Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors: The CHEERS Phase 2 Randomized Clinical Trial.

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

Radiotherapy Use in Muscle-Invasive Bladder Cancer: Review of the Guidelines and Impact of Increased Awareness in Patient Referral at a Tertiary Center in Belgium.

Purpose: Pronounced underuse of radiotherapy (RT) in muscle-invasive bladder cancer (MIBC) is reported. This study aims to assess the awareness about the role of RT in different MIBC settings and see whether this has increased since 2017. Materials and Methods: We reviewed the bladder cancer guidelines of the EAU, ESMO, NCCN, NICE, and AUA/ASCO/ASTRO/SUO, focusing on the role of RT in MIBC. In 2017, we evaluated the use of RT in MIBC in Belgium. This raised awareness about the indications of RT in different MIBC settings. Here, we present a retrospective pattern of care analysis of the RT use for MIBC patients at our center from January 2012 until December 2021. Frequency of RT use, patient, disease and treatment characteristics were compared between two 5-year periods (2012-2016 and 2017-2021). Results: Review of the guidelines suggested that RT can be used as a treatment option in most MIBC settings. However, differences between guideline recommendations existed and high-level evidence was often lacking. Overall, 221 unique MIBC patients received RT at our center. RT use for MIBC was 39% higher in the second 5-year period (Between the same periods, the number of new MIBC registrations increased with 26%). The most pronounced increase, ie, 529%, was observed in the primary setting and was in parallel with patient preference becoming the main indication for RT. Participation in clinical trials seems to have had an important impact on the frequency of RT use in the adjuvant and metastatic setting. Conclusion: We provide a critical overview of the RT indications in MIBC as recommended by the international guidelines. Increased awareness about RT as a treatment option in MIBC seems to have an impact on the treatment choice in clinical practice, as was observed in our tertiary center.

The Changing Landscape of Systemic Therapy in the Treatment of Synchronous Metastatic Hormone-sensitive Prostate Cancer.

INTRODUCTION: To describe the changes in systemic treatments (ST) of synchronous metastatic hormone-sensitive prostate cancer (mHSPC) patients in a "real-world" setting and to explore reasons why contemporary standard of care (SOC) was not administrated to the patient. PATIENTS AND METHODS: Since 2014, we prospectively register mHSPCpatients. Patients were grouped in 4 time periods: group 1 (Time period 1, January 2014-July 2015), group 2 after introduction of docetaxel (Time period 2, August 2015-July 2017), group 3 after introduction of abiraterone acetate (Time period 3, August 2017-February 2018) and group 4 after introduction of apalutamide (Time period 4, March 2018-October 2021). For every time period, we evaluated the initiated additional ST. In case patients received treatment that differed from contemporary SOC according to guidelines, reasons for this difference were explored. RESULTS: In total, 243 patients were included. A progressive decline in ADT monotherapy from 85% to 29% over time was observed. The proportion of patients receiving additional STs increased from 34% to 59%. Forty percent of patients were not treated according to contemporary SOC, but this percentage varied strongly per time period (10%, 67%, 53%, and 32% from time period 1 to time period 4 respectively). Reasons for these variations were heterogenous and varied across the 4 time periods. Patients being unfit for treatment and treating physicians failing to consider additional STs were the most prevalent reasons. The proportion of patients unfit for additional ST decreased from 18% to 4% over time. CONCLUSION: Use of ADT monotherapy declined gradually after the introduction of additional systemic treatments. The proportion of patients unfit for additional ST declined as more treatments became available. Although compliance to SOC increased over time, these real-world data show that adherence to clinical practice guidelines remains suboptimal. Efforts should be made by clinicians to increase the adherence to practice guidelines.

Prospective non-interventional BELOVA/BGOG-ov16 study on safety of frontline bevacizumab in elderly patients with FIGO stage IV ovarian cancer: a study of the Belgian and Luxembourg Gynaecological Oncology Group.

OBJECTIVE: Because elderly patients with ovarian cancer are underrepresented in randomized studies, this study aimed to expand our knowledge on the safety and effectiveness of frontline treatment with bevacizumab in combination with standard carboplatin and paclitaxel chemotherapy in patients aged 70 years and older with a diagnosis of Federation of Gynecology and Obstetrics (FIGO) stage IV ovarian cancer in routine clinical practice in Belgium. METHODS: Patients aged 70 years and older with FIGO stage IV ovarian cancer were included in a multicenter, non-interventional prospective studyto evaluate the safety and effectiveness of treatment with bevacizumab in combination with frontline carboplatin and paclitaxel chemotherapy. Comprehensive geriatric assessments were performed at baseline and during treatment. RESULTS: The most frequently reported adverse events for bevacizumab were hypertension (55%), epistaxis (32%) and proteinuria (21%). The Kaplan-Meier estimate of progression-free survival was 14.5 months. The results of the comprehensive geriatric assessments during treatment indicated a slight improvement in the geriatric eight health status screening tool score for general health status and the mini-nutritional assessment score for nutritional status. The median change from baseline score was close to zero for the instruments measuring independency, activity of daily living and instrumental activities of daily living, and for the mobility-tiredness test measuring self-perceived fatigue. CONCLUSIONS: No new safety signals were registered in this study in patients aged 70 years and older treated with bevacizumab and frontline carboplatin and paclitaxel for FIGO stage IV ovarian cancer. Elderly patients should not be excluded from treatment for advanced ovarian cancer based on age alone. EU PAS REGISTER: ENCEPP/SDPP/13849. CLINICALTRIALSGOV IDENTIFIER: NCT02393898.

Evaluating the impact of 18F-FDG-PET-CT on risk stratification and treatment adaptation for patients with muscle-invasive bladder cancer (EFFORT-MIBC): a phase II prospective trial.

BACKGROUND: The outcome of patients with muscle-invasive bladder cancer (MIBC) remains poor, despite aggressive treatments. Inadequate primary staging, classically performed by computed tomography (CT)-imaging, could lead to inappropriate treatment and might contribute to these poor results. Although not (yet) adapted by international guidelines, several reports have indicated the superiority of 18F-fluorodeoxyglucose-positron emission tomography-CT (18F-FDG-PET-CT) compared to CT in the detection of lymph node and distant metastases. Thereby the presence of extra-vesical disease on 18F-FDG-PET-CT has been correlated with a worse overall survival. This supports the hypothesis that 18F-FDG-PET-CT is useful in stratifying MIBC patients and that adapting the treatment plan accordingly might result in improved outcome. METHODS: EFFORT-MIBC is a multicentric prospective phase II trial aiming to include 156 patients. Eligible patients are patients with histopathology-proven MIBC or ≥ T3 on conventional imaging treated with MIBC radical treatment, without extra-pelvic metastases on conventional imaging (thoracic CT and abdominopelvic CT/ magnetic resonance imaging (MRI)). All patients will undergo radical local therapy and if eligible neo-adjuvant chemotherapy. An 18F-FDG-PET-CT will be performed in addition to and at the timing of the conventional imaging. In case of presence of extra-pelvic metastasis on 18F-FDG-PET-CT, appropriate intensification of treatment with metastasis-directed therapy (MDT) (in case of ≤3 metastases) or systemic immunotherapy (> 3 metastases) will be provided. The primary outcome is the 2-year overall survival rate. Secondary endpoints are progression-free survival, distant metastasis-free survival, disease-specific survival and quality of life. Furthermore, the added diagnostic value of 18F-FDG-PET-CT compared to conventional imaging will be evaluated and biomarkers in tumor specimen, urine and blood will be correlated with primary and secondary endpoints. DISCUSSION: This is a prospective phase II trial evaluating the impact of 18F-FDG-PET-CT in stratifying patients with primary MIBC and tailoring the treatment accordingly. We hypothesize that the information on the pelvic nodes can be used to guide local treatment and that the presence of extra-pelvic metastases enables MDT or necessitates the early initiation of immunotherapy leading to an improved outcome. TRIAL REGISTRATION: The Ethics Committee of the Ghent University Hospital (BC-07456) approved this study on 11/5/2020. The trial was registered on ClinicalTrials.gov (NCT04724928) on 21/1/2021.

Checkpoint inhibition in combination with an immunoboost of external beam radiotherapy in solid tumors (CHEERS): study protocol for a phase 2, open-label, randomized controlled trial.

BACKGROUND: While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors. METHODS/DESIGN: Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study's primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. DISCUSSION: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

Targeting FGFR in bladder cancer: ready for clinical practice?

Objective: To give a brief literature overview of current knowledge regarding FGFR inhibition in bladder cancer.Background: The deeper molecular understanding of bladder urothelial carcinoma (UC) has reshaped the diagnostic and therapeutic landscape of this malignancy. Rapid technological development, including the frequent use of next-generation sequencing (NGS) in clinical practice, has boosted identification and development of potential biomarkers and targeted therapies. Genetic aberrations in the fibroblast growth factor receptor (FGFR)-pathway may drive tumorigenesis and are considered as attractive drug targets in advanced and/or metastatic UC. Several clinical trials have been performed or are ongoing to assess the safety and efficacy of (non-)selective FGFR inhibitors in patients with advanced or metatastic UC.Results: While non-selective FGFR inhibitors have shown limited clinical response with unacceptable toxicity, selective 'pan'-FGFR inhibitors had favourable response rates with manageable toxicity. To predict response, patients were screened for FGFR aberrations using NGS after DNA/RNA extraction of UC tissue specimen or collection of ctDNA or cfDNA.Conclusion: Early clinical trials have shown promising results for targeting FGFR in advanced or metastatic UC, though these findings need to be validated in phase III trials. It seems that FGFR aberrations can be detected in ctDNA and cfDNA as efficiently as in tumour tissue, showing their potential as predictive, non-invasive liquid biomarkers.

Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma.

Preclinical data indicate that radiotherapy works synergistically with pembrolizumab, but the effect and toxicity of this combination may depend on radiotherapy timing. We conducted a randomized phase 1 trial combining pembrolizumab with either sequential (A) or concomitant (B) stereotactic body radiotherapy (SBRT) in metastatic urothelial carcinoma (mUC). No dose-limiting toxicity occurred. Treatment-related adverse events (trAEs; Common Terminology Criteria for Adverse Events v4.0) of grade 1-2 occurred in six of nine and all nine patients in arms A and B, respectively. One grade 3 trAE occurred in arm B. No grade 4-5 trAEs occurred. Overall response rates of 0% and 44.4% were noted in arms A and B, respectively, as per Response Evaluation Criteria in Solid Tumors v1.1. The trial was not powered to compare efficacy between arms. Targeted sequencing of tissue DNA and circulating tumor DNA (ctDNA) revealed high genomic concordance. Treatment response was associated with ctDNA fraction decline. We conclude that sequential and concomitant SBRT can be safely combined with pembrolizumab in mUC and that the effect of SBRT timing on efficacy is worth exploring further. PATIENT SUMMARY: This study assessed the safety of pembrolizumab combined with radiotherapy at two different time points in metastatic bladder cancer. We conclude that the combination treatment was well tolerated.

TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). CONCLUSIONS: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

Evaluating the Current Place of Radiotherapy as Treatment Option for Patients With Muscle Invasive Bladder Cancer in Belgium.

INTRODUCTION: There is a gap between optimal and actual use of radiotherapy (RT) in muscle-invasive bladder cancer (MIBC). We investigated the opinions of radiation-oncologists, urologists, and medical oncologists on use of RT in different cases. Barriers and facilitators for applying guidelines were examined. MATERIAL AND METHODS: A web-based survey was developed at Ghent University Hospital and conducted from November 18, 2016 to July 17, 2017. The place of primary, adjuvant, and palliative RT was evaluated. Additional questions assessed the use of guidelines, barriers, and facilitators. RESULTS: In total, 126 physicians (57 radiation oncologists, 41 urologists, and 28 medical oncologists) completed the survey. Significant differences in use of RT in the primary and adjuvant setting were observed between radiation oncologists and urologists. Younger age and presence of hydronephrosis are perceived as contraindications for RT in the primary setting. In the adjuvant setting, RT was mainly considered in case of positive surgical margins. All radiation oncologists and 96% of medical oncologists considered palliative RT for patients with painful bone metastases, whereas 21% of urologists did not (P < .001). Clinical decisions are mainly based on EAU guidelines. The most important reason for nonadherence to guidelines is external barriers (18%). One strategy to improve awareness of guidelines is a summary of guidelines on the website of national organizations (54%). CONCLUSION: There is controversy regarding the place of RT in MIBC, with a clear variation between professionals. Barriers and facilitators to use RT should be addressed, seeing the gap in RT utilization and predicted increase in patients requiring RT for MIBC.

Circulating tumor cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer.

BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies. DESIGN, SETTINGS, AND PARTICIPANTS: In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10-12 weeks a follow-up sample was collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For baseline analysis, patients were stratified in <5 or ≥5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10-12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression-free survival (PFS), overall survival (OS), and PSA changes at 10-12 weeks were compared between groups. RESULTS: Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9-6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7-24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9-8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2-1.9; P = 0.002) and increasing CTCs at follow-up (HR 3.3, 95%CI 1.4-7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9-25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4-3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4-15; P = 0.01) were independently associated with shorter OS. ≥30% and ≥50% PSA responses less frequently occurred in patients with CTC inclines at 10-12 weeks on therapy (χ2 test: P < 0.01). CONCLUSIONS: CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs.

Pembrolizumab for the treatment of bladder cancer.

INTRODUCTION: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies. Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab. Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.

Combined high dose radiation and pazopanib in metastatic renal cell carcinoma: a phase I dose escalation trial.

BACKGROUND: The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment. METHODS: Treatment-naïve patients received pazopanib according to standard of care. Stereotactic body radiotherapy (SBRT) was delivered concurrently to the largest metastatic lesion at day 8, 10 and 12. SBRT doses were escalated in 3 dose levels (24 Gy/3, 30 Gy/3 and 36 Gy/3). Dose level was assigned using Time-to-Event Continual Reassessment Method with the target dose-limiting toxicity rate set to 0.25. RESULTS: Thirteen patients were included. One patient experienced dose limiting toxicity (DLT) at dose level 3 (grade 4 hypoglycemia). Maximum tolerated dose was not reached with a recommended dose of 36 Gy/3 having a probability of DLT of 11%. One-year local control was 83% (95% confidence interval 61-100) and 1-year progression-free survival was 28% (95% confidence interval 1-55). CONCLUSIONS: SBRT in combination with pazopanib is well tolerated with good local control and response rates outside the radiation field. TRIAL REGISTRATION: This trial was retrospectively registered on clinicaltrials.gov( NCT02334709 ) on January 6th, 2015.

A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma: evaluation of safety and clinical and immunologic response.

BACKGROUND: Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. METHODS: The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon's two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. DISCUSSION: The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564).

Checkpoint inhibition: new treatment options in urologic cancer.

Both urothelial (UC) and renal cell cancer (RCC) are highly immunogenic tumours. Recent advances in cellular immunity understanding have resulted in a successful new class of therapeutic agents. Interaction between the programmed cell death 1 (PD1) on regulatory T-cells (Treg) and programmed cell death 1 ligand (PDL1) on cancer cells inhibits an effective immune response and is an important mechanism for cancer cells to evade the immune system. Monoclonal anti-PD1 and anti-PDL1 antibodies inhibit this interaction and are called checkpoint inhibitors. As in non-small lung cancer and melanoma, these agents have shown to be highly active agents in UC and RCC. In metastatic or inoperable UC, no good second line therapy exists and checkpoint inhibitors have shown to be active. Multiple Randomized Clinical Trials (RCT) are underway both in second line and adjuvant settings which could change daily practice. In RCC, an anti-PD1 antibody, Nivolumab, has already proven to be effective in prolonging overall survival, and is included in current guidelines in metastatic RCC in second and third line. RCTs with other anti-PD1 and anti-PDL1 antibodies are ongoing both in metastatic and adjuvant setting. Checkpoint inhibitors have breathed new life into immunotherapy in urologic cancers and are rapidly being included in practice guidelines.

Parathyroid Adenoma Mimicking a Malignant Lymph Node on 18F-Choline PET-CT.

Prostate carcinoma is the most common cancer in men. After local therapy, disease recurs in many patients. A choline PET/CT is indicated in case of biochemical relapse of prostate carcinoma to determine the site of recurrence (local and/or distant) and to help select the next line of therapy. Choline PET-CT is also known to show an elevated uptake in hyperfunctioning parathyroid adenoma. This case report shows the difficulty to distinguish between both entities if they occur simultaneously in an oncologic patient.

Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations.

Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.

A patient with progressive dyspnoea and a new heart murmur.

A 74-year-old man was referred to the outpatient clinic of the cardiology department with progressive dyspnoea and a new heart murmur. Physical examination of the chest wall showed a hard immobile and painless sternal swelling at the level of the angulus of Ludovici. There was an increase of the velocities across the pulmonary valve (continuous Doppler) on echocardiography as a result of the RVOT and pulmonary trunk stenosis. Computed tomography (CT) of the chest revealed a mass in the anterior mediastinum which had grown through the sternum into the skin, as well as an external compression of the ascending aorta, the truncus pulmonalis and the pericardium. Anatomo-pathological examination revealed a non-small-cell lung carcinoma. PET CT showed another nodule with FDG uptake in the right kidney, suspected for metastasis, and an uptake in a right paratracheal lymph node. The tumour was staged as a cT4cN2M1b. Palliative radiochemotherapy was started. The patient had a good clinical and radiographic response, but relapsed a few months later.