Radiation Therapy after Radical Prostatectomy: Implications for Clinicians.

Depending on the pathological findings, up to 60% of prostate cancer patients who undergo radical prostatectomy (RP) will develop biochemical relapse and require further local treatment. Radiotherapy (RT) immediately after RP may potentially eradicate any residual localized microscopic disease in the prostate bed, and it is associated with improved biochemical, clinical progression-free survival, and overall survival in patients with high-risk pathological features according to published randomized trials. Offering immediate adjuvant RT to all men with high-risk pathological factors we are over-treating around 50% of patients who would anyway be cancer-free, exposing them to unnecessary toxicity and adding costs to the health-care system. The current dilemma is, thus, whether to deliver adjuvant immediate RT solely on the basis of high-risk pathology, but in the absence of measurable prostate-specific antigen, or whether early salvage radiotherapy would yield equivalent outcomes. Randomized trials are ongoing to definitely answer this question. Retrospective analyses suggest that there is a dose-response favoring doses >70 Gy to the prostate bed. The evidence regarding the role of androgen deprivation therapy is emerging, and ongoing randomized trials are underway

Prostate irradiation with focal dose escalation to the intraprostatic dominant nodule: a systematic review.

Radiation therapy (RT) is a curative treatment option for localized prostate cancer. Prostate irradiation with focal dose escalation to the intraprostatic dominant nodule (IDN) is an emerging treatment option that involves the prophylactic irradiation of the whole prostate while increasing RT doses to the visible prostatic tumor. Because of the lack of large multicentre trials, a systematic review was performed in an attempt to get an overview on the feasibility and efficacy of focal dose escalation to the IDN. A bibliographic search for articles in English, which were listed in MEDLINE from 2000 to 2016 to identify publications on RT with focal directed boost to the IDN, was performed. The review was completed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Twenty-two articles describing 1,378 patients treated with RT using focal boost were identified and fulfilled the selection criteria. Intensity-modulated radiation therapy (IMRT) was used in 720 patients (52.3%), volumetric modulated arc therapy was used in 45 patients (3.3%), stereotactic body radiation therapy (SBRT) in 113 patients (8.2%), and low-dose rate and high-dose rate brachytherapy (BT) were used in 305 patients (22.1%) and 195 patients (14.1%), respectively. Use of androgen deprivation therapy varied substantially among series. Biochemical disease-free survival at 5 years was reported for a cohort of 812 (58.9%) patients. The combined median biochemical disease-free survival for this group of patients was 85% (range: 78.8-100%; 95% confidence interval: 77.1-82.7%). The average occurrence of grade III or worse gastrointestinal and genitourinary late toxicity was, respectively, 2.5% and 3.1% for intensity-modulated RT boost, 10% and 6% for stereotactic body RT, 6% and 2% for low-dose rate BT, and 4% and 4.3% for high-dose rate BT. This review shows encouraging results for focal dose escalation to the IDN with acceptable short- to medium-term side effects and biochemical disease control rates. However, owing to the heterogeneity of patient population and the short follow-up, the results should be interpreted with caution. Considering that the clinical endpoint in the studies was biochemical recurrence, the use and duration of androgen deprivation therapy administration should be carefully considered before driving definitive conclusions. Randomized trials with long-term follow-up are needed before this technique can be generally recommended

VEGFR Inhibitors for Uterine Metastatic Perivascular Epithelioid Tumors (PEComa) Resistant to mTOR Inhibitors. A Case Report and Review of Literature.

Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms. PI3K/AKT/mTOR pathway upregulation is critical for their pathogenesis and is often associated with TSC1/TSC2 inactivation. Although first line mTOR inhibitors are an effective treatment, metastatic PEComas eventually progress. A 53-year-old woman presented a 4-month history of post-menopausal vaginal bleeding. Clinical and radiological examination detected a uterine mass and a single S1 bone lesion. The patient underwent a radical hysterectomy and bone biopsy. The anatomopathological evaluation concluded to an oligo-metastatic uterine PEComa. The tumor harbored a heterozygous deletion of 9q34 that contains the TSC1 gene. Concerning the primary lesion, the resection was complete and the single bone metastasis was treated with radiotherapy. Three months later, the patient presented bone, lung and subcutaneous metastatic progression. An everolimus and denosumab treatment was initiated. After 2 years of treatment, a clinically significant bone, lung and subcutaneous progression was detected. Following a literature review of the possible therapeutic options, we initiated a second line treatment by pazopanib. This treatment resulted in regression of the subcutaneous lesions and stability of lung and bone metastases. In this challenging, rare setting, our report suggests single agent, anti-angiogenic, tyrosine kinase inhibitor to be effective as second line treatment of metastatic uterine PEComa progressing on mTOR inhibitors

Outcomes and endpoints of relevance in gynecologic cancer clinical trials.

Drug development is paramount to improve outcomes in patients with gynecologic cancers. A randomized clinical trial should measure whether a clinically relevant improvement is detected with the new intervention compared with the standard of care, using reproductible and appropriate endpoints. Clinically meaningful improvements in overall survival and/or quality of life (QoL) are the gold standards to measure benefit of new therapeutic strategies. Alternative endpoints, such as progression-free survival, provide an earlier measure of the effect of the new therapeutic drug, and are not confounded by the effect of subsequent lines of therapy. Yet, its surrogacy with improved overall survival or QoL is unclear in gynecologic malignancies. Of relevance to studies assessing maintenance strategies are other time-to-event endpoints, such as progression-free survival two and time to second subsequent treatment, which provide valuable information on the disease control in the longer term. Translational and biomarker studies are increasingly being incorporated into gynecologic oncology clinical trials, as they may allow understanding of the biology of the disease, resistance mechanisms, and enable a better selection of patients who might benefit from the new therapeutic strategy. Globally, the endpoint selection of a clinical trial will differ according to the type of study, population, disease setting, and type of therapeutic strategy. This review provides an overview of primary and secondary endpoint selection of relevance for gynecologic oncology clinical trials

Effect of conventional and ultra-high dose rate "FLASH" irradiations on preclinical tumour models: A systematic analysis: Tumour response to CONV and UHDR irradiation.

When compared to conventional dose rate irradiation (CONV), ultra-high dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect", also depends on the tumour toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study re-examines the hypothesis of tumour isoefficacy for UHDR versus CONV and aims to identify potential knowledge gaps to inspire future in vivo studies. A systematic literature search identified publications assessing in vivo tumour responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumour growth and survival data. We identified 66 data sets from 15 publications that compared UHDR and CONV for tumour efficacy. The median number of animals per group was 9 (range: 3-15) and the median follow-up period was 30.5 (range: 11-230) days after the first irradiation. Tumour growth assays were the predominant model used. Combined statistical analyses of tumour growth and survival data are consistent with UHDR isoefficacy compared to CONV. Only one study determined tumour-controlling dose (TCD <sub>50</sub> ) and reported statistically non-significant differences. The combined quantitative analyses of tumour responses support the assumption of UHDR isoefficacy compared to CONV. However, the comparisons are primarily based on heterogeneous tumour growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumour control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radio-resistant tumour sub-clones. Hence, tumour cure experiments, including additional TCD <sub>50</sub> experiments, are needed to confirm the assumption of isoeffectiveness in curative settings

Abscopal effect in a patient with malignant pleural mesothelioma treated with palliative radiotherapy and pembrolizumab.

The abscopal effect describes the ability of locally administered radiotherapy to induce systemic antitumor effects. Although mentioned for the first time in the 1950s, records of abscopal effects, considered to be immune-mediated, are scarce with radiotherapy alone. However, with the continued development and use of immunotherapy, reports on the abscopal effect have become increasingly frequent during the last decade. Here, we report a patient with advanced malignant pleural mesothelioma who had progressive disease while on the anti-PDL1 inhibitor pembrolizumab and showed an abscopal response after palliative radiotherapy

Evaluation of HBV-Like circulation in wild and farm animals from Brazil and Uruguay

The origin of the hepatitis B virus is a subject of wide deliberation among researchers. As a result, increasing academic interest has focused on the spread of the virus in different animal species. However, the sources of viral infection for many of these animals are unknown since transmission may occur from animal to animal, human to human, animal to human, and human to animal. The aim of this study was to evaluate hepadnavirus circulation in wild and farm animals (including animals raised under wild or free conditions) from different sites in Brazil and Uruguay using serological and molecular tools. A total of 487 domestic wild and farm animals were screened for hepatitis B virus (HBV) serological markers and tested via quantitative and qualitative polymerase chain reaction (PCR) to detect viral DNA. We report evidence of HBsAg (surface antigen of HBV) and total anti-HBc (HBV core antigen) markers as well as low-copy hepadnavirus DNA among domestic and wild animals. According to our results, which were confirmed by partial genome sequencing, as the proximity between humans and animals increases, the potential for pathogen dispersal also increases. A wider knowledge and understanding of reverse zoonoses should be sought for an effective One Health response

50-Gy Stereotactic Body Radiation Therapy to the Dominant Intraprostatic Nodule: Results From a Phase 1a/b Trial.

Although localized prostate cancer (PCa) is multifocal, the dominant intraprostatic nodule (DIN) is responsible for disease progression after radiation therapy. PCa expresses antigens that could be recognized by the immune system. We therefore hypothesized that stereotactic dose escalation to the DIN is safe, may increase local control, and may initiate tumor-specific immune responses. Patients with localized PCa were treated with stereotactic extreme hypofractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image-visible DIN (45 Gy, 47.5 Gy, and 50 Gy in 5 fractions). The phase 1a part was designed to determine the recommended phase 1b dose in a "3 + 3" cohort-based, dose-escalation design. The primary endpoint was dose-limiting toxicities defined as ≥grade 3 gastrointestinal (GI) or genitourinary (GU) toxicity (or both) by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) up to 90 days after the first radiation fraction. The secondary endpoints were prostate-specific antigen kinetics, quality of life (QoL), and blood immunologic responses. Nine patients were treated in phase 1a. No dose-limiting toxicities were observed at either level, and therefore the maximum tolerated dose was not reached. Further characterization of tolerability, efficacy, and immunologic outcomes was conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase 1b expansion cohort. Toxicity was 45% and 25% for grades 1 and 2 GU, and 20% and 5% for grades 1 and 2 GI, respectively. No grade 3 or worse toxicity was reported. The average (±standard error of the mean) of the QoL assessments at baseline and at 3-month posttreatment were 0.8 (±0.8) and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% confidence interval, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for the International Prostate Symptom Score (mean difference, 0.87; 95% confidence interval, 0.3-1.9), respectively. A subset of patients developed antigen-specific immune responses against prostate-specific membrane antigen (n = 2), prostatic acid phosphatase (n = 1), prostate stem cell antigen (n = 4), and prostate-specific antigen (n = 2). Irradiation of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN was tolerable and determined as the recommended phase 1b dose. This treatment has promising antitumor activity, which will be confirmed by the ongoing phase 2 part. Preliminary QoL analysis showed minimal impact in GU, GI, and sexual domains. Stereotactic irradiation induced antigen-specific immune responses in a subset of patients

Updates on radiotherapy-immunotherapy combinations: Proceedings of 6th annual ImmunoRad conference.

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference