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Background: Prostate cancer is the second leading cause of death among American men. If detected and treated at an early stage, prostate cancer is often curable. However, an advanced stage such as metastatic castration-resistant prostate cancer (mCRPC) has a high risk of mortality. Multiple treatment options exist, the most common included docetaxel, abiraterone, and enzalutamide. Docetaxel is a cytotoxic chemotherapy, whereas abiraterone and enzalutamide are androgen receptor pathway inhibitors (ARPI). ARPIs are preferred over docetaxel due to lower toxicity. No study has used machine learning with patients' demographics, test results, and comorbidities to identify heterogeneous treatment rules that might improve the survival duration of patients with mCRPC., Objective: This study aimed to measure patient-level heterogeneity in the association of medication prescribed with overall survival duration (in the form of follow-up days) and arrive at a set of medication prescription rules using patient demographics, test results, and comorbidities., Methods: We excluded patients with mCRPC who were on docetaxel, cabaxitaxel, mitoxantrone, and sipuleucel-T either before or after the prescription of an ARPI. We included only the African American and white populations. In total, 2886 identified veterans treated for mCRPC who were prescribed either abiraterone or enzalutamide as the first line of treatment from 2014 to 2017, with follow-up until 2020, were analyzed. We used causal survival forests for analysis. The unit level of analysis was the patient. The primary outcome of this study was follow-up days indicating survival duration while on the first-line medication. After estimating the treatment effect, a prescription policy tree was constructed., Results: For 2886 veterans, enzalutamide is associated with an average of 59.94 (95% CI 35.60-84.28) more days of survival than abiraterone. The increase in overall survival duration for the 2 drugs varied across patient demographics, test results, and comorbidities. Two data-driven subgroups of patients were identified by ranking them on their augmented inverse-propensity weighted (AIPW) scores. The average AIPW scores for the 2 subgroups were 19.36 (95% CI -16.93 to 55.65) and 100.68 (95% CI 62.46-138.89). Based on visualization and t test, the AIPW score for low and high subgroups was significant (P=.003), thereby supporting heterogeneity. The analysis resulted in a set of prescription rules for the 2 ARPIs based on a few covariates available to the physicians at the time of prescription., Conclusions: This study of 2886 veterans showed evidence of heterogeneity and that survival days may be improved for certain patients with mCRPC based on the medication prescribed. Findings suggest that prescription rules based on the patient characteristics, laboratory test results, and comorbidities available to the physician at the time of prescription could improve survival by providing personalized treatment decisions., (©Deepika Gopukumar, Nirup Menon, Martin W Schoen. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 19.11.2024.)

Background: Two randomized trials demonstrated that the survival benefits afforded by triplet therapy were greater than those of doublet therapy, thus changing the treatment paradigm for metastatic castration-sensitive prostate cancer (mCSPC). This is the first study to assess the real-world use, performance, and safety of triplet therapy in Japanese patients., Methods: This retrospective multicenter study included 45 consecutive mCSPC patients who received triplet therapy composed of androgen deprivation therapy (ADT), docetaxel, and darolutamide between January 2023 and June 2024. Baseline patient characteristics and their clinical parameters during triplet therapy were collected. Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events version 5.0, and imaging responses were evaluated following the RECIST criteria. The prostate-specific antigen (PSA) nadir was defined as the lowest PSA value during follow-up, and the PSA decrease was the initial PSA value minus the PSA nadir., Results: The median patient age was 70 years and the median follow-up duration was 10 months. High-volume disease was present in 82.2% of patients. Concurrent administration of docetaxel and darolutamide was scheduled for 22.2% of cases. The incidence of any AE was 86.7%, with 55.5% of patients experiencing grade 3-4 AEs. Neutropenia was common, but prophylactic granulocyte colony-stimulating factor (G-CSF) significantly reduced the incidence of neutropenia of grade 3 or higher. Febrile neutropenia occurred in four patients (8.9%); these patients had not received prophylactic G-CSF. A decline in PSA of 90% was observed in 95.6% of patients, and an imaging response was seen in 97.8%., Conclusions: Triplet therapy with ADT, darolutamide, and docetaxel was highly efficacious and tolerable in Japanese mCSPC patients, particularly those with high-volume disease. Prophylactic G-CSF prescription is crucial to manage neutropenia effectively. Further studies with longer follow-ups are needed to confirm these findings and explore the long-term outcomes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Consultation audio recordings improve patient decision-making but are underutilized. Patient-administered recording apps on mobile devices may increase access, but implementation has not been evaluated., Methods: We conducted a single-arm study delivering education, coaching, and reminders for patients to record their appointment using a mobile recording app. Patients had progressive, advanced prostate cancer and an upcoming appointment where the option of docetaxel would be discussed. We used the RE-AIM framework for evaluation. Reach was the proportion of patients who participated. Effectiveness was change in informed decision-making pre- vs. post-appointment. We used a questionnaire evaluating patient knowledge about docetaxel (0%-100% correct) and the decisional conflict scale-informed subscale (0 = feels extremely uninformed to 100 = extremely informed) to compare means using the paired t-test. Adoption was the proportion of providers agreeing to be recorded. Implementation was coordinator adherence to intervention delivery. We conducted semistructured interviews with patients, caregivers, and providers to assess barriers, facilitators, and suggestions for recording implementation., Results: Of 102 patients approached, 50 (49%) patients participated. Mean age was 75 years, 38 (76%) were Non-Hispanic White, and 43 (86%) had telehealth appointments. Knowledge increased from 44.7% to 49.5% (p = 0.019), particularly about palliative care (42% answering correctly to 60%, p = 0.035). Decisional conflict-informed subscale increased from 48.9 to 70.9 (p < 0.001). Forty-three patients (85%) made a recording, of whom 33 (77%) reported the recording helped treatment decision-making. All 17 providers agreed to be recorded. Coordinator adherence was high. Multi-level barriers, suggestions, and facilitators mostly related to intervention complexity and stakeholder compatibility., Conclusion: Patient-administered audio recordings had a positive effect on decision-making, particularly for palliative care awareness. For broader implementation, efforts should focus on revising institutional policies; teaching patients or caregivers to use existing recording functions on their devices; leveraging artificial intelligence for transcription and summarization; and integrating recording into telehealth technology and electronic patient portals., Trial Registration: https://clinicaltrials.gov/study/NCT05127850., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: In the global ARASENS study (NCT02799602), darolutamide plus androgen-deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57-0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants., Methods: Patients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival., Results: The Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m 2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50-1.64), despite 85% of patients in the placebo group receiving subsequent life-prolonging therapy. Darolutamide prolonged time to castration-resistant prostate cancer (HR 0.31; 95% CI 0.17-0.55). Treatment-emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population., Conclusion: In conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: To evaluate the comparative effectiveness of sotorasib monotherapy versus docetaxel as monotherapy or combination therapy in patients with pretreated KRAS G12C-mutated advanced NSCLC in the real-world., Methods: A US-based electronic health record-derived de-identified database was used in this study. Patients with pretreated KRAS G12C-mutated advanced NSCLC who initiated sotorasib between May 28, 2021, and September 30, 2022, and docetaxel between January 1, 2019, and September 30, 2022 (to enhance sample size), were included, with a minimum of 12-month opportunity for follow-up. Treatment groups were balanced via overlap weighting propensity score methods. Median OS in the 2L and 2L+ settings were calculated using Kaplan-Meier estimates. Hazard ratios (HRs) were estimated via Cox proportional hazard models., Results: Overall, the clinical characteristics in sotorasib and docetaxel cohorts were balanced after propensity score weighting. At baseline, most patients were > 65 years of age, had ECOG performance status of 0-1, were from the community practice setting, had advanced stage at initial diagnosis, and had prior anti-PD-(L)1 treatment and/or platinum-based chemotherapy. In the 2L setting, the median OS (95 % CI) for sotorasib (N=102) and docetaxel (N=58) patients was 10.2 (7.6-16.3) and 6.0 (4.2-11.0) months, respectively, with a corresponding mortality HR (95 % CI) of 0.62 (0.41-0.93). In the 2L+ setting, the median OS (95 % CI) for sotorasib (N=164) and docetaxel (N=116) was 10.2 (8.0-14.6) and 7.2 (5.1-10.6) months, respectively, with a corresponding mortality HR (95 % CI) of 0.65 (0.49-0.87). In patients with prior anti-PD-(L)1 treatment, the mortality HR (95 % CI) in the sotorasib group versus docetaxel was 0.61 (0.39-0.94) and 0.65 (0.48-0.89) in the 2L and 2L+ settings, respectively. Findings from other subgroups were consistent with the primary analyses., Conclusion: In this real-world comparative analysis of patients with pretreated KRAS G12C-mutated advanced NSCLC, sotorasib monotherapy demonstrated a longer median OS compared to docetaxel monotherapy or combination therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Melissa Johnson reports research funding from AbbVie (Inst); Adaptimmune (Inst); Amgen (Inst); Apexigen (Inst); Arcus Biosciences (Inst); Array BioPharma (Inst); ArriVent Biopharma (Inst); Artios (Inst); AstraZeneca (Inst); Atreca (Inst); Bayer (Inst); BeiGene (Inst); BerGenBio (Inst); BioAtla (Inst); Black Diamond Therapeutics (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Calithera Biosciences (Inst); Carisma Therapeutics (Inst); Checkpoint Therapeutics (Inst); City of Hope (Inst); Corvus Pharmaceuticals (Inst); Curis (Inst); CytomX Therapeutics (Inst); Daiichi Sankyo (Inst); Dracen (Inst); Dynavax Technologies (Inst); Elicio Therapeutics (Inst); EMD Serono (Inst); EQRx (Inst); Erasca, Inc (Inst); Exelixis (Inst); Fate Therapeutics (Inst); Genentech/Roche (Inst); Genmab (Inst); Genocea Biosciences (Inst); GlaxoSmithKline (Inst); Gritstone Bio (Inst); Guardant Health (Inst); Harpoon (Inst); Helsinn Healthcare (Inst); Hengrui Pharmaceutical (Inst); Hutchison MediPharma (Inst); IDEAYA Biosciences (Inst); IGM Biosciences (Inst); Immunitas (Inst); Immunocore (Inst); Incyte (Inst); Janssen (Inst); Jounce Therapeutics (Inst); Kadmon (Inst); Kartos Therapeutics (Inst); Lilly (Inst); LockBody Therapeutics (Inst); Loxo (Inst); Lycera (Inst); Memorial Sloan-Kettering Cancer Center (Inst); Merck (Inst); Merus (Inst); Mirati Therapeutics (Inst); Mythic Therapeutics (Inst); NeoImmuneTech (Inst); Neovia Oncology (Inst); Novartis (Inst); Numab (Inst); Nuvalent, Inc. 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(Inst); Turning Point Therapeutics (Inst); University of Michigan (Inst); Vyriad (Inst); WindMIL (Inst); Y-mAbs Therapeutics (Inst), consulting fees from AbbVie (Inst); Alentis Therapeutics (Inst); Amgen (Inst); Arcus Biosciences (Inst); ArriVent Biopharma (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); D3 Bio (Inst); Daiichi Sankyo (Inst); Fate Therapeutics (Inst); Genentech/Roche (Inst); Genmab (Inst); Genocea Biosciences (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); Gritstone Bio (Inst); Hookipa Biotech (Inst); Immunocore (Inst); Janssen Oncology (Inst); Jazz Pharmaceuticals (Inst); Lilly (Inst); Merck (Inst); Mirati Therapeutics (Inst); Molecular Axiom (Inst); Normunity (Inst); Novartis (Inst); Novocure (Inst); Pfizer (Inst); Pyramid Biosciences (Inst); Revolution Medicines (Inst); Sanofi (Inst); SeaGen (Inst); Synthekine (Inst); Takeda (Inst); VBL Therapeutics (Inst), and travel and accommodation grants from AbbVie; AstraZeneca; Genentech; Incyte; Merck; Pfizer; Sanofi. Alexander Spira reports research funding support from AbbVie (Inst); ADC Therapeutics (Inst); ADC Therapeutics (Inst); Alkermes (Inst); Amgen (Inst); Arch Therapeutics (Inst); ArriVent Biopharma (Inst); Astellas Pharma (Inst); Astex Pharmaceuticals (Inst); AstraZeneca (Inst); Black Diamond Therapeutics (Inst); Blueprint Medicines (Inst); BluPrint Oncology (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); CytomX Therapeutics (Inst); Daiichi Sankyo (Inst); Gritstone Bio (Inst); Ignyta (Inst); Incyte (Inst); Janssen Oncology (Inst); LAM Therapeutics; Loxo (Inst); Loxo (Inst); Macrogenics (Inst); Medikine (Inst); MedImmune (Inst); Mersana (Inst); Mirati Therapeutics (Inst); nalo therapeutics (Inst); Novartis (Inst); Plexxikon (Inst); Regeneron; Revolution Medicines (Inst); Revolution Medicines (Inst); Roche (Inst); Rubius Therapeutics (Inst); Scorpion Therapeutics (Inst); Synthekine (Inst); Synthekine (Inst); Takeda (Inst), consulting fees from Amgen; Array BioPharma (Inst); AstraZeneca/MedImmune (Inst); AstraZeneca/MedImmune (Inst); Black Diamond Therapeutics; Blueprint Medicines (Inst); Bristol-Myers Squibb (Inst); Daiichi Sankyo/Astra Zeneca; Gritstone Bio; Gritstone Bio; incyte; Janssen Research & Development; Jazz Pharmaceuticals; Lilly; Merck (Inst); Mersana; Mirati Therapeutics; Novartis; Regeneron; Sanofi; Takeda, honoraria from Amgen; AstraZeneca/MedImmune; Bayer; Bristol-Myers Squibb; CytomX Therapeutics; Janssen Oncology; Merck; Novartis; Takeda, leadership role at Next Oncology, and stock or stock options from Lilly. Diana Younan, Shia T. Kent, Marco Mesa-Frias, and Akhila Balasubramanian are employees and stockholders of Amgen Inc. M Alan Brookhart reports participation in advisory board at Accompany Health, American Academy of Allergy, Asthma & Immunology, Amgen, Astellas/Seagen, Atara Biotherapeutics, Brigham and Women's Hospital, Gilead/Kite, Intercept, National Institute of Diabetes and Digestive and Kidney Diseases, Regeneron, and Vertex and stock or stock options at Accompany Health and Target RWE., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This systematic review and network meta-analysis aimed to assess the comparative effectiveness and safety profiles of current combination therapies based on androgen deprivation therapy (ADT) for the heterogeneous population of individuals with metastatic castration-sensitive prostate cancer (mCSPC)., Methods: We retrieved pertinent literature from PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov, and international conference databases. The study was registered in the Prospective Register of Systematic Reviews (CRD42023453853) for transparency., Results: Our analysis included 20 RCTs involving 14,995 patients, evaluating 15 ADT-based combinations, including systemic therapies, radiotherapy and surgery. In the overall population, the darolutamide triplet (DARO + docetaxel + ADT) demonstrated comparable overall survival (OS) benefits to prostatectomy/radical local therapy (RLT) plus ADT (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.43-1.57). Additionally, the enzalutamide (ENZ) triplet (ENZ + DOC + ADT) appeared to confer the best progression-free survival (HR, 0.34; 95% CI: 0.27-0.43). Subgroup analysis based on metastatic burden indicated that RLT plus ADT had the best OS performance in patients with low burden, while the DARO triplet was associated with the best OS in patients with high burden. Regarding adverse events (AEs), the addition of certain androgen receptor pathway inhibitor (ARPI) agents to ADT led to an increased incidence of severe AEs, while the addition of DOC to the ARPI doublet did not appear to elevate the exposure-adjusted incidence rates., Conclusions: Our findings suggest that combined treatments result in better survival outcomes than does ADT alone. In the current landscape of systemic therapy, the significance of local therapy should not be underestimated, and therapeutic decisions should be tailored with meticulous consideration of clinical heterogeneity among patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC., Experimental Approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC., Key Results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells., Conclusion and Implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The current guidelines for treating metastatic castration-sensitive prostate cancer (mCSPC) recommend treatment intensification of androgen deprivation therapy (ADT) with the addition of an androgen receptor pathway inhibitor (ARPI), with or without docetaxel. However, the adoption of these treatment options has been slow, leading to therapeutic inertia. This real-world study was conducted to investigate the occurrence of adverse events (AEs) among treated patients diagnosed with mCSPC in the United States., Methods: This retrospective claim review estimated the occurrence of AEs among patients with mCSPC from January 2014 to June 2021 in the PharMetrics® Plus data set. The study focused on 10 common AEs (fatigue/asthenia, gastrointestinal [GI] AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, sexual function AEs, anemia, hypertension, pain, and edema) known to occur in ≥10% of patients and ≥2% more prevalent than those treated with ADT alone as selected from the US Food and Drug Administration prescribing information and published results from clinical trials. Proportions of patients experiencing these AEs at Day 90, 180, and then every 180 days until month 30 during the follow-up period were estimated using cumulative hazard plots. Results were adjusted using inverse probability of treatment weighting (IPTW) across four treatment groups: ADT alone, ADT + nonsteroidal anti-androgen (NSAA) (bicalutamide, nilutamide, or flutamide), ADT + docetaxel, and ADT + ARPIs (abiraterone, apalutamide, or enzalutamide). ADT-alone cohort was the reference group for all comparisons., Results: A total of 4145 patients were included (ADT alone: 2318, ADT + NSAA: 632, ADT + docetaxel: 471, ADT + ARPIs: 724). At baseline, median (interquartile range [IQR]) age was 64.3 (60.1-73.1) years; most common sites of metastasis were bone only (n = 1886, 45.5%) and node only (n = 1237, 29.8%); most used medications were pain medications (n = 2182, 52.6%) and corticosteroids (n = 1213, 29.3%). Median (IQR) duration of follow-up 10.2 (6.1-16.6) months in ADT alone, 6.7 (4.1-11.5) months in ADT + NSAA, 5.1 (4.3-5.9) months in ADT + docetaxel, and 11.0 (6.6-17.0) months in ADT + ARPI cohort. The reported AEs increased over time for all assessed AEs, across all treatment groups. Compared with ADT alone, no statistically significant difference in the proportion of patients with AEs was seen in the ADT + ARPI or ADT + NSAA cohorts at months 3 and 12; a significantly higher proportion of patients in the ADT + docetaxel cohort experienced 6 of the 10 assessed AEs at month 3 (fatigue/asthenia, GI AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, anemia). During the follow-up period, on IPTW analysis, compared with ADT alone, a significantly higher proportion of patients experienced AEs with seven AEs in the ADT + docetaxel group (fatigue/asthenia, GI AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, anemia, edema; p < 0.001 for all seven), three AEs in the ADT + ARPI group (hot flash, p = 0.05; anemia, p = 0.01; edema, p = 0.019), and one AE in the ADT + NSAA group (anemia, p = 0.029). The proportion of patients with sexual function AE did not significantly differ between the treatment groups and ADT alone., Conclusion: Results of this large, real-world study demonstrated that all treatment groups experienced an increase in the rates of AEs over time, including ADT alone. Most AE rates with ADT + ARPIs were comparable with ADT + NSAA and not significantly different from ADT alone. ADT + docetaxel cohort was associated with significantly higher rates for all AEs over time except hypertension, sexual dysfunction, and pain. This study provides real-world evidence on AEs, beyond controlled clinical trials, and may assist healthcare providers to make better-informed decisions about disease management among patients with mCSPC., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Objective: To evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer., Design: Randomised, multicentre, open label, phase 3 trial., Setting: 7 cancer centres in China between 3 January 2016 and 17 July 2023., Participants: Female patients aged 18-70 years with early triple negative breast cancer after definitive surgery., Interventions: After risk stratification using the integrated signature, patients at high risk were randomised (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (arm A; n=166) or a standard treatment of four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (arm B; n=170). Patients at low risk received the same adjuvant chemotherapy as arm B (arm C; n=168)., Main Outcome Measures: The primary endpoint was disease-free survival in the intention-to-treat analysis for arm A versus arm B. Secondary endpoints included disease-free survival for arm C versus arm B, recurrence-free survival, overall survival, and safety., Results: Among the 504 enrolled patients, 498 received study treatment. At a median follow-up of 45.1 months, the three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03). The three year recurrence-free survival rate was 92.6% in arm A and 83.2% in arm B (hazard ratio 0.50, 95% CI 0.25 to 0.98; P=0.04). The three year overall survival rate was 98.2% in arm A and 91.3% in arm B (hazard ratio 0.58, 95% CI 0.22 to 1.54; P=0.27). The rates of disease-free survival (three year disease-free survival 90.1% v 80.6%; hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04), recurrence-free survival (three year recurrence-free survival 94.5% v 83.2%; 0.42, 0.22 to 0.81; P=0.007), and overall survival (three year overall survival 100% v 91.3%; 0.14, 0.03 to 0.61; P=0.002) were significantly higher in patients in arm C than in those in arm B with the same chemotherapy regimen. The incidence of grade 3-4 treatment related adverse events were 64% (105/163), 51% (86/169), and 54% (90/166) for arms A, B, and C, respectively. No treatment related deaths occurred., Conclusions: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable triple negative breast cancer. Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity., Trial Registration: ClinicalTrials.gov NCT02641847., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the National Key Research and Development Project of China, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Shanghai Key Laboratory of Breast Cancer, SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals, and CSPC Pharmaceutical Co Ltd, Shijiazhuang, China, for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The LUNAR trial demonstrated the significant efficacy and safety of Tumor Treating Fields (TTFields) plus standard-of-care (SOC) [immune checkpoint inhibitor (ICI) and docetaxel (DTX)] for patients with previously treated metastatic non-small cell lung cancer (mNSCLC). However, it remains uncertain as to whether the high costs are justified by the corresponding survival benefits. Here, the cost-effectiveness of using TTFields plus SOC for treating mNSCLC was evaluated from the perspective of the Chinese healthcare system., Methods: A Markov model with a 15-year time horizon was established and used to comparedeveloped to enable the simulation of treatment-associated costs and patient outcomes when comparing TTFields plus SOC to SOC alone. Primary outcomes for these analyses included total costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER) values. The impact of paramere uncertainty on model outcomes was evaluated through sensitivity analyses. Additional subgroup and scenario analyses were also performed to extend these results., Results: While TTFields plus SOC exhibited a $74,688 increase in total costs relative to SOC ($96,092 vs. $21,404), it was associated with 0.38 additional QALYs (1.08 vs. 0.82 QALYs) for an ICER of $284,490/QALY. This value exceeded the $35,983/QALY willingness-to-pay (WTP) threshold selected for these analyses by a wide margin. Relative to ICI and DTX treatment, the incremental costs of TTFields plus ICI and TTFields plus DTX were $78,115 and $71,307, respectively, with corresponding gains of 0.42 and 0.13 QALYs, yielding ICERs of $187,434/QALY, and $546,386/QALY. The parameter that most strongly impacted the results of these analyses was the cost of TTFields., Conclusion: The results indicated that given current treatment costs, TTFields plus SOC was insufficiently cost-effective in treating patients with mNSCLC in China, although TTFields plus ICI yields substantial health benefits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pei, Xiao and Yang.)

Background: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting., Methods: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation., Results: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups., Conclusions: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms., (© 2024. The Author(s).)

Rationale: The incidence of pregnancy-associated breast cancer (PABC) is relatively low, but it has been increasing in recent years. The onset of PABC causes serious harm to the fetus and the mother due to the unique physiological characteristics of pregnancy, which poses a particular challenge to clinicians. This article reports a case of pregnancy-associated triple-negative breast cancer and describes the patient characteristics and systematic treatment of this type of breast cancer., Patient Concerns: A 33-year-old woman was admitted to hospital with a left breast mass that had appeared more than a year earlier. She was a second-time pregnant woman with a single live intrauterine fetus at 23 + 4 weeks of gestation. During the examination of the left breast, a 6 by 8 cm sized mass can be observed on the upper outer quadrant., Diagnosis: Pregnancy-associated triple-negative breast cancer., Intervention: The patient underwent a breast ultrasound which showed a left breast mass and the diagnosis was confirmed by a puncture biopsy of the left breast mass. The pregnancy was terminated after multidisciplinary discussion, taking into account the wishes of the patient and her family. After termination of the pregnancy, all treatments were given according to the standard triple-negative breast cancer (TNBC) treatment protocol. The patient was treated with neoadjuvant chemotherapy with epirubicin in combination with docetaxel (TE) in cycles of 21 days. After 3 cycles of TE, a modified radical mastectomy for left breast cancer was performed, and the appropriate radiotherapy and chemotherapy treatments were carried out in sequence., Outcomes: After the surgery, the disease-free survival for the patient was 3 months until local metastases were diagnosed. Thus the radiotherapy and chemotherapy were carried out, and then the patient was in good general condition with no recurrence or metastases., Lessons: Clinicians need more research into the diagnosis, treatment and prognosis of PABC. Improving the rate of early diagnosis and using standardized and individualized comprehensive treatment plans will minimize fetal damage and improve survival and quality of life for patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Anlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC., Methods: Locally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common., Conclusions: Anlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted., (© 2024. The Author(s).)

The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN- status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0-2.9, P = 0.034), ypN+ (HR 1.9, 95% CI 1.1-3.6, P = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0-2.9, P = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An 82-year-old woman, who underwent a mastectomy for right breast cancer 35 years ago, presented to our hospital with a chief complaint of general malaise and dyspnea. A chest CT scan revealed a right pleural effusion and multiple bone metastases. Upper gastrointestinal endoscopy revealed a small bulge in the mid gastric fold, which was diagnosed as a metastatic breast cancer lesion, based on pathological diagnosis and immunostaining findings. The patient had triple-negative breast cancer and was started on docetaxel therapy despite her advanced age. The pleural effusion disappeared, tumor marker levels normalized, and treatment was continued. Here, we report a case of late recurrence of breast cancer with gastric metastasis 35 years postoperatively.

Taxanes are one of the most widely used classes of breast cancer (BC) therapeutics. Despite the long history of clinical usage, the molecular mechanisms of their action and cancer resistance are still not fully understood. Here we aimed to identify gene expression and molecular pathway activation biomarkers of BC sensitivity to taxane drugs paclitaxel and docetaxel. We used to our knowledge the biggest collection of clinically annotated publicly available literature BC gene expression data (12 datasets, n  = 1250) and the experimental clinical BC cohort ( n  = 12). Seven literature datasets were used for biomarker discovery ( n  = 914), and the remaining five literature plus one experimental datasets ( n  = 336) - for the validation. We totally found 34 genes and 29 molecular pathways which could strongly discriminate good and poor responders to taxane treatments. The biomarker genes and pathways were associated with molecular processes related to formation of mitotic spindle and centromeres, and with the spindle assembly mitotic checkpoint. Furthermore, we created gene expression and pathway activation signatures predicting BC response to taxanes. These signatures were tested on the validation BC cohort and demonstrated strong biomarker potential reflected by mean AUC values of 0.76 and 0.77, respectively, which outperforms previously reported analogs. Taken together, these findings can deepen our understanding of mechanism of action of taxanes and potentially improve personalization of treatment in BC.

Background: In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL)., Methods: In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m 2 intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes., Results: Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12)., Conclusions: Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC., Competing Interests: Declaration of competing interest David M. Waterhouse received consulting fees from Bristol Myers Squibb (BMS), Amgen, Janssen, Merck, Fresenius Kabi, and Novartis; received honoraria from BMS, AstraZeneca, Amgen, Janssen, EMD Serono, Fresenius Kabi, and Sanofi; received support to attend meetings and/or travel from BMS and Amgen; and participated on a data safety monitoring board or advisory board for BMS, AstraZeneca, AbbVie, Amgen, Janssen, Eisai, EMD Serono, Merck, Pfizer, Fresenius Kabi, Sanofi, Astellas, Gilead, Takeda, Daiichi, and Bayer. Sacha Rothschild received grants or research support from AstraZeneca, Merck Serono, Roche Pharma, and Amgen; received consulting fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck KG, MSD, Novartis, Otsuka, Pfizer, PharmaMar, Roche Pharma, Roche Diagnostics, Sanofi Aventis, and Takeda; received honoraria from Roche Pharma, BMS, AstraZeneca, Amgen, MSD Oncology, Novartis, Roche Diagnostics, and Takeda; received payment for expert testimony from Roche, AstraZeneca, and BMS; received support for attending meetings and/or travel from Roche Pharma, Eli Lilly, BMS, Amgen, AstraZeneca, and MSD; participated on a data safety monitoring board or advisory board for Roche Pharma; and is the vice president of the Swiss Group for Clinical Cancer Research (SAKK) and elected member of the Swiss Federal Drug Commission (Federal Health Office). Christophe Dooms has nothing to disclose. Bertrand Mennecier received honoraria from Amgen, Roche, AstraZeneca, Pharma Mar, Eli Lilly, BMS, MSD, Sanofi, Takeda, and Pfizer; and received support for attending meetings and/or travel from MSD, Roche, BMS, AstraZeneca, and Takeda. Farastuk Bozorgmehr received grant/research support from Roche and AstraZeneca; received honoraria from Novocure, Daiichi Sankyo, GSK, and AstraZeneca, received support for attending meetings and/or travel from Janssen; and participated in a data safety monitoring board or advisory board for Amgen, AstraZeneca, Daiichi Sankyo, and Janssen. Margarita Majem received consulting fees from AstraZeneca, Roche, MSD, Janssen, and Sanofi; received honoraria from MSD, Roche, AstraZeneca, Casen Recordati, Takeda, and Helsinn; received support for attending meetings and/or travel from MSD, Pfizer, Roche, and AstraZeneca, and is the vice president of ICAPEM and a board member of AEC Barcelona. Michel M. van den Heuvel participated on a data safety monitoring board or advisory board for Amgen. Helena Linardou received payment or honoraria for lectures and/or speakers bureaus from Roche, AstraZeneca, Pfizer, BMS, MSD, Novartis, Amgen, and GSK; received support for attending meetings and/or travel from Pfizer and Roche; participated on a data safety monitoring board or advisory board for Roche, AstraZeneca, MSD, BMS, Novartis, Pfizer, and Amgen; and held unpaid positions in non-profit organizations, including president of a scientific committee in the Hellenic Cooperative Oncology Group and board member for Hellenic Foundation of Cancer Research, FairLife Lung Cancer, and W4O-Hellas. Byoung Chul Cho received grant/research support from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridge Biotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS BIO, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG. Rachel Roberts-Thomson received royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; received consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, MedPacto, Blueprint Medicines, RaND Bio, and Hanmi; received honoraria from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer; participated on a scientific advisory board for Kanaph Therapeutics, Bridge Biotherapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, and Amgen; was a board member for J INTS BIO; owned stock in TheraCanVac Inc, Gencurix Inc, Bridge Biotherapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., and J INTS BIO; was employed by Yonsei University Health System and is a founder of DAAN Biotherapeutics. Kentaro Tanaka received consulting fees from Pfizer and received honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Takeda Pharmaceutical, Novartis, Ono Pharmaceutical, Daiichi Sankyo, Merck, MSD, and BMS. Normand Blais received consulting and speakership fees from Amgen. Gustavo Schvartsman received consulting fees from AstraZeneca, BMS, Merck, Sharp & Dome, and Daiichi Sankyo; received honoraria from Roche, Amgen, Adiu, and Pfizer; and received support for attending meetings and/or travel from Merck, Sharp & Dome and Daiichi Sankyo. Karin Holmskov Hansen participated in clinical trial safety meetings for MSD and Incyte (not paid) and was head of the Danish Oncology Group until February 2023 (not paid) and a member of the Expert Committee under the Danish Medicines Council (not paid). Izabela Chmielewska received consulting honoraria from Amgen; and received speakership fees from Amgen, BMS, Takeda, Roche, and MSD. Martin D. Forster received grant/research support from Cancer Research UK Early Detection Committee Program Grant, Bristol Myers Squibb Research Grant, NIHR RfPB Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, Merck Educational Grant, MSD Educational Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, MRC BMC:DPFS Grant Award, and Boehringer Ingelheim Educational Grant and received consulting fees from Amgen and participated in an Advisory Board for Amgen. Christina Giannopoulou is an employee of Amgen Europe GmbH and holds stock in Amgen. Björn Stollenwerk is an employee of Amgen Europe GmbH and holds stock in Amgen. Cynthia C. Obiozor is an employee of and holds stock in Amgen. Yang Wang is an employee of and holds stock in Amgen.Silvia Novello received honoraria from AstraZeneca, Amgen, Thermo Fisher, MSD, Novartis, Sanofi, Roche, Pfizer, Takeda, and Janssen and participated on a data safety monitoring board or advisory board from Pfizer, AstraZeneca, Sanofi, Jannsen, and Daiichi., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lutetium-177 [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 improves survival and quality of life in patients with metastatic castration-resistant prostate cancer, but whether it confers a benefit in hormone-sensitive disease is unknown. We aimed to evaluate [ 177 Lu]Lu-PSMA-617 before docetaxel treatment in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer., Methods: UpFrontPSMA was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 11 Australian hospitals. Eligible patients had prostate adenocarcinoma without clinically significant neuroendocrine differentiation or small-cell histology, were aged 18 years or older, had less than 4 weeks on androgen deprivation therapy, had an Eastern Cooperative Oncology Group performance status of 0-2, and had high-volume PSMA-avid disease on [ 68 Ga]Ga-PSMA-11 PET-CT with no major discordance on 2-[ 18 F] fluorodeoxyglucose-PET-CT. Patients were randomly assigned (1:1) to the experimental treatment ([ 177 Lu]Lu-PSMA-617 followed 6 weeks later by docetaxel) or standard-of-care treatment (docetaxel alone) using computer-based block randomisation with random block sizes, stratified by disease volume by conventional imaging and duration of androgen deprivation therapy at the time of registration. Neither patients nor investigators were masked to treatment assignment. Patients in the experimental group received two cycles of [ 177 Lu]Lu-PSMA-617 7·5 GBq every 6 weeks intravenously, followed 6 weeks later by six cycles of docetaxel 75 mg/m 2 every 3 weeks intravenously, whereas patients in the standard-of-care treatment group received six cycles of docetaxel 75 mg/m 2 every 3 weeks intravenously. All patients received continuous androgen deprivation therapy. The primary endpoint was undetectable prostate-specific antigen (≤0·2 ng/mL) at 48 weeks, assessed using a modified intention-to-treat analysis. The trial is registered with ClinicalTrials.gov, NCT04343885., Findings: Between May 5, 2020, and April 18, 2023, 130 patients were randomly assigned, 63 (48%) to [ 177 Lu]Lu-PSMA-617 plus docetaxel and 67 (52%) to docetaxel alone. All patients were male and no race or ethnicity data were collected. Median follow-up was 2·5 years (IQR 1·8-3·0). Four patients in the docetaxel alone group withdrew consent after randomisation and no data beyond screening were collected. An additional four patients were not evaluable for the primary endpoint at 48 weeks (two in each group). 25 (41%) of 61 patients (95% CI 30-54) in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group had undetectable PSA at 48 weeks compared with ten (16%) of 61 patients (9-28) in the docetaxel alone group (OR 3·88, 95% CI 1·61-9·38; p=0·0020). The most common grade 3 or 4 treatment-related adverse events were febrile neutropenia (seven [11%] of 63 patients in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group vs six [10%] of 63 patients in the docetaxel alone group) and diarrhoea (four [6%] of 63 patients vs none). Serious adverse events occurred in 16 (25%) patients in the [ 177 Lu]Lu-PSMA-617 plus docetaxel group (none were definitely related to [ 177 Lu]Lu-PSMA-617) and 16 (25%) patients in the docetaxel alone group. No treatment-related deaths occurred., Interpretation: [ 177 Lu]Lu-PSMA-617 followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects. Our data potentially support a role for [ 177 Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer., Funding: Prostate Cancer Research Alliance (Movember Foundation and Australian Government Medical Research Future Fund), US Department of Defence Impact Award-Clinical Trials, Endocyte/Advanced Accelerator Applications (a Novartis company), Australian Nuclear Science and Technology Organization, Victorian Cancer Agency, University of Melbourne, and Peter MacCallum Cancer Foundation., Competing Interests: Declaration of interests AAA reports grants from Aptevo Therapeutics (institutional), Astellas (investigator), Astellas (institutional), AstraZeneca (institutional), AstraZeneca (investigator), Bionomics (institutional), Bristol Myers Squibb (institutional), Eli Lilly (institutional), Exelixis (institutional), Gilead Sciences (institutional), GlaxoSmithKline (institutional), Hinova (institutional), Ipsen (institutional), Janssen (institutional), MedImmune (institutional), Merck Serono (investigator), Merck Serono (institutional), Merck Sharpe & Dohme (institutional), Novartis (institutional), Pfizer (institutional), Sanofi Aventis (institutional), and SYNthorx (institutional); consulting fees from Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck, Bayer, Ipsen, Merck Serono, Amgen, and Noxopharm; honoraria from Janssen, Astellas, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharma, Bristol Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm, Daiichi Sankyo, and Arvinas; speakers' bureau fees from Astellas, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol Myers Squibb, and Merck Serono; support for attending meetings from Amgen, Astellas, Bayer, Hinova, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; participation on data safety monitoring or advisory boards for Arvinas, Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck Sharpe & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm, and Daiichi Sankyo. MV reports personal fees from AstraZeneca and Merck Sharpe & Dohme and grants (to their institution) from AstraZeneca, Merck Sharpe & Dohme, Alpine Immune Sciences, Virocure, Hinova, Atridia/Hengrui, Antengene, and Biogene. AJW declares grants to their institution from Merck Sharpe & Dohme; consulting fees from Merck Sharpe & Dohme, Bayer, Bristol Myers Squibb, Pfizer, Ipsen, and Astellas; honoraria from Astellas and Bristol Myers Squibb; and support for attending meetings from Bayer. AG reports grants from Sun Pharma; consulting fees from Regeneron and Bayer; support to attend meetings from Sun Pharma and Bristol Myers Squibb; and participation in a data safety monitoring or advisory board for Regeneron and Bayer. RJF reports committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). LE reports research grant support (to their institution) from Novartis and Clarity Pharma; consulting fees for lectures or advisory boards from Astellas, Janssen, AstraZeneca, Clarity, Novartis, and Telix in the past 5 years; and philanthropic grant support from the Prostate Cancer Foundation, St Vincent's Clinic Research Foundation, and the Curran Foundation. DGM has received reimbursement for advisory board or speaker bureau activity from the following companies (in the past 36 months): Janssen, Astellas, Bayer, AstraZeneca, Mundipharma, Novartis, and Ipsen. AR has received reimbursement for advisory board or speaker bureau activity from the following companies: AstraZeneca, Daiichi Sankyo, Lily, Pfizer, Merck Sharpe & Dohme, Roche, and Novartis. DAP reports personal fees from Eisai. MSH reports grants and receipt of equipment, materials, drugs, medical writing, gifts, or other services from the Prostate Cancer Foundation, NHRMC, Movember, US Department of Defense, Medical Research Future Fund, Bayer, Peter MacCallum Foundation, Isotopia, and the Australian Nuclear Science and Technology Organisation; consulting fees from Merck Sharp & Dohme and Novartis; honoraria from Janssen, Novartis, and AstraZeneca; and support for meetings from Merck Sharp & Dohme, Novartis, Janssen, AstraZeneca, and Astellas. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations., Methods: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m 2 on day 1 and either plinabulin (30 mg/m 2 ) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed., Findings: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group., Interpretation: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population., Funding: BeyondSpring Pharmaceuticals., Competing Interests: Declaration of interests TF received research funding from BeyondSpring Pharmaceuticals to conduct this trial and is a speaker for Sanofi and Sobi. CH received research funding from BeyondSpring Pharmaceuticals to conduct this trial. GHK is President of Kentucky Society of Oncology and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from BMS, Genentech, AstraZeneca, Regeneron, Guardant, EMD Serono, and Novartis; consulting fees from BMS, Genentech, AstraZeneca, Regeneron, and Guardant; and payment for participation on a data safety monitoring board or advisory board from BMS, Genentech, AstraZeneca, and Regeneron. LB has received research support from Beyondspring and consulting fees from Sanofi, Gilead, Pfizer, Boehringer Ingelheim, Neuvogen, Bayer, BioAtla, Daichi, Summit, Anheart, Merck, Abbvie, Regeneron, Janssen, Genentech, Novocure, InterVenn, Elevation Oncology, Turning Point, and Novartis; and has participated on data safety monitoring board or advisory boards for ORIC Pharmaceuticals. JZ, ZJ, BH, FY, ZL, YSu, and JS have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from MSD, BeiGene, Roche, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Programmed cell death-1 (PD-1) blockade improves survival in patients with advanced esophageal squamous cell carcinoma (ESCC). However, the efficacy of taxanes after exposure to PD-1 blockade remains unclear in patients with advanced ESCC., Methods: We retrospectively analyzed the clinical outcomes of advanced ESCC patients treated with taxanes (paclitaxel or docetaxel) with/without prior exposure to PD-1 blockade (Exposed /Naïve group) at National Cancer Center Hospital from June 2016 to December 2020., Results: Ninety-nine patients (Exposed group, n = 32; Naïve group, n = 67) were included. The objective response rate (ORR) of the Exposed group was significantly higher than that of the Naïve group (37.5% vs. 13.4%, p = 0.009). The median progression-free survival was similar between the Exposed and Naïve groups (3.8 vs. 2.8 months, HR 1.12, 95% CI 0.65-1.86, p = 0.66). PD-1 blockade exposure independently predicated higher ORR to taxanes in multivariate analysis. Grade ≥ 3 adverse events were comparable between the Exposed and Naïve groups (45.8% vs. 40.3%, p = 0.64)., Conclusions: Taxanes following PD-1 blockade in advanced ESCC showed a higher ORR but similar PFS compared to taxanes without prior PD-1 exposure., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear., Methods: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI)., Results: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts., Conclusions: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC., Competing Interests: Disclosure Loana Valenca received consulting fees from Janssen and travel grants from Janssen, Astellas, and Bayer. The other authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: To evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ZRC-3277 (pertuzumab biosimilar) with Perjeta® (pertuzumab) in previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)., Patients and Methods: This phase III, multicenter, double-blind study across 38 sites in India randomized (1:1) patients with HER2-positive MBC in either the ZRC-3277 or Perjeta® group. Both groups also received trastuzumab and docetaxel. Of 268 enrolled patients, mITT population had 243 patients (119 and 124 in the ZRC-3277 and Perjeta® groups, respectively). The primary objective was to compare the between-group objective response rate (ORR) after 6 cycles of treatment. ORR was determined by evaluating scans of computed tomography or magnetic resonance imaging following Response Evaluation Criteria in Solid Tumor (RECIST 1.1). Two-sided 95% confidence interval (95% CI) for the difference in ORR was determined to evaluate the noninferiority of ZRC-3277 to Perjeta®. The secondary outcomes included the assessment of PK, immunogenicity, and safety between the 2 groups., Results: In the mITT population, 104 (87.39%) and 114 (91.94%) participants achieved the ORR in the ZRC-3277 and Perjeta® groups, respectively. For predefined -15% noninferiority margin, obtained 2-sided 95% CIs (-12.19%, 3.11%) for the difference in ORR (-4.55%) between the 2 groups demonstrated the noninferiority of ZRC-3277 to Perjeta®. PK, immunogenicity, and safety were not significantly different between the 2 groups., Conclusion: Efficacy, PK, immunogenicity, and safety profiles of ZRC-3277 was found to be similar to those of Perjeta®., Competing Interests: Disclosure Deven Parmar is an employee of Zydus Therapeutics Inc, USA, whereas Maulik Doshi and Rahul Shrivastava are employees of Zydus Lifesciences Ltd. All other authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown., Methods: We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital., Results: Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0-NA] and 10.0 months (95% CI 6.3-15.6), respectively. Median OS [not reached (95% CI 31.5-NA) vs. 21.4 months (95% CI 13.5-33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4-NA) vs. 7.4 months (95% CI 6.0-12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%)., Discussion: The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival., (© 2024. The Author(s).)

Objective: Radical cystectomy (RC) is the standard of care (SOC) in BCG-unresponsive NMIBC and is associated with a significant health-related quality-of-life burden. Recently, promising results have been published on Gemcitabine/Docetaxel, Pembrolizumab, and Hyperthermic Intravesical Chemotherapy (HIVEC) as salvage therapy options trying to increase the rate of bladder preservation. Here, we performed a Cost-Effectiveness-Analysis of those treatment modalities., Patients and Methods: We developed a Markov model from a payer's perspective drawing on clinical data of single-arm trials testing intravesical gemcitabine/docetaxel and pembrolizumab in BCG-unresponsive NMIBC, as well as clinical data from patients receiving hyperthermic intravesical chemotherapy HIVEC (n = 29) as intravesical salvage chemotherapy at our uro-oncological centre in Cologne. Costs were simulated utilising a non-commercial diagnosis-related groups grouper, utilities were derived from comparable cost-effectiveness studies. We used a Monte Carlo simulation to identify the optimal treatment, comparing the incremental cost effectiveness ratios (ICERs) at a willingness-to-pay threshold of €50 000 (euro)/quality-adjusted life year (QALY)., Results: Over a horizon of 10 years, gemcitabine/docetaxel, HIVEC, and pembrolizumab were associated with costs of €48 353, €64 438, and €204 580, as well as a gain of QALYs of 6.16, 6.48, and 6.00, resulting in an ICER of €26 482, €42 567, and €184 533 respectively, in comparison to RC with total costs of €21 871 and a gain of QALYs of 5.01. Monte Carlo simulation identified HIVEC as the treatment of choice under assumption of a WTP of <€50 000., Conclusion: Considering a WTP of <€50 000/QALY, gemcitabine/docetaxel and HIVEC are highly cost-effective therapeutic options in BCG-refractory NMIBC, while RC remains the cheapest option. At its current price, pembrolizumab would only be cost-effective assuming a price reduction of at least 70%., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive cancer-related disease with a dismal clinical course. The patient in this report was a 43-year-old man with metastatic salivary duct carcinoma arising from the parotid gland. Combined androgen blockade therapy was administered started as first-line treatment, but failed after 5 months, followed by docetaxel plus carboplatin therapy as second-line treatment, which failed after 3 months. Genomic profiling revealed a BRAF V600E mutation, and combined BRAF and MEK inhibitor therapy was started as third-line treatment. The cancer remained stable during the first 10 months of third-line treatment, but treatment was subsequently discontinued due to the onset of symptoms of fatigue, myalgia and arthritis. Twenty days after the onset of these symptoms and interruption of third-line treatment, the patient was urgently admitted to hospital with respiratory distress and severe thrombocytopenia. CT images at the time of admission led our radiologist to the possibility of PTTM, but the patient died the day after admission and autopsy findings indicated that PTTM was the cause of death. This report describes a very informative case of PTTM with sequential imaging and detailed autopsy findings were available and provides a literature review., Competing Interests: Declaration of competing interest Three of the authors (Yoshitaka Honma, Ken Kato, Masahiko Kusumoto) declare the following financial interests/personal relationships which may be considered as potential competing interests: 1) Yoshitaka Honma has received compensation as a member of the advisory role of Janssen, Eisai, and Rakuten Medical Japan; received honoraria from Novartis, Chugai pharma, MSD, Ono pharmaceutical, Bristol Myers Squibb, Merck Biopharma, Eisai, Eli Lilly, Nutri, Teijin pharma, Bayer, and Taiho pharmaceutical; and received research funding from Taiho pharmaceutical, Chugai pharma, MSD, GlaxoSmithKline, Janssen, Adlai Nortye Biopharma, Maruho, Merck Biopharma, Genmab, Astellas pharma, Rakuten Medical Japan, and AstraZeneca. 2) Ken Kato reports funding to the institution from Merck Sharp & Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai. 3) Masahiko Kusumoto received honoraria for lecture fees from Daiichi-Sankyo Co.,Ltd. Masahiko Kusumoto received a research grant from Canon medical systems corporation., (Copyright © 2024. Published by Elsevier B.V.)

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Proton pump inhibitors (PPIs) are widely used due to their affordability and minimal severe side effects. However, their influence on the efficacy of cancer treatments, particularly androgen receptor signaling inhibitors (ARSIs), remains unclear. This study investigates the impact of PPI usage on the treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: A total of 117 mCRPC patients were retrospectively analyzed and divided into two groups based on the concomitant use of PPI at the initiation of ARSI treatment: PPI+ (n = 38) and PPI- (n = 79). Patient characteristics, including age at ARSI treatment administered, prostate-specific antigen (PSA) value at ARSI treatment administered, International Society of Urological Pathology grade group at prostate biopsy, metastatic site at ARSI treatment administered, prior docetaxel (DTX) treatment, and type of ARSI (abiraterone acetate or enzalutamide) were recorded. Progression-free survival (PFS), overall survival (OS), and PSA response rates were compared between the two groups. Patients were further stratified by clinical background to compare PFS and OS between the two groups., Results: The PPI- group exhibited significantly extended PFS and a trend toward improved OS. For PSA response (reduction of 50% or more from baseline), the rates were 62.3% and 45.9% in the PPI- group and the PPI+ group, respectively. For deep PSA response (reductions of 90% or more from baseline), the rates were 36.4% and 24.3% in the PPI- group and the PPI+ group, respectively. The effects were consistent across subgroups divided by prior DTX treatment and type of ARSI administered., Conclusions: The administration of PPIs appears to diminish the therapeutic efficacy of ARSIs in mCRPC patients. Further prospective studies are needed to confirm these findings and explore the biological mechanisms involved., (© 2024 Wiley Periodicals LLC.)

Background and Objective: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes., Methods: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses., Key Findings and Limitations: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups., Conclusions and Clinical Implications: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data., Methods: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr., Results: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors., Conclusion: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Docetaxel is commonly used for treatment of castration-resistant prostate cancer. Unfortunately, many prostate cancer patients develop resistance to docetaxel. Clinical markers less invasive than biopsies, such as blood samples, would be ideal for monitoring and predicting patient treatment outcomes to docetaxel. Lipid alterations are often associated with the progression of many cancers, including prostate cancer. This study investigated the use of lipids from whole blood as clinical markers for docetaxel resistance in a small cohort of patients with prostate cancer. Qualitative lipidomics was performed by liquid chromatography-tandem mass spectrometry to assess the lipid composition of prostate cancer cells exposed to docetaxel as well as whole blood from prostate cancer patients before, during and after docetaxel treatment. Three patients had castration resistant prostate cancer, three had castration sensitive prostate cancer, and four had de novo prostate cancer during the extent of the study. Mean decrease accuracy and classical univariate receiving operating characteristic curve analyses were performed to identify potential biomarkers. In total, 245 and 221 altered lipids were identified from a second stage of mass spectrometry analysis of prostate cancer cells and clinical blood samples, respectively. Both models indicated that docetaxel treatment altered ether-linked phosphatidylcholines, lysophosphatidylcholine, diacylglycerols, ceramides, hexosylceramides, and sphingomyelins. The results also indicated several lipid changes were associated with sphingolipid signaling and metabolism, and glycerophospholipid metabolism. Collectively, these data suggest the potential usage of identified lipid species as indicators of docetaxel resistance in prostate cancer., (© 2024. The Author(s).)

Docetaxel is a commonly used taxane chemotherapeutic agent in the treatment of a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer. Docetaxel exerts its anti-cancer effects through inhibition of the cell cycle and induction of proapoptotic activity. However, docetaxel also impacts rapidly proliferating normal cells in the scalp hair follicles (HFs), rendering the HFs vulnerable to docetaxel-induced cell death and leading to chemotherapy-induced alopecia (CIA). In severe cases, docetaxel causes persistent or permanent CIA (pCIA) when hair does not grow back completely six months after chemotherapy cessation. Hair loss has severe negative impacts on patients' quality of life and may even compromise their compliance with treatment. This review discusses the notable prevalence of docetaxel-induced CIA and pCIA, as well as their prevention and management. At this moment, scalp cooling is the standard of care to prevent CIA. Treatment options to promote hair regrowth include but are not limited to minoxidil, photobiomodulation (PBMT), and platelet-rich plasma (PRP). In addition, a handful of current clinical trials are exploring additional agents to treat or prevent CIA. Research models of CIA, particularly ex vivo human scalp HF organ culture and in vivo mouse models with human scalp xenografts, will help expedite the translation of bench findings of CIA prevention and/or amelioration to the clinic.

For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ethnopharmacological Relevance: Traditional Chinese Medicines (TCMs) have emerged as a promising complementary therapy in the management of prostate cancer (PCa), particularly in addressing resistance to Docetaxel (DTX) chemotherapy., Aim of the Review: This review aims to elucidate the mechanisms underlying the development of resistance to DTX in PCa and explore the innovative approach of integrating TCMs in PCa treatment to overcome this resistance. Key areas of investigation include alterations in microtubule proteins, androgen receptor and androgen receptor splice variant 7, ERG rearrangement, drug efflux mechanisms, cancer stem cells, centrosome clustering, upregulation of the PI3K/AKT signaling pathway, enhanced DNA damage repair capability, and the involvement of neurotrophin receptor 1/protein kinase C., Materials and Methods: With "Prostate cancer", "Docetaxel", "Docetaxel resistance", "Natural compounds", "Traditional Chinese medicine", "Traditional Chinese medicine compound", "Medicinal plants" as the main keywords, PubMed, Web of Science and other online search engines were used for literature retrieval., Results: Our findings underscore the intricate interplay of molecular alterations that collectively contribute to the resistance of PCa cells to DTX. Moreover, we highlight the potential of TCMs as a promising complementary therapy, showcasing their ability to counteract DTX resistance and enhance therapeutic efficacy., Conclusion: The integration of TCMs in PCa treatment emerges as an innovative approach with significant potential to overcome DTX resistance. This review not only provides insights into the mechanisms of resistance but also presents new prospects for improving the clinical outcomes of patients with PCa undergoing DTX therapy. The comprehensive understanding of these mechanisms lays the foundation for future research and the development of more effective therapeutic interventions., Competing Interests: Declaration of competing interest We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. All authors have approved the manuscript and agree with submission to your esteemed journal., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD., Methods: In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period., Results: All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated., Conclusion: The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073)., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study., Results: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X 2  = 9.14, p < 0.05) and those below the age of 18 (X 2  = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models., Conclusion: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: The high costs of cancer care can cause significant harm to patients and society. Prostate cancer, the leading nonskin malignancy in men, is responsible for the second-highest out-of-pocket (OOP) payments among all malignancies. Multiple first-line treatment options exist for metastatic castration-resistant prostate cancer (mCRPC); although their costs vary substantially, comparative effectiveness data are limited. There is little evidence of how gross payments made by insurers and OOP payments made by patients differ by treatment and health plan type and how these payment differences relate to utilization., Study Design: Retrospective cohort study., Methods: We used IBM MarketScan databases from 2013-2019 to identify men with prostate cancer who initiated treatment with 1 of 6 drugs approved for first-line treatment of mCRPC. We calculated and compared gross and OOP payments and drug utilization across drug and insurance plan types., Results: We identified 4298 patients who met our inclusion criteria. Insurer payments varied substantially by first-line therapy but were similar across different health plan types, except for docetaxel. OOP payments for a given first-line therapy, in contrast, varied by health plan type. Utilization of first-line therapies varied by plan type in unadjusted analyses, but not after adjusting for patient characteristics., Conclusions: The extent to which patient OOP payments for drugs reflect differences in gross payments made by insurers varies across health insurance plan types. However, even though OOP payments for the same treatment differ across plan types, treatment choice is not significantly different across type of health insurance after controlling for patient characteristics.

Primary ovarian sarcoma is a rare malignancy, with primary ovarian leiomyosarcoma being even rarer because of the lack of smooth muscle in the ovaries. We herein report a case of primary ovarian leiomyosarcoma in a woman in her late 50s who presented with a 6-month history of abdominal pain. Imaging revealed a pelvic mass. The patient underwent surgery and was diagnosed with ovarian leiomyosarcoma. One month postoperatively, she began gemcitabine and docetaxel chemotherapy and continued this treatment for 6 months. Eight months postoperatively, however, recurrence was detected in the pelvic cavity. This case is reported with the aim of raising awareness about this rare disease., Competing Interests: Declaration of conflicting interestThe authors declare that they have no conflict of interest regarding the publication of this research.

Background: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer., Materials and Methods: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab)., Results: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups., Conclusion: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

Background: Guidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce., Methods: A secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method., Results: Median follow-up (f/u) for all patients was 23 months (IQR 13-34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months)., Conclusions: Gem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results., Competing Interests: Declaration of competing interest I affirm that none of the authors have a conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: ARASENS was a randomized, double-blind, phase 3 trial comparing darolutamide + docetaxel + androgen deprivation therapy (ADT) with placebo + docetaxel + ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC)., Objective: To use clinical trial data from ARASENS to understand whether the addition of darolutamide to docetaxel + ADT leads to increased hospitalizations and to estimate the budget impact on the US health care system., Methods: We used mixed-effects negative binomial regression to estimate hospitalization and intensive care unit (ICU) admission rates and length of hospital stay (LoHS) counts. Hospitalization rates were estimated per treatment arm for the period during and after administration of docetaxel. Based on these estimates, a budget impact analysis evaluated the hospitalization costs (including ICU admissions) and standalone ICU hospitalization costs for the totality of the US population over a 5-year time horizon. The analysis compared a scenario without darolutamide vs one with darolutamide included in the US payer formulary. Hospitalization estimates were varied in a one-way sensitivity analysis., Results: The first 4 months of treatment (when patients were receiving docetaxel) were associated with increased hospitalizations across both arms. The addition of darolutamide was associated with a numerical reduction in the rate of hospitalization (per year) due to any reason both during docetaxel treatment (1.01 visits per year [95% CI = 0.82-1.20] vs 1.18 visits per year [95% CI = 0.96-1.41]) and after docetaxel treatment (0.28 visits per year [95% CI = 0.23-0.34] vs 0.33 visits per year [95% CI = 0.27-0.40]). Darolutamide was associated with a marginally longer LoHS per hospitalization compared with placebo (+1.90 days per year) both during and after docetaxel treatment. ICU admissions were low in the ARASENS data; admission rates were assumed to be the same during and after docetaxel treatment. ICU admission rate estimates were equivalent across arms (0.02 visits per year [95% CI = 0.01-0.03]). The budget impact per treated member per month represents a cost-neutral option after Year 5 with a cumulative budget impact of -$9.71., Conclusions: The addition of darolutamide to docetaxel + ADT was associated with a numerically lower rate of hospitalization but marginally longer LoHS compared with docetaxel + ADT alone. Darolutamide represents a cost-neutral alternative per treated member per month compared with docetaxel + ADT with regard to hospitalizations at the end of a 5-year time horizon.

Purpose: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC., Methods: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR)., Results: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients., Conclusion: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence., (© 2024. The Author(s).)

Background/aim: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification., Patients and Methods: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated., Results: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of castration-resistance was also long and significantly longer in the undetectable PSA group than that in the detectable PSA group (median: 124 vs. 17 months, HR=0.20, 95% CI=0.12-0.34, p<0.001)., Conclusion: Patients with low-risk and/or low-volume mCSPC showed long-term survival when undetectable PSA was achieved during conventional ADT. In these patients, skipping upfront treatment intensification does not seem to negatively impact survival., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The aim of this study was to observe the therapeutic effect of sintilimab combined with a modified docetaxel + cisplatin + fluorouracil (DCF) regimen on advanced gastric cancer and its effect on Th1/Th2 immune balance. Ninety-eight cases of advanced gastric cancer patients who visited our hospital from April 2020 to May 2022 were selected and divided into 48 cases each in the conventional group and the research group by random number table method; the DCF regimen was adopted in the conventional group, and sintilimab combined with modified DCF regimen was adopted in the research group, and the therapeutic effects of the patients in the two groups and the changes of Th1/Th2 immune indexes were compared. CEA, CA199, CA242, CD168 AQ3, and IL-4 in the study group were lower than those in the conventional group at the end of three cycles of treatment, and the difference was statistically significant ( P  < 0.001). The levels of IFN-γ and IL-4 in the study group at the end of three cycles of treatment were higher than those in the conventional group ( P  < 0.001). The incidence of adverse reactions during treatment in the study group was lower than that in the conventional group ( P  < 0.001), and the grading of adverse reactions in the study group was milder than that in the conventional group. Sintilimab combined with a modified DCF regimen in the treatment of advanced gastric cancer not only improves the therapeutic effect but also positively affects the Th1/Th2 immune balance, which provides better immune regulation for patients with advanced gastric cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults., Methods: We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed., Results: Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3)., Conclusions: Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy., (© 2024 The Author(s). Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: Radiation associated angiosarcoma (RAAS) of the breast is a rare malignancy with poor survival. Optimal treatment strategies remain uncertain due to a lack of data, and vary between surgery alone and a combination of surgery with (neo)adjuvant chemotherapy (NACT) and/or re-irradiation. The aim of this study was to evaluate the potential benefit of taxane based NACT., Methods: In this retrospective single center study, all patients with RAAS of the breast treated between 1994 and 2024 are included. Since 2018, NACT is considered a treatment option for this patient population in our institute. The difference in oncological outcomes of patients with and without NACT were compared., Results: Thirty-five women were included. Thirteen (37 %) received NACT of which five (39 %) also had neoadjuvant re-irradiation with hyperthermia. Eleven patients (85 %) received paclitaxel, the other two (15 %) had doxorubicine/docetaxel. Complete pathological response was found in 69 % (n = 9). Median follow up was 41 months (range 24-56) for patients with NACT and 44 (range 20-108) for patients without NACT. In the NACT group, only one patient developed a recurrence after 6.5 years. Patients with NACT had improved oncological outcomes compared to patients without NACT in terms of 3-year local recurrence free survival (100% vs. 63.9 %, p = 0.14), distant metastasis free survival (100 % vs. 47.5 %, p = 0.005), and overall survival (100% vs. 56.1 %, p = 0.016)., Conclusion: In this study, neoadjuvant taxanes for RAAS of the breast leads to improved distant metastasis free survival and overal survival in patients treated with NACT compared to no NACT., Competing Interests: Declaration of competing interest N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, Luszana. N Steeghs received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, Merck Sharp & DohmeMerck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. W. van der Graaf: Advisory boards SpringworkTx, Agenus and PTC Therapeutics (all to the institute) and research grants from Eli Lilly (to the Institute). W. van Houdt: advisory boards of Amgen, Boehringer Ingelheim, Sanofi, Novartis, Sirius Pintuition, Belpharma. All payment to the Netherlands Cancer Institute., (Copyright © 2024. Published by Elsevier Ltd.)

Visual predictive checks (VPC) are commonly used to evaluate pharmacometrics models. However their performance may be hampered if patients with worse outcomes drop out earlier, as often occurs in clinical trials, especially in oncology. While methods accounting for dropouts have appeared in literature, they vary in assumptions, flexibility, and performance, and the differences between them are not widely understood. This manuscript aims to elucidate which methods can be used to handle VPC with dropout and when, along with a more informative VPC approach using confidence intervals. Additionally, we propose constructing the confidence interval based on the observed data instead of the simulated data. The theoretical framework for incorporating dropout in VPCs is developed and applied to propose two approaches: full and conditional. The full approach is implemented using a parametric time-to-event model, while the conditional approach is implemented using both parametric and Cox proportional-hazard (CPH) models. The practical performances of these approaches are illustrated with an application to the tumor growth dynamics (TGD) modeling of data from two cancer clinical trials of nivolumab and docetaxel, where patients were followed until disease progression. The dataset consisted of 3504 tumor size measurements from 855 subjects, which were described by a TGD model. The dropout of subjects was described by a Weibull or CPH model. Simulated datasets were also used to further illustrate the properties of the VPC methods. The results showed that the more familiar full approach might not provide meaningful improvement for TGD model evaluation over the naive approach of not adjusting for dropout, and could be outperformed by the conditional approach using either the Weibull model or the Cox proportional hazard model. Overall, including confidence intervals in VPC should improve interpretation, the conditional approach was shown to be more generally applicable when dropout occurs, and the nonparametric approach could provide additional robustness., Competing Interests: Declarations. Competing interest: C. Hu, and A. Kondic, are employees of Bristol Myers Squibb and own stock/stock options. A. Roy is an employee of PumasAI., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In metastatic hormone-sensitive prostate cancer (mHSPC), androgen deprivation therapy and standard of care treatment intensification with docetaxel and/or an androgen receptor signaling inhibitor (ARSI) are associated with improved survival outcomes for appropriate patients., Methods: This retrospective study selected patients with de novo mHSPC diagnosed between 2014 and 2023 from CancerLinQ Discovery®, a United States (US)-based, de-identified clinical database. Patient-level data, including clinical characteristics, treatments, and demographics, were collected from CancerLinQ. Treatment intensification was defined as the use of docetaxel, abiraterone, apalutamide, enzalutamide, or docetaxel plus abiraterone or darolutamide. Patient characteristics and treatment intensification data were analyzed descriptively and using multivariable logistic regression., Results: Of the 3,684 patients with mHSPC, the overall rate of treatment intensification was 58.4% but increased from 32.5% in 2014 to 67.5% in 2023. A relative decline in docetaxel use was accompanied by an increase in ARSI use. Black patients with mHSPC were less likely to receive treatment identification (OR 0.78, 95% CI 0.64-0.95, P = 0.013). Treatment intensification was also less likely for patients of older age and increased ECOG performance status. Despite increasing treatment intensification for Black patients with mHSPC over time, rates of docetaxel use are disproportionately declining relative to White patients., Conclusions: Treatment intensification rates are increasing to include the majority of patients with mHSPC. However, treatment disparities exist for Black patients, who are less likely to receive intensification. These findings illustrate the importance of promoting treatment intensification in appropriate patients and addressing racial treatment disparities., Competing Interests: Declaration of competing interest CJE, EMK, TPR, and SPK have no relevant conflicts of interest to disclose. TWF reports leadership, stock, and other ownership interests in Aurora Oncology; consulting for Seagen and Janssen Oncology; research funding from Novartis, Bavarian Nordic, Dendreon, GTx Janssen Oncology, Medication, Sanofi, Pfizer, Bristol-Myers Squibb, Roche/Genentech, Exelixis, Aragon Pharmaceuticals, Sotio, Tokai Pharmaceuticals, Atrazeneca/MedImmune, Lilly, Astellas Pharma, Agensys, Seagen, La Rocher-Posay, Merck, Seagen, Myovant Sciences, and Criterium; and patents, royalties, and other intellectual property related to 2 patents filed by the University of Colorado related to early-stage bladder cancer treatment and detection (not currently commercialized or in active clinical development)., (Copyright © 2024. Published by Elsevier Inc.)

Background: The relative occurrence of infection in patients treated with cytotoxic chemotherapeutic drugs and molecularly targeted drugs is unclear., Aim: To compare the occurrence of respiratory and urinary tract infections in patients treated for lung cancer with docetaxel versus afatinib and to predict the occurrence of the respiratory and urinary tract infections., Method: Data on patients who received docetaxel or afatinib were obtained from a health insurance claims database. After propensity score matching, the occurrence of respiratory and urinary tract infections in each group was compared. Factors associated with respiratory and urinary tract infections were evaluated using multivariable conditional logistic regression analysis., Results: Each group included 855 patients. The occurrence of respiratory infections was significantly higher in the docetaxel group than in the afatinib group (22.6% [193/855] vs. 13.9% [119/855]; p < 0.01). The occurrence of urinary tract infections did not differ significantly by group. Docetaxel was independently associated with a significantly increased risk of respiratory infections (adjusted odds ratio: 1.68, 95% confidence interval: 1.23-2.29), but not urinary tract infections., Conclusion: Patients with lung cancer treated with docetaxel should be closely monitored for the occurrence of respiratory infection in clinical settings., Competing Interests: Conflicts of interest The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)