reduction in late GI toxicity.

Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.

To compare tumour control and toxicity outcomes with the use of high‐dose intensity‐modulated radiation therapy (IMRT) alone or brachytherapy combined with IMRT (combo‐RT) for patients with intermediate‐risk prostate cancer.

The Natural History and Predictors of Outcome Following Biochemical Relapse in the Dose Escalation Era for Prostate Cancer Patients Undergoing Definitive External Beam Radiotherapy

BACKGROUND The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting. OBJECTIVE We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT. DESIGN, SETTING, AND PARTICIPANTS This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients. INTERVENTION(S) All patients received EBRT at doses of 75.6-86.4 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer-specific mortality (PCSM). RESULTS AND LIMITATIONS From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions. CONCLUSIONS Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF. PATIENT SUMMARY In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes.

Comparison of Tumor Control and Toxicity Outcomes of High Dose Intensity-Modulated Radiotherapy and Brachytherapy for Patients with Favorable Risk Prostate Cancer

OBJECTIVES To compare the long-term, prostate-specific antigen relapse-free survival outcome and incidence of toxicity for patients with low-risk prostate cancer who underwent brachytherapy or intensity-modulated radiotherapy (RT). METHODS A total of 729 consecutive patients underwent brachytherapy (n = 448; prescription dose 144 Gy) or intensity-modulated RT alone (n = 281; prescription dose 81 Gy). The prostate-specific antigen relapse-free survival using the nadir plus 2 ng/mL definition and late toxicity using the National Cancer Institutes Common Terminology Criteria for Adverse Events were determined. RESULTS The 7-year prostate-specific antigen relapse-free survival rate for the brachytherapy and intensity-modulated RT groups was 95% and 89% for low-risk patients, respectively (P = .004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival, even after adjustment for other variables. The incidence of metastatic disease between treatment sessions was low for both treatment groups. Late grade 2 gastrointestinal toxicity was observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated RT groups, respectively (P = .02). No significant differences were seen between treatment groups for late grade 3 or greater rectal complications (brachytherapy 1.1% and intensity-modulated RT 0%; P = .19). Late grade 2 urinary toxicity occurred more often in the brachytherapy group than in the intensity-modulated RT group (15.6% and 4.3%, respectively; P < .0001). No significant differences were seen between the 2 treatment groups for late grade 3 urinary toxicity (brachytherapy 2.2% and intensity-modulated RT 1.4%; P = .62). CONCLUSIONS Among low-risk prostate cancer patients, the 7-year biochemical tumor control was superior for intraoperatively planned brachytherapy compared with high-dose intensity-modulated RT. Although significant toxicities were minimal for both groups, modest, but significant, increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated RT.

Incidence of secondary cancer development after high-dose intensity-modulated radiotherapy and image-guided brachytherapy for the treatment of localized prostate cancer.

PURPOSE To report the incidence and excess risk of second malignancy (SM) development compared with the general population after external beam radiotherapy (EBRT) and brachytherapy to treat prostate cancer. METHODS AND MATERIALS Between 1998 and 2001, 1,310 patients with localized prostate cancer were treated with EBRT (n = 897) or brachytherapy (n = 413). We compared the incidence of SMs in our patients with that of the general population extracted from the National Cancer Institutes Surveillance, Epidemiology, and End Results data set combined with the 2000 census data. RESULTS The 10-year likelihood of SM development was 25% after EBRT and 15% after brachytherapy (p = .02). The corresponding 10-year likelihood for in-field SM development in these groups was 4.9% and 1.6% (p = .24). Multivariate analysis showed that EBRT vs. brachytherapy and older age were the only significant predictors for the development of all SMs (p = .037 and p = .030), with a trend for older patients to develop a SM. The increased incidence of SM for EBRT patients was explained by the greater incidence of skin cancer outside the radiation field compared with that after brachytherapy (10.6% and 3.3%, respectively, p = .004). For the EBRT group, the 5- and 10-year mortality rate was 1.96% and 5.1% from out-of field cancer, respectively; for in-field SM, the corresponding mortality rates were 0.1% and 0.7%. Among the brachytherapy group, the 5- and 10-year mortality rate related to out-of field SM was 0.8% and 2.7%, respectively. Our observed SM rates after prostate RT were not significantly different from the cancer incidence rates in the general population. CONCLUSIONS Using modern sophisticated treatment techniques, we report low rates of in-field bladder and rectal SM risks after prostate cancer RT. Furthermore, the likelihood of mortality secondary to a SM was unusual. The greater rate of SM observed with EBRT vs. brachytherapy was related to a small, but significantly increased, number of skin cancers in the EBRT patients compared with that of the general population.