Individual patient data to allow a more elaborated comparison of trial results with real-world outcomes from first-line immunotherapy in NSCLC.

BACKGROUND: Many studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials. However, any differences observed could be only limitedly explored further for causation because of the unavailability of individual patient data (IPD) from trial participants. The present study aims to explore the additional benefit of comparison with IPD. METHODS: This study compares progression free survival (PFS) and overall survival (OS) of metastatic NSCLC patients treated with second line nivolumab in real-world clinical practice (n = 141) with IPD from participants in the Checkmate-057 clinical trial (n = 292). Univariate and multivariate Cox proportional hazards models were used to construct HRs for real-world practice versus clinical trial. RESULTS: Real-world patients were older (64 vs. 61 years), had more often ECOG PS ≥ 2 (5 vs. 0%) and were less often treated with subsequent anti-cancer treatment (28.4 vs. 42.5%) compared to trial patients. The median PFS in real-world patients was longer (3.84 (95%CI: 3.19-5.49) vs 2.30 (2.20-3.50) months) and the OS shorter than in trial participants (8.25 (6.93-13.2) vs. 12.2 (9.90-15.1) months). Adjustment with available patient characteristics, led to a shift in the hazard ratio (HR) for OS, but not for PFS (HRs from 1.13 (0.88-1.44) to 1.07 (0.83-1.38), and from 0.82 (0.66-1.03) to 0.79 (0.63-1.00), respectively). CONCLUSIONS: This study is an example how IPD from both real-world and trial patients can be applied to search for factors that could explain an efficacy-effectiveness gap. Making IPD from clinical trials available to the international research community allows this.

Effects of structured involvement of the primary care team versus standard care after a cancer diagnosis on patient satisfaction and healthcare use: the GRIP randomised controlled trial.

BACKGROUND: The growing number of cancer survivors and treatment possibilities call for more personalised and integrated cancer care. Primary care seems well positioned to support this. We aimed to assess the effects of structured follow-up of a primary care team after a cancer diagnosis. METHODS: We performed a multicentre randomised controlled trial enrolling patients curatively treated for breast, lung, colorectal, gynaecologic cancer or melanoma. In addition to usual cancer care in the control group, patients randomized to intervention were offered a "Time Out consultation" (TOC) with the general practitioner (GP) after diagnosis, and subsequent follow-up during and after treatment by a home care oncology nurse (HON). Primary outcomes were patient satisfaction with care (questionnaire: EORTC-INPATSAT-32) and healthcare utilisation. Intention-to-treat linear mixed regression analyses were used for satisfaction with care and other continuous outcome variables. The difference in healthcare utilisation for categorical data was calculated with a Pearson Chi-Square or a Fisher exact test and count data (none versus any) with a log-binomial regression. RESULTS: We included 154 patients (control n = 77, intervention n = 77) who were mostly female (75%), mainly diagnosed with breast cancer (51%), and had a mean age of 61 (SD ± 11.9) years. 81% of the intervention patients had a TOC and 68% had HON contact. Satisfaction with care was high (8 out of 10) in both study groups. At 3 months after treatment, GP satisfaction was significantly lower in the intervention group on 3 of 6 subscales, i.e., quality (- 14.2 (95%CI -27.0;-1.3)), availability (- 15,9 (- 29.1;-2.6)) and information provision (- 15.2 (- 29.1;-1.4)). Patients in the intervention group visited the GP practice and the emergency department more often ((RR 1.3 (1.0;1.7) and 1.70 (1.0;2.8)), respectively). CONCLUSIONS: In conclusion, the GRIP intervention, which was designed to involve the primary care team during and after cancer treatment, increased the number of primary healthcare contacts. However, it did not improve patient satisfaction with care and it increased emergency department visits. As the high uptake of the intervention suggests a need of patients, future research should focus on optimizing the design and implementation of the intervention. TRIAL REGISTRATION: GRIP is retrospectively (21/06/2016) registered in the 'Netherlands Trial Register' (NTR5909).

The association between gut microbiome affecting concomitant medication and the effectiveness of immunotherapy in patients with stage IV NSCLC.

Several observational studies suggested that gut microbiome-affecting-medication impairs the effectiveness of immunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We postulated that if the effectiveness of immunotherapy is affected by drug-related changes of the microbiome, a stronger association between the use of co-medication and overall survival (OS) will be observed in patients treated with immunotherapy as compared to patients treated with chemotherapy. In a retrospective matched cohort study, immunotherapy patients were matched (1:1) to patients treated with chemotherapy in the pre immunotherapy era. The association between the use of antibiotics, opioids, proton pump inhibitors, metformin and other antidiabetics on OS was assessed with multivariable cox-regression analyses. Interaction tests were applied to investigate whether the association differs between patients treated with immuno- or chemotherapy. A total of 442 patients were studied. The use of antibiotics was associated with worse OS (adjusted Hazard Ratio (aHR) 1.39, p = 0.02) independent of the type of therapy (chemotherapy or immunotherapy). The use of opioids was also associated with worse OS (aHR 1.33, p = 0.01). The other drugs studied showed no association with OS. Interaction term testing showed no effect modification by immuno- or chemotherapy for the association of antibiotics and opioids with OS. The use of antibiotics and opioids is similarly associated with worse outcomes in both chemotherapy and immunotherapy treated NSCLC patients. This suggests that the association is likely to be a consequence of confounding rather than disturbing the composition of the microbiome.

The Dutch Lung Cancer Audit: Nationwide quality of care evaluation of lung cancer patients.

OBJECTIVES: This study describes the initiation of the Dutch Lung Cancer Audit for Lung Oncology (DLCA-L) and reports the first results of three years of clinical auditing. METHODS: The initiation, dataset, and data quality of the DLCA-L are described. For the analyses, all patients registered from 2017 to 2019 were included. Descriptive statistics were used to assess the first outcomes of the DLCA-L, including results from quality indicators, patient- and tumor characteristics, and the real-world use of immunotherapy. RESULTS: The DLCA-L was initiated after the surgery and radiotherapy audit for lung cancer. In total, 33.788 NSCLC patients and 4.293 SCLC patients were registered in the DLCA-L from 2017 to 2019. Seventy-three (97 %) Dutch hospitals participated in the DLCA-L in 2019. The registry became nation-wide in 2020. The data quality improved over the years, with complete cases in 90 % of the NSCLC patients. In total, 15 quality indicators were established based on DLCA-L data to improve processes and clinical outcomes. An example of these quality indicators was brain imaging at diagnosis of stage III NSCLC patients, which increased from 80 % in 2017 to 90 % in 2019 and hospital variation was reduced. The DLCA-L provided data on immunotherapy use in stage IV NSCLC (n = 4.415) patients. These patients had a median age of 67 years and 11 % of the patients had an ECOG PS ≥ 2. The number of patients treated with immunotherapy in different hospitals varied between 2 patients to 163 patients per hospital. CONCLUSION: The DLCA-L has become a valuable and complete data source with national coverage in 2020. A high number of registered patients and limited missing data resulted in better insights into hospital processes and outcomes of lung cancer care. Quality indicators were, with success, used to establish improvements and minimize hospital variation. The DLCA-L also provides hospitals real-world information on the use of (systemic) therapies.

Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the National Immunotherapy Registry.

OBJECTIVE: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials. MATERIALS AND METHODS: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied. RESULTS: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively). CONCLUSIONS: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 + .

Decision support systems for incurable non-small cell lung cancer: a systematic review.

BACKGROUND: Individually tailored cancer treatment is essential to ensure optimal treatment and resource use. Treatments for incurable metastatic non-small cell lung cancer (NSCLC) are evolving rapidly, and decision support systems (DSS) for this patient population have been developed to balance benefits and harms for decision-making. The aim of this systematic review was to inventory DSS for stage IIIB/IV NSCLC patients. METHODS: A systematic literature search was performed in Pubmed, Embase and the Cochrane Library. DSS were described extensively, including their predictors, model performances (i.e., discriminative ability and calibration), levels of validation and user friendliness. RESULTS: The systematic search yielded 3531 articles. In total, 67 articles were included after additional reference tracking. The 39 identified DSS aim to predict overall survival and/or progression-free survival, but give no information about toxicity or cost-effectiveness. Various predictors were incorporated, such as performance status, serum and inflammatory markers, and patient and tumor characteristics. Some DSS were developed for the entire incurable NSCLC population, whereas others were specifically for patients with brain or spinal metastases. Few DSS had been validated externally using recent clinical data, and the discrimination and calibration were often poor. CONCLUSIONS: Many DSS have been developed for incurable NSCLC patients, but DSS are still lacking that are up-to-date with a good model performance, while covering the entire treatment spectrum. Future DSS should incorporate genetic and biological markers based on state-of-the-art evidence, and compare multiple treatment options to estimate survival, toxicity and cost-effectiveness.

Costs of non-small cell lung cancer in the Netherlands.

OBJECTIVES: Real-world resource use and cost data on non-small cell lung cancer (NSCLC) are scarce. This data is needed to inform health-economic modelling to assess the impact of new diagnostic and/or treatment technologies. This study provides detailed insight into real-world medical resource use and costs of stage I-IV NSCLC in the Netherlands. MATERIALS AND METHODS: A random sample of patients newly diagnosed with NSCLC (2009-2011) was selected from four Dutch hospitals. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Resource use was multiplied by Dutch unit costs expressed in EUR 2012. Total mean costs were corrected for censoring using the Bang and Tsiatis weighted complete-case estimator. Furthermore, costs of adverse events, costs per phase of NSCLC management and costs of second opinions are presented. RESULTS: Data was collected on 1067 patients. Total mean costs for NSCLC diagnosis, treatment and follow-up are €28,468 during the study period and €33,143 when corrected for censoring. Adverse events were recorded in the patient charts for 369 patients (41%) and 82 patients (9%) experienced an adverse event of grade III or higher. For these patients, adverse event-related hospital admissions cost on average €2,091. Mean total costs are €1,725 for the diagnostic period, €17,296 for first treatment line, and €13,236 for each later treatment line. Costs of providing a second opinion are €2,580 per patient. CONCLUSIONS: Total mean hospital costs per NSCLC patient are €33,143 for the total duration of the disease. Ignoring censoring in our data underestimates these costs by 14%. Main limitations of the study relate to the short follow-up time, staging difficulties and missing data. Its main strength is that it provides highly detailed, real-world data on the costs of NSCLC.

Variation in treatment and outcome in patients with non-small cell lung cancer by region, hospital type and volume in the Netherlands.

BACKGROUND: Care processes for patients with NSCLC can vary by provider, which may lead to unwanted variation in outcomes. Therefore, in modern health care an increased focus on guideline development and implementation is seen. It is expected that more guideline adherence leads to a higher number of patients receiving optimal treatment for their cancer which could improve overall survival. OBJECTIVE: The aim of this study was to evaluate variations in treatment patterns and outcomes of patients with NSCLC treated in different (types of) hospitals and regions in the Netherlands. Especially, variation in the percentage of patients receiving the optimal treatment for the stage of their disease, according to the Dutch national guideline of 2004, was analyzed. METHODS: All patients with a histological confirmed primary NSCLC diagnosed in the period 2001-2006 in all Dutch hospitals (N = 97) were selected from the population-based Netherlands Cancer Registry. Hospitals were divided in groups based on their region (N = 9), annual volume of NSCLC patients, teaching status and presence of radiotherapy facilities. Stage-specific differences in optimal treatment rates between (groups of) hospitals and regions were evaluated. RESULTS: In the study period 43 544 patients were diagnosed with NSCLC. The resection rates for stage I/II NSCLC patients increased during the study period, but resection rates varied by region and were higher in teaching hospitals for thoracic surgeons (OR 1.5; 95%CI 1.2-1.9, p = 0.001) and in hospitals with a diagnostic volume of more than 50/year (OR 1.3; 95%CI 1.1-1.5, p = 0.001). Also the use of chemoradiation in stage III patients increased, though marked differences between hospitals in the use of chemoradiation for stage III patients were revealed. Differences in optimal treatment rates between hospitals led to differences in survival. CONCLUSION: Treatment patterns and outcome of NSCLC patients in the Netherlands varied by region and the hospital their cancer was diagnosed in. Though resection rates were higher in hospitals training thoracic surgeons, variation between individual hospitals was much more distinct. Hospital characteristics like a high diagnostic volume, teaching status or availability of radiotherapy facilities proved no guarantee for optimal treatment rates.

[Treatment of patients with stage III non-small cell lung cancer: concurrent high-dose chemotherapy and radiotherapy]. / Behandeling van patiënten met niet-kleincellig longcarcinoom stadium III: gelijktijdig hooggedoseerde chemotherapie en radiotherapie.

The treatment of patients with locally advanced non-small cell lung cancer (stage III) has changed significantly in the past few years. Patients with a non-resectable stage IIIA/B tumour are given combined treatment consisting ofchemotherapy and radiotherapy. These can be administered sequentially or concurrently. It has been shown recently that concurrent chemoradiotherapy gives a survival advantage in comparison with sequential chemoradiotherapy. Cisplatin and etoposide are usually the drugs of choice for chemotherapy in patients with stage III cancer. A biologically effective dose of radiotherapy equivalent to 60-66 Gy, over a maximum of 6.5 weeks, should be given. Surgery is possible for a selected group of patients, provided a complete objective mediastinal response has been achieved after chemoradiotherapy and a complete resection appears to be technically feasible. It is recommended to apply this treatment in a research setting. High-dose concurrent chemoradiotherapy is advised as the standard treatment for stage III non-small cell lung cancer in patients in good physical condition.

Sequential versus concurrent chemo-radiotherapy in inoperable stage III non-small cell lung cancer.

AIM: To define the best sequence of radiotherapy and chemotherapy for inoperable stage III non-small cell lung (NSCL) tumours. MATERIALS AND METHODS: A systematic review was performed on the clinical results of radiotherapy, combined or not with chemotherapy, for inoperable NSCL cancer stage III. The mean median survival time (MST) and mean overall survival (OS) percentages were derived for radiotherapy only, for sequential and for concurrent chemo-radiotherapy. RESULTS: The mean median survival duration +/- standard deviation for radiotherapy only was 10.4 +/- 1.8 months. For sequential chemo- and radiotherapy it was increased to 13.0 +/- 1.2 months. When radiotherapy in the sequential regimen was accompanied by chemotherapy, the mean median duration was 15.8 +/- 2.6 months. For concurrent radio-chemotherapy it was further increased to 16.4 +/- 2.7 months. The mean 2- and 3-year overall survivals for radiotherapy alone, sequential and concurrent radio-chemotherapy were 17.1 +/- 4.6 and 10, 23.8 +/- 6.3 and 18.5 +/- 7.0, and 32.5 +/- 8.7 and 25.7 +/- 6.3%, respectively. CONCLUSION: Concurrent chemo-radiotherapy demonstrated increased efficacy over sequential chemotherapy and radiotherapy and should be the treatment of choice. Further improvements may be obtained by optimising the conditions for concurrent chemo-radiotherapy.

[Oesophageal endoscopic ultrasound with fine-needle aspiration biopsy in the staging of non-small-cell lung carcinoma; results from 43 patients]. / Slokdarmendo-echografie met dunnenaaldaspiratie ter stadiëring bij niet-kleincellig longcarcinoom; resultaten bij 43 patiënten.

OBJECTIVE: To calculate the number of cervical mediastinoscopies that need not be carried out ifoesophageal endoscopic ultrasound and fine-needle aspiration biopsy (EUS-FNA) are included in the staging of patients with non-small-cell lung carcinoma (NSCLC). DESIGN: Retrospective, descriptive. METHOD: Patients referred to the St. Antonius Hospital in Nieuwegein, the Netherlands, with NSCLC from January to December 2003 routinely underwent EUS-FNA during the staging process. If mediastinal or distant metastases were found to be present then cervical mediastinoscopy was not carried out as the patient was not eligible for operation. If no metastases were demonstrated then cervical mediastinoscopy was carried out. The value of EUS-FNA was calculated. RESULTS: A total of 43 patients underwent EUS-FNA: 32 men and 11 women with an average age of 64 (range: 45-77). In 22 (51%) of them, cervical mediastinoscopy was not performed as EUS-FNA demonstrated malignant cells in the lymph nodes of the mediastinum or abdomen, in the left adrenal gland or in the primary tumour which had grown into the mediastinum. In 2 of the 21 other patients malignant cells were found on mediastinoscopy showing the EUS-FNA results in 2 of 43 patients (5%) to be false-negative. No complications occurred. CONCLUSION: Based on the findings from EUS-FNA, cervical mediastinoscopy was not performed in 51% of the patient group.

[Haemoptysis as a complication of Behçet's disease]. / Hemoptoë als complicatie van de ziekte van behçet.

Three patients, two Moroccan men aged 27 and 25 and a Turkish man aged 25, presented with haemoptysis caused by pulmonary aneurysm. The aneurysms had formed as a complication of Behçet's disease. Two of them were treated with high doses of corticosteroids. One man recovered and another died as a consequence of massive haemoptysis. The third man underwent emergency thoracotomy and pneumectomy due to massive haemoptysis. Postoperatively he was treated with cyclosporine resulting in full recovery. Behçet's disease is a multisystem vasculitis characterised by orogenital ulcerations and uveitis. In a minority of cases pulmonary aneurysms develop, often causing massive haemoptysis. Aneurysms are often accompanied by venous thrombosis. Treatment consists of immunosuppressive therapy. Nevertheless a considerable number of patients die following massive haemoptysis.

A randomised phase II trial of docetaxel vs docetaxel and irinotecan in patients with stage IIIb-IV non-small-cell lung cancer who failed first-line treatment.

Response rate and toxicity of second-line therapy with docetaxel (75 mg m(-2)) or docetaxel, irinotecan, and lenogastrim (60 mg m(-2), 200 mg m(-2), and 150 microg m(-2) day(-1), respectively) were compared in 108 patients with stage IIIb-IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity.

Lung function changes and pulmonary complications in patients with stage III non-small cell lung cancer treated with gemcitabine/cisplatin as part of combined modality treatment.

INTRODUCTION: Lung cancer is the leading cause of cancer mortality. Chemotherapy, ideally a platinum-based regimen as part of combined modality treatment, is appropriate for selected patients with locally advanced stage III non-small cell lung cancer (NSCLC) who have a good performance status. However, chemotherapy can induce side effects including lung function changes. AIM OF THE STUDY: Retrospective analysis of lung function changes in 44 patients with stage III NSCLC treated with neoadjuvant chemotherapy (NCT) followed by surgery and/or radiotherapy. PATIENTS AND METHODS: NCT consisted of three cycles of gemcitabine/cisplatin. The following data were analysed: age, sex, the presence of chronic obstructive pulmonary disease (COPD), smoking behaviour, response, complications after surgery and/or radiotherapy, and VC, FEV(1), DL(co) and K(co) before and after chemotherapy. DL(co) values were corrected for haemoglobin concentrations. RESULTS: We found a significant decline of K(co) (-13.5% of pred; 95% CI: -16.6 to -10.4; P<0.0001), independent of tumor response or presence and severity of COPD. FEV(1) and FEV(1)/VC showed significant increases irrespective of tumor response. Significantly more pulmonary complications were recorded in the radiotherapy group after NCT (P=0.009) compared to patients who underwent surgical therapy after NCT. CONCLUSIONS: Patients diagnosed with NSCLC stadium III who were treated with NCT consisting of cisplatin and gemcitabine showed a significant decline of DL(co) and K(co), irrespective of tumor response, presence and severity of COPD, sex and number of cycles of chemotherapy. Significantly more pulmonary complications were seen in patients treated with NCT and radiotherapy compared with patients treated with NCT and surgery. Questions concering the pathophysiological mechanisms of lung function changes and long term follow-up of pulmonary toxicity due to NCT remain still unanswered and have to be subject of future studies.

[Dyspnoea and dysphagia in an adult caused by a tracheo-esophageal fistula]. / Dyspnoe en dysfagie door een tracheo-oesofageale fistel bij een volwassene.

In a 64-year-old man who was suffering from chronic obstructive pulmonary disease, recurrent airway infections, dysphagia, and weight loss, achalasia was diagnosed on the basis of endoscopic and radiological examinations. Afterwards he underwent flexible bronchoscopy, which revealed a benign looking fistula between trachea and oesophagus. This appeared to be a congenital tracheo-oesophageal fistula. The fistula was closed surgically. Three months later breathlessness and a sputum-producing cough were the only remaining symptoms. This rare anomaly is mostly diagnosed during childhood, but can also manifest itself in adulthood. If a tracheo-oesophageal fistula is suspected, the diagnostic procedures of choice are a barium oesophagogram in a forward-sitting or supine position or endoscopy of the trachea. Treatment consists of division and closure of the fistula. The prognosis is good.

Vasculitis due to gemcitabine.

We report the first occurrence of gemcitabine-induced vasculitis. It concerns a 45-year-old man diagnosed with non-small lung cancer since 2 months. After the first cycle of chemotherapy, consisting of gemcitabine and cisplatin, he developed myalgia and swelling of arms and legs with impairment of movement. This re-occurred during the second cycle of chemotherapy. Further anemia, elevated ESR and increased creatininephosphokinase. A surgical biopsy showed leucocytoclastic vasculitis and necrosis of muscle tissue. The chemotherapy was stopped and the complaints disappeared and did not return.