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ESMO Open Apr 2023Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in... (Review)
Review
Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in cancer treatment, however not all patients benefit from it. Thus new therapies are under investigation, such as anti-TIGIT [anti-T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains] antibodies. TIGIT is an immune checkpoint inhibiting lymphocyte T cells by several mechanisms. In vitro models showed its inhibition could restore antitumor response. Furthermore, its association with anti-PD-(L)1 therapies could synergistically improve survival. We carried out a review of the clinical trial about TIGIT referenced in the PubMed database, finding three published clinical trials on anti-TIGIT therapies. Vibostolimab was evaluated in a phase I alone or in combination with pembrolizumab. The combination had an objective response rate of 26% in patients with a non-small-cell lung cancer (NSCLC) naïve of anti-programmed cell death protein 1 (anti-PD-1). Etigilimab was tested in a phase I alone or in combination with nivolumab, but the study was stopped due to business reasons. In the phase II CITYSCAPE trial, tiragolumab demonstrated higher objective response rate and progression-free survival in combination with atezolizumab than atezolizumab alone in advanced PD-L1-high NSCLC. The ClinicalTrials.gov database references 70 trials of anti-TIGIT in patients with cancer, 47 of them with ongoing recruitment. Only seven were phase III, including five about patients with NSCLC, mostly with combination therapy. Data from phase I-II trials highlighted that targeting TIGIT represents a safe therapeutic approach, with an acceptable toxicity profile maintained when adding anti-PD-(L)1 antibodies. Frequent adverse events were pruritus, rash, and fatigue. Grade 3-4 adverse events were reported in nearly one in three patients. Anti-TIGIT antibodies are under development as a novel immunotherapy approach. A promising research area includes the combination with anti-PD-1 therapies in advanced NSCLCs.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Nivolumab
PubMed: 36933320
DOI: 10.1016/j.esmoop.2023.101184 -
Alimentary Pharmacology & Therapeutics Oct 2021Advances in imaging technology have the potential to transform the early diagnosis and treatment of hepatocellular carcinoma (HCC) through quantitative image analysis.... (Review)
Review
BACKGROUND
Advances in imaging technology have the potential to transform the early diagnosis and treatment of hepatocellular carcinoma (HCC) through quantitative image analysis. Computational "radiomic" techniques extract biomarker information from images which can be used to improve diagnosis and predict tumour biology.
AIMS
To perform a systematic review on radiomic features in HCC diagnosis and prognosis, with a focus on reporting metrics and methodologic standardisation.
METHODS
We performed a systematic review of all full-text articles published from inception through December 1, 2019. Standardised data extraction and quality assessment metrics were applied to all studies.
RESULTS
A total of 54 studies were included for analysis. Radiomic features demonstrated good discriminatory performance to differentiate HCC from other solid lesions (c-statistics 0.66-0.95), and to predict microvascular invasion (c-statistic 0.76-0.92), early recurrence after hepatectomy (c-statistics 0.71-0.86), and prognosis after locoregional or systemic therapies (c-statistics 0.74-0.81). Common stratifying features for diagnostic and prognostic radiomic tools included analyses of imaging skewness, analysis of the peritumoural region, and feature extraction from the arterial imaging phase. The overall quality of the included studies was low, with common deficiencies in both internal and external validation, standardised imaging segmentation, and lack of comparison to a gold standard.
CONCLUSIONS
Quantitative image analysis demonstrates promise as a non-invasive biomarker to improve HCC diagnosis and management. However, standardisation of protocols and outcome measurement, sharing of algorithms and analytic methods, and external validation are necessary prior to widespread application of radiomics to HCC diagnosis and prognosis in clinical practice.
Topics: Carcinoma, Hepatocellular; Hepatectomy; Humans; Liver Neoplasms; Prognosis; Retrospective Studies
PubMed: 34390014
DOI: 10.1111/apt.16563 -
Journal of Thoracic Oncology : Official... Feb 2011Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung... (Review)
Review
International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.
INTRODUCTION
Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.
METHODS
An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach.
RESULTS
The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized.
CONCLUSIONS
This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.
Topics: Adenocarcinoma; Humans; Lung Neoplasms; Neoplasm Staging; Societies, Medical
PubMed: 21252716
DOI: 10.1097/JTO.0b013e318206a221 -
BMC Cancer May 2019Breast cancer (BC) is the most common type of cancer in women worldwide. Post-treatment, patients suffer from side effects and have various rehabilitation needs, which...
BACKGROUND
Breast cancer (BC) is the most common type of cancer in women worldwide. Post-treatment, patients suffer from side effects and have various rehabilitation needs, which means that individualization is fundamental for optimal rehabilitation. This systematic review (SR) of SRs aims to evaluate the current evidence on rehabilitation interventions in female patients following BC treatment.
METHODS
Full-text SRs published in English from 2009 were searched in Embase, PubMed, Cinahl Complete, PsycINFO, AMED, SCOPUS, and Cochrane Library.
INCLUSION CRITERIA
SRs of randomized or non-randomized controlled trials investigating the effects of rehabilitation interventions in women following BC treatment. All outcomes were considered. Methodological quality was evaluated using the AMSTAR 2 tool and interrater agreement was evaluated. Out of 1269 citations retrieved, 37 SRs were included.
RESULTS
Five rehabilitation areas were identified: exercise and physical activity (PA), complementary and alternative medicine (CAM), yoga, lymphoedema treatment, and psychosocial interventions. The most solid evidence was found in exercise/PA and yoga. Exercise interventions improved outcomes such as shoulder mobility, lymphoedema, pain, fatigue and quality of life (QoL). Effects of yoga were shown on QoL, anxiety, depression, sleep disturbance, fatigue and gastrointestinal symptoms. The effect of CAM was shown on nausea, pain, fatigue, anger and anxiety but these results need to be interpreted with caution because of low methodological quality in included studies in the SRs. Among the lymphoedema treatments, positive effects were seen for resistance training on volume reduction and muscle strength and psychosocial interventions such as cognitive behavioural therapy had positive effects on QoL, anxiety, depression and mood disturbance.
CONCLUSIONS
This SR of SRs show solid positive effects of exercise/PA and yoga for women following BC treatment, and provides extended knowledge of the effects of CAM, yoga, lymphoedema treatment and psychosocial interventions. It is evident that more than one intervention could have positive effects on a specific symptom and that the effects depend not only on intervention type but also on how and when the intervention is provided. The results can be used as a foundation for individualized rehabilitation and aid health care professionals in meeting patients' individual needs and preferences.
TRIAL REGISTRATION
PROSPERO ( CRD42017060912 ).
Topics: Breast Neoplasms; Exercise; Female; Humans; Lymphedema; Quality of Life; Resistance Training; Systematic Reviews as Topic; Treatment Outcome; Yoga
PubMed: 31109309
DOI: 10.1186/s12885-019-5648-7 -
JAMA Oncology Feb 2018If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown.
OBJECTIVE
To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens.
DATA SOURCES
A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase."
STUDY SELECTION
Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors.
DATA EXTRACTION AND SYNTHESIS
The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models.
MAIN OUTCOMES AND MEASURES
Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes.
RESULTS
Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events.
CONCLUSIONS AND RELEVANCE
Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cell Cycle Checkpoints; Endocrine Glands; Endocrine System Diseases; Humans; Immunotherapy; Incidence; Neoplasms; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 28973656
DOI: 10.1001/jamaoncol.2017.3064 -
Clinical Microbiology and Infection :... Jan 2019The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored.
OBJECTIVES
To examine the contemporary epidemiology, clinical manifestations, diagnosis and causative pathogens of mucormycosis.
DATA SOURCES
Ovid MEDLINE and Ovid EMBASE from January 2000 to January 2017.
STUDY ELIGIBILITY CRITERIA
Published case reports/series of proven/probable mucormycosis.
PARTICIPANTS
Patients ≥18 years old.
METHODS
Patient characteristics, disease manifestations and causative pathogens were summarized descriptively. Categorical variables were assessed by chi-square test or Fischer's exact test, and continuous variables by the Wilcoxon-Mann-Whitney or Kruskal-Wallis test. Risk factors for the different clinical manifestations of mucormycosis were identified using multivariate logistic regression.
RESULTS
Initial database searches identified 3619 articles of which 600 (851 individual patient cases) were included in the final analysis. Diabetes mellitus was the commonest underlying condition (340/851, 40%) and was an independent risk for rhino-orbital-cerebral mucormycosis (odds ratio (OR) 2.49; 95% CI 1.77-3.54; p < 0.001). Underlying haematological malignancy was associated with disseminated infection (OR 3.86; 95% CI 1.78-8.37; p 0.001), whereas previous solid organ transplantation was associated with pulmonary (OR 3.19; 95% CI 1.50-6.82; p 0.003), gastrointestinal (OR 4.47; 95% CI 1.69-11.80; p 0.003), or disseminated (OR 4.20; 95% CI 1.68-10.46; p 0.002) mucormycosis. Eight genera (24 species) of Mucorales organisms were identified in 447/851 (53%) cases, of which Rhizopus spp. (213/447, 48%) was the most common. Compared with other genera, Rhizopus spp. was predominantly observed in patients with rhino-orbital-cerebral mucormycosis (75/213, 35% versus 34/234, 15%; p < 0.001). Death was reported in 389/851 (46%) patients. Mortality associated with Cunninghamella infections was significantly higher than those caused by other Mucorales (23/30, 71% versus 185/417, 44%; p < 0.001). However, Cunninghamella spp. were isolated primarily in patients with pulmonary (17/30, 57%) or disseminated disease (10/30, 33%).
CONCLUSIONS
Findings from the current review have helped ascertain the association between various manifestations of mucormycosis, their respective predisposing factors and causative organisms.
Topics: Diabetes Mellitus; Hematologic Neoplasms; Humans; Mucorales; Mucormycosis; Rhizopus; Risk Factors
PubMed: 30036666
DOI: 10.1016/j.cmi.2018.07.011 -
The Cochrane Database of Systematic... Nov 2012Cancer-related fatigue is recognised as an important symptom associated with cancer and its treatment. A number of studies have investigated the effects of physical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cancer-related fatigue is recognised as an important symptom associated with cancer and its treatment. A number of studies have investigated the effects of physical activity in reducing cancer-related fatigue. This is an updated version of the original Cochrane review published in The Cochrane Library (2008, Issue 1). The original review identified some benefits of physical activity on fatigue in cancer both during and after adjuvant treatment. We identified a number of limitations in the evidence, providing clear justification for an updated review.
OBJECTIVES
To evaluate the effect of exercise on cancer-related fatigue both during and after cancer treatment.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2011), MEDLINE (1966 to March 2011), EMBASE (1980 to March 2011), CINAHL (1982 to March 2011), British Nursing Index (January 1984 to March 2011), AMED (1985 to March 2011), SIGLE (1980 to March 2011) and Dissertation Abstracts International (1861 to March 2011) using key words. We also searched reference lists off all studies identified for inclusion and relevant reviews. In addition, we handsearched relevant journals and contacted experts in the field of cancer-related fatigue.
SELECTION CRITERIA
We sought and included randomised controlled trials (RCTs) that investigated the effect of exercise on cancer-related fatigue in adults.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the risk of bias of studies and extracted data based upon predefined criteria. Where data were available we performed meta-analyses for fatigue using a random-effects model.
MAIN RESULTS
For this update we identified a total of 56 studies (4068 participants) for inclusion (28 from the original search and 28 from the updated search), with the majority carried out in participants with breast cancer (28 studies). A meta-analysis of all fatigue data, incorporating 38 comparisons, provided data for 1461 participants who received an exercise intervention and 1187 control participants. At the end of the intervention period exercise was seen to be statistically more effective than the control intervention (standardised mean difference (SMD) -0.27, 95% confidence interval (CI) -0.37 to -0.17). Benefits of exercise on fatigue were observed for interventions delivered during or post-adjuvant cancer therapy. In relation to diagnosis, we identified benefits of exercise on fatigue for breast and prostate cancer but not for those with haematological malignancies. Finally, aerobic exercise significantly reduced fatigue but resistance training and alternative forms of exercise failed to reach significance.
AUTHORS' CONCLUSIONS
The findings of the updated review have enabled a more precise conclusion to be made in that aerobic exercise can be regarded as beneficial for individuals with cancer-related fatigue during and post-cancer therapy, specifically those with solid tumours. Further research is required to determine the optimal type, intensity and timing of an exercise intervention.
Topics: Adult; Exercise; Fatigue; Female; Humans; Male; Neoplasms; Randomized Controlled Trials as Topic
PubMed: 23152233
DOI: 10.1002/14651858.CD006145.pub3 -
The Oncologist Feb 2020The loss of muscle mass, known as sarcopenia, is a natural process of aging that is associated with adverse health outcomes regardless of age. Because cancer is a... (Review)
Review
BACKGROUND
The loss of muscle mass, known as sarcopenia, is a natural process of aging that is associated with adverse health outcomes regardless of age. Because cancer is a disease of aging, interest in sarcopenia and its potential impact in multiple cancer populations has increased significantly. Bioelectrical impedance analysis (BIA) is a guideline-accepted method for sarcopenia detection. This systematic review assesses the literature pertaining to BIA use in the detection of sarcopenia in adults with cancer.
MATERIALS AND METHODS
In this systematic review, a search of the literature for randomized controlled trials and observational studies was conducted using MEDLINE, Cochrane CENTRAL, and EMBASE, through July 15, 2019. The study is registered at Prospero (CRD 42019130707). For study inclusion, patients had to be aged 18 years or older and diagnosed with solid or hematological neoplasia, and BIA had to be used to detect sarcopenia.
RESULTS
Through our search strategy, 5,045 articles were identified, of which 24 studies were selected for inclusion in the review (total number of 3,607 patients). In five studies, BIA was rated comparable to axial computed tomography (CT) scan, calf circumference, or grip strength for sarcopenia screening. In 14 studies, BIA-identified sarcopenia was associated with adverse clinical outcomes.
CONCLUSION
BIA is an accurate method for detecting sarcopenia in adults with cancer prior to treatment and is a viable alternative to CT, dual-energy x-ray absorptiometry, and magnetic resonance imaging in oncology clinical practice.
IMPLICATIONS FOR PRACTICE
Bioelectrical impedance analysis (BIA) is an attractive method for identifying sarcopenic patients in clinical practice because it provides an affordable, noninvasive test that can be completed within a few minutes during a clinic visit. BIA does not require highly skilled personnel, and results are immediately available. This systematic review summarizes the literature pertaining to BIA assessment of sarcopenia in adults with cancer, with a focus on its use in diverse cancer populations.
Topics: Absorptiometry, Photon; Adult; Body Composition; Electric Impedance; Humans; Neoplasms; Sarcopenia
PubMed: 32043785
DOI: 10.1634/theoncologist.2019-0600 -
Drugs Jun 2022Trastuzumab deruxtecan (T-DXd) is a novel anti-ERBB2 antibody drug conjugate that appears to be associated with an increased risk of lung toxicity. We performed a...
BACKGROUND AND OBJECTIVE
Trastuzumab deruxtecan (T-DXd) is a novel anti-ERBB2 antibody drug conjugate that appears to be associated with an increased risk of lung toxicity. We performed a systematic review to describe the incidence, severity, and management of T-DXd-induced interstitial lung disease (ILD) or pneumonitis.
METHODS
We searched PubMed/MEDLINE, Embase, Cochrane, and Web of Sciences through to 1 January, 2022, for human clinical trials that assessed T-DXd in adults with ERBB2-positive advanced solid tumors and described the rate of ILD/pneumonitis. Study screening was performed by two researchers. Data were extracted from the full-text articles.
RESULTS
Fourteen studies with a total of 1193 patients with different types of advanced solid malignancies were included in our systematic review. The overall incidence of all-grade ILD/pneumonitis cases that were adjudicated by an independent committee was 11.40% (ILD/pneumonitis cases, n = 136 out of total n = 1193). Grading of the adjudicated T-DXd-induced ILD/pneumonitis was reported in 122 patients with the majority of the cases (78.69%, n = 96) occurring as grade 1 or 2. Death was reported in 13 out of 122 (10.66%) patients. The highest incidence of ILD/pneumonitis was seen in patients with uterine carcinomatosis (26.47%) and non-small cell lung cancer (24.77%). Interstitial lung disease/pneumonitis events were treated with a dose interruption or reduction, treatment discontinuation, corticosteroids, and supportive care.
CONCLUSIONS
Interstitial lung disease/pneumonitis is a well-described, serious, and potentially life-threatening adverse event that is associated with T-DXd. Further studies are needed to identify the risk factors and the underlying pathophysiology of T-DXd-induced ILD/pneumonitis to prevent occurrence and to develop effective management strategies.
Topics: Adult; Camptothecin; Carcinoma, Non-Small-Cell Lung; Humans; Immunoconjugates; Lung Diseases, Interstitial; Lung Neoplasms; Pneumonia; Receptor, ErbB-2; Trastuzumab
PubMed: 35759121
DOI: 10.1007/s40265-022-01736-w -
The Cochrane Database of Systematic... Jan 2022Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines.
OBJECTIVES
To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC.
SEARCH METHODS
We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021.
SELECTION CRITERIA
We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib' with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement.
MAIN RESULTS
Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement. ALK inhibitor versus chemotherapy Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment. ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence). ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period. ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy. Next-generation ALK inhibitor versus crizotinib Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases. Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib. Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib. Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting.
AUTHORS' CONCLUSIONS
Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal.
Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors
PubMed: 34994987
DOI: 10.1002/14651858.CD013453.pub2