The development of potent novel androgen receptor inhibitors (ARi) such as apalutamide have improved the life expectancy in men with castration-resistant prostate cancer (CRPCa). However, some ...serious toxicity can occur limiting the choice of treatment in CRPCa. In our case, the patient experienced severe toxicity after initiation of apalutamide. Diagnostic PSMA-PET/CT confirmed the recurrence and tailored the treatment with 177Lu-PSMA-617 (RLT), a beta emitter radionuclide. RLT resulted in prolonged progression-free survival, thus postponing the commonly seen additional toxicity of chemotherapy.
The case highlights the possibility of early RLT in PSMA avid tumors, a treatment with minimal side-effects.
Prostate cancer (PCa) is the most common noncutaneous solid organ malignancy among men worldwide. Radiation therapy is a standard of care treatment option that has historically been delivered in the ...form of small daily doses of radiation over the span of multiple weeks. PCa appears to have a unique sensitivity to higher doses of radiation per fraction, rendering it susceptible to abbreviated forms of treatment. Stereotactic body radiation therapy (SBRT) and high-dose-rate brachytherapy (HDRBT) are both modern radiation modalities that allow the precise delivery of ablative doses of radiation to the prostate while maximally sparing sensitive surrounding normal structures. In this review, we highlight the evidence regarding the radiobiology, oncological outcomes, toxicity and dose/fractionation schemes of SBRT and HDRBT monotherapy in men with low-and intermediate-risk PCa.
•Germline variants in SNPs disrupting microRNA targets (mirSNPs) predict late GU toxicity.•A model based on 22 mirSNPs predicts GU toxicity after CF-RT.•A model based on 32 mirSNPs predicts GU ...toxicity after SBRT.•The model predicting for toxicity after SBRT does not predict for toxicity after CF-RT, and vice versa.
The purpose of this study was to determine whether single nucleotide polymorphisms disrupting microRNA targets (mirSNPs) can serve as predictive biomarkers for toxicity after radiotherapy for prostate cancer and whether these may be differentially predictive depending on radiation fractionation.
We identified 201 men treated with two forms of definitive radiotherapy for prostate cancer at two institutions: 108 men received conventionally-fractionated radiotherapy (CF-RT) and 93 received stereotactic body radiotherapy (SBRT). Germline DNA was evaluated for the presence of functional mirSNPs. Random forest, boosted trees and elastic net models were developed to predict late grade ≥2 GU toxicity by the RTOG scale.
The crude incidence of late grade ≥2 GU toxicity was 16% after CF-RT and 15% after SBRT. An elastic net model based on 22 mirSNPs differentiated CF-RT patients at high risk (71.5%) versus low risk (7.5%) for toxicity, with an area under the curve (AUC) values of 0.76–0.81. An elastic net model based on 32 mirSNPs differentiated SBRT patients at high risk (64.7%) versus low risk (3.9%) for toxicity, with an area under the curve (AUC) values of 0.81–0.87. These models were specific to treatment type delivered. Prospective studies are warranted to further validate these results.
Predictive models using germline mirSNPs have high accuracy for predicting late grade ≥2 GU toxicity after either CF-RT or SBRT, and are unique for each treatment, suggesting that germline predictors of late radiation sensitivity are fractionation-dependent. Prospective studies are warranted to further validate these results.
The side effects of androgen deprivation therapy (ADT) as general treatment against prostate cancer are known to impair quality of life. However, the optimal onset of ADT at PSA relapse is unknown, ...especially in patients with normal testosterone. In our case a limited PSMA avid lymph node was detected on PET/CT. Our case highlights the importance of metastasis-directed therapy balancing general versus tailored treatment in the decision making in the era of advanced molecular imaging. By using PSMA-PET/CT and radiation we were able to pinpoint the metastasis prolonging the ADT-free survival, thus sparing the patient the side-effects of continuous ADT.
Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific ...mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear.
This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression.
Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 95% CI, 0.57-3.75; P = .42) or DM (sHR, 0.72, 95% CI, 0.30-1.71; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 95% CI, 0.48-5.81; P = .42; DM: sHR, 0.56 95% CI, 0.15-2.04; P = .38).
In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.
The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate ...cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa.
High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.
Recurrent high-risk prostate cancer after initial external beam radiation therapy (EBRT) or EBRT with brachytherapy boost follows an aggressive clinical course. Distant metastases are frequent and occur early, with 60% of metastases occurring within 1 yr. Prostate cancer–specific mortality occurs in 30% of patients.
BackgroundTherapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer ...vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years.Methods52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses.ResultsIn total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-γ and tumor necrosis factor-α on interaction with their antigen.ConclusionLong-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.
Up to half of patients with localized prostate cancer experience biochemical relapse within 10 years after definitive radiotherapy. The aim of this prospective study was to investigate the toxicity, ...dose to the organs at risk (OARs), and efficacy of dose-intensified focal salvage radiotherapy.
Thirty-three patients (median age 68.8 years) with histologically confirmed relapse after primary definitive radiotherapy were enrolled between 2012 and 2019. No patients had metastases at imaging or in bone marrow aspiration. Twenty-three patients were treated with high dose-rate brachytherapy to the recurrent tumor, defined at multiparametric MRI, with 3 fractions of 10 Gy with two weeks interval, and 10 patients by stereotactic body radiotherapy with 35 Gy to the local recurrence and 25 Gy to the whole prostate in 5 fractions. We used the RTOG-scoring system to grade genitourinary (GU) and gastrointestinal toxicity (GI) at three months (acute), and at 12, 24, and 36 months (late). Dose-volume histogram parameters to the local recurrence and the OARs were obtained and 2 Gy equivalent (EQD2) total dose was calculated using the linear-quadratic model with α/β = 3 Gy. Efficacy was assessed by the progression-free interval and overall survival.
Median follow-up time was 81 months (range 21-115). The cumulative moderate to severe GI and GU toxicities were 3.0% (1/33) and 15.2% (5/33). Six patients had grade 1 acute GI toxicity, none had grade 2 or 3. One patient had grade 3 acute GU toxicity, two had grade 2, and fourteen had grade 1. One patient had late GI toxicity grade 2 and eight had grade 1. Four patients had late GU toxicity grade 2 and eight had grade 1. No patients had grade 3 late toxicity. The mean total D90 to the recurrent tumor was 77.7 ± 17.0 Gy. The mean total rectum D2cc was 17.0 ± 7.9 Gy and the mean total urethra D0.1cc was 29.1 ± 8.2 Gy. Twenty-eight patients had re-irradiation without androgen deprivation therapy (ADT). Nine of these are still relapse-free and 10 had a recurrence-free interval longer than 2 years.
The toxicity of salvage radiotherapy was mild to moderate. One-third of the patients achieved long-term stable disease without ADT and one-third had a recurrence-free interval longer than 2 years. Some patients progressed rapidly and probably did not benefit from re-irradiation.
Pituitary apoplexy is a clinical syndrome caused by hemorrhage or infarction of a pituitary adenoma. There have been a few reports in the literature of rapid onset of pituitary apoplexy after ...goserelin injection. To the best of our knowledge, there is no publication in the literature reporting re-introducing goserelin therapy for patients with prostate cancer after the onset of pituitary apoplexy. In this case report, we present the onset and clinico-radiological course of pituitary apoplexy induced by the initiation of goserelin and during continuation of goserelin with up to five-years follow-up.
We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant ...change in immunostaining of the hypoxia marker pimonidazole had occurred.
Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry.
A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001).
AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to tumor regression. HIF1α expression is probably not a useful hypoxia biomarker during ADT in prostate cancer.
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