Background: Metastatic prostate carcinoma over-expresses the prostate specific membrane antigen (PSMA) making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience in a series of 73 castrate resistant prostate carcinoma patients treated with 225Ac-PSMA-617, identifying variables predictive for overall and progression free survival following 225Ac-PSMA-617 treatment. 
Methods:225Ac-PSMA-617 was administered to patients with mCRPC who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. 68Ga-PSMA PET/CT was obtained at baseline, prior to every treatment cycle and on follow-up for patients’ selection for treatment, to determine the activity of treatment agent to be adminsitered and for response assessment. Serial (prostate specific antigen) PSA was obatianed for PSA response assessment. 
Results: Seventy-three men (mean age=69 years, range:45-85) with mCRPC were treated with 210 cycles of 225Ac-PSMA-617. In 70% of patients, a PSA decline of ≥50% was obtained while 83% of patients had any PSA decline. In 29% of patients, all lesions on 68Ga-PSMA-PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression while 13 patients died from their disease. The estimated median progression free survival (PFS) and overall survival (OS) were 15.2 months (95% CI: 13.1 – 17.4) and 18 months (95% CI: 16.2 – 19.9) respectively. On univariate analyses factors such as baseline PSA, any PSA decline, PSA decline ≥50%, prior chemotherapy, prior radiation therapy, baseline hemoglobin level were associated with longer PFS and OS (all p<0.05). On multivariate analyses, only prior Lu-PSMA therapy and a PSA decline ≥50% remained significant in their association with a longer PFS while only PSA decline ≥50% remained significantly associated with OS. Xerostomia was seen in 85% of patients, none was severe enough to warrant discontinuing treatment. Anaemia was seen in 27 patients, no patients with grade IV bone marrow toxicity was seen. Renal failure grade III-IV was seen in five patients with baseline renal impairement. 
Conclusion: In this study, a PSA decline of > 50% proved significantly associated with OS and PFS in multivariate analysis following treatment with 225Ac-PSMA-617. Furthermore, previous 177Lu-PSMA treatment was negatively associated with PFS in both uni- and multivariate analysis.

https://jnm.snmjournals.org/content/jnumed/61/1/62.full.pdf

Predictors of Overall and Disease-Free Survival in Metastatic Castration-Resistant Prostate Cancer Patients Receiving 225Ac-PSMA-617 Radioligand Therapy

Abstract Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology. 

/pdf/clinical-trial-design-in-the-era-of-precision-medicine-2btcio4g.pdf

Clinical trial design in the era of precision medicine

The analysis of real‐world evidence to answer clinical and policy‐relevant questions in the field of oncology has gained increased interest in recent years. This article highlights the strengths and weaknesses of the use of real‐world evidence in cancer care.

https://theoncologist.onlinelibrary.wiley.com/doi/pdf/10.1634/theoncologist.2019-0647

Real-World Evidence in Oncology: Opportunities and Limitations

/pdf/clinical-trial-design-in-the-era-of-precision-medicine-2lk4t17l.pdf

For patients with esophageal adenocarcinoma or cancer of the gastroesophageal junction, radical esophagectomy with 2-field lymphadenectomy is the cornerstone of the multimodality treatment with curative intent. Both conventional minimally invasive esophagectomy (MIE) and robot assisted minimally invasive esophagectomy (RAMIE) were shown to be superior compared to open transthoracic esophagectomy considering postoperative complications. However, no randomized comparison exists between MIE and RAMIE in the Western World for patients with esophageal adenocarcinoma. This is an investigator-initiated and investigator-driven multicenter randomized controlled parallel-group superiority trial. All adult patients (age ≥ 18 and ≤ 90 years) with histologically proven, surgically resectable (cT1-4a, N0–3, M0) esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 218) with resectable esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction are randomized to either RAMIE (n = 109) or MIE (n = 109). The primary outcome of this study is the total number of resected abdominal and mediastinal lymph nodes specified per lymph node station. This is the first randomized controlled trial designed to compare RAMIE to MIE as surgical treatment for resectable esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal junction in the Western World. The hypothesis of the proposed study is that RAMIE will result in a higher abdominal and mediastinal lymph node yield specified per station compared to conventional MIE. Short-term results and the primary endpoint (total number of resected abdominal and mediastinal lymph nodes per lymph node station) will be analyzed and published after discharge of the last randomized patient within this trial. ClinicalTrials.gov
 Identifier: NCT04306458
 . Registered 13th March 2020, https://clinicaltrials.gov/ct2/show/NCT04306458;
 Date of first enrolment 18.01.2021; Target sample size 218; Recruitment status: Recruiting; Protocol version 2; Issue date 10.03.2020; Rev. 02.02.2021; Authors ET, PCvdS, PPG.

/pdf/robot-assisted-minimally-invasive-thoraco-laparoscopic-18sdv19jo1.pdf

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus minimally invasive esophagectomy for resectable esophageal adenocarcinoma, a randomized controlled trial (ROBOT-2 trial).

With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated. This retrospective, observational study collected data from chemotherapy-naive mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment. Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0–81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2–133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2–11.1) and the median PFS was 10.8 months (95%CI: 9.6–11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001). This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naive patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.

/pdf/abiraterone-acetate-plus-prednisone-for-the-management-of-13u8d2zbjm.pdf

Abiraterone acetate plus prednisone for the Management of Metastatic Castration-Resistant Prostate Cancer (mCRPC) without prior use of chemotherapy: report from a large, international, real-world retrospective cohort study.

Primary leiomyosarcoma of the seminal vesicle is exceedingly rare. We report a case of a 59-year-old man with tumour detected by rectal symptoms and ultrasonography. Computed tomography and magnetic resonance imaging suggested an origin in the right seminal vesicle. Transperineal biopsy of the tumour revealed leiomyosarcoma. A radical vesiculo-prostactectomy with bilateral pelvic lymphadenectomy was performed. Pathological examination showed a grade 2 leiomyosarcoma of the seminal vesicle. The patient received adjuvant radiotherapy. He developed distant metastases 29 months after diagnosis, and received chemotherapy. Metastatic disease was controlled by second-line gemcitabine-docetaxel combination. Fifty-one months after diagnosis of the primary tumour, and 22 months after the first metastases, the patient is alive with excellent performance status, and multiple asymptomatic stable lung and liver lesions. We report the eighth case of primary leiomyosarcoma of the seminal vesicle and the first one with a so long follow-up.

https://link.springer.com/content/pdf/10.1186%2F1471-2407-11-323.pdf

Primary leiomyosarcoma of the seminal vesicle: Case report and review of the literature

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Abiraterone acetate plus prednisone for the Management of Metastatic Castration-Resistant Prostate Cancer (mCRPC) without prior use of chemotherapy: report from a large, international, real-world retrospective cohort study.

Primary leiomyosarcoma of the seminal vesicle: Case report and review of the literature