Pub Date : 2024-06-12DOI: 10.1016/j.critrevonc.2024.104421
Yazid Belkacemi , Meena S. Moran , Burcu Celet Ozden , Yazan Masannat , Fady Geara , Mohamed Albashir , Nhu Hanh To , Kamel Debbi , Mahmoud El Tamer
Breast reconstruction (BR) after mastectomy is important to consider for a woman’s body image enhancement and psychological well-being. Although post-mastectomy radiation (PMRT) significantly improves the outcome of patients with high-risk breast cancer (BC), PMRT after BR may affect cosmetic outcomes and may compromise the original goal of improving quality of life (QoL). With the lack of practical guidelines, it seems essential to work on a consensus and provide some “expert agreements” to offer patients the best option for PMRT after BR. We report a global “expert agreement” that results from a critical review of the literature on BR and PMRT during the 6th international multidisciplinary breast conference in March 2023.
{"title":"Post-mastectomy radiation therapy after breast reconstruction: from historic dogmas to practical expert agreements based on a large literature review of surgical and radiation therapy considerations","authors":"Yazid Belkacemi , Meena S. Moran , Burcu Celet Ozden , Yazan Masannat , Fady Geara , Mohamed Albashir , Nhu Hanh To , Kamel Debbi , Mahmoud El Tamer","doi":"10.1016/j.critrevonc.2024.104421","DOIUrl":"10.1016/j.critrevonc.2024.104421","url":null,"abstract":"<div><p>Breast reconstruction (BR) after mastectomy is important to consider for a woman’s body image enhancement and psychological well-being. Although post-mastectomy radiation (PMRT) significantly improves the outcome of patients with high-risk breast cancer (BC), PMRT after BR may affect cosmetic outcomes and may compromise the original goal of improving quality of life (QoL). With the lack of practical guidelines, it seems essential to work on a consensus and provide some “expert agreements” to offer patients the best option for PMRT after BR. We report a global “expert agreement” that results from a critical review of the literature on BR and PMRT during the 6th international multidisciplinary breast conference in March 2023.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141322160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.1016/j.critrevonc.2024.104402
Ying-Ying Zhu , Wen-Xuan Wang , Shui-Kit Cheuk , Guan-Rui Feng , Xing-Ge Li , Jia-Ying Peng , Ying Liu , Shao-Rui Yu , Jin-Ling Tang , Shein-Chung Chow , Ji-Bin Li
Background
The use of adaptive designs in cancer trials has considerably increased worldwide in recent years, along with the release of various guidelines for their application. This systematic review aims to comprehensively summarize the key methodological and executive features of adaptive designs in cancer clinical trials.
Methods
A comprehensive search from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted to screen eligible clinical trials that employed adaptive designs and were conducted in cancer patients. The methodological and executive characteristics of adaptive designs were the main measurements extracted. Descriptive analyses, primarily consisting of frequency and percentage, were employed to analyzed and reported the data.
Results
A total of 180 cancer clinical trials with adaptive designs were identified. The first three most common type of adaptive design was the group sequential design (n=114, 63.3 %), adaptive dose-finding design (n=22, 12.2 %), and adaptive platform design (n=16, 8.9 %). The results showed that 4.4 % (n=8) of trials conducted post hoc modifications, and around 29.4 % (n=53) did not provide the methods for controlling type I errors. Among phase II or above trials, 79.9 % (112/140) applied the surrogate endpoint as the primary outcome in these trials. Importantly, 27.2 % (49/180) of trials did not report clear information on the independent data monitoring committee (iDMC), and 13.3 % (n=24) without clear information on interim analyses. Interim analyses suggested 34.4 % (62/180) of trials being stopped for futility, 10.6 % (n=19) for efficacy, and 2.2 % (n=4) for safety concerns in the early stage.
Conclusions
This study emphasizes adaptive designs in cancer trials face significant challenges in their design or strict implementation according to protocol, which might significantly compromise the validity and integrity of trials. It is thus important for researchers, sponsors, and policymakers to actively oversee and guide their application.
背景:近年来,随着各种应用指南的发布,适应性设计在癌症试验中的应用在全球范围内大幅增加。本系统综述旨在全面总结适应性设计在癌症临床试验中的主要方法和执行特点:方法:我们对PubMed、EMBASE和Cochrane对照试验中央登记册进行了全面检索,筛选出符合条件的采用适应性设计并在癌症患者中开展的临床试验。适应性设计的方法和执行特征是提取的主要测量指标。采用描述性分析(主要包括频率和百分比)来分析和报告数据:结果:共发现了 180 项采用适应性设计的癌症临床试验。前三种最常见的适应性设计分别是分组序贯设计(n=114,63.3%)、适应性剂量探索设计(n=22,12.2%)和适应性平台设计(n=16,8.9%)。结果显示,4.4%(8 例)的试验进行了事后修改,约 29.4%(53 例)的试验未提供控制 I 型误差的方法。在二期或二期以上的试验中,79.9%(112/140)的试验将替代终点作为主要结果。重要的是,27.2%(49/180)的试验没有明确报告独立数据监测委员会(iDMC)的信息,13.3%(24)的试验没有明确报告中期分析的信息。中期分析表明,34.4%(62/180)的试验因无效而停止,10.6%(19人)因疗效而停止,2.2%(4人)因早期安全性问题而停止:本研究强调,癌症试验中的适应性设计在设计或严格按照方案实施方面面临巨大挑战,可能会严重影响试验的有效性和完整性。因此,研究人员、申办者和政策制定者必须积极监督和指导其应用。
{"title":"A landscape of methodology and implementation of adaptive designs in cancer clinical trials","authors":"Ying-Ying Zhu , Wen-Xuan Wang , Shui-Kit Cheuk , Guan-Rui Feng , Xing-Ge Li , Jia-Ying Peng , Ying Liu , Shao-Rui Yu , Jin-Ling Tang , Shein-Chung Chow , Ji-Bin Li","doi":"10.1016/j.critrevonc.2024.104402","DOIUrl":"10.1016/j.critrevonc.2024.104402","url":null,"abstract":"<div><h3>Background</h3><p>The use of adaptive designs in cancer trials has considerably increased worldwide in recent years, along with the release of various guidelines for their application. This systematic review aims to comprehensively summarize the key methodological and executive features of adaptive designs in cancer clinical trials.</p></div><div><h3>Methods</h3><p>A comprehensive search from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted to screen eligible clinical trials that employed adaptive designs and were conducted in cancer patients. The methodological and executive characteristics of adaptive designs were the main measurements extracted. Descriptive analyses, primarily consisting of frequency and percentage, were employed to analyzed and reported the data.</p></div><div><h3>Results</h3><p>A total of 180 cancer clinical trials with adaptive designs were identified. The first three most common type of adaptive design was the group sequential design (<em>n</em>=114, 63.3 %), adaptive dose-finding design (<em>n</em>=22, 12.2 %), and adaptive platform design (<em>n</em>=16, 8.9 %). The results showed that 4.4 % (<em>n</em>=8) of trials conducted post hoc modifications, and around 29.4 % (<em>n</em>=53) did not provide the methods for controlling type I errors. Among phase II or above trials, 79.9 % (112/140) applied the surrogate endpoint as the primary outcome in these trials. Importantly, 27.2 % (49/180) of trials did not report clear information on the independent data monitoring committee (iDMC), and 13.3 % (<em>n</em>=24) without clear information on interim analyses. Interim analyses suggested 34.4 % (62/180) of trials being stopped for futility, 10.6 % (<em>n</em>=19) for efficacy, and 2.2 % (<em>n</em>=4) for safety concerns in the early stage.</p></div><div><h3>Conclusions</h3><p>This study emphasizes adaptive designs in cancer trials face significant challenges in their design or strict implementation according to protocol, which might significantly compromise the validity and integrity of trials. It is thus important for researchers, sponsors, and policymakers to actively oversee and guide their application.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141289075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1016/j.critrevonc.2024.104405
Fiorenza Santamaria , Michela Roberto , Dorelsa Buccilli , Mattia Alberto Di Civita , Paola Giancontieri , Giulia Maltese , Francesco Nicolella , Andrea Torchia , Simone Scagnoli , Simona Pisegna , Giacomo Barchiesi , Iolanda Speranza , Andrea Botticelli , Daniele Santini
In the last two-decades, innovative drugs have revolutionized cancer treatments, demonstrating a significant improvement in overall survival. These drugs may present several pharmacokinetics interactions with non-oncological drugs, and vice versa, and, non-oncological drugs can modify oncological treatment outcome both with pharmacokinetic interaction and with an “off-target impact” on the tumor microenvironment or on the peripheral immune response. It’s supposed that the presence of a drug-drug interaction (DDI) is associated with an increased risk of reduced anti-tumor effects or severe toxicities. However, clinical evidence that correlate the DDI presence with outcome are few, and results are difficult to compare because of difference in data collection and heterogeneous population. This review reports all the clinical evidence about DDI to provide an easy-to-use guide for DDI management and dose adjustment in solid tumors treated with inhibitors of the cyclin-dependent kinases CDK4–6, Antibody-drug conjugates, Poly ADPribose polymerase inhibitors, androgen-receptor targeted agents, or immunecheckpoints inhibitors.
{"title":"Clinical implications of the Drug-Drug Interaction in Cancer Patients treated with innovative oncological treatments","authors":"Fiorenza Santamaria , Michela Roberto , Dorelsa Buccilli , Mattia Alberto Di Civita , Paola Giancontieri , Giulia Maltese , Francesco Nicolella , Andrea Torchia , Simone Scagnoli , Simona Pisegna , Giacomo Barchiesi , Iolanda Speranza , Andrea Botticelli , Daniele Santini","doi":"10.1016/j.critrevonc.2024.104405","DOIUrl":"10.1016/j.critrevonc.2024.104405","url":null,"abstract":"<div><p>In the last two-decades, innovative drugs have revolutionized cancer treatments, demonstrating a significant improvement in overall survival. These drugs may present several pharmacokinetics interactions with non-oncological drugs, and vice versa, and, non-oncological drugs can modify oncological treatment outcome both with pharmacokinetic interaction and with an “off-target impact” on the tumor microenvironment or on the peripheral immune response. It’s supposed that the presence of a drug-drug interaction (DDI) is associated with an increased risk of reduced anti-tumor effects or severe toxicities. However, clinical evidence that correlate the DDI presence with outcome are few, and results are difficult to compare because of difference in data collection and heterogeneous population. This review reports all the clinical evidence about DDI to provide an easy-to-use guide for DDI management and dose adjustment in solid tumors treated with inhibitors of the cyclin-dependent kinases CDK4–6, Antibody-drug conjugates, Poly ADPribose polymerase inhibitors, androgen-receptor targeted agents, or immunecheckpoints inhibitors.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141263478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1016/j.critrevonc.2024.104403
Yiming Meng , Jing Sun , Guirong Zhang
Anti-PD-1 immunotherapy is a cancer therapy that focuses explicitly on the PD-1 receptor found on the surface of immune cells. This targeted therapeutic strategy is specifically designed to amplify the immune system's innate capacity to detect and subsequently eliminate cells that have become cancerous. Nevertheless, it should be noted that not all patients exhibit a favourable response to this particular therapeutic modality, necessitating the exploration of novel strategies to augment the effectiveness of immunotherapy. Previous studies have shown that fecal microbiota transplantation (FMT) can enhance the efficacy of anti-PD-1 immunotherapy in advanced melanoma patients. To investigate this intriguing possibility further, we turned to PubMed and conducted a comprehensive search for studies that analyzed the interplay between FMT and anti-PD-1 therapy in the context of tumor treatment. Our search criteria were centred around two key phrases: "fecal microbiota transplantation" and "anti-PD-1 therapy." The studies we uncovered all echo a similar sentiment. They pointed towards the potential of FMT to improve the effectiveness of immunotherapy. FMT may enhance the effectiveness of immunotherapy by altering the gut microbiota and boosting the patient’s immunological response. Although promising, additional investigation is needed to improve the efficacy of FMT in the context of cancer therapy and attain a comprehensive understanding of the possible advantages and drawbacks associated with this therapeutic strategy.
{"title":"A viable remedy for overcoming resistance to anti-PD-1 immunotherapy: Fecal microbiota transplantation","authors":"Yiming Meng , Jing Sun , Guirong Zhang","doi":"10.1016/j.critrevonc.2024.104403","DOIUrl":"10.1016/j.critrevonc.2024.104403","url":null,"abstract":"<div><p>Anti-PD-1 immunotherapy is a cancer therapy that focuses explicitly on the PD-1 receptor found on the surface of immune cells. This targeted therapeutic strategy is specifically designed to amplify the immune system's innate capacity to detect and subsequently eliminate cells that have become cancerous. Nevertheless, it should be noted that not all patients exhibit a favourable response to this particular therapeutic modality, necessitating the exploration of novel strategies to augment the effectiveness of immunotherapy. Previous studies have shown that fecal microbiota transplantation (FMT) can enhance the efficacy of anti-PD-1 immunotherapy in advanced melanoma patients. To investigate this intriguing possibility further, we turned to PubMed and conducted a comprehensive search for studies that analyzed the interplay between FMT and anti-PD-1 therapy in the context of tumor treatment. Our search criteria were centred around two key phrases: \"fecal microbiota transplantation\" and \"anti-PD-1 therapy.\" The studies we uncovered all echo a similar sentiment. They pointed towards the potential of FMT to improve the effectiveness of immunotherapy. FMT may enhance the effectiveness of immunotherapy by altering the gut microbiota and boosting the patient’s immunological response. Although promising, additional investigation is needed to improve the efficacy of FMT in the context of cancer therapy and attain a comprehensive understanding of the possible advantages and drawbacks associated with this therapeutic strategy.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141263415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite substantial progress in pediatric cancer treatment, poor prognosis remained for patients with recurrent or metastatic disease, given the limitations of approved targeted treatments and immunotherapies. RNA therapeutics offer significant potential for addressing a broad spectrum of diseases, including cancer. Advances in manufacturing and delivery systems are paving the way for the rapid development of therapeutic RNAs for clinical applications. This review summarizes therapeutic RNA classifications and the mechanisms of action, highlighting their potential in manipulating major cancer-related pathways and biological effects. We also focus on the pre-clinical investigation of RNA molecules with efficient delivery systems for their therapeutic potential targeting pediatric solid tumors.
{"title":"Targeting pediatric solid tumors in the new era of RNA therapeutics","authors":"Parunya Chaiyawat , Surasak Sangkhathat , Wararat Chiangjong , Patompon Wongtrakoongate , Suradej Hongeng , Dumnoensun Pruksakorn , Somchai Chutipongtanate","doi":"10.1016/j.critrevonc.2024.104406","DOIUrl":"10.1016/j.critrevonc.2024.104406","url":null,"abstract":"<div><p>Despite substantial progress in pediatric cancer treatment, poor prognosis remained for patients with recurrent or metastatic disease, given the limitations of approved targeted treatments and immunotherapies. RNA therapeutics offer significant potential for addressing a broad spectrum of diseases, including cancer. Advances in manufacturing and delivery systems are paving the way for the rapid development of therapeutic RNAs for clinical applications. This review summarizes therapeutic RNA classifications and the mechanisms of action, highlighting their potential in manipulating major cancer-related pathways and biological effects. We also focus on the pre-clinical investigation of RNA molecules with efficient delivery systems for their therapeutic potential targeting pediatric solid tumors.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1040842824001495/pdfft?md5=b9b0b567021bf493057a955d992734b9&pid=1-s2.0-S1040842824001495-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-02DOI: 10.1016/j.critrevonc.2024.104407
Vladimir N. Pak , Igor A. Sherman
The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit—immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.
{"title":"Comprehensive approach to cancer immunotherapy – Simultaneous targeting of myeloid-derived suppressor cells and cancer cells with AFP conjugates","authors":"Vladimir N. Pak , Igor A. Sherman","doi":"10.1016/j.critrevonc.2024.104407","DOIUrl":"10.1016/j.critrevonc.2024.104407","url":null,"abstract":"<div><p>The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit—immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-28DOI: 10.1016/j.critrevonc.2024.104401
Anna La Salvia , May-Lucie Meyer , Fred R. Hirsch , Keith M. Kerr , Lorenza Landi , Ming-Sound Tsao , Federico Cappuzzo
Several observations indicate that protein expression analysis by immunohistochemistry (IHC) remains relevant in individuals with non-small-cell lung cancer (NSCLC) when considering targeted therapy, as an early step in diagnosis and for therapy selection. Since the advent of next-generation sequencing (NGS), the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. We discuss how protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies in oncogene- and non-oncogene-addicted cases and in patients eligible for immunotherapy, suggesting that IHC testing should be reconsidered in clinical practice. We also argue how a panel of IHC tests should be considered complementary to NGS and other genomic assays. This is relevant to current clinical diagnostic practice but with potential future roles to optimize the selection of patients for innovative therapies. At the same time, strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed.
{"title":"Rediscovering immunohistochemistry in lung cancer","authors":"Anna La Salvia , May-Lucie Meyer , Fred R. Hirsch , Keith M. Kerr , Lorenza Landi , Ming-Sound Tsao , Federico Cappuzzo","doi":"10.1016/j.critrevonc.2024.104401","DOIUrl":"10.1016/j.critrevonc.2024.104401","url":null,"abstract":"<div><p>Several observations indicate that protein expression analysis by immunohistochemistry (IHC) remains relevant in individuals with non-small-cell lung cancer (NSCLC) when considering targeted therapy, as an early step in diagnosis and for therapy selection. Since the advent of next-generation sequencing (NGS), the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. We discuss how protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies in oncogene- and non-oncogene-addicted cases and in patients eligible for immunotherapy, suggesting that IHC testing should be reconsidered in clinical practice. We also argue how a panel of IHC tests should be considered complementary to NGS and other genomic assays. This is relevant to current clinical diagnostic practice but with potential future roles to optimize the selection of patients for innovative therapies. At the same time, strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-28DOI: 10.1016/j.critrevonc.2024.104404
M. Sirico , F. Jacobs , C. Molinelli , Guilherme Nader-Marta , V. Debien , H. Faith Dewhurst , M. Palleschi , F. Merloni , C. Gianni , U. De Giorgi , Evandro de Azambuja
The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as PIK3CA, AKT, PTEN mutations, insulin levels, 18 F-FDG-PET/TC, only the PIK3CA-mutations (PIK3CA-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect PIK3CA/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.
{"title":"Navigating the complexity of PI3K/AKT pathway in HER-2 negative breast cancer: biomarkers and beyond","authors":"M. Sirico , F. Jacobs , C. Molinelli , Guilherme Nader-Marta , V. Debien , H. Faith Dewhurst , M. Palleschi , F. Merloni , C. Gianni , U. De Giorgi , Evandro de Azambuja","doi":"10.1016/j.critrevonc.2024.104404","DOIUrl":"10.1016/j.critrevonc.2024.104404","url":null,"abstract":"<div><p>The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have <em>PIK3CA</em>/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as <em>PIK3CA</em>, AKT, PTEN mutations, insulin levels, <sup>18 F-</sup>FDG-PET/TC, only the <em>PIK3CA</em>-mutations (<em>PIK3CA</em>-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect <em>PIK3CA</em>/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of <em>PI3KCA</em> in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1040842824001471/pdfft?md5=79fe99d6a6faad27a231e120af2aaee9&pid=1-s2.0-S1040842824001471-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-27DOI: 10.1016/j.critrevonc.2024.104398
Simran Tyagi , Anoop Kumar
Background
The exact safety profile of Immune checkpoint inhibitors (ICIs) is unclear so far.
Aim
The aim of the current study is to analyse the safety profile of ICIs in cancer patients.
Methodology
The updated comprehensive disproportionality analysis of post-marketing data using the FAERS database and meta-analysis of randomized clinical trials (RCTs) was conducted. Disproportionality measures were calculated in terms of PRR associated with chi-square value and ROR with 95% confidence intervals whereas overall estimate measures with 95% CIs, publication bias and heterogeneity were calculated using RevMan 5.4. The GRADE analysis was also done to check the quality of evidence for each outcome.
Results
Various novel signals such as cholangitis, encephalitis, anuria, myelosuppression, and cachexia related to different system organ class were identified with ICIs. The sensitivity analysis results have indicated the influence of concomitant drugs on the identified signals. The meta-analysis results have shown a good safety profile of atezolizumab in non-small cell lung cancer (NSCLC) and melanoma, pembrolizumab in gastro-oesophageal cancer, urothelial cancer and head and neck squamous cell carcinoma (HNSCC), nivolumab in HNSCC as compared to the non-ICI group.
Conclusion
The safety of ICIs is dependent on their types as well as on the types of cancer.
{"title":"Safety of immune checkpoint inhibitors: An updated comprehensive disproportionality analysis and meta-analysis","authors":"Simran Tyagi , Anoop Kumar","doi":"10.1016/j.critrevonc.2024.104398","DOIUrl":"10.1016/j.critrevonc.2024.104398","url":null,"abstract":"<div><h3>Background</h3><p>The exact safety profile of Immune checkpoint inhibitors (ICIs) is unclear so far.</p></div><div><h3>Aim</h3><p>The aim of the current study is to analyse the safety profile of ICIs in cancer patients.</p></div><div><h3>Methodology</h3><p>The updated comprehensive disproportionality analysis of post-marketing data using the FAERS database and meta-analysis of randomized clinical trials (RCTs) was conducted. Disproportionality measures were calculated in terms of PRR associated with chi-square value and ROR with 95% confidence intervals whereas overall estimate measures with 95% CIs, publication bias and heterogeneity were calculated using RevMan 5.4. The GRADE analysis was also done to check the quality of evidence for each outcome.</p></div><div><h3>Results</h3><p>Various novel signals such as cholangitis, encephalitis, anuria, myelosuppression, and cachexia related to different system organ class were identified with ICIs. The sensitivity analysis results have indicated the influence of concomitant drugs on the identified signals. The meta-analysis results have shown a good safety profile of atezolizumab in non-small cell lung cancer (NSCLC) and melanoma, pembrolizumab in gastro-oesophageal cancer, urothelial cancer and head and neck squamous cell carcinoma (HNSCC), nivolumab in HNSCC as compared to the non-ICI group.</p></div><div><h3>Conclusion</h3><p>The safety of ICIs is dependent on their types as well as on the types of cancer.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-27DOI: 10.1016/j.critrevonc.2024.104385
Florent Ferrer , Pauline Tetu , Léa Dousset , Céleste Lebbe , Joseph Ciccolini , David Combarel , Nicolas Meyer , Angelo Paci , Stéphane Bouchet
Real-life populations are more heterogeneous than those included in prospective clinical studies. In cancer patients, comorbidities and co-medications favor the appearance of severe adverse effects which can significantly impact quality of life and treatment effectiveness. Most of tyrosine kinase inhibitors (TKI) have been developed with flat oral dosing exposing patients to the risk of poor adherence due to side effects. Additionally, genetic or physiological factors, differences in diet, and drug-drug interactions can lead to inter-individual variability affecting treatment outcomes and increasing the risk of adverse events. Knowledge of the different factors of variability allows individualized patient management. This review examines the effects of adherence, food intake, and pharmaceutical form on the pharmacokinetics of oral TKI, as well as evaluating pharmacokinetics considerations improving TKI management. Concentration-effectiveness and concentration-toxicity data are presented for the selected TKI, and a simple therapeutic drug monitoring schema is outlined to help individualize dosing of oral TKI.
{"title":"Tyrosine kinase inhibitors in cancers: Treatment optimization – Part II","authors":"Florent Ferrer , Pauline Tetu , Léa Dousset , Céleste Lebbe , Joseph Ciccolini , David Combarel , Nicolas Meyer , Angelo Paci , Stéphane Bouchet","doi":"10.1016/j.critrevonc.2024.104385","DOIUrl":"10.1016/j.critrevonc.2024.104385","url":null,"abstract":"<div><p>Real-life populations are more heterogeneous than those included in prospective clinical studies. In cancer patients, comorbidities and co-medications favor the appearance of severe adverse effects which can significantly impact quality of life and treatment effectiveness. Most of tyrosine kinase inhibitors (TKI) have been developed with flat oral dosing exposing patients to the risk of poor adherence due to side effects. Additionally, genetic or physiological factors, differences in diet, and drug-drug interactions can lead to inter-individual variability affecting treatment outcomes and increasing the risk of adverse events. Knowledge of the different factors of variability allows individualized patient management. This review examines the effects of adherence, food intake, and pharmaceutical form on the pharmacokinetics of oral TKI, as well as evaluating pharmacokinetics considerations improving TKI management. Concentration-effectiveness and concentration-toxicity data are presented for the selected TKI, and a simple therapeutic drug monitoring schema is outlined to help individualize dosing of oral TKI.</p></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}