Therapeutic Advances in Medical Oncology最新文献

Bladder cancer was the 10th most commonly diagnosed cancer worldwide in 2020. Extracellular vesicles (EVs) are nano-sized membranous structures secreted by all types of cells into the extracellular space. EVs can transport proteins, lipids, or nucleic acids to specific target cells. What brings more attention and potential implications is the fact that cancer cells secrete more EVs than non-malignant cells. EVs are widely studied for their role in cancer development. This publication summarizes the impact of EVs secreted by urinary bladder cancer cells on urinary bladder cancer development and metastasis. EVs isolated from urinary bladder cancer cells affect other lower-grade cancer cells or normal cells by inducing different metabolic pathways (transforming growth factor β/Smads pathway; phosphoinositide 3-kinase/Akt pathway) that promote epithelial-mesenchymal transition. The cargo carried by EVs can also induce angiogenesis, another critical element in the development of bladder cancer, and modulate the immune system response in a tumor-beneficial manner. In summary, the transfer of substances produced by tumor cells via EVs to the environment influences many stages of tumor progression. An in-depth understanding of the role EVs play in the development of urinary bladder cancer is crucial for the development of future anticancer therapies.

Background: Sorafenib is a first-line treatment option for patients with hepatocellular carcinoma (HCC). However, the impact of sorafenib resistance type on patient survival prediction and choice of second-line treatment regimen is unknown.

Objectives: This study aims to explore the factors predicting resistance in patients with HCC receiving sorafenib, the impact of resistance on survival, and the optimal second-line treatment regimen.

Design: This was a retrospective cohort study.

Methods: We recruited all patients with advanced HCC who received first-line sorafenib from January 2019 to January 2023 in two medical centers in China. They were divided into primary and secondary resistance groups according to tumor progression within 3 months. Resistance was the primary outcome of this study. The secondary outcomes were progression-free survival (PFS) and overall survival (OS).

Results: A total of 424 patients met the inclusion criteria, including 165 patients (38.9%) in the primary group and 259 patients (61.1%) in the secondary group. The independent risk factors for primary resistance were alpha-fetoprotein (AFP) > 400 ng/mL and alanine aminotransferase (ALT) > 40 U/L. Patients in the primary group had significantly shorter median OS than those in the secondary group (9.0 months vs 23.0 months, p < 0.001). Compared with tyrosine kinase inhibitor (TKI) monotherapy, the use of TKI plus PD-1 inhibitor combination therapy as second-line treatment conferred a longer median PFS (6.0 vs 10.0 months, p < 0.001) and OS (13.0 vs 22.0 months, p < 0.001).

Conclusion: Sorafenib has a high incidence of primary resistance and short survival in patients who develop primary resistance. AFP and ALT are influential factors in primary resistance, and it is valuable to use these two metrics to guide the use of sorafenib. As second-line therapy, a TKI plus PD-1 inhibitor regimen should be preferentially recommended.

Objectives: A combination of chemotherapy and radiotherapy is employed in the curative and postoperative treatment of locally advanced head and neck cancers (HNC). Integrated chemoradiation (CRT) treatments result in a non-negligible rate of severe toxic effects. Treatment-related death (TRD) is a crucial topic for physicians involved in the curative treatment of HNC. This meta-analysis aimed to better address TRD in locally advanced HNC patients treated with CRT through available and relevant literature.

Methods: We performed a systematic review of the literature according to the PRISMA statement. The studies fulfilling these criteria included the following: concurrent or alternating CRT; both radical and postoperative settings; published from 2000 to 2020; involving 100+ patients; and available toxicity data. TRD was defined as death occurring from CRT start until a month from the end of CRT. Potential TRD predictors were evaluated.

Results: In all, 65 studies were retrieved, with a total of 235 TRDs reported accounting for an overall risk rate of 1.4%. At meta-regression analysis, T stage and neutropenia grade >3 were potential predictors of higher TRD risk, both in univariate and multivariate analyses. Considering only the studies reporting at least one event, laryngeal/hypopharyngeal, oral cavity subsites and renal failure were significant predictors for TRD. The oropharyngeal subsite was protective in both analyses. None of the predictors proved to be independently correlated with TRD at multivariable analysis.

Conclusion: CRT in HNC resulted in 1.4% of TRDs. TRD rate reduction may imply better patient selection and more intensive supportive care programs.

Introduction: Desmoid tumors are soft-tissue neoplasms that can have profound impacts on the lives of people living with such diseases. As they are rare tumors, patients often have difficulty finding teams specialized in sarcomas and support networks. In low- and middle-income countries, the challenges are exacerbated due to a need for established networks and medication access.

Discussion: In this setting, patient advocacy groups are important in supporting affected people. To this end, the Desmoid Tumor Brazilian Association (DTBA) was established to help mitigate those challenges. This paper highlights the perspectives of patients with desmoid tumors living in Brazil, obtained in a nationwide survey, and discusses aspects related to access to specialists, medications, education, and awareness in Brazil.

Conclusions: The most commonly reported challenges in Brazil are access to educational material and specialists. The DTA continues to strive to improve support for people living in Brazil through initiatives such as Scientific and Educational Meetings, improving awareness, fostering science, and working on methods to facilitate access to medication and specialists.

Recently, attention has increasingly centered on non-small-cell lung cancer (NSCLC) with immune checkpoint inhibitors application. Numerous clinical studies have underscored the potential of immunotherapy in treating resectable NSCLC, highlighting its role in improving patient outcomes. However, despite these promising results, there is ongoing debate regarding the efficacy of immunological combination therapy strategies, the prevalence of treatment-related side effects, the identification of predictive biomarkers, and various other challenges within the neoadjuvant context. Careful consideration is essential to maximize the benefits of immunotherapy for patients with resectable NSCLC. This article offers a detailed overview of recent advancements in neoadjuvant immunotherapy for resectable NSCLC. By examining these developments, we aim to provide new perspectives and valuable insights into the benefits and challenges of applying neoadjuvant immunotherapy in clinical settings.

Treatment with pegylated nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (folinic acid; 5-FU/LV) has demonstrated remarkable efficacy for metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical trials. However, real-world data on the effectiveness of nal-IRI+5-FU/LV is heterogeneous and is lacking in Spain. To assess the effectiveness and safety of nal-IRI+5-FU/LV in real-life PDAC patients in Spain. A multicenter retrospective study was conducted. Patients aged ⩾18 years who had received at least one cycle of nal-IRI+5-FU/LV as second- or third-line therapy for PDAC were included. The primary endpoint was overall survival (OS) from nal-IRI+5-FU/LV treatment initiation and OS from the diagnosis of metastatic disease (metOS). Overall, 200 evaluable patients were included (⩾3 metastatic sites: 22%; liver/lung metastases: 71.5%/36.9%; and Eastern Cooperative Oncology Group 0-1: 87% at nal-IRI+5FU/LV treatment initiation). Patients received a median of four cycles of nal-IRI+5FU/LV for 2.8 months (range 1.4-7.2), and the treatment was received in the second line by 80% of the patients. The median OS was 7.2 months (6- and 12-month OS rates: 58.1% and 28.9%, respectively), with 27.2% of the patients achieving OS ⩾12 months. The median metOS was 17.5 months, with 30.2% of the patients experiencing metOS ⩾ 24 months. The median progression-free survival (PFS) was 3.7 months (6- and 12-month PFS rate: 37.6% and 15.3%, respectively). The disease control rate was 35.5%. The median CA 19-9 levels decreased by at least 50% in 28.2% of the cases during treatment. Overall, 36% of the patients experienced at least one grade 3-4 adverse event during treatment, the most common being diarrhea (42.6%) and asthenia (30.9%). This real-world study shows that treatment with nal-IRI+5-FU/LV for advanced or metastatic PDAC affords benefit in terms of survival, radiological and CA 19-9 response, and PFS comparable to that reported in the clinical trial setting with a manageable safety profile.

Background: Encorafenib plus cetuximab (EC) is the standard of care for pre-treated BRAF ^V600E mutated metastatic colorectal cancer (mCRC). Depth of response (DpR) and early tumour shrinkage (ETS) previously showed a strong correlation with survival outcomes of first-line chemotherapy ± biological agents.

Objectives: We aimed to assess potential predictors of primary resistance to EC ± binimetinib (B) and relationships of DpR/ETS with survival outcomes and clinical characteristics.

Design: This is a retrospective real-world cohort study of BRAF ^V600E mutated mCRC patients treated with second-line EC ± B at 20 Italian centres.

Methods: Measurable disease according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 at baseline and at least one subsequent computed tomography (CT) scan were mandatory for inclusion. Clinical features associated with primary resistance, DpR and ETS were investigated. Relationships of DpR and ETS, both as binary, according to conventional (30% for DpR and 20% for ETS) and median cut-off values, and continuous variables, with progression-free (PFS), overall survival (OS) and duration of response (DoR) were assessed in non-primary resistant patients.

Results: A total of 105 patients were included. The primary resistance rate was 28% (29/105) and was associated with baseline peritoneal metastases (p = 0.04). Disease control and overall response rates were 72% (76/105) and 24% (25/105), respectively, with a median DpR of 15% and an ETS rate of 37% (28/76). Mucinous histology was associated with a significantly lower magnitude of DpR (p = 0.005) and a lower rate of ETS (p = 0.002). In the multivariable models, DpR significantly correlated with longer PFS as a dichotomous variable, according both to conventional (hazard ratio (HR)_{DpR ⩾ 30%}: 0.52, 95% CI: 0.30-0.90, p = 0.02) and median cut-off values (HR_DpR⩾15%: 0.55, 95% CI: 0.33-0.92, p = 0.03), and as a continuous variable (HR per 10% increment: 0.88, 95% CI: 0.78-0.98, p = 0.02), while correlations with OS were not confirmed. DpR was also significantly associated with longer DoR (p _DpR⩾30% = 0.04; p _DpR⩾15% = 0.04; p _cont. = 0.02), whereas no relationships of ETS with PFS, OS or DoR were detected.

Conclusion: A DpR of at least 15% independently predicts PFS benefit in BRAF ^V600E mutated mCRC patients treated with second-line EC ± B.

Background: Infiltrative hepatocellular carcinoma (HCC) is often associated with an unfavorable prognosis, posing a challenge in determining the optimal therapeutic approach. Immunotherapy, employing immune checkpoint inhibitors (ICIs), has become a preferred first-line treatment for advanced HCC. However, the overall effectiveness of ICIs in patients with infiltrative HCC remains unclear. This study aims to compare the effect of ICI treatment on clinical outcomes between patients with infiltrative and non-infiltrative HCC.

Materials and methods: A retrospective cohort consisting of unresectable HCC patients who underwent immunotherapy with ICIs, categorized into infiltrative and non-infiltrative groups was studied. Primary outcomes comprised treatment response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, progression-free survival (PFS), and overall survival (OS).

Results: Of 198 patients, 60 (30.3%) had infiltrative HCC, while 138 (69.7%) had non-infiltrative HCC. In the infiltrative group, the objective response rate (ORR) was 36.7% and the disease control rate (DCR) was 55.0%. For the non-infiltrative group, the ORR was 33.3% and the DCR was 56.5%, showing no significant difference between the two groups. However, patients in the infiltrative group had significantly shorter median of PFS and OS following immunotherapy, with a PFS of 4.1 months (95% CI: 2.5-6.7; p = 0.0409) and an OS of 10.4 months (95% CI: 6.7-14.4; p = 0.0268), compared with the non-infiltrative group, which had a PFS of 5.5 months (95% CI: 3.2-7.6) and an OS of 17.0 months (95% CI: 12.8-21.8).

Conclusion: For immunotherapy, infiltrative HCC exhibits treatment responses similar to non-infiltrative HCC. Nonetheless, infiltrative HCC is associated with shorter survival outcomes, compared with non-infiltrative type. Our findings emphasize the essential of considering type discrepancies when developing management strategies for immunotherapy.

Background: Both the antibody-drug conjugate (ADC) enfortumab vedotin (EV) and programmed death-1 inhibitor pembrolizumab have been shown to provide survival benefits in patients previously treated with locally advanced or metastatic urothelial carcinoma (la/mUC). Cost-effectiveness is necessary to consider whether the increased efficacy of the two therapies will lead to higher prices for first-line treatment of previously untreated la/mUC.

Objectives: To guide the choice of EV plus pembrolizumab or chemotherapy for patients with previously untreated la/mUC.

Design: The cost-effective analysis.

Methods: A Markov model was developed to simulate the lifetime of patients with previously untreated la/mUC to assess the overall cost and efficacy of EV plus pembrolizumab and chemotherapy based on the EV-302/KEYNOTE-A39 trial. Primary outcomes included total cost, life-years (LYs), quality-adjusted LYs (QALYs), the incremental cost-effectiveness ratio (ICER), and incremental net health benefits at the USA and Chinese willingness-to-pay threshold of $150,000/QALY and $35,173/QALY, respectively. Model stability was examined through sensitivity and subgroup analyses.

Results: EV plus pembrolizumab and chemotherapy treatment regimens were associated with 2.07-2.16 and 1.04-1.06 QALYs with corresponding costs of $288,347-$532,362 and $24,773-$267,568, respectively. ICERs in the United States and China are $267,491/QALY and $254,339/QALY, respectively. The factors that most strongly influenced model outcomes in unidirectional sensitivity analyses were patient weight and the cost of EV. To achieve greater cost-effectiveness, EV costs would need to be reduced by over 75% and 10% in the United States and China, respectively.

Conclusion: While first-line EV plus pembrolizumab has significant health benefits compared to chemotherapy for patients with previously untreated la/mUC, this regimen is not cost-effective at the current price in the United States or China.

The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. EZH2 is frequently mutated and/or its expression is deregulated in various cancer types. The cancer sensitivity to inhibitors of EZH2 enzymatic activity and state-of-the-art approaches to deplete EZH2 with chemical degraders are discussed. This review also presents the clinical trials in various phases that evaluate the use of EZH2 inhibitors, both as monotherapy and in combination with other agents for the treatment of patients with diverse types of cancers.