Disentangling the reasons why older adults do not readily participate in cancer trials: a socio-epidemiological mixed methods approach.

BACKGROUND: Few studies of the under-representation of older adults in cancer clinical trials (CTs) have encompassed the entire pathway from a trial being available in a cancer centre to the patient's invitation to participate and then agreement or refusal to participate. OBJECTIVES: The study's primary objective was to evaluate CT non-invitation and refusal rates. The secondary objectives were to identify factors associated with non-invitation and refusal and to assess experiences of CT participation from the patients' and professionals' perspectives. METHODS: Here, we used mixed methods and a socio-epidemiological approach to analyse reasons for the non-participation of eligible older patients with a solid cancer in cancer CTs in France. RESULTS: We found that non-invitation and low CT participation are mainly related to the patients' sociodemographic characteristics and living conditions (such as social isolation, being single, divorced or widowed, not having children and the absence of close family members) and the healthcare professionals' perceptions of insufficient informal support or a high homecare requirement. CONCLUSION: Our results suggest that efforts to increase fair inclusion and the participation of older adults in CTs should target the physician-patient relationship, the medical profession and hospital funding, rather than the patient alone.

Effectiveness of a digital telemonitoring platform for cancer care of older patients: The ConnectElderlyPatientToDoctor study.

While telemedicine has been shown to improve the quality of care for cancer patients, it remains underused for older patients (OP), partly due to the assumption that OPs are unabled or unwilling to use digital tools. However, more than 50% of new cancers are diagnosed in people over 70. The ConnectElderlyPatientToDoctor study aimed to evaluate the OP compliance with the use of the digital telemonitoring platform Cureety in oncology. All cancer patients followed at the Military Hospital Bégin were eligible for the study. Patients were invited to respond to a symptomatology questionnaire personalized to their pathology and treatment. An algorithm evaluated the health status of the patient based on the reported adverse events. The population was divided into two groups, OP and younger patients (YP), based on a cut-off at 70 years. The primary endpoint was to assess the compliance of OPs with the use of the digital oncology platform Cureety, compared to YP. From July 2020 to September 2021, a total of 117 patients were included in our study. We found that 66% of the patients were compliant, with no difference between the two groups (71.2% of YP, 61.7% of OP, P = .29). In OPs, progression free survival (PFS) ratio at 6-months was 64.6% in the tolerant patients vs 23.4% in the nontolerant patients (HR = 0.1980, 95% CI = 0.04431-0.8845, P = .0339). The median PFS was 23.3 months in the tolerant group vs 3.3 months in the nontolerant group (P = .0339). The data of overall survival are immature. OPs had a clear benefit from using this platform, similar to what was observed for YP. Patients felt less isolated and felt that they benefited from personalized care with early ambulatory medical care of adverse events. We also found that the health indicators collected with the platform in the first month of treatment are predictive of the progression of the disease. This solution makes it possible to streamline and improve the care pathway of OP.

Revolutionizing Radiotoxicity Management with Mesenchymal Stem Cells and Their Derivatives: A Focus on Radiation-Induced Cystitis.

Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients' quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.

Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer.

BACKGROUND: The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear. METHODS: We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed. RESULTS: A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed. CONCLUSIONS: Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).

What management for epidermal growth factor receptor-mutated non-small-cell lung cancer, with squamous cell transformation and T790M-acquired resistance mechanisms? A Case report and review of literature.

Histological transformation into squamous cell carcinoma (SCC) is a rare mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Its pathophysiology remains unclear and its management is particularly challenging. We report on tumor progression with SCC histological transformation associated with the T790M mutation in a patient with stage IV bronchial adenocarcinoma with an L858R mutation of the EGFR gene and treated with gefitinib. We will discuss the importance of liquid and tumor biopsy in the diagnostic management of resistance mechanisms as well as therapeutic management options.

Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study. METHODS: CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m2 intravenously every 3 weeks, 10 mg daily prednisone, and granulocyte colony-stimulating factor) versus abiraterone (1000 mg orally once daily plus 5 mg prednisone twice daily) or enzalutamide (160 mg orally daily). Stratification factors were ECOG performance status, time to disease progression on the previous androgen signalling-targeted inhibitor, and timing of the previous androgen signalling-targeted inhibitor. The primary endpoint was radiographic progression-free survival; here, we present more detailed analyses of pain (assessed using item 3 on the Brief Pain Inventory-Short Form [BPI-SF]) and symptomatic skeletal events, alongside preplanned patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L). Efficacy analyses were done in the intention-to-treat population. Pain response was analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of BPI-SF item 3, and patient-reported outcomes (PROs) were analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of either FACT-P or EQ-5D-5L (PRO population). Analyses of skeletal-related events were also done in the intention-to-treat population. The CARD study is registered with ClinicalTrials.gov, NCT02485691, and is no longer enrolling. FINDINGS: Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060). INTERPRETATION: Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor. FUNDING: Sanofi.

Endocrine disrupting-chemicals and biochemical recurrence of prostate cancer after prostatectomy: A cohort study in Guadeloupe (French West Indies).

Previous studies have suggested that exposure to environmental chemicals with hormonal properties, also called endocrine disrupting chemicals, may be involved in the occurrence of prostate cancer (PCa). Such exposure may also influence the treatment outcome as it is still present at the time of diagnosis, the beginning of therapy, and beyond. We followed 326 men in Guadeloupe (French West Indies) who underwent radical prostatectomy as primary treatment of localized PCa. We analyzed the relationship between exposure to the estrogenic chlordecone, the antiandrogenic dichlorodiphenyldichloroethylene (DDE, the main metabolite of the insecticide DDT), and the nondioxin-like polychlorinated biphenyl congener 153 (PCB-153) with mixed estrogenic/antiestrogenic properties and the risk of biochemical recurrence (BCR) after surgery. After a median follow-up of 6.1 years after surgery, we found a significant increase in the risk of BCR, with increasing plasma chlordecone concentration (adjusted hazard ratio = 2.51; 95% confidence interval: 1.39-4.56 for the highest vs. lowest quartile of exposure; p trend = 0.002). We found no associations for DDE or PCB-135. These results shown that exposure to environmental estrogens may negatively influence the outcome of PCa treatment.

Feasibility and efficacy of a supervised home-based physical exercise program for metastatic cancer patients receiving oral targeted therapy: study protocol for the phase II/III - UNICANCER SdS 01 QUALIOR trial.

BACKGROUND: Currently, oral targeted therapies are known to be effective and are frequently used to treat metastatic cancer patients, but fatigue is a frequently reported early side effect of these treatments. This fatigue may impact the patient's treatment adherence and result in a negative impact on quality of life. Physical exercise significantly improved the general well-being and quality of life of advanced cancer patients. However, there is no specific physical activity program adapted for patients with advanced disease. METHODS: QUALIOR is a two-part, randomized, open-label, and multicenter with two arms phase II/III trial. Patients (phase II: n = 120; phase III: n = 312) with metastatic cancer (breast cancer, kidney cancer, lung cancer, and other cancers [including but not limited to colon cancer, melanoma, sarcoma, or hepatocarcinoma]) treated with a first- or second-line oral targeted therapy without chemotherapy will be included. Patients will be randomized (2:1) to a 3-month supervised home-based standardized physical activity program or to a recommended adapted physical activity (via a booklet). The primary objective of the phase II is to evaluate the feasibility of the supervised program. The primary objective of the phase III is the evaluation of the benefit of the supervised home-based program compare to the recommended program in terms of fatigue and quality of life at 3 months. The secondary objectives aim to evaluate the impact of the supervised program on fatigue over time, pain, physical capacities, psychosocial and cognitive functions, general quality of life, frequency of dose reduction and patients' adherence to the targeted therapy, overall survival, and progression-free survival. This study will also evaluate the medico-economic impact of supervised program compared to the recommended adapted physical activity program. DISCUSSION: The aim of this study is to evaluate home-based physical exercise program for metastatic cancer patients treated with oral targeted therapies to help patients to cope with fatigue and improve quality of life. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov since May 2017 ( NCT03169075 ).

Acute pulmonary embolism in non-hospitalized COVID-19 patients referred to CTPA by emergency department.

OBJECTIVES: To evaluate the prevalence of acute pulmonary embolism (APE) in non-hospitalized COVID-19 patients referred to CT pulmonary angiography (CTPA) by the emergency department. METHODS: From March 14 to April 6, 2020, 72 non-hospitalized patients referred by the emergency department to CTPA for COVID-19 pneumonia were retrospectively identified. Relevant clinical and laboratory data and CT scan findings were collected for each patient. CTPA scans were reviewed by two radiologists to determinate the presence or absence of APE. Clinical classification, lung involvement of COVID-19 pneumonia, and CT total severity score were compared between APE group and non-APE group. RESULTS: APE was identified in 13 (18%) CTPA scans. The mean age and D-dimer of patients from the APE group were higher in comparison with those from the non-APE group (74.4 vs. 59.6 years, p = 0.008, and 7.29 vs. 3.29 µg/ml, p = 0.011). There was no significant difference between APE and non-APE groups concerning clinical type, COVID-19 pneumonia lung lesions (ground-glass opacity: 85% vs. 97%; consolidation: 69% vs. 68%; crazy paving: 38% vs. 37%; linear reticulation: 69% vs. 78%), CT severity score (6.3 vs. 7.1, p = 0.365), quality of CTPA (1.8 vs. 2.0, p = 0.518), and pleural effusion (38% vs. 19%, p = 0.146). CONCLUSIONS: Non-hospitalized patients with COVID-19 pneumonia referred to CT scan by the emergency departments are at risk of APE. The presence of APE was not limited to severe or critical clinical type of COVID-19 pneumonia. KEY POINTS: • Acute pulmonary embolism was found in 18% of non-hospitalized COVID-19 patients referred by the emergency department to CTPA. Two (15%) patients had main, four (30%) lobar, and seven (55%) segmental acute pulmonary embolism. • Five of 13 (38%) patients with acute pulmonary embolism had a moderate clinical type. • Severity and radiological features of COVID-19 pneumonia showed no significant difference between patients with or without acute pulmonary embolism.

Haemoglobin level increase as an efficacy biomarker during axitinib treatment for metastatic renal cell carcinoma: a retrospective study.

BACKGROUND: Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A known side effect is the increase of haemoglobin level (HbL) during treatment with a suspected correlation with better outcome. Our objective was to examine whether HbL increase during the first three months of axitinib treatment is associated with better prognosis. METHODS: Retrospective multicentre analysis including patients with mRCC treated with axitinib for at least three months from 2012 to 2014. Progression-free survival (PFS) was analysed by a Cox model according to gender, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score, high blood pressure (hBP), and maximum increase in HbL within the first three months of treatment. RESULTS: Ninety-eight patients were analysed (71% men; median age at treatment initiation: 62 years; IMDC: 24%, 50%, and 26% in the favourable, intermediate, and poor-risk group, respectively). Patients received axitinib for a median of 8 months. During the first three months, the median increase of HbL was +2.3 g/dL (-1.1; 7.2). Fifty-six (57%) patients developed hBP. In multivariate analysis, after adjustment for performance status (P < 0.0001) and gender (P = 0.0041), the combination of HbL increase ≥2.3 g/dL and any grade hBP was significantly associated with longer PFS (HR = 0.40, 95%CI [0.24; 0.68]). CONCLUSIONS: Early HbL increase during axitinib treatment combined with hBP is an independent predictive factor of PFS. These results require validation in a prospective setting.

Patients aged over 75 years enrolled in Phase I clinical trials: the Gustave Roussy experience.

Although a third of all cancers are diagnosed after the age of 75, only 9% of elderly people are recruited in clinical trials, because of fear of the risk of toxicity. The aim of this study was to compare the tolerance and efficacy observed in Phase I trials among patients aged over 75 years with that observed in younger patients. Patients treated from 2007 to 2012 at Institut Gustave Roussy in Phase I trials were included. The conditional Cox proportional hazards model was used to compare the occurrence of AE and overall survival in a subpopulation of elderly people (EP, aged >75 years) matched with patients aged <75 years (YP) according to the same Phase I protocol and the same Royal Marsden Hospital (RMH) prognostic score. Among the 32 EP and the 158 YP, 63% and 61% experienced Grade 3-4 AEs and dose-limiting toxicities occurred in 6% and 11% in each group respectively. Age over 75 years was neither associated with a greater risk of high toxicity (HR=0.90 [CI95%, 0.47-1.70], p = 0.74) nor of death (HR=0.86; CI95%: 0.38-1.93; p = 0.71). Age over 75 years had no impact on the occurrence of either high toxicity or of death.

Immune checkpoint inhibitors in advanced nonsmall cell lung cancer.

PURPOSE OF REVIEW: Targeting immune checkpoints has led to promising results in metastatic nonsmall cell lung cancer (NSCLC). By restoring antitumor immunity, these treatments are able to induce prolonged clinical responses. The level of activity and the durability of responses observed in phase I trials has led most companies to launch phases II and III trials whose results are highly expected. RECENT FINDINGS: In this review, we present efficacy and toxicity results of the different immune checkpoint inhibitors (ICIs) currently developed in NSCLC and report other checkpoints currently explored. The specific profile of tumor responses and immune-related toxicity observed with immunotherapy will be addressed. Finally, to illustrate the new insights into the development of these drugs, we will give an overview of the different ICIs combination studies evaluated in NSCLC and will discuss the role of programmed cell death-L1 as a potential biomarker. SUMMARY: This review will address some of the future challenges of ICIs in NSCLC.

Parotid gland metastasis from prostate cancer: is docetaxel still the best treatment option?

Metastases of prostate cancer originating from the parotid gland are rare. However, this presentation raises the question of the management of visceral metastasis in castration-resistant prostate cancer. We report the case of an 87-year-old man who presented with a right painless parotid mass in the context of castration-resistant prostate cancer, indicating progression of the disease. He received medical treatment based on docetaxel. Here, we discuss the impact of new hormonotherapies such as enzalutamide and abiraterone acetate, which may be used for the management of these patients.

Safety of spinal radiotherapy in metastatic cancer patients receiving bevacizumab therapy: a bi-institutional case series.

We retrospectively assessed the outcome of patients receiving emergency spinal radiation therapy (RT) concurrently with bevacizumab. Clinical records of 18 consecutive patients receiving emergency spinal RT for symptomatic vertebral metastases during the course of bevacizumab-based therapy were examined. Patients were receiving biweekly bevacizumab combined with paclitaxel (n=17) or with docetaxel/carboplatin (n=1) or as a single agent (n=1) for advanced metastatic carcinoma. RT was delivered at doses of 30 Gy in 10 fractions (n=8), 20 Gy in five fractions (n=9) or 18 Gy in nine fractions (n=1). In 10 patients (56%), irradiation field encompassed the thoracic vertebrae. The median time interval between the bevacizumab infusion and the RT course was 1.5 days (0-8 days). The median follow-up was 8.3 months (2 days-42 months). A clinical benefit of RT was reported in 13 patients (72%), including four patients with complete pain relief. Two of the three patients with neurological impairment at the time of RT experienced a partial improvement in their symptoms. No pain recrudescence was reported within the irradiated field after RT completion. All toxicities were mild to moderate, with no acute toxicity reported in 13 patients (72%). No RT disruption was necessary because of acute toxicity. No delayed toxicity was reported within RT fields among 11 patients with at least 6 months of follow-up. Spinal RT during the course of bevacizumab-based therapy was not associated with the occurrence of unexpected adverse effects. This suggests that emergency RT should not be contraindicated in these patients, provided that doses and treatment volumes are defined carefully.

Revolutionizing Localized Lung Cancer Treatment: Neoadjuvant Chemotherapy plus Immunotherapy for All?

Lung cancer poses a significant public health challenge, with resectable non-small cell lung cancer (NSCLC) representing 20 to 25% of all NSCLC cases, staged between I and IIIA. Despite surgical interventions, patient survival remains unsatisfactory, with approximately 50% mortality within 5 years across early stages. While perioperative chemotherapy offers some benefit, outcomes vary. Therefore, novel therapeutic approaches are imperative to improve patient survival. The combination of chemotherapy and immunotherapy emerges as a promising avenue. In this review, we explore studies demonstrating the benefits of this combination therapy, its impact on surgical procedures, and patient quality of life. However, challenges persist, particularly for patients failing to achieve pathologic complete response (pCR), those with stage II lung cancer, and individuals with specific genetic mutations. Additionally, identifying predictive biomarkers remains challenging. Nevertheless, the integration of immunotherapy and chemotherapy in the preoperative setting presents a new paradigm in managing resectable lung cancer, heralding more effective and personalized treatments for patients.

Multidisciplinary real-world management of metastatic castration-sensitive prostate cancer: A French national study (PROFILE study).

While androgen deprivation therapy (ADT) has been the standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC), recent strategies like intensification of systemic treatment (Rozet et al., 2020) (i.e. adding another treatment to ADT) and radiotherapy have improved overall survival. PROFILE, a national retrospective multicentric real-world study, involved patients with mCSPC recruited by medical oncologists, urologists, and radiation oncologists, and who started treatment between November 2020 and May 2021. Patients by sites were included consecutively. Data were collected from medical records. Primary objectives were to: (1) describe retrospectively the characteristics of whole population of patients with mCSPC as well as subgroups defined by prognostic factors in France at diagnosis; (2) identify current practices for managing mCSPC in a real-life clinical setting. Among the 416 patients with mCSPC included in the PROFILE study, 315 (76%) were synchronous (metastasis at the initial diagnosis) and 101 (24%) were metachronous patients (metastasis diagnosed post-progression). A majority (83% of synchronous and 73% of metachronous patients) received an intensified systemic treatment (ADT plus ARSI [androgen-receptor signaling inhibitors]±chemotherapy±primary tumour radiotherapy±metastasis-directed therapy [MDT]), while only 40% of low-volume patients received prostate radiotherapy. This study depicts the standardization of new therapeutic strategies for patients with mCSPC in France with most of them receiving an intensified treatment, mainly with ADT+ARSI (64% of synchronous intensified patients and 76% of metachronous intensified patients). Most of patients were assessed using conventional imaging (CT scan and/or bone scan). Overall, PROFILE results are in line with French and European guidelines for diagnosis, management, and follow-up of such patients (Rozet et al., 2020; Cornford et al., 2021).

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA.

BACKGROUND: Darolutamide and enzalutamide are second-generation androgen receptor inhibitors with activity in men with castrate-resistant prostate cancer (CRPC) and different toxicity profiles. OBJECTIVE: ODENZA is a prospective, randomized, multicenter, cross-over, phase 2 trial designed to assess preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic CRPC (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: Patients were randomized 1:1 to receive either darolutamide 1200 mg/d for 12 wk followed by enzalutamide 160 mg/d for 12 wk or enzalutamide followed by darolutamide. In both arms, the second treatment was given in absence of cancer progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was patient preference between the two drugs, as assessed by a preference questionnaire (p value calculated with the Prescott test). After week 24, patients entered an extension period during which they received their preferred treatment until progression or toxicity. The main secondary objectives included reasons for patient preference, response at week 12, tolerance of each drug, and measurement compared with baseline of cognitive outcomes assessed using tablet questionnaires. RESULTS AND LIMITATIONS: Overall, 249 patients, with a median age of 72 yr, were randomized. Among the 200 patients who fulfilled the preplanned criteria for the evaluation of the primary endpoint of preference, 97 (49% [41; 56]), 80 (40% [33; 47]), and 23 (12% [7; 16]) chose darolutamide, chose enzalutamide, and had no preference, respectively (p = 0.92). Reduced fatigue, easier administration, and better quality of life were the main criteria that influenced patient choice. A moderate benefit in episodic memory from darolutamide was observed for the acquisition of new information (least square [LS] means difference = 2.2, effect size = 0.5) and for the recall of that information after a brief delay (LS means difference = 0.7, effect size = 0.3). Using the Brief Fatigue Inventory questionnaire, patients reported greater fatigue with enzalutamide (3.3 [3.0; 3.6]) than with darolutamide (2.7 [2.4; 3.0]). There was no difference in terms of depression, seizures, and falls. CONCLUSIONS: The study did not show a difference in preference between the two treatments. In men with mCRPC, darolutamide was associated with a clinically meaningful benefit in episodic memory and less fatigue compared with enzalutamide. PATIENT SUMMARY: Preference between darolutamide and enzalutamide was well balanced in men with castrate-resistant prostate cancer. Darolutamide was associated with a significant benefit in verbal learning and less fatigue compared with enzalutamide.

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

New perspectives on metabolic imaging in the management of prostate cancer in 2022: A focus on radiolabeled PSMA­PET/CT (Review).

Nuclear medicine is an essential part of prostate cancer management concerning initial staging, patient follow-up and even therapy. Prostate-specific membrane antigen (PSMA) is a glutamate carboxypeptidase II transmembrane glycoprotein expressed by 80% of prostatic cells. The interest in this protein is due to its specificity for prostatic tissue. The use of 68GaPSMA PET/CT in the context of disease staging is thus well-established and recommended, especially for high-risk disease with metastases and lymph node involvement. However, the risk of false positives raises questions regarding its place in the management of patients with prostate cancer. The present study aimed to determine the use of PET-PSMA in the care of patients with prostate cancer but also to assess its limits of use.

Impact of radiation therapy on healthy tissues.

Radiation therapy has a fundamental role in the management of cancers. However, despite a constant improvement in radiotherapy techniques, the issue of radiation-induced side effects remains clinically relevant. Mechanisms of acute toxicity and late fibrosis are therefore important topics for translational research to improve the quality of life of patients treated with ionizing radiations. Tissue changes observed after radiotherapy are consequences of complex pathophysiology, involving macrophage activation, cytokine cascade, fibrotic changes, vascularization disorders, hypoxia, tissue destruction and subsequent chronic wound healing. Moreover, numerous data show the impact of these changes in the irradiated stroma on the oncogenic process, with interplays between tumor radiation response and pathways involved in the fibrotic process. The mechanisms of radiation-induced normal tissue inflammation are reviewed, with a focus on the impact of the inflammatory process on the onset of treatment-related toxicities and the oncogenic process. Possible targets for pharmacomodulation are also discussed.