Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial.

BACKGROUND: Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management. MATERIALS AND METHODS: NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review. RESULTS: From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis. CONCLUSIONS: Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab.

"Radiotherapy for thymic epithelial tumors: What is the optimal dose? A systematic review."

Thymic epithelial tumors (TETs) are rare thoracic tumors, often requiring multimodal approaches. Surgery represents the first step of the treatment, possibly followed by adjuvant radiotherapy (RT) and, less frequently, chemotherapy. For unresectable tumors, a combination of chemotherapy and RT is often used. Currently, the optimal dose for patients undergoing radiation is not clearly defined. Current guidelines on RT are based on studies with a low level of evidence, where 2D RT was widely used. We aim to shed light on the optimal radiation dose for patients with TETs undergoing RT through a systematic review of the recent literature, including reports using modern RT techniques such as 3D-CRT, IMRT/VMAT, or proton-therapy. A comprehensive literature search of four databases was conducted following the PRISMA guidelines. Two investigators independently screened and reviewed the retrieved references. Reports with < 20 patients, 2D-RT use only, median follow-up time < 5 years, and reviews were excluded. Two studies fulfilled all the criteria and therefore were included. Loosening the follow-up time criteria to > 3 years, three additional studies could be evaluated. A total of 193 patients were analyzed, stratified for prognostic factors (histology, stage, and completeness of resection), and synthesized according to the synthesis without meta-analysis (SWIM) method. The paucity and heterogeneity of eligible studies led to controversial results. The optimal RT dose neither for postoperative, nor primary RT in the era of modern RT univocally emerged. Conversely, this overview can spark new evidence to define the optimal RT dose for each TETs category.

Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study.

PURPOSE: To analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort. METHODS: In this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET)-staged subgroup. RESULTS: 11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and ⩾ 3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p < 0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p < 0.001), for ⩾ 3 versus 1 organ(s) 1.91 (p < 0.001). Results were confirmed in the (18)FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and ⩾ 3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p < 0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p < 0 .001)]. (18)FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p < 0.001). CONCLUSION: Patients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease.

Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study.

BACKGROUND: Patients with stage III non-small-cell lung cancer (NSCLC) and limited disease small-cell lung cancer are excluded from concurrent chemoradiation mostly on the basis of comorbidity and age. The purpose of this prospective study was to get insight in what proportion of patients with locally advanced lung cancer would be suitable for concurrent chemoradiation. PATIENTS AND METHODS: From 2002 to 2005, all patients with a pathological diagnosis of lung cancer and with locally advanced disease in the Maastricht Cancer Registry, the Netherlands, comorbidity were prospectively assessed. Patients were regarded as noneligible for concurrent chemoradiation if they had one or more important comorbidity or were 75 years or older. RESULTS: In all, 711 patients were included, 577 with NSCLC and 134 with SCLC. Overall, 166 patients (23.3%) were 75 years or older. Of the 526 patients <75 years, comorbidities were as follows: 278 (52.9%) 0, 188 (35.7%) 1, and 56 (11.4%) 2 or more. In all, 408/686 (59%) of the whole patient group were considered as ineligible for concurrent chemoradiation. CONCLUSIONS: More than half of patients with stage III lung cancer were theoretically not eligible for concurrent chemoradiation. Less toxic alternatives are needed for these patients.

Maximal neutropenia during chemotherapy and radiotherapy is significantly associated with the development of acute radiation-induced dysphagia in lung cancer patients.

BACKGROUND: Acute dysphagia is a distressing dose-limiting toxicity after concurrent chemoradiation or high-dose radiotherapy for lung cancer. We therefore identified factors associated with the occurrence of acute dysphagia in lung cancer patients receiving radiotherapy alone or combined with chemotherapy. PATIENTS AND METHODS: Radiotherapy, chemotherapy and patient characteristics were analyzed using ordinal regression analysis as possible predictors for acute dysphagia (CTCAE 3.0) in 328 lung cancer patients treated with curative intent. RESULTS: The most significant association was seen between the maximal grade of neutropenia during chemoradiation and dysphagia, with an odds ratio increasing from 1.49 [95% confidence interval (CI) 0.63-3.54, P = 0.362] for grade 1-2 neutropenia to 19.7 (95% CI 4.66-83.52, P < 0.001) for patients with grade 4 neutropenia. Twice-daily schedule, mean esophageal dose and administration of chemotherapy were significant predictive factors. By combining these factors, a high-performance predictive model was made. On an individual patient level, 64% of patients were correctly classified and only 1.2% of patients were misclassified by more than one grade. CONCLUSIONS: The maximal neutrophil toxicity during concurrent chemotherapy and radiotherapy is strongly associated with the development of acute dysphagia. A multivariate predictive model was developed.

MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment?

Magnetic resonance imaging (MRI) of the brain and extensive neurological examination by a neurologist was performed as part of initial staging evaluation of 91 neurologic asymptomatic patients with large cell carcinoma or adenocarcinoma of the lung. Patients were followed up for at least 6 months. Evidence of metastatic brain disease was documented in 13 (14%) patients. Two of these patients were found suspective of brain metastases (BM) by the neurologist. The detection of BM resulted in upstaging of 1 (3%) patient in stage I/II, 4 (21%) patients in stage IIIA and 2 (11%) patients in IIIB. Especially for patients in stage III this upstaging is of importance as aggressive locoregional treatment can be abandoned. Evaluation of the brain with MRI is a sensitive method of detecting BM in neurologic asymptomatic patients and is recommended as part of the initial staging of patients with large cell carcinoma or adenocarcinoma of the lung in stage III. Additional examination by the neurologist is of little value to provide information of the neurologic status.

Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis.

PURPOSE: In this study we evaluated the usefulness of MR-imaging in the detection of asymptomatic brain metastases (BM) at the initial diagnosis in patients with small cell lung cancer (SCLC) and studied the follow-up of these patients. PATIENTS AND METHODS: One-hundred and twenty-five patients with SCLC were investigated with MR-imaging. RESULTS: In 112 patients with normal neurological findings, MR-imaging of the brain demonstrated BM in 17 patients (15%). Six of these 17 patients were therefore upgraded to extensive disease (ED). Two of these 17 patients died during chemotherapy because of progressive disease and 3 patients became neurologic symptomatic with progressive disease on MR-imaging of the brain. After completion of chemotherapy a repeated MR-imaging of the brain in the remaining 12 patients showed 1 complete remission, 4 partial remission and 7 progressive disease of the BM. CONCLUSION: This study showed that at presentation an unexpectedly high percentage of SCLC patients had asymptomatic BM on MR-imaging. We propose that MR-imaging of the brain should be included in the staging of SCLC patients as well for staging, prognosis and therapy.

In-111 octreotide imaging in staging of small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) tumors have neuroendocrine features. In vitro and in vivo studies have demonstrated that 50%-75% of SCLC tumors express receptors for somatostatin. This might enable in vivo localization of the primary tumor and its metastases by using scintigraphy with a radiolabeled somatostatin analogue, such as octreotide. PURPOSE AND METHODS: The efficacy of scanning with In-111 labeled octreotide (octreotide scan) was studied in the staging of SCLC patients and compared with the results of conventional staging (liver ECHO, bone scintigraphy, MRI of the brain, spine, and pelvis). Imaging was performed in 29 patients with histologically confirmed SCLC at 4, 24, and 48 hours after intravenous injection of 185 MBq In-111 octreotide. RESULTS: In 24 of 29 patients, the primary tumor was visualized. In these 24 patients, 26 metastases were demonstrated with conventional staging, of which only nine were visualized with octreotide scan. Octreotide scans showed two metastases in the brain that were not visualized by MRI. In the other five patients, five metastases were demonstrated with conventional staging. Only two of these were detected with octreotide scan. However, octreotide scan did show a further metastasis in the brain that was not visualized by MR imaging. CONCLUSION: Octreotide imaging has a limited use in the detection of SCLC metastases compared to conventional staging. It might have some specific value in the detection of brain involvement in patients with limited disease.

Adrenomyeloneuropathy: a rare cause of Addison's disease?

A 31-year-old male patient is reported who presented with neurological symptoms. He developed a urinary tract infection and an Addisonian crisis. This was due to adrenomyeloneuropathy, a form of X-linked adrenoleukodystrophy and characterized by accumulation of very-long-chain fatty acids in the adrenal cortex and nervous tissues.

Detection of bone marrow metastases in small cell lung cancer. Comparison of magnetic resonance imaging with standard methods.

In small cell lung cancer (SCLC), bone marrow metastases are frequently detected by bone scintigraphy (BS) and/or unilateral bone marrow biopsy and aspiration (BMBA). In this study, the value of magnetic resonance imaging (MRI) of thoracic spine and pelvis was compared with BS and BMBA and its clinical implication was evaluated in 42 patients with SCLC. Patients were staged (including BS, BMBA, CT thorax, Liver ECHO) as limited (LD) or extensive disease (ED) before and after MRI. MRI was positive in 12 BS negative (P = 0.003) and in 14 BMBA negative patients (P < 0.001), while in 8 patients, MRI was the only sign of ED, which resulted in a decrease of patients categorised with LD from 52 to 33%. However, in this small group of LD patients, there was no significant survival difference between LD (MRI pos) and LD (MRI neg) patients. It is concluded that MRI can be of value in the staging of LD patients, but it has no influence on survival.

Abscess of the spleen.

Two unusual cases are presented of splenic abscesses caused by metastatic infection with different organisms. The patients were treated with splenectomy and antibiotics.