Contemporary Concise Review 2023: Advances in lung cancer and interventional pulmonology.

Eligibility criteria for lung cancer screening increasingly need to consider family history of lung cancer, as well as age and smoking status. Lung cancer screening will reveal a multitude of incidental findings, of variable clinical significance, and with a need for clear pathways of management. Pulmonary nodule sampling is enhanced by intra-procedural imaging and cutting-edge robotic technology. Systematic thoracic lymph node sampling has implications for treatment efficacy. Bronchoscopic ablative techniques are feasible for peripheral lung cancers. Bronchoscopic sampling continues to have a high yield for lung cancer molecular characterization. Immunotherapy indications have expanded to include early stage and resectable lung cancer.

Contemporary Concise Review 2021: Pulmonary nodules from detection to intervention.

The US Preventive Task Force (USPSTF) has updated screening criteria by expanding age range and reducing smoking history required for eligibility; the International Lung Screen Trial (ILST) data have shown that PLCOM2012 performs better for eligibility than USPSTF criteria. Screening adherence is low (4%-6% of potential eligible candidates in the United States) and depends upon multiple system and patient/candidate-related factors. Smoking cessation in lung cancer improves survival (past prospective trial data, updated meta-analysis data); smoking cessation is an essential component of lung cancer screening. Circulating biomarkers are emerging to optimize screening and early diagnosis. COVID-19 continues to affect lung cancer treatment and screening through delays and disruptions; specific operational challenges need to be met. Over 70% of suspected malignant lesions develop in the periphery of the lungs. Bronchoscopic navigational techniques have been steadily improving to allow greater accuracy with target lesion approximation and therefore diagnostic yield. Fibre-based imaging techniques provide real-time microscopic tumour visualization, with potential diagnostic benefits. With significant advances in peripheral lung cancer localization, bronchoscopically delivered ablative therapies are an emerging field in limited stage primary and oligometastatic disease. In advanced stage lung cancer, small-volume samples acquired through bronchoscopic techniques yield material of sufficient quantity and quality to support clinically relevant biomarker assessment.

Unexpected case of accelerated silicosis in a female quarry worker.

Silicosis is a progressive and irreversible fibrotic occupational lung disease caused by inhalation of respirable crystalline silica (RCS). Recently, outbreaks have been reported in industries involving direct work with high silica-containing materials, such as artificial stone. Here, we describe an unexpected diagnosis made in an asymptomatic 33-year-old female worker employed for 4 years at a quarry for rhyodacite and rhyolite which contain 70% silicon dioxide. Chest computed tomography demonstrated small nodules in the upper lobes and larger ill-defined areas of opacity. Bronchoalveolar lavage revealed fine birefringent material within the cytoplasm of alveolar macrophages, representing silica. Transbronchial biopsies of lung parenchyma and endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes did not reveal features of sarcoidosis, tuberculosis, or malignancy. As such, a diagnosis of accelerated silicosis was confirmed and represents the first reported case in a female worker at a rhyodacite and rhyolite quarry.

Lung cancer screening in Australia and New Zealand: the evidence and the challenge.

Lung cancer remains the commonest cause of cancer death in Australia and New Zealand. Targeted screening of individuals at highest risk of lung cancer aims to detect early stage disease, which may be amenable to potentially curative treatment. While current policy recommendations in Australia and New Zealand have acknowledged the efficacy of lung cancer screening in clinical trials, there has been no implementation of national programmes. With the recent release of findings from large international trials, the evidence and experience in lung cancer screening has broadened. This article discusses the latest evidence and implications for Australia and New Zealand.

Silica-associated lung disease: An old-world exposure in modern industries.

Despite silica dust exposure being one of the earliest recognized causes of lung disease, Australia, USA, Israel, Turkey and other countries around the world have recently experienced significant outbreaks of silicosis. These outbreaks have occurred in modern industries such as denim jean production, domestic benchtop fabrication and jewellery polishing, where silica has been introduced without recognition and control of the hazard. Much of our understanding of silica-related lung disease is derived from traditional occupations such as mining, whereby workers may develop slowly progressive chronic silicosis. However, workers in modern industries are developing acute and accelerated silicosis over a short period of time, due to high-intensity silica concentrations, oxidative stress from freshly fractured silica and a rapid pro-inflammatory and pro-fibrotic response. Appropriate methods of screening and diagnosis remain unclear in these workers, and a significant proportion may go on to develop respiratory failure and death. There are no current effective treatments for silicosis. For those with near fatal respiratory failure, lung transplantation remains the only option. Strategies to reduce high-intensity silica dust exposure, enforced screening programmes and the identification of new treatments are urgently required.

Diagnostic utility and accuracy of rapid on-site evaluation of bronchoscopic brushings.

The aim of the study was to determine the accuracy of rapid on-site examinations, performed on transbronchial brushings of peripheral pulmonary lesions, in determining final bronchoscopic diagnosis. In addition to determining if rapid on-site examination impacts procedural outcomes. A prospective cohort study of consecutive patients with peripheral pulmonary lesions, which had been located by radial endobronchial ultrasound, was undertaken. Bronchoscopy was terminated if rapid on-site examination demonstrated diagnostic malignant material. Non-diagnostic rapid on-site examination resulted in further bronchoscopic sampling, including transbronchial lung biopsy and/or sampling from different locations. 128 peripheral pulmonary lesions were located by endobronchial ultrasound in 118 patients. The final bronchoscopic diagnoses included nonsmall cell lung cancer (n=76), carcinoid (n=3), and metastatic malignancy (n=3). Procedure times were significantly shorter for procedures when rapid on-site examinations demonstrated malignancy compared to those where rapid on-site examination was non-diagnostic (19±8 min versus 31±11 min, respectively; p<0.0001). In four procedures, initial negative rapid on-site examination results prompted redirection of sampling from alternate bronchial segments, resulting in positive diagnostic tissue being obtained. Positive and negative predictive value of rapid on-site examination for a malignant bronchoscopic diagnosis was 63 (97%) out of 65, and 43 (68%) out of 63, respectively. Rapid on-site examination of brushing specimens has a very high, positive, predictive value for bronchoscopic diagnosis of cancer and shortens the bronchoscopy procedure times. It has the potential to reduce complications, improve cost-effectiveness, and may improve diagnostic performance via live feedback.

Nebulised granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) results from impaired macrophage-mediated clearance of alveolar surfactant lipoproteins. Whole lung lavage has been the first-line treatment but recent reports suggest the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF). We aimed to review the efficacy and safety of nebulised GM-CSF in aPAP. METHODS: We conducted a systematic review and meta-analysis searching Embase, CINAHL, MEDLINE and Cochrane Collaborative databases (1946-1 April 2022). Studies included patients aged >18 years with aPAP receiving nebulised GM-CSF treatment and a comparator cohort. Exclusion criteria included secondary or congenital pulmonary alveolar proteinosis, GM-CSF allergy, active infection or other serious medical conditions. The protocol was prospectively registered with PROSPERO (CRD42021231328). Outcomes assessed were St George's Respiratory Questionnaire (SGRQ), 6-min walk test (6MWT), gas exchange (diffusing capacity of the lung for carbon monoxide (D LCO) % predicted) and arterial-alveolar oxygen gradient. RESULTS: Six studies were identified for review and three for meta-analysis, revealing that SGRQ score (mean difference -8.09, 95% CI -11.88- -4.3, p<0.0001), functional capacity (6MWT) (mean difference 21.72 m, 95% CI -2.76-46.19 m, p=0.08), gas diffusion (D LCO % predicted) (mean difference 5.09%, 95% CI 2.05-8.13%, p=0.001) and arterial-alveolar oxygen gradient (mean difference -4.36 mmHg, 95% CI -7.19- -1.52 mmHg, p=0.003) all significantly improved in GM-CSF-treated patients with minor statistical heterogeneity (I2=0%). No serious trial-related adverse events were reported. CONCLUSIONS: Patients with aPAP treated with inhaled GM-CSF demonstrated significant improvements in symptoms, dyspnoea scores, lung function, gas exchange and radiology indices after treatment with nebulised GM-CSF of varying duration. There is an important need to review comparative effectiveness and patient choice in key clinical outcomes between the current standard of care, whole lung lavage, with the noninvasive treatment of nebulised GM-CSF in aPAP.

Overexpression of MRPL19 in predicting poor prognosis and promoting the development of lung adenocarcinoma.

Background: Mitochondrial ribosomal protein L19 (MRPL19) is a member of the mitochondrial ribosomal protein (MRP) family. MRPs have a role in the progression of many cancers. However, the role of MRPL19 in lung adenocarcinoma (LUAD) is yet unknown. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, real-time polymerase chain reaction, and immunohistochemistry (IHC) were used to assess MRPL19 expression and clinical relevance. Gene Expression Profiling Interactive Analysis (GEPIA) and the online Kaplan-Meier (KM) Plotter database were used to determine the prognostic significance. Through use of LinkedOmics, genes that were coexpressed with MRPL19 and its regulators were identified. The biological roles of MRPL19 were investigated through R-implemented packages and RNA interference. The Tumor Immune Estimation Resource (TIMER) was employed to assess the connection between MRPL19 expression and infiltrated immune cells in LUAD. Results: MRPL19 expression in LUAD was upregulated and was correlated with lymph node metastasis, differentiation level, and tumor status. MRPL19 was prognostic and associated with poor prognosis. Functional network analysis revealed that MRPL19 may be associated with the cell cycle, cell adhesion molecules, spliceosome, and T-helper cell differentiation and was regulated by several microRNA and the E2F family. The gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network indicated that MRPL19 was correlated with cancer proliferation signaling pathways. The immune infiltration analysis revealed a correlation between MRPL19 expression and the extent of B cells, CD4+ T cells, and dendritic cells' infiltration in LUAD. Additionally, MRPL19 knockdown in LUAD cells substantially reduced cell growth, migration, and invasion of malignant cells. Conclusions: The poor prognosis and immunological infiltration in LUAD were significantly associated with MRPL19, which may have pro-oncogenic effects on the disease.

Heterogeneity of tumour mutational burden in metastatic NSCLC demonstrated by endobronchial ultrasound sampling.

Introduction: Tumour mutational burden (TMB) is an important emerging biomarker for immune checkpoint inhibitors (ICI). The stability of TMB values across distinct EBUS tumour regions is not well defined in advanced lung cancer patients. Methods: This study included a whole-genome sequencing cohort (n=11, LxG cohort) and a targeted Oncomine TML panel cohort (n=10, SxD cohort), where paired primary and metastatic samples were obtained by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA). Results: The LxG cohort displayed a strong correlation between the paired primary and metastatic sites, with a median TMB score of 7.70 ± 5.39 and 8.31 ± 5.88 respectively. Evaluation of the SxD cohort demonstrated greater inter-tumoural TMB heterogeneity, where Spearman correlation between the primary and metastatic sites fell short of significance. Whilst median TMB scores were not significantly different between the two sites, 3 out of 10 paired samples were discordant when using a TMB cut-off of 10 mutations per Mb. In addition, PD-L1 copy number and KRAS mutations were assessed, demonstrating the feasibility of performing multiple molecular tests relevant to ICI treatment using a single EBUS sample. We also observed good consistency in PD-L1 copy number and KRAS mutation, where cut-off estimates were consistent across the primary and metastatic sites. Conclusions: Assessment of TMB acquired by EBUS from multiple sites is highly feasible and has the potential to improve accuracy of TMB panels as a companion diagnostic test. We demonstrate similar TMB values across primary and metastatic sites, however 3 out of 10 samples displayed inter-tumoural heterogeneity that would alter clinical management.

Differential organ-specific tumor response to first-line immune checkpoint inhibitor therapy in non-small cell lung cancer-a retrospective cohort study.

Background: Immune checkpoint inhibitors (ICIs) possess remarkable clinical effectiveness in non-small cell lung cancer (NSCLC). Different immune profiles of tumors may play a key role in the efficacy of treatment with ICIs. This article aimed to determine the differential organ responses to ICI in individuals with metastatic NSCLC. Methods: This research analyzed data of advanced NSCLC patients receiving first-line treatment with ICIs. Major organs such as the liver, lung, adrenal glands, lymph nodes and brain were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST-improved organ-specific response criteria. Results: A retrospective analysis was conducted on a total of 105 individuals with advanced NSCLC with programmed death ligand-1 (PD-L1) expression ≥50% who received single agent anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies as first-line therapy. Overall, 105 (100%), 17 (16.2%), 15 (14.3%), 13 (12.4%), and 45 (42.8%) individuals showed measurable lung tumors and liver, brain, adrenal, and other lymph node metastases at baseline. The median size of the lung, liver, brain, adrenal gland, and lymph nodes were 3.4, 3.1, 2.8, 1.9, and 1.8 cm, respectively. The results recorded mean response times of 2.1, 3.4, 2.5, 3.1, and 2.3 months, respectively. Organ-specific overall response rates (ORRs) were 67%, 30.6%, 34%, 39%, and 59.1%, respectively, with the liver having the lowest remission rate and lung lesions having the highest remission rate. There were 17 NSCLC patients with liver metastasis at baseline, and 6 had different responses to ICI treatment, with remission in the primary lung site and progressive disease (PD) in the metastatic liver site. At baseline, the mean progression-free survival (PFS) of the 17 patients with liver metastasis and 88 patients without liver metastasis was 4.3 and 7 months, respectively (P=0.02, 95% CI: 0.691 to 3.033). Conclusions: The liver metastases of NSCLC may be less responsive to ICIs than other organs. The lymph nodes respond most favorably to ICIs. Further strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.

Methods for assessment of the tumour microenvironment and immune interactions in non-small cell lung cancer. A narrative review.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. Immunotherapy with immune checkpoint inhibitors (ICI) has significantly improved outcomes in some patients, however 80-85% of patients receiving immunotherapy develop primary resistance, manifesting as a lack of response to therapy. Of those that do have an initial response, disease progression may occur due to acquired resistance. The make-up of the tumour microenvironment (TME) and the interaction between tumour infiltrating immune cells and cancer cells can have a large impact on the response to immunotherapy. Robust assessment of the TME with accurate and reproducible methods is vital to understanding mechanisms of immunotherapy resistance. In this paper we will review the evidence of several methodologies to assess the TME, including multiplex immunohistochemistry, imaging mass cytometry, flow cytometry, mass cytometry and RNA sequencing.

Association between the modified lung immune predictive index and clinical outcomes of advanced non-small cell lung cancer treated with first-line immune checkpoint inhibitors combined with chemotherapy.

Background: As revealed by previous studies, the modified lung immune predictive index (mLIPI) can predict outcomes in patients with lung cancer receiving single-agent immunotherapy. However, the application value of the mLIPI for patients treated with combination immunotherapy requires further investigation. In this study, we aimed to explore the relationship between the mLIPI and the efficacy of treatment together with the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving first-line immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy. Methods: In this retrospective study, we enrolled patients with advanced NSCLC treated with ICIs plus chemotherapy from March 2019 to June 2022. The patients were classified into good, intermediate, and poor/very poor groups according to their mLIPI before treatment. We further calculated the disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the three groups. The predictive ability of the mLIPI was evaluated by plotting a time-dependent receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Results: A total of 209 patients were included in this study. There were 75 patients in the good group, 114 patients in the intermediate group, and 20 patients in the poor/very poor group. The median PFS was 11.2 months [95% confidence interval (CI): 8.763-13.704] in the good group; 8.1 months (95% CI: 7.354-8.846) in the intermediate group; and 5.4 months (95% CI: 2.142-8.658) in the poor/very poor group. The median OS was not reached in the good group, 29.5 months (95% CI: 23.555-35.512) in the intermediate group, and 14.5 months (95% CI: 8.567-20.366) in the poor/very poor group (P<0.05). Multivariate analysis showed that the mLIPI was independently associated with PFS and OS (P<0.05); the AUC values of the mLIPI for predicting PFS at 3, 6, and 9 months were 0.673, 0.637, and 0.614, respectively, and for predicting OS at 6, 12, and 24 months were 0.715, 0.655, and 0.625, respectively. Conclusions: The pretreatment mLIPI could be used to predict outcomes in patients with NSCLC receiving first-line ICIs plus chemotherapy.

Hospital-based multidisciplinary lung cancer care in Australia: a survey of the landscape in 2021.

INTRODUCTION: Lung cancer is the leading cause of cancer death in Australia and has the highest cancer burden. Numerous reports describe variations in lung cancer care and outcomes across Australia. There are no data assessing compliance with treatment guidelines and little is known about lung cancer multidisciplinary team (MDT) infrastructure around Australia. METHODS: Clinicians from institutions treating lung cancer were invited to complete an online survey regarding the local infrastructure for lung cancer care and contemporary issues affecting lung cancer. RESULTS: Responses from 79 separate institutions were obtained representing 72% of all known institutions treating lung cancer in Australia. Most (93.6%) held a regular MDT meeting although recommended core membership was only achieved for 42/73 (57.5%) sites. There was no thoracic surgery representation in 17/73 (23.3%) of MDTs and surgery was less represented in regional and low case volume centres. Specialist nurses were present in just 37/79 (46.8%) of all sites. Access to diagnostic and treatment facilities was limited for some institutions. IT infrastructure was variable and most sites (69%) do not perform regular audits against guidelines. The COVID-19 pandemic has driven most sites to incorporate virtual MDT meetings, with variable impact around the country. Clinician support for a national data-driven approach to improving lung cancer care was unanimous. DISCUSSION: This survey demonstrates variations in infrastructure support, provision and membership of lung cancer MDTs, in particular thoracic surgery and specialist lung cancer nurses. This heterogeneity may contribute to some of the well-documented variations in lung cancer outcomes in Australia.

Rate and risk factors of recurrent immune checkpoint inhibitor-related pneumonitis in patients with lung cancer.

Background: Immune checkpoint inhibitors (ICIs) have become standard treatments for lung cancer patients. Immune checkpoint inhibitor-related pneumonitis (CIP) was the leading cause of death among ICIs-related adverse events (irAEs). Recurrent episodes of CIP without rechallenge of ICIs were reported in several cases and maybe a unique feature of CIP. Knowledge gaps remain regarding the rate and risk factors associated to CIP's recurrence. Methods: Data from 1,102 lung cancer patients receiving ICIs treatment between January 2016 and January 2021 were retrospectively collected and analyzed. CIP was diagnosed according to typical clinical features and/or new typical imaging changes. Recurrence of CIP (CIP-R) was defined as recurrent CIP after initial CIP improved after proper treatment. Logistic regression was used to assess risk factors associated with CIP recurrence. Results: Eighty out of 1,102 (7.26%) patients were diagnosed with CIP. Twenty of those 78 (25.64%) patients suffered CIP-R, 2 patients died and were therefore excluded from the denominator. The median onset of initial pneumonitis for patients without and with recurrence was 3.49 months [interquartile range (IQR), 0.26-31.93 months] and 2.78 months (IQR, 1.22-20.93 months), respectively (P=0.48). The median interval duration between initial CIP and CIP-R was 1.54 months (IQR, 0.98-16.70 months). Recurrence of CIP was more common in males (P=0.03), squamous histology (P=0.016), and in patients who received chest radiotherapy (P=0.049). The duration of prednisolone equivalent dose ≥15 mg/day in CIP-R was significantly shorter, at 3.71 weeks (2.86-6.57 weeks) compared with 6.36 weeks in those without recurrence (IQR, 3.12-9.86 weeks) (P=0.001). Non-squamous histology [odds ratio (OR), 0.182; 95% confidence interval (CI): 0.038-0.860; P=0.031] and prolonged administration of prednisolone equivalent dose ≥15 mg/day for more than 4 weeks (OR, 0.082; 95% CI: 0.02-0.342; P=0.001) were independently associated with a decreased odds of CIP-R development. Conclusions: CIP-R in a real-world lung cancer cohort is not uncommon, both in patients with and without rechallenge of ICIs. A duration of prednisolone equivalent dose ≥15 mg/day of at least 4 weeks during the tapering process of corticosteroids were recommend in patients with CIP.

Impact of smoking status and chronic obstructive pulmonary disease on pulmonary complications post lung cancer surgery.

INTRODUCTION: Smoking and chronic obstructive pulmonary disease (COPD) are associated with an increased risk of post-operative pulmonary complications (PPCs) following lung cancer resection. It remains unclear whether smoking cessation reduces this risk. METHODS: Retrospective review of a large, prospectively collected database of over 1000 consecutive resections for lung cancer in a quaternary lung cancer centre over a 23-year period. RESULTS: One thousand and thirteen patients underwent curative-intent lobectomy or pneumonectomy between 1995 and 2018. Three hundred and sixty-two patients (36%) were ex-smokers, 314 (31%) were current smokers and 111 (11%) were never smokers. A pre-operative diagnosis of COPD was present in 57% of current smokers, 57% of ex-smokers and 20% of never smokers. Just over 25% of patients experienced a PPC. PPCs were more frequent in current smokers compared to never smokers (27% vs 17%, p = 0.036), however, no difference was seen between current and ex-smokers (p = 0.412) or between never and ex-smokers (p = 0.113). Those with a diagnosis of COPD, independent of smoking status, had a higher frequency of both PPCs (65% vs 35%, p<0.01) and overall complications (60% vs 40%, p<0.01) as well as a longer length of hospital stay (10 vs 9 days, p<0.01). CONCLUSION: Smoking and COPD are both associated with a higher rate of PPCs post lung cancer resection. COPD, independent of smoking status, is also associated with an increased overall post-operative complication rate and length of hospital stay. An emphasis on COPD treatment optimisation, rather than smoking cessation in isolation, may help improve post-operative outcomes.

A cohort study of the efficacy and safety of immune checkpoint inhibitors plus anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world.

Background: Anlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and has been shown to have antitumor effects and synergistic antitumor effects with immunotherapy only in animal studies and in the 2nd-line treatment in small clinical trials. A real-world study with large sample to compare the efficacy and safety of anlotinib plus immune checkpoint inhibitors (ICIs) with ICIs alone in the multiline treatment of advanced non-small cell lung cancer (NSCLC) was urgently needed. Methods: The data of 535 advanced NSCLC patients were collected from January 1, 2018, to December 31, 2021. The patients were divided into 2 groups: (I) ICI monotherapy (230 patients); (II) ICI + anlotinib (305 patients). After propensity-score matching (PSM) to reduce the effects of biases and confounding variables, the progression-free survival time (PFS), occurrence of adverse events, disease control rate (DCR), and objective response rate (ORR) of the 2 groups were compared. The effects of clinical factors, including age, gender, gene mutations, tumor proportion score, metastases, and combined radiotherapy, were also analyzed. Results: After PSM, the baseline clinical characteristics were well balanced and the 2 group had a good comparability. Patients in the ICI + anlotinib group had significantly longer median PFS in both the 2nd-line treatment (7.73 vs. 4.70 months; P=0.003) and 3rd-line treatment (5.90 vs. 3.37 months; P=0.020), but the difference lacked statistical significance in the 1st-line treatment (8.40 vs. 5.20 months; P=0.229). The overall median PFS of patients in the ICI + anlotinib group was also much longer than that of patients in the ICI monotherapy group (6.37 vs. 3.90 months; P<0.001). The ICI + anlotinib group also tended to have a higher DCR, a higher ORR, and a higher probability of severe adverse drug reactions during the treatment than the ICI monotherapy group, but the differences were not statistically significant. Combining ICI + anlotinib could improve the outcomes of patients with bone metastasis. Conclusions: Anlotinib + ICI therapy could have greater efficacy in the treatment of advanced NSCLC patients than ICI monotherapy. The probability of adverse events might increase in the combined treatment, but could be controlled.