Systemic Therapy In Patients Research Articles

Transarterial Chemoembolization With or Without Systemic Therapy for Unresectable Hepatocellular Carcinoma: A Retrospective Comparative Study.

Standard treatments provide limited benefits for patients with intermediate- or advanced-stage hepatocellular carcinoma (HCC). This retrospective observational study aimed to assess the potential improvements in outcomes associated with systemic therapies in patients receiving transarterial chemoembolization (TACE) for initially unresectable HCC. Between February 2019 and March 2023, we reviewed patients diagnosed with intermediate-to-advanced HCC who were treated with either TACE or TACE combined with antiangiogenic agents and immune checkpoint inhibitors (combination therapy) as their initial treatment. To address potential confounding biases, patients were further stratified into surgical and non-surgical cohorts, and separate analyses were conducted. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with safety profiles also evaluated. Among 279 patients with initially unresectable intermediate or advanced HCC, 156 successfully underwent curative-intent liver resection after preoperative treatments (TACE group, n = 69; combination group, n = 87), while 123 patients continued with non-surgical treatments (TACE group, n = 31; combination group, n = 92). After propensity score matching, 26 matched patient pairs were generated within the non-surgical cohort. The combination group exhibited significantly improved PFS in non-surgical patients compared with the TACE group (9.4 vs. 7.2 months, p = 0.043). Cox proportional hazards analysis further confirmed that combination therapy was associated with improved PFS (hazard ratio = 0.476, 95% confidence interval: 0.257-0.883, p = 0.019). For surgical patients exceeding the up-to-seven criteria, the combination group demonstrated superior median PFS (18.0 vs. 14.6 months, p = 0.03) and OS (not reached vs. 50.1 months, p = 0.049) compared with the TACE group. Adverse events were manageable, with no treatment-related fatalities reported. Combination therapy with TACE demonstrated enhanced survival benefits for patients with intermediate to advanced HCC, particularly in surgical patients with higher tumor burdens.

Cross-sectional study of treatment approaches of luminal HER2negative metastatic breast cancer in real practice in Moscow

Introduction: The systemic therapy of patients with metastatic luminal HER2‑negative breast cancer (mBC) in‑ cludes various options, which can be fundamentally divided into endocrine therapy and chemotherapy. According to the Clinical Guidelines, both international and Russian, the “gold standard” of the 1st line therapy for patients with metastatic luminal HER2‑negative breast cancer (mBC) is a combination of cyclindependent kinase inhib‑ itors 4 / 6 (iCDK4 / 6) with endocrine therapy (ET). However, until recently we did not have complete data on the characteristics of the Russian population of patients with luminal HER2‑breast cancer, their treatment options, and the results of this therapy.Aim: To analyze the patients’ profile and current treatment approaches for patients with luminal HER2 mBC in routine clinical practice in Moscow.Materials and methods: The study was performed as an observational, crosssectional and retrospective study. The data of 2,500 patients from medical institutions in Moscow who received systemic therapy for luminal HER2 mBC in AugustOctober 2021 were analyzed.Results: The largest number of patients received iCDK4 / 6 + ET in the first and second lines: 69.0 % and 52.0 %, respectively. In the first line, 54.6 % of patients received ribociclib, 43.1 % palbociclib and 2.3 % abemaciclib. In the second line, 50.6 % of patients received ribociclib, 47.8 % palbociclib and 1.6 % abemaciclib. As the pretreatment of patients increased, preference was given to other treatment methods, therefore the proportion of combined ET decreased to 34.0 % in the third line and 25.0 % in the fourth and subsequent lines.Conclusion: The data obtained indicate that the appointment of iCDK4 / 6 + ET is made in accordance with the Clinical Guidelines for the treatment of breast cancer of the Ministry of Health of the Russian Federation from 2021 and the preferred firstline treatment option for patients with luminal HER2 mBC in Moscow is combined endocrine therapy.

Demographic Features, Diagnoses and Real-World Clinical Management of Uveitis in Japan

ABSTRACT Purpose This study aimed to investigate demographic features, diagnoses of uveitis (intraocular inflammation), and real-world clinical practice in the use of local and systemic therapies for patients with uveitis in Tokyo, Japan. Methods Clinical records of 1,174 consecutive new patients (480 males, 694 females) referred to the Kyorin Eye Center, Kyorin University Hospital between January 2011 and December 2018 were retrospectively reviewed. Results Mean age at presentation was 52.6 years (range 4–94 years). By anatomic location, 439 patients (37.4%) had anterior uveitis, 18 (1.5%) had intermediate uveitis, 214 (18.2%) had posterior uveitis and 503 (42.8%) had panuveitis. The 3 most common diagnoses were sarcoidosis (9.1%), Vogt-Koyanagi-Harada (VKH) disease (8.3%), and acute anterior uveitis (5.7%). Compared to our previous study, rates of herpetic anterior uveitis and cytomegalovirus (CMV) retinitis increased while tuberculosis-related uveitis decreased. Unclassified uveitis remained the most common diagnosis (44.9%). Systemic corticosteroids and/or immunomodulatory agents were used in only 18.3% of patients. Immunomodulatory drugs including biologic agents were utilized in 4.9% of patients. Conclusions The most common uveitis anatomic type was panuveitis due mainly to high rates of sarcoidosis and VKH disease. Diagnoses of herpetic anterior uveitis and CMV retinitis increased, while tuberculosis-related uveitis decreased. Less than one-fifth of uveitis patients required systemic treatment.

Systemic therapy for patients with metastatic pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors derived from the paraganglia. These tumors frequently secrete excessive amounts of catecholamines leading to cardiovascular and gastrointestinal complications. While all pheochromocytomas and paragangliomas possess the potential for metastasis, actual metastatic occurrences are observed in approximately one third of cases. The metastases primarily affect the lymph nodes, skeletal system, liver, and lungs. Furthermore, patients often experience a reduced overall survival rate attributed to factors such as tumor size, disease advancement, and excessive catecholamine secretion. For several decades, treatment options for patients diagnosed with metastatic pheochromocytomas and paragangliomas have primarily included combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine, along with Iodine-131-metaiodobenzylguanidine. However, significant advancements in scientific research over the past 25 years have enabled a comprehensive characterization of these tumors from biochemical, molecular, and diagnostic standpoints, resulting in the identification of new therapeutic alternatives for affected patients. In the last decade, we have witnessed the introduction of innovative systemic therapies specifically designed for those with metastatic pheochromocytomas and paragangliomas. In this review, we aim to present findings on the efficacy, safety, and overall activity from prospective clinical trials involving radiopharmaceuticals and tyrosine kinase inhibitors, and we will also outline the prospective advantages of additional novel therapies currently under evaluation.

Diagnostic accuracy and inter-reader agreement of the nacVI-RADS for bladder cancer treated with neoadjuvant chemotherapy: a prospective validation study.

The primary aim was to determine the performance of neoadjuvant chemotherapy VI-RADS (nacVI-RADS) in predicting response to systemic therapy in patients with MIBC and to evaluate its inter-reader agreement. Prospective study, including patients with non-metastatic muscle-invasive bladder cancer (MIBC) who underwent neoadjuvant chemotherapy before radical cystectomy (RC). Patients underwent pre- and post-treatment MRI. Radiological response was evaluated by two experienced radiologists using nacVI-RADS scoring system. Reference standard was defined using histopathological findings. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy were calculated to assess nacVI-RADS performance for each reader. Inter-reader agreement was determined with Cohen's k statistics. Fifty-five patients with non-metastatic MIBC, 46 males (84%) and 9 females (16%) with a median age of 69 (interquartile range (IQR) 66-72 years) were enrolled. Diagnostic performance of nacVI-RADS in detecting complete response to neoadjuvant chemotherapy showed a sensitivity of 76.5-85.3% and specificity of 76.2-81%. The area under the curve was 0.93 (95% CI: 0.86-0.99) for detecting any residual tissue, for the more experienced reader. Inter-reader agreement was optimal with a K of 0.85. In the multivariable logistic regression model, the variables showing independent correlation with response prediction to neoadjuvant therapy were nacVI-RADS score (p = 0.01 for the more experienced reader) and tumor regression grade (TRG; p < 0.001). NacVI-RADS scoring system offers a reliable and reproducible approach, employing a well-structured and easily interpretable method, to assess the response to systemic therapy in patients with MIBC. Question There is a lack of a standardized approach to distinguish between responders and non-responders to neoadjuvant chemotherapy for muscle-invasive bladder cancer. Findings The neoadjuvant chemotherapy VI-RADS (nacVI-RADS)score diagnostic performance for detecting complete response to neoadjuvant chemotherapy showed 85.3% sensitivity, 81% specificity, and an AUC of 0.93. Clinical relevance NacVI-RADS score represents a valid predictor of response to neoadjuvant systemic therapy, impacting therapeutic decision-making and improving overall patients' management.

Later lines of systemic therapy in patients with metastatic colorectal cancer: real-world data from a setting with barriers to access cancer therapies.

Regorafenib and trifluridine/tipiracil (TFD/TPI) are oral systemic therapies with survival benefit in chemorefractory metastatic colorectal cancer (mCRC) patients, but they are not widely available worldwide. We aimed to evaluate the treatment patterns and outcomes of patients with limited access to these drugs. Retrospective study involving 510 patients with mCRC who were treated at five different centers in Brazil, from January 2011 to December 2019. We analyzed the characteristics and clinical outcomes of patients who were exposed to third-line and beyond systemic therapy (N=148). A total of 148 (29%) and 73 (14%) patients received third- and fourth-line therapies, respectively. Most patients had left-sided tumors (80%) and had undergone primary tumor resection (87%) and metastasectomy (62%). From the initiation of third-line therapy, median follow-up was 17.8 months and median overall survival (OS) was 13.1 months (95% confidence interval: 8.1-18.0) (58% of deaths). The most adopted therapies were reexposure to previous chemotherapy regimens (85% third-line and 71% fourth-line), followed by regorafenib (13% and 25%) and TFD/TPI (2% and 4%). In multivariable analysis, male patients and right-sided tumors were significant unfavorable prognostic factors for OS. In a real-world setting with barriers to accessing the standard of care of chemorefractory mCRC, reexposure to chemotherapy was the main therapeutic strategy, with potential negative influence on OS. Our study highlights how barriers hamper the achievement of health equity in cancer care and increases the awareness of patients and stakeholders, contributing to engaging them in ensuring equitable access to high-quality cancer care.

Use of advanced systemic therapy in patients with moderate-to-severe atopic dermatitis in the TARGET-DERM AD Registry

Background Moderate-to-severe atopic dermatitis (AD) significantly impacts quality of life. Advanced systemic therapeutics (AST) represent a new generation of medications targeting AD pathogenesis, but many who may benefit from these medications are AST-naïve. We compared patients in the United States who had started AST with those who had not started AST to evaluate associated characteristics. Methods TARGET-DERM AD, (NCT03661866, “A Longitudinal Observational Study of Patients Undergoing Therapy for IMISC (TARGET-DERM)” launched in 2019, is an ongoing, longitudinal, observational study of patients managed at 37 United States sites. Patients were aged 12 years and above, had moderate-to-severe AD based on validated Investigator Global Assessment (vIGA) at enrollment, at least one follow-up visit post-enrollment, and treatment with any of the following: a topical/systemic corticosteroid, immunomodulator, or phototherapy. AST included dupilumab and upadacitinib. Variables of interest gathered at enrollment included demographics, vIGA and Body Surface Area (BSA), patient-reported outcomes, and all recorded therapeutics. Results Of 3,076 patients, 436 qualified for inclusion, 52 were AST-treated adolescents and 141 AST-treated adults. Both groups had increased likelihood of AST initiation if they had private insurance and higher BSA, vIGAxBSA, or Patient-Oriented SCORing Atopic Dermatitis scores. Adults were more likely to start AST based on minority/ethnicity, more severe vIGA, higher patient-reported outcomes, or if treated at a community clinic. Substantial numbers of adolescent and adult patients (47 and 58%, respectively) with severe disease were AST-naïve. Conclusions Disease severity and patient access to AST are major factors driving AST initiation. However, some patients are undertreated. This analysis supports AD patient advocacy for those inadequately managed with conventional therapies. Further investigations are necessary to delineate AST initiation barriers and relevant outcomes.

Distinct metabolic phenotype renders β-catenin mutant hepatocellular carcinoma susceptible to treatment-induced ischemia.

Transarterial chemoembolization (TACE) is the most common treatment for hepatocellular carcinoma (HCC) worldwide; however, response rates and durability vary widely. With the growing armamentarium of therapies for HCC patients, identifying predictors of response to TACE has become increasingly important for a patient population with limited hepatic reserve. We hypothesized that a distinct metabolic phenotype associated with β-catenin pathway mutations render HCC tumors more susceptible to TACE-induced ischemia. HCC patients referred for TACE were enrolled in a prospective cohort study at two academic medical centers from April 2016 to October 2021. Liver biopsies were acquired at the time of TACE, and mutational profiles were determined using next generation sequencing. Tumor response was determined by MRI using modified Response Evaluation Criteria in Solid Tumors. HCC cell lines with and without B-catenin mutations were grown in standard and ischemic cell culture conditions (1% O 2 , low nutrient media). Cell viability was measured by WST-1 reagent and Annexin-V PI assay. ATP concentration and metabolites were measured using CellTiter Glo and a YSI biochemical analyzer, respectively. Mitochondrial function was assessed through Seahorse XF Mito Stress Test. 53 HCC tumors from 50 HCC patients were biopsied prior to TACE, including 22/53 (41.5%) tumors with β-catenin pathway mutations. Despite larger tumor size (4.9 cm vs 3.0 cm p=0.01), tumors with these mutations demonstrated increased rates of complete response after TACE at first imaging (9/22, 40.9% vs 6/31, 19.4%, p=0.06) and best response (12/22, 54.5% vs 7/31, 22.6%, p=0.02), as well as a longer time to tumor progression (median not yet reached vs 8.3 months, p=0.02). In vitro modeling confirmed that β-catenin mutant HCC cells have reduced viability (21.4% vs 59.9%, p<0.01) and ATP levels (8.47 vs 4.26 pM/cell, p<0.001) under ischemic conditions compared to β-catenin wild type HCC cells. β-catenin mutant HCC cells had a dramatic increase in their susceptibility to glycolysis inhibition that was not seen in wild type HCC cells (0.09 vs 0.79 IC50 ration for ischemic vs standard conditions, p=0.004), suggesting a change from predominantly aerobic to anaerobic metabolism under ischemia specific to β-catenin mutant. This was further supported by increased sensitivity of β-catenin mutant cells to inhibition of the electron transport chain (43.9% vs 59.5%, p=0.02,) as well as significantly higher basal oxygen consumption rates (0.74 vs 0.39 pmoles/min, p=0.04), maximal respiratory capacity (1.46 vs 0.51 pmoles/min, p=0.01) and ATP-linked respiration (0.58 vs 0.29 pmoles/min, p=0.04). HCC tumors with activating B-catenin pathway mutations demonstrate a superior response to TACE, driven by enhanced susceptibility to ischemia due to a greater dependence on oxidative phosphorylation for bioenergetic homeostasis. These findings hold the potential to provide a molecular basis for treatment selection in patients with HCC. With the growing armamentarium of locoregional and systemic therapies for patients with HCC, identifying predictors of response to individual therapies has become increasingly important for a patient population with limited hepatic reserve. Current treatment guidelines fail to incorporate molecular biomarkers to inform therapy. In a prospective clinical study of HCC patients undergoing transarterial chemoembolization (TACE), we demonstrated that tumors with activating mutations in the Wnt/B-catenin pathway have increased rates of complete response and longer time to local progression. We further characterized this finding in vitro by modeling the post-TACE ischemic environment and demonstrated that B-catenin mutant HCC cells have a distinct metabolic phenotype that renders this subtype more susceptible to ischemia. These findings provide the rationale for genotype-based strategies to enable precision medicine for patients with HCC patients.

Systemic therapy for head and neck cancer-highlights of the 2024 ASCO Annual Meeting

Systemic therapy of head and neck squamous cell carcinoma (HNSCC), in contrast to local therapy, is avery general term for the use of drugs that affect the entire organism. Immunotherapy is asubtype of systemic therapy, although the boundaries are hard to define, since the immune system is likely to play an essential role in all treatments. This article focuses on systemic therapy. All abstracts and presentations on systemic therapy of HNSCC from the American Society of Clinical Oncology (ASCO) 2024 annual congress were assessed for relevance. The main contributions were reviewed and summarized. For the first time, arandomized trial demonstrated asurvival advantage for systemic therapy in patients with apoor performance status over best supportive care (BSC). Clinical studies using antibody-drug conjugates (ADCs) show apromising response. In addition, the neoadjuvant approach was resumed through various study approaches. Even in patients with areduced general condition, systemic therapy can lead to asubstantial improvement in overall survival. The systemic therapy approach remains exciting for HNSCC, with new substances and areas of application not only in the palliative situation.

Treatment of Colorectal Lung Metastases: Two Centers Retrospective Study

Introduction: Clear guidelines for colorectal lung metastasis (LM) treatment are not available. This study aimed to provide insight into the treatment strategies and efficacy of local and systemic therapy in patients with LM eligible for (potentially) curative treatment. Methods: This was a retrospective study of patients with ≤5 LM discussed in two tertiary referral centers. Patient and tumor characteristics were compared between treatment groups. Treatment strategies were compared between centers and survival data between treatment groups, local treatment modalities, and treating centers. Results: Ninety-two patients (median 2 LMs) were included. Seventy-one (77%) patients underwent local treatment (17 surgery, 13 ablation, 38 radiotherapy, 3 combination of local treatments) and 21 (23%) with systemic therapy alone. The latter group more frequently had extrapulmonary metastases (81.0% vs. 26.8%, p < 0.001) and synchronous presentation of LM (23.8% vs. 7.0%, p = 0.045). Choice of local versus systemic therapy and time to start treatment after diagnosis (median 109 days, IQR 44–240 vs. 88 days, IQR 53–168) were comparable between centers. Three-year survival rates did not differ between treatment groups, local treatment modalities, or treating centers. Conclusion: Treatment strategies and oncological outcomes were rather similar between centers. Survival outcomes were not different between locally and systemically treated patients.

Adding Metastasis-Directed Therapy to Standard-of-Care Systemic Therapy for Oligometastatic Breast Cancer (EXTEND): A Multicenter, Randomized Phase 2 Trial

Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer. EXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures. From September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34-2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration. Among patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms.

When You Get to the Fork in the Road, Take It: The Challenges in Managing Patients With Advanced Prostate Cancer.

As is the case with most solid tumors, the heterogeneity of the disease biology of prostate cancer presents clinicians managing this disease with daily challenges. However, in contrast to other common cancers such as breast, lung, and colorectal cancers, there are unique challenges in prostate cancer management, including the variety of clinicians who manage aspects of the disease (urologists, medical oncologist, radiation oncologists) and the striking absence of prospective comparative data to inform the optimal sequence of systemic therapy in patients with metastatic castration-resistant disease. The purpose of this review is to attempt to assist practicing oncologists with sorting through the myriad of prostate cancer disease subsets and the challenges in making therapeutic decisions in multiple data-free zones given the absence of level 1 comparative clinical trials in the metastatic hormone-sensitive and castration-resistant states.

Prioritizing Radiation and Targeted Systemic Therapies in Patients with Resected Brain Metastases from Lung Cancer Primaries with Targetable Mutations: A Report from a Multi-Site Single Institution.

Background/Objectives: Brain metastases (BrMs) are a common complication of non-small cell lung cancer (NSCLC), present in up to 50% of patients. While the treatment of BrMs requires a multidisciplinary approach with surgery, radiotherapy (RT), and systemic therapy, the advances in molecular sequencing have improved outcomes in patients with targetable mutations. With a push towards the molecular characterization of cancers, we evaluated the outcomes by treatment modality at our institution with respect to prioritizing RT and targeted therapies. Methods: We identified the patients with NSCLC BrMs treated with surgical resection. The primary endpoints were in-brain freedom from progression (FFP) and overall survival (OS). The secondary endpoint included index lesion recurrence. The tumor molecular profiles were reviewed. The outcomes were evaluated by treatment modality: surgery followed by adjuvant RT and/or adjuvant systemic therapy. Results: In total, 155/272 (57%) patients who received adjuvant therapy with adequate follow-up were included in this analysis. The patients treated with combination therapy vs. monotherapy had a median FFP time of 10.72 months vs. 5.38 months, respectively (p = 0.072). The patients of Hispanic/Latino vs. non-Hispanic/Latino descent had a statistically significant worse OS of 12.75 months vs. 53.15 months, respectively (p = 0.015). The patients who received multimodality therapy had a trend towards a reduction in index lesion recurrences (χ2 test, p = 0.063) with a statistically significant improvement in the patients receiving immunotherapy (χ2 test, p = 0.0018). Conclusions: We found that systemic therapy combined with RT may have an increasing role in delaying the time to progression; however, there was no statistically significant relationship between OS and treatment modality.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial

The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n=59) or progressive disease after radiotherapy (cohort B, n=19) were enrolled and received pyrotinib (400mg once daily) and capecitabine (1000mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Impact of diabetes mellitus and hypertension on renal function during first-line targeted therapy for metastatic renal cell carcinoma: a retrospective multicenter study.

Renal function deterioration during systemic therapy in patients with metastatic renal cell carcinoma (mRCC) is a long-term concern in treatment planning. Although hypertension (HTN) and diabetes mellitus (DM) are the most common factors that affect chronic kidney disease (CKD) development and progression, their impact on renal function during targeted therapy is unclear. This study investigated whether DM and HTN were associated with a decline in renal function during first-line targeted therapy for mRCC. This retrospective multicenter study analyzed patients receiving first-line targeted therapy for mRCC. They were classified as follows: group 1: HTN-, DM-; group 2: HTN+, DM-; group 3: HTN-, DM+; and group 4: HTN+, DM+. Changes in renal function and factors affecting progression to stage 4 CKD after targeted therapy were analyzed. Among the 424 enrolled patients, 303 (71.5%) and 121 (28.5%) were treated with sunitinib and pazopanib, respectively [median duration: 10.3 months, interquartile range (IQR), 3.1-37.0 months]. Although all groups showed a decreased mean estimated glomerular filtration rate (eGFR) after treatment (P<0.001 for group 1, group 2, and group 4, P=0.02 for group 3, respectively), there were no significant differences in changes in eGFR (∆eGFR) between groups (P=0.10). However, actual renal function change calculated using percent ∆eGFR (%∆eGFR) showed differences between groups (P=0.02); the %∆eGFR of group 4 was significantly lower compared with group 1 (P=0.008). The mean progression time to stage 4 CKD in group 4 (38.6 months) was significantly shorter compared to the other groups (P<0.001). Multivariate analysis identified increased age (P=0.008), increased number of metastatic sites (P=0.047), and DM and HTN coexistence (P<0.001) as predictors of progression to stage 4 CKD. Patients with DM and HTN experienced further decline in renal function and had a higher risk of progression to stage 4 CKD after targeted therapy compared to patients without these risk factors. Recognition and proactive management of DM and HTN are necessary to facilitate the proper administration of life-prolonging oncological treatments.

ASO Visual Abstract: The Prevalence of Sentinel Lymph Node Positivity and Implications for the Utility of Frozen Section Diagnosis Following Neoadjuvant Systemic Therapy in Patients with Clinically Node-Negative HER2-Positive or Triple-Negative Breast Cancer.

ASO Visual Abstract: The Prevalence of Sentinel Lymph Node Positivity and Implications for the Utility of Frozen Section Diagnosis Following Neoadjuvant Systemic Therapy in Patients with Clinically Node-Negative HER2-Positive or Triple-Negative Breast Cancer.

ENGOT-EN20/GOG-3083/XPORT-EC-042 – A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design

BackgroundPatients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and...

The Prevalence of Sentinel Lymph Node Positivity and Implications for the Utility of Frozen Section Diagnosis Following Neoadjuvant Systemic Therapy in Patients with Clinically Node-Negative HER2-Positive or Triple-Negative Breast Cancer.

Axillary dissection is the standard of care for patients with positive sentinel lymph nodes (SLNs) following neoadjuvant systemic therapy. Frozen section can provide intraoperative information regarding the need for axillary dissection during the index operation. However, there are limited data on the utility of frozen section in patients with clinically node-negative (cN0) HER2-positive or triple-negative breast cancer. We conducted a single-institution observational cohort study including patients with non-inflammatory, cN0, HER2-positive or triple-negative breast cancer treated with neoadjuvant systemic therapy between 2015 and 2019. We estimated the prevalence of SLN positivity and the diagnostic test characteristics of SLN frozen section. Overall, 662 patients were eligible for inclusion, and 44 patients had one or more positive SLNs (prevalence: 6.6%, 95% confidence interval [CI] 4.9-8.8). There were 490 (74.0%) patients who had intraoperative frozen section, and 19 (3.9%) tested positive among 33 (6.7%) with positive final pathology. Frozen section sensitivity was 57.6% (95% CI 39.2-74.5), specificity was 100% (95% CI 99.2-100), positive predictive value was 100% (95% CI 82.4-100), and negative predictive value was 97.0% (95% CI 95.1-98.4). The sensitivity of frozen section for detection of micrometastases or isolated tumor cells was 35.3% (95% CI 14.2-61.7). In patients with cN0 HER2-positive or triple-negative breast cancer who have been treated with neoadjuvant therapy, positive SLNs are uncommon and frozen section sensitivity is modest. Decisions to defer SLN evaluation to final pathology, which may be reasonable in many settings, can be informed, in part, by these findings.

Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials

ObjectiveTo evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis.MethodsThe literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens.ResultsA total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs.ConclusionIn summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.

Systemic treatment of patients with metastatic neuroendocrine Neoplasia

Due to the complexity and heterogeneity of metastatic NEN an interdisciplinary expert team should be involved in an individualized treatment strategy. SSA is the mainstay of antisecretory treatment in most functioning tumors. In antiproliferative intention SSA are first line treatment in receptor positive low proliferative NET. In intestinal metastatic disease PRRT is best established second line treatment. Further options are Everolimus (labeled) and tyrosine kinase inhibitors (off-label). Everolimus is the only approved drug for antiproliferative treatment in patients with metastatic lung NET, whereas in pancreatic NET more therapeutic options are available (SSA, chemotherapy, PRRT, Sunitinib, Everolimus) without a standard of best sequence. In patients with metastatic NEC standard first line treatment (platinum + etoposide) has not changed for decades and new treatment options for this fatal disease are urgently needed. Benefit of immunotherapy is limited to a small subset of patients - new combinations are under investigation. This review summarizes the standard of care, criteria of treatment selection and new developments for systemic therapy in patients with metastatic NEN.