Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients.

PURPOSE: To explore the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in high-risk prostate cancer (HRPCa) in a consortium of 7 institutional phase 2 trials and prospective registries. METHODS AND MATERIALS: Individual patient data were pooled for 344 patients with a minimum follow-up of 24 months. Biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) were estimated using a Kaplan-Meier framework. Fine and Gray competing risk and Cox proportional hazards regression models were developed to assess the association between time to BCR and time to distant metastasis and prespecified variables of interest. Logistic regression models were developed to evaluate associations between acute and late grade ≥2 genitourinary and gastrointestinal and the following a priori-specified variables: age, dose per fraction, ADT use, and nodal radiation therapy. RESULTS: Median follow-up was 49.5 months. Seventy-two percent of patients received ADT, with a median duration of 9 months, and 19% received elective nodal radiation therapy. Estimated 4-year BCRFS and DMFS rates were 81.7% (95% CI, 77.2%-86.5%) and 89.1% (95% CI, 85.3%-93.1%). The crude incidences of late grade ≥3 genitourinary and gastrointestinal toxicity were 2.3% and 0.9%. CONCLUSIONS: These data support a favorable toxicity and efficacy profile for SBRT for HRPCa. Further prospective studies are needed to evaluate the optimal dose and target volume in the context of SBRT for HRPCa.

Dose-response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control.

BACKGROUND AND PURPOSE: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens. MATERIALS AND METHODS: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS). RESULTS: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ≤0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (≥93% for all regimens, p ≥ 0.21). CONCLUSION: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.

Prostate-specific antigen kinetics and biochemical control following stereotactic body radiation therapy, high dose rate brachytherapy, and low dose rate brachytherapy: A multi-institutional analysis of 3502 patients.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT), low dose rate brachytherapy (LDR-BT) and high dose rate brachytherapy (HDR-BT) are ablative-intent radiotherapy options for prostate cancer (PCa). These vary considerably in dose delivery, which may impact post-treatment prostate-specific antigen (PSA) patterns and biochemical control. We compared PSA kinetics between SBRT, HDR-BT, and LDR-BT, and assessed their relationships to biochemical recurrence-free survival (BCRFS). METHODS AND MATERIALS: Retrospective PSA data were analyzed for 3502 men with low-risk (n = 2223; 63.5%), favorable intermediate-risk (n = 869; 24.8%), and unfavorable intermediate-risk (n = 410; 11.7%) PCa treated with SBRT (n = 1716; 49.0%), HDR-BT (n = 512; 14.6%), or LDR-BT (n = 1274; 36.4%) without upfront androgen deprivation therapy at 10 institutions from 1990 to 2017. We compared nadir PSA (nPSA), time to nPSA, achievement of nPSA <0.2 ng/mL and <0.5 ng/mL, rates of nPSA <0.4 ng/mL at 4 years, and BCRFS. RESULTS: Median follow-up was 72 months. Median nPSA and nPSA <0.2 ng/mL were stratified by risk group (interaction p ≤ 0.001). Median nPSA and time to nPSA were 0.2 ng/mL at 44 months after SBRT, 0.1-0.2 ng/mL at 37 months after HDR-BT, and 0.01-0.2 ng/mL at 51 months after LDR-BT (mean log nPSA p ≤ 0.009 for LDR-BT vs. SBRT or HDR-BT for low/favorable intermediate-risk). There were no differences in nPSA <0.4 ng/mL at 4 years (p ≥ 0.51). BCRFS was similar for all three modalities (p ≥ 0.27). Continued PSA decay beyond 4 years was predictive of durable biochemical control. CONCLUSION: LDR-BT led to lower nPSAs with longer continued decay compared to SBRT and HDR-BT, but no differences in BCRFS.

Multi-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy.

PURPOSE: Understanding prostate-specific antigen (PSA) kinetics after radiation therapy plays a large role in the management of patients with prostate cancer (PCa). This is particularly true in establishing expectations regarding PSA nadir (nPSA) and PSA bounces, which can be disconcerting. As increasingly more patients are being treated with stereotactic body radiation therapy (SBRT) for low- and intermediate-risk PCa, it is imperative to understand the PSA response to SBRT. METHODS AND MATERIALS: PSA data from 5 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2004 to 2016. Patients received 35 to 40 Gy in 5 fractions, per institutional standards. Patients who had less than 12 months of PSA data or received androgen deprivation therapy were excluded from this study. Linear and logistic multivariable analysis were performed to identify predictors of nPSA, bounce, and biochemical recurrence, and joint latent class models were developed to identify significant predictors of time to biochemical failure. RESULTS: A total of 1062 patients were included in this study. Median follow-up was 66 months (interquartile range [IQR], 36.4-89.9 months). Biochemical failure per the Phoenix criteria occurred in 4% of patients. Median nPSA was 0.2 ng/mL, median time to nPSA was 40 months, 84% of patients had an nPSA ≤0.5 ng/mL, and 54% of patients had an nPSA ≤0.2 ng/mL. On multivariable analysis, nPSA was a significant predictor of biochemical failure. Benign PSA bounce was noted in 26% of patients. The median magnitude of PSA bounce was 0.52 ng/mL (IQR, 0.3-1.0 ng/mL). Median time to PSA bounce was 18.1 months (IQR, 12.0-31.1 months). On multivariable analysis, age and radiation dose were significantly associated with a lower incidence of bounce. Joint latent class models modeling found that nPSA and radiation dose were significantly associated with longer time to biochemical failure. CONCLUSIONS: In this multi-institutional cohort of patients with long-term follow-up, we found that SBRT led to low nPSAs. In turn, lower nPSAs are associated with reduced incidence of, and longer time to, biochemical failure. Benign PSA bounces occurred in a quarter of patients, as late as several years after treatment. Further studies are needed to directly compare the PSA response of patients who receive SBRT versus other treatment modalities.

IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer.

The expression of IMP3, an oncofetal protein, has been strongly associated with aggressive cancers. In this study, we investigated whether IMP3 can serve as a biomarker to predict invasive squamous cell carcinoma (SCC) in patients with cervical intraepithelial neoplasia (CIN) II and III. A total of 1249 patients with no dysplasia, CINs, or invasive SCC were studied for IMP3 expression. The 710 patients with CIN II and III in their cervical biopsies were further evaluated for invasive cancer-free survival analysis. The role of IMP3 in the regulation of cell proliferation and migration of HeLa cervical cancer cells was examined by modification of IMP3 expression with small interference RNA. Compared with CIN I or cervical tissues without dysplasia, IMP3 expression was significantly increased not only in invasive SCC but also most importantly in a subset of CIN III cases with concurrent invasive SCC. Importantly, invasive cancer was found only in patients with IMP3-positive CIN II and III, whereas no invasive cancer was detected in patients with IMP3-negative CIN II and III in their follow-up resections (P<0.0001). Reduction of IMP3 expression in cervical cancer cells significantly reduced cell migration without altering cell proliferation. IMP3 plays a critical role in the development of invasive SCC from cervical dysplasia. IMP3 can be used at the time of initial diagnosis of CIN to identify a group of patients with an increased chance of developing invasive cancer.

Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Sp1 is a sequence-specific DNA binding protein that is important in the transcription of a number of regulatory genes involved in cancer cell growth, differentiation, and metastasis. In this study, we investigated Sp1 expression in pancreatic ductal adenocarcinoma and its association with clinical outcome. We studied 42 patients with primary pancreatic adenocarcinoma. The expression of Sp1 in pancreatic adenocarcinoma was evaluated by immunohistochemical staining. All 42 patients had clinical follow-up information and were evaluated for survival. Sp1 protein was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. These tumors all developed metastasis, whereas none of the primary tumors without lymph node metastasis showed Sp1 overexpression. Statistically, Sp1 overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.036, and P < 0.0001, respectively). Additionally, patients of this subset had a much shorter overall survival than patients without Sp1 overexpression, as evidenced by Kaplan-Meier plots and the log-rank test (P = 0.002). The 5-year overall survival rate was 19% in patients with Sp1 overexpression, compared with 55% in patients without Sp1 overexpression. The median survival was only 13 months for patients with Sp1 overexpression, compared with 65 months for patients without Sp1 overexpression. In conclusion, Sp1 is a new biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior. It can be used at initial diagnosis of pancreatic adenocarcinoma to identify patients with an increased probability of cancer metastasis and much shortened overall survival.