A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors

BackgroundWhile immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).ObjectiveWe aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.Design, setting, and participantsPatients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.Outcome measurements and statistical analysisWe used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.Results and limitationsAmong 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.ConclusionsWe developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.Patient summaryWith multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE  HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases each one point, with a higher score being associated with worse overall survival

Periprocedural Bridging in Patients with Venous Thromboembolism: A Systematic Review.

BACKGROUND Vitamin K antagonists (VKA) are the most widely used anticoagulants, and bridging is commonly administered during periprocedural VKA interruption. Given the unclear benefits and risks of periprocedural bridging in patients with previous venous thromboembolism, we aimed to assess recurrent venous thromboembolism and bleeding outcomes with and without bridging in this population. METHODS We performed a systematic review searching the PubMed and EMBASE databases from inception to December 7, 2017 for randomized and non-randomized studies that included adults with previous venous thromboembolism requiring VKA interruption to undergo an elective procedure, and that reported venous thromboembolism or bleeding outcomes. Quality of evidence was graded by consensus. RESULTS We included 28 cohort studies (20 being single-arm cohorts) with overall 6915 procedures for analysis. In 27 studies reporting perioperative venous thromboembolism outcomes, the pooled incidence of recurrent venous thromboembolism with bridging was 0.7% (95% confidence interval [CI] 0.4-1.2%) and 0.5% (95% CI 0.3-0.8%) without bridging. Eighteen studies reported major and/or non-major bleeding outcomes. The pooled incidence of any bleeding was 3.9% (95% CI 2.0-7.4%) with bridging and 0.4% (95% CI 0.1-1.7%) without bridging. In bridged patients at high thromboembolic risk, the pooled incidence for venous thromboembolism was 0.8% (95% CI 0.3-2.5) and 7.5% (95% CI 3.1-17.4%) for any bleeding. Quality of available evidence was very low, primarily due to a high risk of bias of included studies. CONCLUSIONS Periprocedural bridging increases the risk of bleeding compared to VKA interruption without bridging, without a significant difference in periprocedural venous thromboembolism rates

Prostate-specific membrane antigen (PSMA)-based imaging in localized and advanced prostate cancer: a narrative review.

Combined molecular and morphologic imaging modalities have emerged in recent years as an alternative to conventional imaging in prostate cancer (PC). In particular, novel prostate-specific membrane antigen (PSMA) radiotracers have demonstrated increased sensitivity and specificity for the initial staging of men with clinically localized PC, as well as for PC detection in the setting of biochemical recurrence (BCR). Molecular imaging is increasingly used to guide treatment decisions in these patients-though its impact on survival has yet to be established. Improved PC detection in men with BCR has also helped to identify a subset of patients with oligometastatic disease. The optimal management of oligometastatic PC and the role of metastasis-directed therapies (MDT) are the subjects of ongoing studies. In comparison to clinically localized or biochemically recurrent PC, the role of molecular imaging in men with advanced disease is less established. In metastatic castration-resistant PC (mCRPC), PSMA-based imaging has primarily been investigated as a companion diagnostic tool to predict and monitor response to PSMA-targeted radioligand therapy (RLT). More recent efforts have focused on using molecular imaging to monitor treatment response to conventional chemohormonal therapies. However, despite promising early results, several barriers remain to the widespread use of PSMA-based imaging in metastatic PC: temporary flares in PSMA uptake have been described in a subset of patients after initiation of therapy, and the underlying mechanism and clinical implications of this phenomenon are still poorly understood. Furthermore, whereas PSMA is invariably expressed in hormone-sensitive PC, loss of PSMA expression is increasingly recognized in a subset of mCRPC patients with aggressive disease. Although this may limit the use of PSMA-based imaging as a standalone modality in advanced PC, loss of PSMA uptake may also provide non-invasive and clinically relevant molecular insight on patients' underlying tumor biology

Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the prostate

Treatment-associated small cell neuroendocrine carcinoma of the prostate (t-SCNC) is an aggressive prostate cancer variant with rising incidence. Although morphologically similar to de novo small cell prostate cancer, t-SCNC is thought to emerge from metastatic castration-resistant prostate cancer (mCRPC) under the selective pressure of prolonged AR-targeted therapies. t-SCNC is associated with a distinct transcriptional landscape, characterized by the upregulation of stem cell-associated and neuronal programs (e.g., SOX2, N-MYC, FOXA2) and decreased canonical AR signaling. In addition, as with other neuroendocrine carcinomas, RB1 loss and inactivating TP53 mutations are key genomic hallmarks of t-SCNC. Nevertheless, despite their histologic, molecular, and clinical differences, there is a striking degree of genomic overlap between t-SCNC and its adenocarcinoma counterpart. This finding underscores the clonal evolution of t-SCNC from mCRPC, as well as the importance of epigenetic mechanisms in regulating tumor phenotype. In this review, we summarize the key genomic, transcriptional, and epigenetic features of t-SCNC and discuss how recent advances in our understanding of molecular drivers of t-SCNC have contributed to improving the diagnosis and treatment of this aggressive disease

Early changes of PSMA PET signal after initiation of androgen receptor signaling inhibitors in mCRPC: An international multicenter retrospective study.

peer reviewedBackground: Androgen receptor signaling inhibitors (ARSi) play a relevant role in the treatment of prostate cancer. A potential influence of ARSi on PSMA expression has been described. We evaluated early changes of PSMA-expression by PET in mCRPC patients. Methods: This retrospective study included 5 international sites. Patients with mCRPC undergoing 68Ga-PSMA-11 PET/CT prior to (PET1) and early after ARSi (PET2 within 29 days maximum) were included. Whole-body (WB) PSMA-positive tumor volume (PSMA-TV) was evaluated using a liver-specific semi-automatically threshold (Affinity 3.0.2, Hermes Medical Solutions). WB PSMA-TV, SUVmean and SUVmax and their respective changes (%) were analyzed. PSA changes between PET 1 and PET2 were evaluated. Median values and ranges are provided. Results: 54 patients were included in the analysis. ARSi was initiated 1 day (range 0 – 28) after PET1 while PET2 was performed 14 days (range 7 – 29) after ARSi initiation. PSA at PET1 and PET2 was 9.5 ng/ml (range 0.2 – 490.0) and 8.7 ng/ml (range 0.1 – 732.0), respectively (p = 0.035): -33.0% (range -98% – +496%). The WB PSMA-TV at PET1 and PET2 was 89.9 ml (0.0 – 3097.0) and 112.2 ml (0.0 – 3133.0) ml, respectively (p = 0.016; change of +6.0% (range -88% – +260%). WB PSMA SUVmean and SUVmax at PET1 and PET2 was 9.0 (range 5.0 – 43.7) and 9.3 (range 0.0 – 42.5) and 26.5 (range 0.0 – 125.0) and 28.5 (range 0.0 – 212.0), respectively (p = 0.194 and p = 0.353): % change of +3 % (-85% – +71%) and 0% (-55% – +232%). Four of 7 patients with PSA increases at PET2 had an increasing PSMA-TV, 6/7 showed an increasing SUVmean and 5/7 presented with an increased SUVmax. Decreasing WB-PSMA-TV in 18/54 (33%) patients was accompanied by decreasing SUVs in 10 of them (56%). Percent PSA change was unrelated to changes in PSMA-TV, SUVmean and SUVmax. Conclusions: PSMA-PET performed early after ARSI revealed slight increases in the WB-PSMA-TV, stable WB-PSMA SUVs while serum PSA decreased in most of the patients. We conclude that ARSi does not have a strong effect on PSMA expression within 30 days after treatment initiation

Real-World Experience with 177Lu-PSMA-617 Radioligand Therapy After Food and Drug Administration Approval

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy