Influenza season influence on outcome of new nodules in the NELSON study.

We evaluated the impact of the influenza season on outcome of new lung nodules in a LDCT lung cancer screening trial population. NELSON-trial participants with ≥ 1 new nodule detected in screening rounds two and three were included. Outcome (resolution or persistence) of new nodules detected per season was calculated and compared. Winter (influenza season) was defined as 1st October to 31st March, and compared to the summer (hay-fever season), 1st April to 30th September. Overall, 820 new nodules were reported in 529 participants. Of the total new nodules, 482 (59%) were reported during winter. When considering the outcome of all new nodules, there was no statistically significant association between summer and resolving nodules (OR 1.07 [CI 1.00-1.15], p = 0.066), also when looking at the largest nodule per participant (OR 1.37 [CI 0.95-1.98], p = 0.094). Similarly, there was no statistically significant association between season and screen detected cancers (OR 0.47 [CI 0.18-1.23], p = 0.123). To conclude, in this lung cancer screening population, there was no statistically significant association between influenza season and outcome of new lung nodules. Hence, we recommend new nodule management strategy is not influenced by the season in which the nodule is detected.

Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer.

Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients.

Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.

Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer.

PURPOSE: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). METHODS: At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. RESULTS: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. CONCLUSIONS: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation? : A planning study.

BACKGROUND: After lung-sparing radiotherapy for malignant pleural mesothelioma (MPM), local failure at sites of previous gross disease represents the dominant form of failure. Our aim is to investigate if selective irradiation of the gross pleural disease only can allow dose escalation. MATERIALS AND METHODS: In all, 12 consecutive stage I-IV MPM patients (6 left-sided and 6 right-sided) were retrospectively identified and included. A magnetic resonance imaging-based pleural gross tumor volume (GTV) was contoured. Two sets of planning target volumes (PTV) were generated for each patient: (1) a "selective" PTV (S-PTV), originating from a 5-mm isotropic expansion from the GTV and (2) an "elective" PTV (E-PTV), originating from a 5-mm isotropic expansion from the whole ipsilateral pleural space. Two sets of volumetric modulated arc therapy (VMAT) treatment plans were generated: a "selective" pleural irradiation plan (SPI plan) and an "elective" pleural irradiation plan (EPI plan, planned with a simultaneous integrated boost technique [SIB]). RESULTS: In the SPI plans, the average median dose to the S­PTV was 53.6 Gy (range 41-63.6 Gy). In 4 of 12 patients, it was possible to escalate the dose to the S­PTV to >58 Gy. In the EPI plans, the average median doses to the E­PTV and to the S­PTV were 48.6 Gy (range 38.5-58.7) and 49 Gy (range 38.6-59.5 Gy), respectively. No significant dose escalation was achievable. CONCLUSION: The omission of the elective irradiation of the whole ipsilateral pleural space allowed dose escalation from 49 Gy to more than 58 Gy in 4 of 12 chemonaive MPM patients. This strategy may form the basis for nonsurgical radical combined modality treatment of MPM.

Pulmonary metastasis of a meningioma presenting as a solitary pulmonary nodule: 2 case reports.

Distant metastases of meningioma are rare, especially in grade 1 meningiomas. In a recent literature review, only 115 cases were found. In almost all published cases, the meningioma was treated several years before the metastasis was diagnosed. The lungs are the most frequent site of metastasis. We describe two patients treated for meningioma (one case grade 1, the other grade 3) who were referred to the Respiratory Oncology Unit because of the incidental finding of a pulmonary nodule on routine chest radiography. Both had undergone several neurosurgical procedures but the last operation was more than 7 years before in both cases. Positron emission tomography scan was suggestive of a malignant lung tumour. The lesions were surgically removed. Pathology confirmed meningioma in both cases with the same WHO grade, immunohistochemical and genetic profiles as the original meningioma. Both patients recovered well from thoracic surgery. The patient with grade 3 meningioma died three years later from intracranial recurrence. When a patient previously treated for meningioma develops a nodular lung lesion, metastasis of the meningioma should be in the differential diagnosis list. Because of the occurrence of distant metastasis even in grade I meningiomas, we suggest that the grading system should take into account genetic changes in the meningioma. Chromosome 1p and 14q losses possibly explain the aggressive behaviour of the grade 1 meningioma.

Comparison of diagnostic accuracy of (111)In-pentetreotide SPECT and (68)Ga-DOTATOC PET/CT: A lesion-by-lesion analysis in patients with metastatic neuroendocrine tumours.

OBJECTIVES: To compare the diagnostic accuracy of (111)In-pentetreotide-scintigraphy with (68)Ga-DOTATOC-positron emission tomography (PET)/computed tomography (CT) in patients with metastatic-neuroendocrine tumour (NET) scheduled for peptide receptor radionuclide therapy (PRRT). Incremental lesions (ILs) were defined as lesions observed on only one modality. METHODS: Fifty-three metastatic-NET-patients underwent (111)In-pentetreotide-scintigraphy (24 h post-injection; planar+single-photon emission CT (SPECT) abdomen) and whole-body (68)Ga-DOTATOC-PET/CT. SPECT and PET were compared in a lesion-by-lesion and organ-by-organ analysis, determining the total lesions and ILs for both modalities. RESULTS: Significantly more lesions were detected on (68)Ga-DOTATOC-PET/CT versus (111)In-pentetreotide-scintigraphy. More specifically, we observed 1,098 lesions on PET/CT (range: 1-105; median: 15) versus 660 on SPECT (range: 0-73, median: 9) (p<0.0001), with 439 PET-ILs (42/53 patients) and one SPECT-IL (1/53 patients). The sensitivity for PET/CT was 99.9 % (95 % CI, 99.3-100.0), for SPECT 60.0 % (95 % CI, 48.5-70.2). The organ-by-organ analysis showed that the PET-ILs were most frequently visualized in liver and skeleton. CONCLUSION: Ga-DOTATOC-PET/CT is superior for the detection of NET-metastases compared to (111)In-pentetreotide SPECT. KEY POINTS: Somatostatin receptor PET is superior to SPECT in detecting NET metastases. PET is the scintigraphic method for accurate depiction of NET tumour burden. The sensitivity of PET is twofold higher than the sensitivity of SPECT.

Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline: a randomized, placebo-controlled trial.

The efficacy and safety of retreatment with varenicline in smokers attempting to quit were evaluated in this randomized, double-blind, placebo-controlled, multicenter trial (Australia, Belgium, Canada, the Czech Republic, France, Germany, the United Kingdom, and the United States). Participants were generally healthy adult smokers (≥ 10 cigarettes/day) with ≥ 1 prior quit attempt (≥ 2 weeks) using varenicline and no quit attempts in ≤ 3 months; they were randomly assigned (1:1) to 12 weeks' varenicline (n = 251) or placebo (n = 247) treatment, with individual counseling, plus 40 weeks' nontreatment follow-up. The primary efficacy end point was the carbon monoxide-confirmed (≤ 10 ppm) continuous abstinence rate for weeks 9-12, which was 45.0% (varenicline; n = 249) vs. 11.8% (placebo; n = 245; odds ratio: 7.08; 95% confidence interval: 4.34, 11.55; P < 0.0001). Common varenicline group adverse events were nausea, abnormal dreams, and headache, with no reported suicidal behavior. Varenicline is efficacious and well tolerated in smokers who have previously taken it. Abstinence rates are comparable with rates reported for varenicline-naive smokers.

Predictors of quit success in Belgian participants of a varenicline observational smoking cessation study.

BACKGROUND: We evaluated efficacy, predictors of quitting success and the safety profile of varenicline for smoking cessation in the Belgian participants in an observational, "real world" study. METHODS: In this post-hoc analysis of a prospective, observational, non-comparative study, participants were adult smokers who were motivated to quit and were prescribed varenicline in accordance with the recommendations of the European Summary of Product Characteristics. The 7-day point prevalence of abstinence at Weeks 12 and 24 was determined based on patient reporting, and these data were further analysed by time to first cigarette on waking and by the use of behavioural support. The safety profile of varenicline was also assessed. RESULTS: Overall, 61.1% of participants (n= 226) successfully quit smoking by the end of Week 12. There was a significant association between abstinence and time to first cigarette on waking (Week 12: OR, 0.69 [95% CI, 0.50-0.94], p = 0.02; Week 24: OR, 0.70 [95% CI, 0.52-0.94], p=0.02) and the use of behavioural support (Week 12: OR, 6.18 [95% CI, 3.41-11.2], p<0.01; Week 24: OR, 5.37 [95% CI, 2.89-9.98], p<0.01). The most frequent treatment-emergent adverse event was nausea (9.3%). CONCLUSIONS: In this post-hoc analysis, varenicline was an effective smoking cessation aid with an acceptable safety profile in real world clinical practice in Belgian smokers. Significant predictors of abstinence were time to first cigarette on waking and use of behavioural support.

Clinical factors predictive of long-term survival in advanced non-small cell lung cancer.

PURPOSE: While the overall prognosis of non-molecularly selected advanced non-small cell lung cancer (NSCLC) patients is poor, a subset of these patients has durable survival. We examined which clinical factors might be predictive for this favourable outcome. PATIENTS AND METHODS: Long-term NSCLC survivors (LTS, i.e. >2 years) were retrieved from all our out- and in-patient contacts in a 6 month period (March-August 2009). LTS records were compared with a group of short-term survivors (STS). Both baseline clinical factors (sex, age, smoking status, weight loss, performance status, co-morbidity, histological subtype, place and number of metastasis) and treatment-related features (number and type of therapeutic lines, response, duration of treatment-free interval) were compared. RESULTS: 31 LTS were retrieved (stage IV patients with potentially radical treatment options, e.g. solitary brain or adrenal metastasis, were excluded), and compared with 34 STS. In the LTS group, median survival was 53 months, with 47% of patients alive at 5 years, in the STS patients this was 9.7 months, with 24% alive at 1-year. Baseline factors had little predictive value, but response to 1st line therapy (P = 0.0001), response duration (P = 0.009), and the number of systemic lines (P = 0.0023) were of importance. CONCLUSION: These data confirm the existence of LTS in patients with advanced NSCLC. There are very little clinical factors at the time of diagnosis that help to distinguish future LTS from STS patients. Factors related to the effect of 1st line treatment are important, and further prospects of patients achieving a 2-year survival are in general quite good.

Pathologic complete remission of malignant pleural mesothelioma after combined modality treatment: a case report.

A 50-year-old patient with malignant pleural mesothelioma (epithelial subtype, clinically staged cT1bN0M0) underwent a combined modality treatment, including induction chemotherapy, followed by extrapleural pneumonectomy (EPP) and radical radiotherapy. After pathologic examination of the surgical specimen, a complete remission (pT0N0) was observed. The complete disappearance of solid tumour tissue after induction chemotherapy is a rarely observed and documented finding in the combined modality treatment of malignant pleural mesothelioma. The real prognostic value of the pathologic complete remission of a malignant pleural mesothelioma definitely needs to be further evaluated in a larger series of patients.

Screening and early detection of lung cancer.

The greatest news of the past year in this field was the first large-scale early detection trial that could prove a 20% reduction in lung cancer-related mortality by screening high-risk individuals with low-dose computed tomography (LDCT). Several expert groups and medical societies have assessed the data and concluded that LDCT screening for lung cancer is, however, not ready for large-scale population-based implementation. Too many open questions remain, such as definition of the at-risk population, timing and intervals of screening, optimal method of acquisition and interpretation of the images, how to handle (false) positive findings, and especially cost-effectiveness in relation to other lung cancer prevention strategies, mainly smoking cessation. Further analyses and several ongoing European trials are eagerly awaited. Much hope also resides in the use of biomarkers, as their use in, e.g., blood or exhaled air may provide more easy-to-use tests to better stratify high-risk populations for screening studies. While exciting research is ongoing in this domain--e.g. with microRNAs--none of the tests has yet reached sufficient validation for clinical use. Early central lung cancers are more difficult to visualise by CT. For these patients, standard bronchoscopy, complemented by autofluoresence endoscopy, has been studied in different screening and follow-up settings.

Blinded and uniform cause of death verification in a lung cancer CT screening trial.

Disease-specific mortality is the final outcome of a lung cancer screening trial, therefore cause of death verification is crucial. The use of death certificates for this purpose is debated because of bias, inaccurate completion and incorrect ante mortem diagnoses. A cause of death evaluation process was designed to ensure a uniform and unbiased determination of the graduation of certainty that lung cancer was the underlying cause of death. An independent clinical expert committee will review the medical files of all deceased participants once diagnosed with lung cancer and will make use of a flow chart and predetermined criteria. A pilot study of fifty cases was conducted to determine the performance of this process and to compare the outcome with the official death certificates. The independent review has shown an agreement of 90% (kappa 0.65), which demonstrates a uniform classification. The sensitivity and specificity of the death certificates for lung cancer specific mortality were 95.2 and 62.5%. This demonstrates a limited distinctive character of the death certification process in lung cancer patients. Our results imply that the final outcome of a lung cancer screening trial cannot reliably be established without predetermined criteria and an independent review of blinded cases.

Late recurrent ovarian carcinoma metastatic to the thoracic wall.

Ovarian cancer is the second most common gynaecologic malignancy. Ovarian carcinomas typically metastasize to multiple sites via exfoliation, lymphatic spread or direct invasion. We present a rare case of a very late recurrence of ovarian carcinoma into the thoracic wall, heralded by thoracic pain in a patient otherwise disease-free for 23 years. This unusual and late presentation of an ovarian cancer metastasis underscores the need for continued awareness and attention to new symptoms in patients with ovarian cancer who show prolonged disease-free intervals.

Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: results from 2 phase I studies.

BACKGROUND: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. PATIENTS AND METHODS: Treatment naïve patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy). RESULTS: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. CONCLUSIONS: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy.

A 63-year-old man with peripheral facial nerve paralysis and a pulmonary lesion.

BACKGROUND: Occasionally, malignant neoplasms may cause peripheral facial nerve paralysis as a presenting symptom. CASE REPORT: A 63-year-old man was referred to the Emergency Department because of a peripheral facial nerve paralysis, lasting for 10 days. Initial diagnostic examinations revealed no apparent cause for this facial nerve paralysis. Chest X-ray, however, showed a suspicious tumoural mass, located in the right hilar region, as confirmed by CAT scan. The diagnosis of an advanced stage lung adenocarcinoma was finally confirmed by bronchial biopsy. MRI scanning showed diffuse brain metastases and revealed a pontine lesion as the most probable underlying cause of this case of peripheral facial nerve paralysis. Platin-based palliative chemotherapy was given, after an initial pancranial irradiation. RESULTS: According to the MRI findings, the pontine lesion was responsible for the peripheral facial nerve paralysis, as an initial presenting symptom in this case of lung adenocarcinoma. CONCLUSION: This clinical case of a peripheral facial nerve paralysis was caused by a pontine brain metastasis and illustrates a rather rare presenting symptom of metastatic lung cancer.

Coccidioidomycosis: an unexpected diagnosis in a patient with persistent cough.

Coccidioidomycosis is an endemic fungal infection of the new world caused by Coccidioides immitis. Because of its low incidence in the European continent, the disease is not well known in Belgium. A 34-year-old male was referred by his general physician with a chronic cough and a nodular infiltrate on chest X-ray. Because a malignant tumour was suspected, a diagnostic work-up was performed and, finally, a broad excision of the pulmonary lesion was carried out. The unsuspected diagnosis of chronic coccidioidomycosis was eventually made based on identification of the filamentous fungus in mycological culture of the lung tissue, and the presence of the typical spherules with endospores upon histopathologic examination. The patient later admitted to have been travelling to Arizona frequently in the past year for professional reasons. Coccidioides spp. should always be considered as a possible aetiologic agent of pulmonary infection in former residents and recent travellers to regions where the fungus is endemic.