Expert Review of Anticancer Therapy最新文献

Introduction: Combinations of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) can be responsible for major adverse cardiovascular events (MACEs). We performed a meta-analysis to assess the relative risk (RR) of MACEs and hypertension in cancer patients treated with ICI+TKI combinations.

Research design and methods: We selected prospective trials through MEDLINE/PubMed, Cochrane Library, and ASCOMeeting abstracts. We calculated combined ORs, RRs, and 95% CIs using RevMansoftware for meta-analysis (v.5.2.3).

Results: Seven studies were selected for the analysis of MACEs (3849 patients). The incidence MACEs were 0.8% with ICI+TKI combinations, compared to 0.2% in the control arms for both any- and high-grade. ICI+TKI combinations significantly increased the risk of any- (OR = 3.21; p = 0.01) and high-grade MACEs (OR = 2.72; p = 0.05). Ten studies were selected for the analysis of hypertension (5744 patients). The incidence of treatment-related hypertension of any-grade and high-grade was41.3% (vs. 20.8%) and 26.1% (vs. 12.3%) with ICI+TKI combinations, respectively. ICI+TKI combinations significantly increased the risk of treatment-related hypertension of any-grade (RR = 2.10; p = 0.001), but not of high-grade (p = 0.11).

Conclusions: ICI+TKI combinations increase the risk of MACEs compared to controls, although the absolute incidence is eventually low. Routine cardiovascular monitoring in asymptomatic patients is therefore not recommended.

Introduction: As a vital mechanism of survival, lymphopoiesis requires the collaboration of different signaling molecules to orchestrate each step of cell development and maturation. The PI3K pathway is considerably involved in the maturation of lymphatic cells and therefore, its dysregulation can immensely affect human well-being and cause some of the most prevalent malignancies. As a result, studies that investigate this pathway could pave the way for a better understanding of the lymphopoiesis mechanisms, the undesired changes that lead to cancer progression, and how to design drugs to solve this issue.

Areas covered: The present review addresses the aforementioned aspects of the PI3K pathway and helps pave the way for future therapeutic approaches. In order to access the articles, databases such as Medicine Medline/PubMed, Scopus, Google Scholar, and Science Direct were utilized. The search formula was established by identifying main keywords including PI3K/Akt/mTOR pathway, Lymphopoiesis, Lymphoid malignancies, and inhibitors.

Expert opinion: The PI3K pathway is crucial for lymphocyte development and differentiation, making it a potential target for therapeutic intervention in lymphoid cancers. Studies are focused on developing PI3K inhibitors to impede the progression of hematologic malignancies, highlighting the pathway's significance in lymphoma and lymphoid leukemia.

Introduction: Despite the considerable progress made in cancer treatment through the development of target therapies, pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance to this category of drugs. As a result, chemotherapy combination regimens remain the primary treatment approach for this aggressive cancer.

Areas covered: In this review, we provide an in-depth analysis of past and ongoing trials on both well-known and novel targets that are being explored in PDAC, including PARP, EGFR, HER2, KRAS, and its downstream and upstream pathways (such as RAF/MEK/ERK and PI3K/AKT/mTOR), JAK/STAT pathway, angiogenesis, metabolisms, epigenetic targets, claudin, and novel targets (such as P53 and plectin). We also provide a comprehensive overview of the significant trials for each target, allowing a thorough glimpse into the past and future of target therapy.

Expert opinion: The path toward implementing a target therapy capable of improving the overall survival of PDAC is still long, and it is unlikely that a monotherapy target drug will fulfill a meaningful role in addressing the complexity of this cancer. Thus, we discuss the future direction of target therapies in PDAC, trying to identify the more promising target and combination treatments, with a special focus on the more eagerly awaited ongoing trials.

Introduction: The link between talcum powder use and cancer, particularly ovarian cancer, has been a topic of scientific research and legal debate for several years. Studies have suggested a potential association between long-term talcum powder use in the genital area and an increased risk of ovarian cancer.

Areas covered: The following report includes up-to-date evidence to support the potential link between talcum powder use and the risk of developing ovarian cancer. The International Agency for Research on Cancer, which is part of the World Health Organization, classified talc-based body powder as possibly carcinogenic to humans when used in the female genital area. However, other studies have not consistently supported this association, and thus more research is needed to establish a clear and definitive link between talcum powder use and cancer. Despite this, recent molecular-level data have linked talc to alterations in redox balance, gene mutations, and inflammatory responses. Specifically, we have identified a role for talc to induce the pro-oxidant state, inhibit apoptosis, and more importantly induced cellular transformation in normal ovarian cells.

Expert opinion: We presented unequivocal evidence to support our opinion that talc is not biologically inert and induces molecular changes that mimic the hallmarks of cancer.

Background: Neoadjuvant treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is controversial and requires a comprehensive analysis for optimal therapy assessment. Therefore, a two-step Bayesian network meta-analysis (NMA) was performed to compare the efficacy and safety of different neoadjuvant regimens.

Research design and methods: Phase II/III randomized clinical trials comparing various neoadjuvant therapies for HR+/HER2- breast cancer were included. NMA and pairwise meta-analyses were conducted using Stata (version 14), R (version 4.2.3), and Review Manager 5.4.

Results: Twenty-eight studies (5,625 patients) were eligible. NMA of objective response rate (ORR) indicated the highest SUCRA for chemotherapy (CT) and chemotherapy with anthracycline (CT(A)). Pathologic complete response (PCR) NMA demonstrated significant PCR improvement with chemotherapy regimens containing programmed cell death protein-1 and programmed cell death ligand-1 inhibitors (PD-1i/PD-L1i) and poly ADP-ribose polymerase inhibitors (PARPi). Combined analysis considering both the ORR and safety highlighted CT(A)'s efficacy and toxicity balance.

Conclusions: CT(A) and CT showed improved ORR compared with alternative regimens. CT(A) combined with PD-1/PD-L1 or PARP inhibitors significantly increased PCR rates. Comprehensive assessment of both ORR and safety indicated that CT(A) represents an optimal neoadjuvant therapy for HR+/HER2- breast cancer, whereas AI + CDK4/6 inhibitors rank solely behind chemotherapy.

Registration: PROSPERO Registration: CRD42024538948. International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) registration number INPLASY202440092.

Introduction: The classic paradigm for the management of locally advanced rectal cancer (LARC) consists of (chemo)radiotherapy (C)RT), total mesorectal excision, and adjuvant chemotherapy (CHT). At present, due to the high rate of distant metastasis (up to 30%), the total neoadjuvant therapy (TNT) with the administration of systemic CHT in the neoadjuvant setting has gained acceptance as standard of care.Our aim is to critically review the current literature on LARC management and summarize the different approaches recently proposed to improve clinical outcomes. It represents a starting step to develop an effective strategy that ultimately could harmonize the standard of care in daily clinical practice.

Areas covered: Studies reporting the impact of TNT approaches were deemed eligible. De-escalation strategies, including non-operative management (NOM) after TNT, as well as RT omission or systemic therapy alone, were also investigated.

Expert opinion: The year 2020 has seen promising new data from randomized phase III trials in the field of LARC management. Nowadays, TNT strategy has been accepted as the primary treatment for LARC. The role of de-escalation strategies is still unknown. The goal is to achieve better survival outcomes with improving quality of life. Only selected patients are likely to benefit from NOM or immunotherapy alone.

Introduction: This study aimed to estimate the toxicities of PARP inhibitors (PARPis), based on randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS) database.

Methods: Four electronic databases were searched from inception to 16 April 2024, for RCTs of approved PARPis. The primary and secondary outcomes were grade 3-5 adverse events (AEs) and grade 3-5 hematological AE, respectively. We conducted network meta-analyses to calculate the relative risks (RRs) and 95% confidence intervals (CIs) of outcomes. A disproportionality analysis was conducted to estimate the signals of hematological AEs associated with PARPis from the FAERS database.

Results: Overall, 27 RCTs involving 11,067 patients with cancer were included. Olaparib had the best safety profile for any grade 3-5 AEs and hematological AEs among four approved PARPis. Olaparib did not increase the risk of thrombocytopenia (RR: 1.48; 95%CI: 0.64-3.39), but other PARPis did. Furthermore 14,780 hematological AE reports associated with PARPis were identified in the FAERS database, and all PARPis were associated with strong hematological AE signals. Hematological AEs mainly occurred within the first 3 months (80.84%) after PARPi initiation.

Conclusion: Olaparib had the best safety profile among five PARPis. PARPi-associated hematological AEs mainly occurred within the first 3 months.

Registration: PROSPERO (CRD42022385274).

Introduction: APC-associated polyposis is a rare hereditary disorder characterized by the development of multiple adenomas in the digestive tract. Individuals with APC-associated polyposis need to be managed by specialized multidisciplinary teams in dedicated centers.

Areas covered: The study aimed to review the literature on Familial adenomatous polyposis (FAP) to provide an update on diagnostic and surgical management while focusing on strategies to minimize the risk of desmoid-type fibromatosis, cancer in anorectal remnant, and postoperative complications. FAP individuals require a comprehensive approach that includes diagnosis, surveillance, preventive surgery, and addressing specific extracolonic concerns such as duodenal and desmoid tumors. Management should be personalized considering all factors: genotype, phenotype, and personal needs. Total colectomy and ileo-rectal anastomosis have been shown to yield superior QoL results when compared to Restorative Procto colectomy and ileopouch-anal anastomosis with acceptable oncological risk of developing cancer in the rectal stump if patients rigorously adhere to lifelong endoscopic surveillance. Additionally, a low-inflammatory diet may prevent adenomas and cancer by modulating systemic and tissue inflammatory indices.

Expert opinion: FAP management requires a multidisciplinary and personalized approach. Integrating genetic advances, innovative surveillance techniques, and emerging therapeutic modalities will contribute to improving outcomes and quality of life for FAP individuals.

Introduction: Soft tissue sarcomas (STS) are a rare and diverse group of tumors. Curative options are limited to localized disease, with surgery being the mainstay. Advanced stages are associated with a poor prognosis. Currently, the prognosis of the patient is based on histological classification and clinical characteristics, with only a few biomarkers having entered clinical practice.

Areas covered: This article covers extensive recent research that has established novel potential biomarkers based on genomics, proteomics, and clinical characteristics. Validating and incorporating these biomarkers into clinical practice can improve prognosis, prediction of recurrence, and treatment response. Relevant literature was collected from PubMed, Scopus, and clinicaltrials.gov databases (November 2023).

Expert opinion: Currently, defining prognostic markers in soft tissue sarcomas remains challenging. More studies are required, especially to personalize treatment through advanced genetic profiling and analysis using individual tumor and patient characteristics.

Introduction: Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach deep level of responses and extend survival outcomes.

Areas covered: Antibody-drug conjugates (ADCs) and T-cell redirecting treatments, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells therapy, have been recently introduced in the treatment of RRMM. Some agents have already received regulatory approval, while newer constructs, novel combinations, and applications in earlier lines of therapy are currently being explored. This review discusses the current landscape and possible development of ADCs, BsAbs and CAR-T cells immunotherapies.

Expert opinion: ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, triple-class exposed (TCE) MM patients, and T-cell redirecting treatments represent new standards of care after third (European Medicines Agency, EMA), or fourth (Food and Drug Administration, FDA), line of therapy. All these three immunotherapies carry advantages and disadvantages, with different accessibility and new toxicities that require appropriate management and guidelines. Multiple on-going programs include combinations therapies and applications in earlier lines of treatment, as well as the development of novel agents or construct to enhance potency, reduce toxicity and facilitate administration. Sequencing is a challenge, with few data available and mechanisms of resistance still to be unraveled.