Rapid reduction in the incidence of cancer of unknown primary. A population-based study

<div><p></p><p><i>Background.</i> Cancer of unknown primary (CUP) carries a dismal prognosis due to the two hallmarks of 1) being metastatic with 2) no known specific treatment. An organ-labeled diagnosis of cancer should therefore be sought. In this study, we have analyzed population-based incidence and survival data of CUP over the latest 40 years. <i>Material and methods.</i> Complete national data on 23 004 CUP-patients from the Cancer Registry of Norway sampled from 1971 to 2010 are presented, with absolute and age-adjusted incidence rates correlated to the total cancer incidence. One-year relative survival rates were calculated. <i>Results.</i> The incidence of CUP increased both in absolute numbers and as a fraction of total cancer incidence during the first half of the period. There has been a substantial decrease in incidence over the latest 20 years, now being responsible of only 1.7% and 1.2% of the total cancer incidence in females and males, respectively, with an age-adjusted incidence rate of 3.5 and 3.8, respectively. The one-year relative survival rate has increased and was slightly below 20% for both sexes in 2010. <i>Conclusion.</i> Better diagnostics, both radiological and pathological, is probably responsible for a substantially lower incidence. Improved treatment for cancers in general also benefits the CUP-group.</p></div

Presentation_1_Improvements in survival for patients with stage IV adenocarcinoma in the lung, diagnosed between 2010 – 2020 - A population-based registry study from Norway.pdf

ObjectivesWe investigated how the prognosis for Norwegian patients with stage IV, adenocarcinoma (NSCLC) has developed during the last decade, to observe if increased survival coincides with the introduction of immunotherapy at a population level.Materials and methodsIncidence data from the Cancer Registry of Norway are virtually complete and includes information about histological subtypes and biomarkers. The data was used to analyze median and relative survival for females and males diagnosed with stage IV NSCLC, divided by histological subgroups and age-groups.ResultsDuring 2010 – 2020, 14472 patients were diagnosed with lung cancer in stage IV, in Norway. Among them 6351 patients (43%) were classified with adenocarcinoma. The median survival has increased for both sexes, but the largest increase is seen in females. From 2010 to 2020, median survival for females in the 0-69 group increased from 6.7 months to 12 months and from 3.7 months to 10 months for the 70+ age group. For the equivalent male age groups, we see an increase from 6.1 months to 7.7 months for the 0-69 group, and an increase from 3.8 months to 4.5 months for the 70+ group. When excluding patients with EGFR/ALK mutations from the survival analysis, the groups continue to display an increased survival from 2010 to 2020, although modest in the male 70+ group. The 1-year relative survival (RS) has increased for both sexes, from 32.4% to 51.2 in females and 25.4% to 44.5% in males. When EGFR/ALK positive patients were excluded from the analysis 1-year RS in females rose from 32.4% to 47.4% and for males from 25.4% to 41.8%.ConclusionA real-world patient population of stage IV, NSCLC adenocarcinoma have had a clinically meaningful increase in both median and relative survival from 2010 – 2020. The steepest survival increase has taken place after 2016, the time point where immunotherapy was implemented as a treatment option for the stage IV, adenocarcinoma population not harboring targetable mutations (EGFR/ALK).</p

Initial investigation of using Norwegian health data for the purpose of external comparator arms - an example for non-small cell lung cancer

Using real-world (RW) data from registries to mimic or substitute a comparator arm of clinical trials is increasingly investigated. The feasibility of using data sources for this purpose depends on the source’s completeness of the wide spectrum of a disease characteristics and relevant endpoints, which could allow for proper matching of important variables. This is a Norwegian study using data from three population-based registries, the Cancer Registry (CRN), the National Patient Registry (NPR), and the Norwegian Prescribed Drug Registry (LMR). We assessed if the registries contained the information necessary for selecting a RW cohort of patients with characteristics that mimicked the inclusion and exclusion criteria from the control arm of the phase 3 trial (KeyNote-407) on patients with stage IV, squamous NSCLC. We did this both on an aggregated - and individual data level. We also described the survival in the RW-cohorts and compared it with the survival in the control arm of the KN-407 trial. Using aggregated data from the CRN allowed us to find the patients based on some clinically relevant inclusion criteria, but only to a limited extent could we apply the exclusion criteria of KN-407. When we used individual data from the CRN, NPR and the LMR we could create a patient cohort that shared more criteria corresponding to the eligibility criteria from KN-407, including exclusion criteria. Compared to the 11.3 months (CI 95% 9.5, 14.8) median survival in the control arm of KN-407, both RW-cohorts had a shorter median survival, 7.07 months (CI 95% 6.7, 9.5) (individual) and 8.0 months (CI 95% 5.8, 10.5) (aggregated). Even if we demonstrated that the registries contain clinically relevant information necessary to mimic the eligibility criteria of a selected RCT, the survival is shorter for RW patients compared to their control arm counterpart in the RCT.</p

Circulating microRNAs associated with prolonged overall survival in lung cancer patients treated with nivolumab

<p><b>Background:</b> The introduction of immune check-point inhibition in non-small cell lung cancer (NSCLC) therapy represents improved prospects for the patients. The response rates to check-point inhibitors are approximately 20% in unselected NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with higher response rates. However, patients with low PD-L1 levels may also have durable responses, and improved strategies for patient stratification are needed.</p> <p><b>Material and methods:</b> In this study, we investigated circulating microRNAs aiming to identify circulating predictive biomarkers associated with increased overall survival after immune check-point treatment. Using next generation sequencing, we performed microRNA profiling in serum from NSCLC patients (<i>n</i> = 20) treated with nivolumab. Serum samples from 31 patients were used for validation using qPCR assays. Serum samples were collected prior to immune therapy initiation.</p> <p><b>Results:</b> Based on multivariate regression analysis, we identified a signature of seven microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p, miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) > 6 months in discovery cohort (<i>p</i> = .0003). We further validated this in another similar set of samples (<i>n</i> = 31) and the model was significantly associated with overall survival (OS) > 6 months (<i>p</i> = .001) with sensitivity and specificity of 71% and 90%, respectively.</p> <p><b>Conclusions:</b> In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.</p

Additional file 1 of Distribution and characteristics of malignant tumours by lung lobe

Supplementary Material

DataSheet_1_Circulating T Cell Activation and Exhaustion Markers Are Associated With Radiation Pneumonitis and Poor Survival in Non-Small-Cell Lung Cancer.docx

IntroductionPersistent inflammation and immune activation in the lungs are associated with adverse outcomes such as radiation pneumonitis (RP) and poor survival in non-small-cell lung cancer (NSCLC) patients. However, it is unknown how this is reflected by leukocyte activation markers in serum.ObjectiveThe aim was to evaluate the serum levels of activation of different leukocyte subsets and to examine those in relation to the pathogenesis of RP and survival in NSCLC.MethodsWe analyzed the serum levels of MPO, sCD25, sTIM-3, sPD-L1, sCD14, sCD163, CCL19 and CCL21 in 66 inoperable NSCLC patients with stage IA-IIIA disease. The patients were treated with stereotactic body radiation therapy (SBRT) or concurrent chemoradiation therapy (CCRT), followed by regular blood sampling for 12 months after treatment and for 5 years for survival.ResultsNineteen (29%) patients developed RP, which occurred more frequently and earlier in patients receiving CCRT than in those receiving SBRT. Increases in sCD25, sTIM-3 and CCL21 levels were observed at the last 6 months of follow-up in patients who had RP after SBRT. Patients who had RP after CCRT had higher sTIM-3 levels during the first 3 months of follow-up. Baseline sCD25 was independently associated with both 2- and 5-year mortality outcomes, while baseline sTIM-3 was independently associated with 2-year mortality.ConclusionWe showed that T cell activation and exhaustion markers such as sCD25 and sTIM-3 are enhanced in patients developing RP and are associated with poor survival in NSCLC.</p

A new method to assess pulmonary changes using ¹⁸F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy

<p><b>Background:</b>¹⁸F-fluoro-2-deoxyglucose positron emission tomography (¹⁸F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on ¹⁸F-FDG-PET improves radiotherapy (RT) dose–response quantification for lung cancer patients.</p> <p><b>Material and methods:</b> Sixteen patients with lung cancer undergoing fractionated RT were examined by ¹⁸F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (μ) and standard deviation (<i>σ</i>) maps were calculated based on cubes in the lung (3 × 3 × 3 voxels), where the spread in pre-therapy μ and <i>σ</i> was characterized by a covariance ellipse in a sub-volume of 3 × 3 × 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure ‘<i>S</i>’ maps. The structural difference maps (Δ<i>S</i>) and mean difference maps (Δμ) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated.</p> <p><b>Results:</b> Δ<i>S</i> identified new areas of interest in the lung compared to conventional Δμ maps. Δ<i>S</i> for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (<i>p</i> < .05). Dose–response analyses by linear regression showed that Δ<i>S</i> between pre- and post-therapy for ¹⁸F-FDG-PET was the only parameter significantly associated with local lung dose (<i>p</i> = .04).</p> <p><b>Conclusions:</b> The new method using local structures on ¹⁸F-FDG-PET provides a clearer uptake dose–response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity.</p

Biplot showing principal component analysis of <i>CK19</i>, <i>CEACAM5</i>, <i>DSG3</i>, <i>SFTPA</i> and <i>SFTPC</i> mRNA level in the 55 primary tumor biopsies.

<p>Black numbers indicate histology type (1 = adenocarcinoma, 2 = adenosquamous carcinoma, 3 = bronchioloalveolar carcinoma, 4 = carcinoid, 5 = large cell carcinoma, 6 = small cell carcinoma, 7 = squamous cell carcinoma).</p

Clinicopathological parameters according to molecular examination of regional LNs and peripheral blood samples.

*<p>Mann-Whitney test.</p

Marker levels in non-small cell lung cancer (NSCLC) tumors (T), normal LNs (nN), patient LNs (ptN), normal blood (nB) and patient blood (ptB).

<p>Median values are indicated by short horizontal lines, whereas samples with levels below the limit of detection (LOD) are indicated below the dashed horizontal line. The levels of the different markers are relative to a calibrator sample and are not directly comparable.</p