Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study.

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30-40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma.

The Danish metastatic melanoma database (DAMMED): A nation-wide platform for quality assurance and research in real-world data on medical therapy in Danish melanoma patients.

BACKGROUND: Clinical trials enroll patients with specific diseases based on certain pre-defined eligibility criteria. Disease registries are crucial to evaluate the efficacy and safety of new expensive oncology medicines in broad non-trial patient populations. METHODS: We provide detailed information on the structure, including variables, and the scientific results from a nation-wide Danish database covering advanced melanoma, illustrating the importance of continuous real-world data registration. Disease status and treatment-related information on all patients with American Joint Committee on Cancer (AJCC) 8th edition stage III or IV melanoma candidates to medical treatment in Denmark are prospectively registered in the Danish Metastatic Melanoma Database (DAMMED). RESULTS: By January 1st, 2021, DAMMED includes 4156 patients and 7420 treatment regimens. Response rates and survival data from published randomized clinical trial data are compared with real-world efficacy data from DAMMED and presented. Overall, nine independent manuscripts highlighting similarities and discrepancies between real-world and clinical trial results are already reported to date. CONCLUSION: Nation-wide disease registries take into consideration the complexity of daily clinical practice. We show a concrete example of how disease registries can complement clinical trials' information, improving clinical practice, and support health-related technology assessment.

The completeness of chest X-ray procedure codes in the Danish National Patient Registry.

OBJECTIVE: The aim of this validation study was to assess the completeness of the registrations of chest X-rays (CXR) in two different versions of the Danish National Patient Registry (DNPR). MATERIAL AND METHODS: We included electronic record data on CXR performed on patients aged 40 to 99 years from nine radiology departments covering 20 Danish hospitals. From each department, we included data from three randomly selected weeks between 2004 and 2011 (reference standard). In two versions of the DNPR from the State Serum Institute (SSI) and Statistics Denmark, respectively, we investigated the proportion of registered CXR compared to the reference standard. Furthermore, we compared the completeness of the recorded data according to the responsible department (main department). RESULTS: We identified 11,235 patients and 12,513 CXR in the reference standard. The data from the SSI contained 12,265 (98%) CXR, whereas the data from Statistics Denmark comprised 9,151 (73.1%) CXR. The completeness of the SSI data was fairly constant across years, radiology departments, medical specialties, and age groups. The data from Statistics Denmark was almost complete in 2011 (95.8%). However, for the remaining study period, the data with radiology departments registered as the main department were lacking in the version from Statistics Denmark, and so the overall completeness was 73.1%. CONCLUSION: The completeness of CXR registrations varied between 98% and 73% depending on the information source, and this should be considered when investigating radiology services in the basis of DNPR.

Development of an algorithm to identify urgent referrals for suspected cancer from the Danish Primary Care Referral Database.

BACKGROUND: Accurate identification of specific patient populations is a crucial tool in health care. A prerequisite for exploring the actions taken by general practitioners (GPs) on symptoms of cancer is being able to identify patients urgently referred for suspected cancer. Such system is not available in Denmark; however, all referrals are electronically stored. This study aimed to develop and test an algorithm based on referral text to identify urgent cancer referrals from general practice. METHODS: Two urgently referred reference populations were extracted from a research database and linked with the Primary Care Referral (PCR) database through the unique Danish civil registration number to identify the corresponding electronic referrals. The PCR database included GP referrals directed to private specialists and hospital departments, and these referrals were scrutinized. The most frequently used words were integrated in the first version of the algorithm, which was further refined by an iterative process involving two population samples from the PCR database. The performance was finally evaluated for two other PCR population samples against manual assessment as the gold standard for urgent cancer referral. RESULTS: The final algorithm had a sensitivity of 0.939 (95% confidence intervals [CI]: 0.905-0.963) and a specificity of 0.937 (95% CI: 0.925-0.963) compared to the gold standard. The positive and negative predictive values were 69.8% (95% CI: 65.0-74.3) and 99.0% (95% CI: 98.4-99.4), respectively. When applying the algorithm on referrals for a population without earlier cancer diagnoses, the positive predictive value increased to 83.6% (95% CI: 78.7-87.7) and the specificity to 97.3% (95% CI: 96.4-98.0). CONCLUSION: The final algorithm identified 94% of the patients urgently referred for suspected cancer; less than 3% of the patients were incorrectly identified. It is now possible to identify patients urgently referred on cancer suspicion from general practice by applying an algorithm for populations in the PCR database.

The effect of direct access to CT scan in early lung cancer detection: an unblinded, cluster-randomised trial.

BACKGROUND: Lower lung cancer survival rates in Britain and Denmark compared with surrounding countries may, in part, be due to late diagnosis. The aim of this study was to evaluate the effect of direct access to low-dose computed tomography (LDCT) from general practice in early lung cancer detection on time to diagnosis and stage at diagnosis. METHODS: We conducted a cluster-randomised, controlled trial including all incident lung cancer patients (in 19-month period) listed with general practice in the municipality of Aarhus (300,000 citizens), Denmark. Randomisation and intervention were applied at general practice level. A total of 266 GPs from 119 general practices. In the study period, 331 lung cancer patients were included. The intervention included direct access to low-dose CT from primary care combined with a 1 h lung cancer update meeting. Indication for LDCT was symptoms or signs that raised the GP's suspicion of lung cancer, but fell short of satisfying the fast-track referral criteria on red flag' symptoms. RESULTS: The intervention did not significantly influence stage at diagnosis and had limited impact on time to diagnosis. However, when correcting for non-compliance, we found that the patients were at higher risk of experiencing a long diagnostic interval if their GPs were in the control group. CONCLUSION: Direct low-dose CT from primary care did not statistically significantly decrease time to diagnosis or change stage at diagnosis in lung cancer patients. Case finding with direct access to LDCT may be an alternative to lung cancer screening. Furthermore, a recommendation of low-dose CT screening should consider offering symptomatic, unscreened patients an access to CT directly from primary care. TRIAL REGISTRATION: www.clinicaltrials.gov, registration ID number NCT01527214.

Bronchoscopy in patients with haemoptysis and normal computed tomography of the chest is unlikely to result in significant findings.

INTRODUCTION: The standard evaluation of haemoptysis in a department of respiratory medicine would currently consist of chest radiography, contrast-enhanced computed tomography (CT) and fibre-optic bronchoscopy (FOB), regardless of the result of the CT. Our aim was to evaluate whether patients presenting with haemoptysis but no positive finding on a contrast-enhanced CT of the chest are at risk for having serious disease, first of all lung cancer, and thus whether FOB is mandatory for such patients. METHODS: We searched the literature and retrospectively reviewed all records of patients referred with haemoptysis between 2000 and 2010 at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Denmark. RESULTS: A total of 379 patient records were reviewed for inclusion in the clinical part of the study. Of these, 269 had the information required for the study and had been examined with CT. In all, 16 of the 269 patients were diagnosed with lung cancer. In all of these, a tumour or other findings indicating a possible tumour were seen on the chest CT. No additional cases of lung cancer were discovered during FOB, and no cases had been missed by the CT. CONCLUSION: CT should be used as first-line examination in patients with a history of haemoptysis. Furthermore, in patients above 40 years of age with positive findings of any kind on the CT, further examination with FOB is indicated. However, if the chest CT is without pathological findings, it is most unlikely that FOB will reveal anything of significance. FUNDING: none. TRIAL REGISTRATION: not relevant.

The effect of direct referral for fast CT scan in early lung cancer detection in general practice. A clinical, cluster-randomised trial.

UNLABELLED: This PhD thesis is based on the project "The effect of direct referral for fast CT scan in early lung cancer detection in general practice. A clinical, cluster-randomised trial", performed in Denmark in 2010-2013. The thesis includes four papers and focuses on early lung cancer diagnostics in general practice. INTRODUCTION: A total of 4200 new cases of lung cancer are diagnosed in Denmark annually. The stage of the disease is an important prognostic factor; thus, the opportunity for curative treatment declines with more advanced tumour stage. Lung cancer patients in Denmark (like in the UK) have a poorer prognosis than lung cancer patients in other European countries. One explanation could be delayed diagnosis. A fast-track pathway was therefore introduced in an attempt to expedite the diagnosis of cancer. However, it seems that not all patients can be diagnosed through this pathway. In order to ensure fast and early lung cancer diagnosis, it is crucial to examine the initial diagnostic process in general and the role general practice plays in lung cancer diagnostics in particular. The specific areas of investigation include the pathways to diagnosis, the characteristics of patients who are at special risk of delayed diagnosis and the level of prediagnostic activity in general practice. A chest radiograph is often the first choice in the investigation of lung cancer. Unfortunately, radiographs are less suitable for central and small tumours. Low-dose computer tomography (LDCT), however, has a high sensitivity for lung cancer which implies that it can be used to detect patients with localised, potentially curable disease. AIM: The aim of this thesis was to increase our knowledge of the initial stages of lung cancer diagnostics in general practice. The thesis also examined the effect of a direct referral from general practice to an additional diagnostic test, the LDCT. The aims of this thesis were: 1) To describe Danish patients' pathways to the diagnosis of lung cancer in general and the prediagnostic activity leading up to diagnosis in particular. An additional aim was to explore the diagnostic intervals for specific patient groups (Paper I). 2) In a randomised, controlled trial including all patients referred for the existing fast-track scheme to either direct chest and upper abdomen CE-MDCT or to evaluation by the chest physician, (i) to test: Fast-track performance measured by the number of CE-MDCT scans and chest physician specialist time per diagnosis  (Paper II) 3) In a two-arm, clinical, controlled, cluster-randomised trial where direct referral to CT together with a lung cancer update is compared with usual practice, (i) to test how CT is used in this group of patients and the outcome of CT (Paper III); and (ii) to test the effect of either modality on the time to lung cancer diagnosis, the TNM stage and the use of the fast-track pathway for lung cancer (Paper IV). METHODS: Study I was a national registry-based cohort study of 971 consecutive, incident lung cancer patients in 2010 Data were derived from national registries and questionnaires filled in by general practitioners (GPs). Study II was a randomised, controlled trial enrolling 493 patients referred from general practice to a fast-track evaluation. Half of the patients were randomly assigned to the intervention and went straight to a chest CT before a chest physician evaluation. Studies III and IV were a cluster-randomised, controlled trial (IV) and a cohort study nested in the trial (III). A total of 199 general practices with 266 GPs were randomised into two groups. Intervention GPs were offered direct access to a low-dose chest CT combined with a meeting on early lung cancer detection. Study III concerned the intervention arm solely and reported uses and outcomes of the scans. Study IV evaluated the effect of direct low-dose CT on the time to diagnosis and stage at diagnoses for patients from intervention and control GPs. RESULTS: In Study I, we found that GPs were involved in 2/3 of all lung cancer diagnostic pathways. One quarter of the patients followed the obvious pathway from general practice to fast-track detection. At least one radiograph was performed in 85.6% of patients, whereas 1/3 of all patients had two or more radiograph performed during the 90 days preceding diagnosis. Patients with co-morbidity or unspecific symptoms more often had two or more X-rays performed than patients without these characteristics. In Study II, there was no difference between the groups in the number of CTs performed. In the intervention group, chest physicians spent mean 13.3 minutes less per referred patient than in the control group. In Study III, we found that 648 patients were referred to low-dose CT during a 19-month period. Half of the referred patients needed further work-up, and 15 (2.3%) of the patients had lung cancer, 60% in a localised stage. For all patients, 6.8% were diagnosed with a severe lung disease. In all, 2/3 of the GPs used the CT opportunity; and the referral rate was 61% higher for GPs participating in the lung cancer meeting than for GPs who did not participate in such meetings. In Study IV, we found that direct, low-dose CT from primary care did not significantly influence stage at diagnosis and had only a limited impact on time to diagnosis. CONCLUSION AND PERSPECTIVES: This thesis contributes to the knowledge of the early diagnosis of lung cancer in Denmark. General practice was found to play an important role, but only a small part of Danish lung cancer patients were diagnosed from general practice through the fast-track pathway. This together with the fact that a high proportion of patients had two or more radiographs within the 90 days preceding the diagnosis indicate that other diagnostic strategies should be tested in an attempt to provide GPs with the best opportunity for early diagnosis. This thesis provides evidence that GPs are, indeed, able to refer patients straight-to-test in the fast-track pathway. This knowledge may be used when organising other fast tracks. Furthermore, GPs participating in education about early lung cancer diagnosis were willing to refer patients direct to low-dose CT (LDCT) from primary care. Half of the patients needed further diagnostic work-up, and 2.3% of all patients referred were diagnosed with lung cancer. In addition, many lung diseases were diagnosed by LDCT. No effect on time to diagnosis or stage at diagnosis was found when patients from intervention GPs were compared with patients from control GPs. The effect of combining direct access to LDCT with referral to the existing fast-track pathway should be analysed as it may ensure earlier and faster lung cancer detection in primary care. Direct access to LDCT scan may also be an alternative to lung cancer screening. Furthermore, if a LDCT screening program is going to be implemented, it should be considered to supplement the program with access to CT directly from primary care for the symptomatic, not-screened patients.

The role of general practice in routes to diagnosis of lung cancer in Denmark: a population-based study of general practice involvement, diagnostic activity and diagnostic intervals.

BACKGROUND: Lung cancer stage at diagnosis predicts possible curative treatment. In Denmark and the UK, lung cancer patients have lower survival rates than citizens in most other European countries, which may partly be explained by a comparatively longer diagnostic interval in these two countries. In Denmark, a pathway was introduced in 2008 allowing general practitioners (GPs) to refer patients suspected of having lung cancer directly to fast-track diagnostics. However, symptom presentation of lung cancer in general practice is known to be diverse and complex, and systematic knowledge of the routes to diagnosis is needed to enable earlier lung cancer diagnosis in Denmark. This study aims to describe the routes to diagnosis, the diagnostic activity preceding diagnosis and the diagnostic intervals for lung cancer in the Danish setting. METHODS: We conducted a national registry-based cohort study on 971 consecutive incident lung cancer patients in 2010 using data from national registries and GP questionnaires. RESULTS: GPs were involved in 68.3% of cancer patients' diagnostic pathways, and 27.4% of lung cancer patients were referred from the GP to fast-track diagnostic work-up. A minimum of one X-ray was performed in 85.6% of all cases before diagnosis. Patients referred through a fast-track route more often had diagnostic X-rays (66.0%) than patients who did not go through fast-track (49.4%). Overall, 33.6% of all patients had two or more X-rays performed during the 90 days before diagnosis. Patients whose symptoms were interpreted as non-alarm symptoms or who were not referred to fast-track were more likely to experience a long diagnostic interval than patients whose symptoms were interpreted as alarm symptoms or who were referred to fast-track. CONCLUSIONS: Lung cancer patients followed several diagnostic pathways. The existing fast-track pathway must be supplemented to ensure earlier detection of lung cancer. The high incidence of multiple X-rays warrants a continued effort to develop more accurate lung cancer tests for use in primary care.

Implementing direct access to low-dose computed tomography in general practice--method, adaption and outcome.

BACKGROUND: Early detection of lung cancer is crucial as the prognosis depends on the disease stage. Chest radiographs has been the principal diagnostic tool for general practitioners (GPs), but implies a potential risk of false negative results, while computed tomography (CT) has a higher sensitivity. The aim of this study was to describe the implementation of direct access to low-dose CT (LDCT) from general practice. METHODS: We conducted a cohort study nested in a randomised study. A total of 119 general practices with 266 GPs were randomised into two groups. Intervention GPs were offered direct access to chest LDCT combined with a Continuing Medical Education (CME) meeting on lung cancer diagnosis. RESULTS: During a 19-month period, 648 patients were referred to LDCT (0.18/1000 adults on GP list/month). Half of the patients needed further diagnostic work-up, and 15 (2.3%, 95% CI: 1.3-3.8%) of the patients had lung cancer; 60% (95% CI: 32.3-83.7%) in a localised stage. The GP referral rate was 61% higher for CME participants compared to non-participants. CONCLUSION: Of all patients referred to LDCT, 2.3% were diagnosed with lung cancer with a favourable stage distribution. Half of the referred patients needed additional diagnostic work-up. There was an association between participation in CME and use of CT scan. The proportion of cancers diagnosed through the usual fast-track evaluation was 2.2 times higher in the group of CME-participating GPs. The question remains if primary care case-finding with LDCT is a better option for patients having signs and symptoms indicating lung cancer than a screening program. Whether open access to LDCT may provide earlier diagnosis of lung cancer is yet unknown and a randomised trial is required to assess any effect on outcome. TRIAL REGISTRATION: Clinicaltrials.gov NCT01527214.

Reduced specialist time with direct computed tomography for suspected lung cancer in primary care.

INTRODUCTION: Lung cancer (LC) is the most common cause of cancer death in Denmark, and triaging patients through fast-track diagnostic pathways is recommended to improve patient outcome. Data on the most efficient triage organisation of such pathways are limited. The aim of this study was to test a strategy of a straight-to-test model for patients referred to the fast-track pathway. Outcomes were number of computed tomographies (CT) performed, use of specialist time and staff acceptability. MATERIAL AND METHODS: We performed a randomised controlled study enrolling 493 patients who were referred from general practice to fast-track LC evaluation (1 January-1 December 2012). Half of the patients were randomly assigned to the intervention and went straight to a chest CT before chest-physician evaluation. Time was measured for patients at random days. Acceptability was examined in a focus group interview. RESULTS: In the intervention group, 95.5% of patients had a CT performed compared with 97.2% in the control group. There was no difference in the number of CTs between the groups (risk difference (RD) = 1.3% (95% confidence interval (CI): 4.4-2.0; p = 0.454)). In the intervention group, chest-physician time was 13.3 min. (min.-max.: 7.7-19.5 min.) lower per referred patient than in the control group. CONCLUSION: Giving general practitioners direct access to a CT did not change the number of CTs performed and significantly reduced chest-physician time per patient. In addition, the strategy was associated with high levels of staff acceptability. FUNDING: The project was supported by the Danish Cancer Research Foundation, the Danish Cancer Society and the Novo Nordisk Foundation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01779726.