Purpose To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with ...erlotinib for non–small cell lung cancer. Design Retrospective observational case series. Methods Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non–small cell lung cancer. The US Food & Drug Administration–recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG). Results Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss. Conclusions These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1–2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.
Background
Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). ...Recently, an SPLC risk‐prediction model (called SPLC‐RAT) was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking. The predictive performance of SPLC‐RAT was evaluated in a hospital‐based cohort of lung cancer survivors.
Methods
The authors analyzed data from 8448 ever‐smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997–2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC‐RAT and further explored the potential of improving SPLC detection through risk model‐based surveillance using SPLC‐RAT versus existing clinical surveillance guidelines.
Results
Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person‐years. The application of SPLC‐RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10‐year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC‐RAT development cohort), the observed SPLC incidence was significantly elevated in the high‐risk versus low‐risk subgroup (13.1% vs. 1.1%, p < 1 × 10–6). The risk‐based surveillance through SPLC‐RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow‐ups needed to detect one SPLC (162 vs. 202).
Conclusion
In a large, hospital‐based cohort, the authors validated the predictive performance of SPLC‐RAT in identifying high‐risk survivors of SPLC and showed its potential to improve SPLC detection through risk‐based surveillance.
Plain Language Summary
Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC).
However, no evidence‐based guidelines for SPLC surveillance are available for lung cancer survivors.
Recently, an SPLC risk‐prediction model was developed and validated using data from population‐based epidemiological cohorts and clinical trials, but real‐world validation has been lacking.
Using a large, real‐world cohort of lung cancer survivors, we showed the high predictive accuracy and risk‐stratification ability of the SPLC risk‐prediction model.
Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model‐based surveillance strategies compared to the existing consensus‐based clinical guidelines, including the National Comprehensive Cancer Network.
Given the rapidly growing number of lung cancer survivors who are now at high risk of developing second primary lung cancer (SPLC), previous studies have identified SPLC risk factors and developed SPLC risk‐prediction models, but they lack insight into real‐world validation to help improve clinical decision‐making in SPLC surveillance for lung cancer survivors. Using a large, hospital‐based real‐world cohort of lung cancer survivors, the authors validated the predictive accuracy of an SPLC risk‐prediction model (area under the curve of 0.81), that can identify high‐risk lung cancer survivors for SPLC and can be incorporated into clinical decision‐making for SPLC surveillance to improve the systematic management of lung cancer survivors.
Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer ...from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of "liquid biopsies" from cancer patients.
Abstract
Background
Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), but little is known about the survival impact of SPLC diagnosis.
Methods
We analyzed data ...from 138 969 patients in the Surveillance, Epidemiology, and End Results (SEER), who were surgically treated for initial primary lung cancer (IPLC) in 1988-2013. Each patient was followed from the date of IPLC diagnosis to SPLC diagnosis (for those with SPLC) and last vital status through 2016. We performed multivariable Cox regression to evaluate the association between overall survival and SPLC diagnosis as a time-varying predictor. To investigate potential effect modification, we tested interaction between SPLC and IPLC stage. Using data from the Multiethnic Cohort Study (MEC) (n = 1540 IPLC patients with surgery), we evaluated the survival impact of SPLC by smoking status. All statistical tests were 2-sided.
Results
A total of 12 115 (8.7%) patients developed SPLC in SEER over 700 421 person-years of follow-up. Compared with patients with single primary lung cancer, those with SPLC had statistically significantly reduced overall survival (hazard ratio HR = 2.12, 95% confidence interval CI = 2.06 to 2.17; P < .001). The effect of SPLC on reduced survival was more pronounced among patients with early stage IPLC vs advanced-stage IPLC (HR = 2.14, 95% CI = 2.08 to 2.20, vs HR = 1.43, 95% CI = 1.21 to 1.70, respectively; Pinteraction < .001). Analysis using MEC data showed that the effect of SPLC on reduced survival was statistically significantly larger among persons who actively smoked at initial diagnosis vs those who formerly or never smoked (HR = 2.31, 95% CI = 1.48 to 3.61, vs HR = 1.41, 95% CI = 0.98 to 2.03, respectively; Pinteraction = .04).
Conclusions
SPLC diagnosis is statistically significantly associated with decreased survival in SEER and MEC. Intensive surveillance targeting patients with early stage IPLC and active smoking at IPLC diagnosis may lead to a larger survival benefit.
•Patients with HER2-mutant advanced/metastatic NSCLC used a wide range of therapies.•Duration of treatment across lines of therapy was modest.•HER2-directed therapy was infrequently used in early ...lines of treatment before 2021.
Real-world data for advanced/metastatic non–small-cell lung cancer (NSCLC) with mutations in human epidermal growth factor 2 (HER2) are scarce. We aimed to assess treatment patterns and outcomes among patients with HER2-mutant advanced/metastatic NSCLC.
This retrospective nationwide electronic health record study evaluated patient characteristics, treatment patterns, treatment duration, and overall survival for adults with HER2-mutant advanced/metastatic NSCLC without epidermal growth factor receptor mutation.
Of 55 included patients, median (quartile 1 Q1–quartile 3 Q3) age was 63.0 (58.0-72.0) years, 42 (76%) were women, and 39 (71%) were current/former smokers. In first-line therapy, 14 regimens were used for median (Q1-Q3) duration of 3.1 (2.4-6.2) months, with most patients (n = 39, 71%) receiving platinum-based chemotherapy alone or in combination with other agents. Median (95% CI) overall survival from first-line treatment initiation was 19.0 (12.2–not estimable) months, with no significant association with age, sex, or smoking status. Thirty-five (64%) patients received second-line therapy for median (Q1-Q3) duration of 3.3 (2.0-5.2) months. Fourteen second-line regimens were used; most commonly immunotherapy alone or in combination with other agents (n = 16, 46%). Sixteen (46%) patients received third-line therapy for median (Q1-Q3) duration of 1.9 (1.3-2.7) months. Nine third-line regimens were used, with 7 (44%) patients receiving HER2-directed agents.
First- and second-line treatments for HER2-mutant NSCLC varied widely and treatment duration was short. The approval of trastuzumab deruxtecan for NSCLC supports wider HER2 testing to identify eligible patients for HER2-directed therapy.
Real-world treatment patterns and outcomes of patients with HER2-mutant advanced/metastatic non–small-cell lung cancer (NSCLC) are not well-described. This study used data from 2016 to 2020 to reveal wide variability and modest durations of treatment, with HER2-directed therapies not used until later lines. Recent approval of HER2-directed monoclonal antibody trastuzumab deruxtecan offers another treatment option and supports wider HER2 testing.
In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and ...radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. Furthermore, although radiographic surrogate end points, such as PFS and response rate, generally correlate with clinical benefit in the setting of cytotoxic chemotherapy and molecular targeted therapies, novel immunotherapies might have atypical response kinetics, which confounds radiographic interpretation. In this Review, we discuss the need to develop alternative or surrogate end points for lung cancer clinical trials, and focus on several new biomarkers that could serve as surrogate end points, including functional imaging biomarkers, circulating factors (tumour proteins, DNA, and cells), and pharmacodynamic tumour markers. By enabling the size, duration, and complexity of cancer trials to be reduced, biomarker end points hold the promise to accelerate drug development and improve patient outcomes.
Many studies have shown that invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis can mimic radiographic and clinical features of primary lung cancer. However, more research surveying ...the incidence and outcomes of these fungal infections among patients with a history of lung cancer is needed. The aim of this study was to describe the occurrence and clinical outcomes of opportunistic invasive fungal infections that can mimic tumors in non–small-cell lung cancer patients.
Patients seen at Stanford University Medical Center from January 1, 2007, to May 1, 2020, with pulmonary aspergillosis, cryptococcosis, or mucormycosis after non–small-cell lung cancer (NSCLC) diagnosis were reviewed. The European Organization for Research and Treatment of Cancer National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to classify patients with evidence of proven or probable invasive fungal infection within our cohort.
A total of 12 patients with proven or probable invasive mold infection (including 8 cases of aspergillosis) and 1 patient with proven cryptococcosis were identified, without any cases of mucormycosis. Of this cohort, 6 patients (46%) showed radiographic findings that were found to be most consistent with lung cancer by radiologists. Eight cases (62%) were suspected of cancer recurrence or progression by the treatment team on the basis of additional considerations of medical history and clinical symptoms. Most patients had active NSCLC or had a history of recurrence without active NSCLC at the time of fungal discovery (11 patients; 85%). Most patients died without full recovery (7 patients; 54%).
Invasive pulmonary aspergillosis and cryptococcosis can often be mistaken as cancer recurrence or progression in patients with a history of NSCLC because of mimicking radiographic and clinical characteristics.
Presentations of opportunistic fungal infections, including invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis, can mimic radiographic and clinical manifestations of pulmonary neoplasms. In patients with a history of lung cancer, these findings may initially be presumed to reflect cancer recurrence or progression. In this retrospective study, we aimed to study the occurrence and nature of invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis in patients with a history of non–small-cell lung cancer. In our cohort, 62% of proven or probable aspergillosis or cryptococcosis were initially suspected to be metastatic or recurrent cancer by treatment teams, underscoring the importance that fungal infectious diseases should be considered as part of the differential diagnosis of new pulmonary lesions.
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