We performed a meta-analysis of fatal pulmonary events associated with erlotinib, gefitinib or afatinib in patients with non-small-cell lung cancer (NSCLC). Eligible studies included randomized ...trials of patients with NSCLC on the three drugs describing events of high-grade pulmonary events. The relative risk of high-grade interstitial lung disease, pneumonitis, pneumonia, pulmonary embolism and hemoptysis were 4.18 (95% CI: 2.49-7.01; p < 0.00001), 1.94 (95% CI: 0.93-4.06; p = 0.08), 1.28 (95% CI: 0.92-1.77; p = 0.14), 1.6 (95% CI: 0.81-3.18 p = 0.17), 1.00 (95% CI: 0.14-7.08 p = 0.35), respectively. Our meta-analysis has demonstrated that erlotinib, gefitinib and afatinib are associated with an increased risk of high-grade interstitial lung disease in patients with NSCLC.
Purpose
To develop a head and neck normal structures autocontouring tool that could be used to automatically detect the errors in autocontours from a clinically validated autocontouring tool.
Methods
...An autocontouring tool based on convolutional neural networks (CNN) was developed for 16 normal structures of the head and neck and tested to identify the contour errors from a clinically validated multiatlas‐based autocontouring system (MACS). The computed tomography (CT) scans and clinical contours from 3495 patients were semiautomatically curated and used to train and validate the CNN‐based autocontouring tool. The final accuracy of the tool was evaluated by calculating the Sørensen–Dice similarity coefficients (DSC) and Hausdorff distances between the automatically generated contours and physician‐drawn contours on 174 internal and 24 external CT scans. Lastly, the CNN‐based tool was evaluated on 60 patients' CT scans to investigate the possibility to detect contouring failures. The contouring failures on these patients were classified as either minor or major errors. The criteria to detect contouring errors were determined by analyzing the DSC between the CNN‐ and MACS‐based contours under two independent scenarios: (a) contours with minor errors are clinically acceptable and (b) contours with minor errors are clinically unacceptable.
Results
The average DSC and Hausdorff distance of our CNN‐based tool was 98.4%/1.23 cm for brain, 89.1%/0.42 cm for eyes, 86.8%/1.28 cm for mandible, 86.4%/0.88 cm for brainstem, 83.4%/0.71 cm for spinal cord, 82.7%/1.37 cm for parotids, 80.7%/1.08 cm for esophagus, 71.7%/0.39 cm for lenses, 68.6%/0.72 for optic nerves, 66.4%/0.46 cm for cochleas, and 40.7%/0.96 cm for optic chiasm. With the error detection tool, the proportions of the clinically unacceptable MACS contours that were correctly detected were 0.99/0.80 on average except for the optic chiasm, when contours with minor errors are clinically acceptable/unacceptable, respectively. The proportions of the clinically acceptable MACS contours that were correctly detected were 0.81/0.60 on average except for the optic chiasm, when contours with minor errors are clinically acceptable/unacceptable, respectively.
Conclusion
Our CNN‐based autocontouring tool performed well on both the publically available and the internal datasets. Furthermore, our results show that CNN‐based algorithms are able to identify ill‐defined contours from a clinically validated and used multiatlas‐based autocontouring tool. Therefore, our CNN‐based tool can effectively perform automatic verification of MACS contours.
Background: We performed a systematic review and meta-analysis of the risk of oral and gastrointestinal (GI) mucosal injury associated with ramucirumab.
Patients and methods: Eligible studies ...included randomized Phase II and III trials of patients with solid tumors on ramucirumab: describing events of stomatitis, diarrhea, GI perforation and GI hemorrhage.
Results: Our search strategy yielded 167 potentially relevant citations from Pubmed/Medline, CENTRAL Cochrane registry, European society of medical oncology meeting abstracts and American Society of Clinical Oncology meeting library. After exclusion of ineligible studies, a total of 11 clinical trials were considered eligible for the meta-analysis. The RR of all-grade stomatitis, diarrhea, GI perforation and GI hemorrhage were 1.62 (95% CI 1.31 - 2.00; p < 0.00001), 1.15 (95% CI 1.07 - 1.24; p < 0.0001), 3.29 (95% CI 1.54 - 7.04; p = 0.002) and 1.92 (95% CI 1.03 - 3.57; p = 0.04), respectively. The RR of high-grade stomatitis, diarrhea, GI perforation and GI hemorrhage were 2.72 (95% CI 1.76 - 4.19; p < 0.00001), 1.28 (95% CI 0.96 - 1.71; p = 0.09), 3.37 (95% CI 1.51 - 7.54; p = 0.03) and 1.26 (95% CI 0.79 - 2.01; p = 0.34), respectively.
Conclusions: Our meta-analysis has demonstrated that ramucirumab-based combination treatment is associated with an increased risk of high-grade stomatitis and GI perforation compared to control treatment.
We performed a meta-analysis of the risk of hematological adverse events associated with ramucirumab.
Eligible studies included randomized Phase II and III trials of patients with solid tumors on ...ramucirumab, describing events of anemia, leucopenia, neutropenia, febrile neutropenia and thrombocytopenia.
A total of 11 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade anemia, leucopenia, neutropenia, febrile neutropenia and thrombocytopenia were 0.88 (95% CI: 0.80-0.96; p = 0.007), 1.13 (95% CI: 0.85-1.49; p = 0.41), 1.25 (95% CI: 1.08-1.44; p = 0.002), 1.63 (95% CI: 1.30-2.06; p < 0.0001), 1.91 (95% CI: 1.52-2.42; p < 0.00001), respectively.
Our meta-analysis has demonstrated an increased risk of febrile neutropenia, all-grade and high-grade neutropenia and thrombocytopenia with ramucirumab-based treatment compared with control.
We performed a meta-analysis of S-1-containing regimens versus control in the management of locally advanced/metastatic non-small-cell lung cancer.
Eligible studies included randomized studies ...evaluating S-1-containing regimens in the settings of locally advanced, first-line metastatic or second-line metastatic non-small-cell lung cancer.
Pooled odds ratio for overall response rate was 1.09 (95% CI: 0.85-1.38; p = 0.2), the pooled hazard ratio for progression-free survival was 0.98 (95% CI: 0.88-1.09; p = 0.69) and the pooled hazard ratio for overall survival was 0.98 (95% CI: 0.88-1.10; p = 0.75) for S-1-based regimens versus control. Moreover, the relative risk of febrile neutropenia was 0.34 (95% CI: 0.20-0.59; p = 0.0001).
Our meta-analysis has demonstrated that S-1-based regimens are associated with similar efficacy outcomes and better hematological tolerability.
2011
Background: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and ...fractionation schemes are prescribed with a “one-size-fits-all” approach. We sought to develop a DNA-based signature of radiation-based efficacy among patients with BrM, utilizing readily testable genes, to identify subpopulations at greater vs. lesser risk of recurrence. Methods: We retrospectively identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one tumor specimen. Local recurrence was assessed in a manner consistent with Response Assessment in Neuro-Oncology – Brain Metastases guidelines (i.e., radiographic enlargement of >20% in maximal cross-sectional diameter). Enlarging lesions managed with salvage treatment prior to >20% enlargement were considered to have recurred on the date of salvage therapy. Fine/Gray’s competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 OncoPanel genes with a mutational frequency >0.5%. Genes with a q-value<0.10 were utilized to develop a numeric “Brain-Radiation Prediction Score” (“Brain-RPS”) to quantify local recurrence risk. Results: Genomic alterations of potential biological relevance in 11 ( ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes ( FBXW 7 and AURKA) were associated with a decreased or increased risk of local recurrence, respectively (q-value<0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray’s competing risks regression, RPS 1.66 (1.44-1.92, p<0.001), metastasis-associated edema 1.89 (1.38-2.59), p<0.001 and receipt of WBRT without SRS/SRT or neurosurgical resection 2.73 (1.78-4.20), p<0.001 were independent predictors of local failure. Conclusions: We developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not been BrM-specific and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in clinical practice. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genomic personalization of radiation treatment among patients with BrM.
We performed a systematic review and meta-analysis of the risk of proteinuria associated with ramucirumab.
Eligible studies included randomized phase II and III trials of patients with solid tumors ...on ramucirumab, describing events of all-grade and high-grade proteinuria.
Our search strategy yielded 170 potentially relevant citations from PubMed/Medline, CENTRAL Cochrane database, ASCO and ESMO meeting libraries. After exclusion of ineligible studies, a total of 11 clinical trials were considered eligible for the meta-analysis. The relative risk (RR) of all-grade proteinuria was 3.31 (95% CI 2.48-4.42; p < 0.00001). Moreover, the RR of high-grade proteinuria was 5.28 (95% CI 2.32-12.01; p < 0.0001).
Our meta-analysis has demonstrated that ramucirumab use is associated with an increased risk of all-grade and high-grade proteinuria. Early detection strategies should be employed in those patients to prevent the progression to more sinister renal disease.
Automating and standardizing the contouring of clinical target volumes (CTVs) can reduce interphysician variability, which is one of the largest sources of uncertainty in head and neck radiation ...therapy. In addition to using uniform margin expansions to auto-delineate high-risk CTVs, very little work has been performed to provide patient- and disease-specific high-risk CTVs. The aim of the present study was to develop a deep neural network for the auto-delineation of high-risk CTVs.
Fifty-two oropharyngeal cancer patients were selected for the present study. All patients were treated at The University of Texas MD Anderson Cancer Center from January 2006 to August 2010 and had previously contoured gross tumor volumes and CTVs. We developed a deep learning algorithm using deep auto-encoders to identify physician contouring patterns at our institution. These models use distance map information from surrounding anatomic structures and the gross tumor volume as input parameters and conduct voxel-based classification to identify voxels that are part of the high-risk CTV. In addition, we developed a novel probability threshold selection function, based on the Dice similarity coefficient (DSC), to improve the generalization of the predicted volumes. The DSC-based function is implemented during an inner cross-validation loop, and probability thresholds are selected a priori during model parameter optimization. We performed a volumetric comparison between the predicted and manually contoured volumes to assess our model.
The predicted volumes had a median DSC value of 0.81 (range 0.62-0.90), median mean surface distance of 2.8 mm (range 1.6-5.5), and median 95th Hausdorff distance of 7.5 mm (range 4.7-17.9) when comparing our predicted high-risk CTVs with the physician manual contours.
These predicted high-risk CTVs provided close agreement to the ground-truth compared with current interobserver variability. The predicted contours could be implemented clinically, with only minor or no changes.
Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the ...graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly.
A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA.
Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies.
Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.
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