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Frontiers in Immunology 2024There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs).
METHODS
We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS.
RESULTS
61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HR and HR both had a strong surrogacy value (R = 0.74 and R = 0.81, respectively). In comparisons testing ICI as monotherapy, HR was the best surrogate, although having a moderate correlation (R = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R ranging from 0.01 to 0.22.
CONCLUSION
In RCTs testing ICIs, the value of potential surrogates for HR was strongly affected by the type of treatment(s) tested. The evidence available supports HR as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST.
Topics: Humans; Immune Checkpoint Inhibitors; Randomized Controlled Trials as Topic; Neoplasms; Biomarkers; Proportional Hazards Models
PubMed: 38348030
DOI: 10.3389/fimmu.2024.1340979 -
Journal of Clinical Medicine Mar 2024The optimal management of duodenal neuroendocrine neoplasms (dNENs) sized 10-20 mm remains controversial and although endoscopic resection is increasingly performed... (Review)
Review
The optimal management of duodenal neuroendocrine neoplasms (dNENs) sized 10-20 mm remains controversial and although endoscopic resection is increasingly performed instead of surgery, the therapeutic approach in this setting is not fully standardized. We performed a systematic review of the literature and a meta-analysis to clarify the outcomes of endoscopic resection for 10-20 mm dNENs in terms of efficacy (i.e., recurrence rate) and safety. A computerized literature search was performed using relevant keywords to identify pertinent articles published until January 2023. Seven retrospective studies were included in this systematic review. The overall recurrence rate was 14.6% (95%CI 5.4-27.4) in 65 patients analyzed, without significant heterogeneity. When considering studies specifically focused on endoscopic mucosal resection, the recurrence rate was 20.5% (95%CI 10.7-32.4), without significant heterogeneity. The ability to obtain the free margin after endoscopic resection ranged between 36% and 100%. No complications were observed in the four studies reporting this information. Endoscopic resection could be the first treatment option in patients with dNENs sized 10-20 mm and without evidence of metastatic disease. Further studies are needed to draw more solid conclusions, particularly in terms of superiority among the available endoscopic techniques.
PubMed: 38592317
DOI: 10.3390/jcm13051466 -
Cancer Medicine Feb 2024While evidence of hyperprogressive disease (HPD) continues to grow, the lack of a consensual definition obscures a proper characterization of HPD incidence. We examined... (Meta-Analysis)
Meta-Analysis
BACKGROUND
While evidence of hyperprogressive disease (HPD) continues to grow, the lack of a consensual definition obscures a proper characterization of HPD incidence. We examined how HPD incidence varies by the tumor type or the type of definition used.
METHODS
We searched PubMed, Embase, the Cochrane Library of Systematic Reviews, and Web of Science from database inception to June 21, 2022. Observational studies reporting HPD incidence, in patients diagnosed with solid malignant tumors and treated with immune checkpoint inhibitors (ICI), were included. Random-effects meta-analyses were performed, and all statistical tests were 2-sided.
RESULTS
HPD incidence was 12.4% (95% CI 10.2%-15.0%) with evidence of heterogeneity (Q = 119.32, p < 0.001). Meta-regression showed that the risk of developing HPD was higher in patients with advanced gastric cancer (adjusted odds ratio [OR], 10.83; 95% CI, 2.14-54.65; p < 0.001), hepatocellular carcinoma (adjusted OR, 7.99; 95% CI, 1.68-38.13; p = 0.006), non-small cell lung cancer (adjusted OR, 7.14; 95% CI, 1.58-32.29; p = 0.005), and mixed or other types (adjusted OR, 5.09; 95% CI, 1.12-23.14, p = 0.018) than in patients with renal cell carcinoma. Across definitions, HPD defined as a tumor growth kinetics ratio ≥ 2 (adjusted OR, 1.82; 95% CI, 1.08-3.07; p = 0.025) based on the Response Evaluation Criteria in Solid Tumors (RECIST) reported higher incidence than when HPD was defined as RECIST-defined progressive disease and a change in the tumor growth rate (TGR) exceeding 50% (∆TGR > 50).
CONCLUSIONS
The incidence of immunotherapy-related HPD may vary across tumor types and definitions used, supporting the argument for a uniform and improved method of HPD evaluation for informed clinical decision-making.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Incidence; Immunotherapy; Liver Neoplasms; Kidney Neoplasms; Disease Progression
PubMed: 38400685
DOI: 10.1002/cam4.6970 -
Clinical and Experimental Medicine Oct 2023Cancer patients are more vulnerable to COVID-19 compared to the general population, but it remains unclear which types of cancer have the highest risk of... (Meta-Analysis)
Meta-Analysis Review
Cancer patients are more vulnerable to COVID-19 compared to the general population, but it remains unclear which types of cancer have the highest risk of COVID-19-related mortality. This study examines mortality rates for those with hematological malignancies (Hem) versus solid tumors (Tumor). PubMed and Embase were systematically searched for relevant articles using Nested Knowledge software (Nested Knowledge, St Paul, MN). Articles were eligible for inclusion if they reported mortality for Hem or Tumor patients with COVID-19. Articles were excluded if they were not published in English, non-clinical studies, had insufficient population/outcomes reporting, or were irrelevant. Baseline characteristics collected included age, sex, and comorbidities. Primary outcomes were all-cause and COVID-19-related in-hospital mortality. Secondary outcomes included rates of invasive mechanical ventilation (IMV) and intensive care unit (ICU) admission. Effect sizes from each study were computed as logarithmically transformed odds ratios (ORs) with random-effects, Mantel-Haenszel weighting. The between-study variance component of random-effects models was computed using restricted effects maximum likelihood estimation, and 95% confidence intervals (CIs) around pooled effect sizes were calculated using Hartung-Knapp adjustments. In total, 12,057 patients were included in the analysis, with 2,714 (22.5%) patients in the Hem group and 9,343 (77.5%) patients in the Tumor group. The overall unadjusted odds of all-cause mortality were 1.64 times higher in the Hem group compared to the Tumor group (95% CI: 1.30-2.09). This finding was consistent with multivariable models presented in moderate- and high-quality cohort studies, suggestive of a causal effect of cancer type on in-hospital mortality. Additionally, the Hem group had increased odds of COVID-19-related mortality compared to the Tumor group (OR = 1.86 [95% CI: 1.38-2.49]). There was no significant difference in odds of IMV or ICU admission between cancer groups (OR = 1.13 [95% CI: 0.64-2.00] and OR = 1.59 [95% CI: 0.95-2.66], respectively). Cancer is a serious comorbidity associated with severe outcomes in COVID-19 patients, with especially alarming mortality rates in patients with hematological malignancies, which are typically higher compared to patients with solid tumors. A meta-analysis of individual patient data is needed to better assess the impact of specific cancer types on patient outcomes and to identify optimal treatment strategies.
Topics: Humans; COVID-19; Hospitalization; Intensive Care Units; Neoplasms; Hematologic Neoplasms
PubMed: 36795239
DOI: 10.1007/s10238-023-01004-5 -
PloS One 2023Electrochemotherapy has gained international traction and commendation in national guidelines as an effective tool in the management of cutaneous malignancies not... (Review)
Review
Electrochemotherapy vs radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies: A systematic review and narrative synthesis.
BACKGROUND
Electrochemotherapy has gained international traction and commendation in national guidelines as an effective tool in the management of cutaneous malignancies not amenable to surgical resection. Despite this, no level 5 evidence exists comparing it to radiotherapy in the treatment of cutaneous malignancies. This systematic review aimed to examine the literature directly and indirectly comparing electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies.
MATERIALS & METHODS
The protocol for this review was registered on the PROSPERO International Prospective Register of Systematic Reviews with the protocol ID CRD42021285415. Searches of MEDLINE, Embase, CINAHL, CENTRAL and ClinicalTrials.gov databases were undertaken from database inception to 28 December 2021. Studies in humans comparing treatment with electrochemotherapy to radiotherapy and reporting tumour response with a minimum four week follow-up were eligible. Risk of bias was assessed using the ROBINS-I tool. Results are provided as a narrative synthesis.
RESULTS
Two case series with a total of 92 patients were identified as relevant to this study. Both case series examined patients with cutaneous squamous cell carcinoma. One case series examined elderly patients with predominantly head/neck lesions. The other examined younger patients with predominantly limb lesions who had cutaneous squamous cell carcinoma directly attributable to a rare skin condition.
CONCLUSION
There is little literature presenting comparative data for electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases. Included studies were marred by serious risk of bias particularly due to confounding. The inherent bias and heterogeneity of the included studies precluded synthesis of a consolidated comparison of clinical outcomes between the two therapies. Further research is required in this domain in the form of clinical trials and observational studies to inform guidelines for electrochemotherapy treatment.
Topics: Humans; Aged; Skin Neoplasms; Carcinoma, Squamous Cell; Electrochemotherapy
PubMed: 37440502
DOI: 10.1371/journal.pone.0288251 -
Frontiers in Immunology 2024The objective of this study was to investigate the risk of cardiovascular toxicities related to PD-1/PD-L1 inhibitors in solid tumors. (Meta-Analysis)
Meta-Analysis
PURPOSE
The objective of this study was to investigate the risk of cardiovascular toxicities related to PD-1/PD-L1 inhibitors in solid tumors.
METHODS
A literature search was performed following the participants, interventions, comparisons, outcomes, and study design (PICOS) principles, and the study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analysis was conducted using Review Manager version 5.4.
RESULTS
This meta-analysis included 69 randomized controlled trials (RCTs) divided into five groups based on the treatment regimens: PD-1/PD-L1 + chemotherapy versus chemotherapy, PD-1/PD-L1 versus chemotherapy, PD-1/PD-L1 versus placebo, PD-1/PD-L1 + CTLA-4 versus PD-1/PD-L1 and PD-1/PD-L1 + CTLA-4 versus chemotherapy. Compared to chemotherapy treatment alone, PD-1/PD-L1 +chemotherapy significantly increased the risk of hypertension [all-grade (OR = 1.27, 95% CI [1.05, 1.53], p = 0.01); grade 3-5 (OR = 1.36, 95% CI [1.04, 1.79], p = 0.03)], hypotension [all-grade (OR = 2.03, 95% CI [1.19, 3.45], p = 0.009); grade 3-5 (OR = 3.60, 95% CI [1.22, 10.60], p = 0.02)], arrhythmia [all-grade (OR = 1.53, 95% CI [1.02, 2.30], p = 0.04); grade 3-5 (OR = 2.91, 95% CI [1.33, 6.39], p = 0.008)] and myocarditis [all-grade (OR = 2.42, 95% CI [1.06, 5.54], p = 0.04)]. The risk of all-grade hypotension (OR = 2.87, 95% CI [1.26, 6.55], p = 0.01) and all-grade arrhythmia (OR = 2.03, 95% CI [1.13, 3.64], p = 0.02) significantly increased when treated with PD-1/PD-L1 inhibitors compared to the placebo. The risks of cardiovascular toxicities are significantly higher with PD-1+CTLA-4 compared to PD-1 alone (OR = 2.02, 95% CI [1.12, 3.66], p = 0.02).
CONCLUSION
PD-1/PD-L1 inhibitor leads to an increased risk of cardiovascular toxicities, especially hypertension, hypotension, arrhythmia, and myocarditis.
Topics: Humans; Arrhythmias, Cardiac; B7-H1 Antigen; CTLA-4 Antigen; Hypertension; Hypotension; Immune Checkpoint Inhibitors; Myocarditis; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 38318172
DOI: 10.3389/fimmu.2024.1255825 -
BMC Oral Health Apr 2024Oral leukoplakia (OLK) is a prevalent precancerous lesion with limited non-pharmacological treatment options. Surgery and various lasers are the mainstay of treatment;... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Oral leukoplakia (OLK) is a prevalent precancerous lesion with limited non-pharmacological treatment options. Surgery and various lasers are the mainstay of treatment; however, their relative efficacy and optimal choice remain unclear. This first network meta-analysis compared the effects of different lasers and surgical excision on post-treatment recurrence and comfort in OLK patients.
METHODS
We searched four databases for relevant randomized controlled trials (RCTs) up to April 2023. The primary outcome was post-treatment recurrence, and secondary outcomes included intraoperative hemorrhage and postoperative pain scores. The Cochrane Risk of Bias tool was used to assess the study quality. Meta-analysis and network meta-analysis were employed to determine efficacy and identify the optimal intervention.
RESULTS
A total of 11 RCTs including 917 patients and 1138 lesions were included. Er,Cr:YSGG laser treatment showed significantly lower recurrence rates compared to CO laser (OR: 0.04; 95% CI: 0.01-0.18), CO laser with margin extension (OR: 0.06; 95% CI: 0.01-0.60), Er:YAG laser (OR: 0.10; 95% CI: 0.03-0.37), electrocautery (OR: 0.03; 95% CI: 0.00-0.18), and standard care (OR: 0.08; 95% CI: 0.02-0.33). Er,Cr:YSGG laser also ranked the best for reducing recurrence, followed by standard care and CO laser combined with photodynamic therapy (PDT). Er:YAG and Er:Cr:YSGG lasers minimized bleeding and pain, respectively. None of the interventions caused severe adverse effects.
CONCLUSION
For non-homogeneous OLK, Er:YAG, Er:Cr:YSGG, and CO laser combined with PDT offer promising alternatives to surgical excision, potentially reducing recurrence and improving patient comfort. Further high-quality RCTs are necessary to confirm these findings and determine the optimal laser-PDT combination for OLK treatment.
Topics: Humans; Network Meta-Analysis; Carbon Dioxide; Patient Comfort; Laser Therapy; Leukoplakia, Oral; Lasers, Solid-State
PubMed: 38632580
DOI: 10.1186/s12903-024-04179-9 -
International Journal of Molecular... May 2024Chemokines orchestrate many aspects of tumorigenic processes such as angiogenesis, apoptosis and metastatic spread, and related receptors are expressed on tumor cells as... (Meta-Analysis)
Meta-Analysis Review
Chemokines orchestrate many aspects of tumorigenic processes such as angiogenesis, apoptosis and metastatic spread, and related receptors are expressed on tumor cells as well as on inflammatory cells (e.g., tumor-infiltrating T cells, TILs) in the tumor microenvironment. Expressional changes of chemokines and their receptors in solid cancers are common and well known, especially in affecting colorectal cancer patient outcomes. Therefore, the aim of this current systematic review and meta-analysis was to classify chemokines as a prognostic biomarker in colorectal cancer patients. A systematic literature search was conducted in PubMed, CENTRAL and Web of Science. Information on the chemokine expression of 25 chemokines in colorectal cancer tissue and survival data of the patients were investigated. The hazard ratio of overall survival and disease-free survival with chemokine expression was examined. The risk of bias was analyzed using Quality in Prognosis Studies. Random effects meta-analysis was performed to determine the impact on overall respectively disease survival. For this purpose, the pooled hazard ratios (HR) and their 95% confidence intervals (CI) were used for calculation. Twenty-five chemokines were included, and the search revealed 5556 publications. A total of thirty-one publications were included in this systematic review and meta-analysis. Overexpression of chemokine receptor CXCR4 was associated with both a significantly reduced overall survival (HR = 2.70, 95%-CI: 1.57 to 4.66, = 0.0003) as well as disease-free survival (HR = 2.68, 95%-CI: 1.41 to 5.08, = 0.0026). All other chemokines showed either heterogeneous results or few studies were available. The overall risk of bias for CXCR4 was rated low. At the current level of evidence, this study demonstrates that CXCR4 overexpression in patients with colorectal cancer is associated with a significantly diminished overall as well as disease-free survival. Summed up, this systematic review and meta-analysis reveals CXCR4 as a promising prognostic biomarker. Nevertheless, more evidence is needed to evaluate CXCR4 and its antagonists serving as new therapeutic targets.
Topics: Humans; Colorectal Neoplasms; Prognosis; Biomarkers, Tumor; Chemokines; Receptors, CXCR4; Disease-Free Survival
PubMed: 38791414
DOI: 10.3390/ijms25105374 -
The Journal of Histochemistry and... Dec 2023Fluorescence confocal microscopy (FCM) is a novel technology that enables rapid high-resolution digital imaging of non-formalin-fixed tissue specimens and offers... (Review)
Review
Fluorescence confocal microscopy (FCM) is a novel technology that enables rapid high-resolution digital imaging of non-formalin-fixed tissue specimens and offers real-time positive surgical margin identification. In this systematic review, we evaluated the accuracy metrics of ex vivo FCM for intraoperative margin assessment of different tumor types. A systematic search of MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus was performed for relevant papers (PROSPERO ID: CRD42022372558). We included 14 studies evaluating four types of microscopes in six different tumor types, including breast, prostate, central nervous system, kidney, bladder, and conjunctival tumors. Using the Quality Assessment of Diagnostic Accuracy Studies tool, we identified a high risk of bias in patient selection (21%) and index test (36%) of the included studies. Overall, we found that FCM has good accuracy metrics in all tumor types, with high sensitivity and specificity (>80%) and almost perfect concordance (>90%) against final pathology results. Despite these promising findings, the quality of the available evidence and bias concerns highlight the need for adequately designed studies to further define the role of ex vivo FCM in replacing the frozen section as the tool of choice for intraoperative margin assessment.
Topics: Male; Humans; Microscopy, Confocal; Microscopy, Fluorescence; Neoplasms
PubMed: 37968920
DOI: 10.1369/00221554231212948 -
International Journal of Molecular... Jul 2023In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options... (Review)
Review
In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.
Topics: Humans; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Immunotherapy; Lung Neoplasms; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Interleukin-1beta
PubMed: 37511306
DOI: 10.3390/ijms241411547