Sayed M.S. Hashemi

Outcomes of Hypofractionated High-Dose Radiotherapy in Poor-Risk Patients with “Ultracentral” Non–Small Cell Lung Cancer

Introduction: We defined “ultracentral” lung tumors as centrally located non–small cell lung cancers with planning target volumes overlapping the trachea or main bronchi. Increased toxicity has been reported after both conventional and stereotactic radiotherapy for such lesions. We studied outcomes after 12 fractions of 5 Gy (BED10 = 90 Gy, heterogeneous dose distribution) to ultracentral tumors in patients unfit for surgery or conventional chemoradiotherapy. Methods: Clinical outcomes and dosimetric details were analyzed in 47 consecutive patients with single primary or recurrent ultracentral non–small cell lung cancer treated between 2010 and 2015. Those irradiated previously or with metastasis to sites other than the brain and adrenal glands were excluded. Treatments were delivered using volumetric modulated arc therapy. Results: The median age was 77.5 years, 49% of patients had a World Health Organization performance score of 2 or higher, and the median planning target volume was 104.5cm3 (range 17.7–508.5). At a median follow‐up of 29.3 months, median overall survival was 15.9 months, and 3‐year survival was 20.1%. No isolated local recurrences were observed. Grade 3 or higher toxicity was recorded in 38% of patients, with 21% scored as having a “possible” (n = 2) or “likely” (n = 8) treatment‐related death between 5.2 and 18.2 months after treatment. Fatal pulmonary hemorrhage was observed in 15% of patients. Conclusions: Unfit patients with ultracentral tumors who were treated using this scheme had a high local control and a median survival of 15.9 months. Despite manifestation of rates of a fatal lung bleeding comparable to those seen with conventional radiotherapy for endobronchial tumors, the overall rate of G5 toxicity is of potential concern. Additional work is needed to identify tumor and treatment factors related to hemorrhage.

Patterns of Disease Recurrence after SABR for Early Stage Non-Small-Cell Lung Cancer: Optimizing Follow-Up Schedules for Salvage Therapy.

Introduction: Stereotactic ablative radiotherapy is a guideline-recommended treatment for early stage non–small-cell lung cancer. We report on incidence and salvage of local recurrences (LR) and second primary lung cancers (SPLC) in a large series of patients with long-term follow-up, to generate data for evidence-based follow-up regimens. Methods: We excluded all patients with double tumors, TNM-stages other than T1-T2N0M0, biologically effective dose less than 100 Gy10 and previous treatment for the index tumor from our institutional database. LR was defined as recurrence in/adjacent to the planning target volume. A diagnosis of SPLC was determined using criteria described by Martini et al. Results: The 855 patients included had a median follow-up of 52 months. Forty-six patients developed LR after a median of 22 months (range 7–87 months). Actuarial local control rates at 3 and 5 years were 92.4% and 90.9%, respectively. Fifty-four percent had isolated LR and 13% had LR in combination with regional recurrences. Ten patients underwent radical salvage treatment; surgery (N = 6), high-dose radiotherapy (N = 3), or chemoradiation (N = 1). Median overall survival following LR was 13 months, but it was 36 months in patients who underwent radical salvage. A SPLC was diagnosed in 79 patients, after a median interval of 34 months. Actuarial cumulative incidences of SPLC at 3 and 5 years were 11.7% and 16.7%, respectively. Radical salvage for SPLC was performed in 63 patients (80%). Conclusions: Both the timing of LR and persistent risk of SPLC serve as rationale for long-term follow-up using computed tomography scans in patients fit enough to undergo any radical treatment.

A randomized controlled trial comparing indwelling pleural catheters with talc pleurodesis (NVALT-14)

BACKGROUND Symptomatic malignant pleural effusion (MPE) occurs frequently in patients with metastatic cancer. The associated prognosis is poor and the success rate of talc pleurodesis (TP) is low. Indwelling pleural catheters (IPCs) are commonly inserted when TP has been unsuccessful. METHODS We compared talc pleurodesis with the use of an indwelling pleural catheter in patients with recurrent MPE in a multicenter randomized controlled trial (superiority design). The primary endpoint was improvement from baseline in Modified Borg Score (MBS) 6weeks after randomized treatment. Secondary endpoints were hospitalization days, re-interventions, and adverse events. RESULTS Dyspnea improved significantly (p<0.01) after either treatment, but the magnitude of this improvement did not differ significantly between arms (median 3 and 1 for TP:IPC respectively in rest, p=0.16, (TP 13:IPC 16) and 3 and 1 during exercise, p=0.72 (TP 13:IPC 17)). There was no difference in dyspnea during exercise between TP and IPC at week 6 following treatment, while at rest TP patients (n=13) reported less dyspnea than IPC patients (n=18) (median 0 vs 1, p=0.002). Compared to TP, patients with an IPC had significantly less hospital days during randomized treatment (median: 0 vs 5, p<0.0001), and total hospitalizations for all causes (median: 1.6 vs 1.0, p=0.0035). Fewer IPC patients underwent more than one re-intervention (7/45 vs 15/43, p=0.09). The mean number of re-interventions was lower following IPC (0.21 vs 0.53, p=0.05). Equal number of adverse events occurred. CONCLUSIONS IPC was not superior in the primary endpoint, improvement of the modified Borg scale (MBS). However, IPC patients had lower hospital stay, fewer admissions and fewer re-interventions. The IPC is an effective treatment modality in patients with symptomatic malignant pleural effusion.

High PD-1 expression on regulatory and effector T-cells in lung cancer draining lymph nodes

The treatment of advanced nonsmall cell lung cancer (NSCLC) with PD-1/PD-L1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find better biomarkers than PD-L1 immunohistochemistry (IHC) that will identify patients likely to benefit from this therapy. In this exploratory study we assessed the differences in T-cell subsets and PD-1 expression levels on T-cells in tumour-draining lymph nodes (TDLNs) and peripheral blood mononuclear cells (PBMCs). To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine-needle aspirates (FNA) from TDLNs of patients with NSCLC, and the results were compared to paired PBMC samples. For a select number of patients, we were also able to obtain cells from a non-TDLN (NTDLN) sample. Our data show that the frequency of PD-1+ CD4+ and CD8+ T-cells, as well as the PD-1 expression level on activated regulatory T (aTreg) and CD4+ and CD8+ T-cells, are higher in TDLNs than in PBMCs and, in a small sub-analysis, NTDLNs. These elevated PD-1 expression levels in TDLNs may reflect tumour-specific T-cell priming and conditioning, and may serve as a predictive or early-response biomarker during PD-1 checkpoint blockade. PD-1 in NSCLC tumour-draining lymph nodes as a potential biomarker http://ow.ly/QedU30bqJ6d

Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion–Positive Advanced NSCLC

Introduction: EGFR exon 20 insertions comprise 4% to 9% of EGFR mutated NSCLC. Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. Methods: Four patients with EGFR exon 20 insertion–positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250 mg/m2 to 500 mg/m2 every 2 weeks. Results: All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n = 4) and EGFR TKI (n = 2). Three of four patients showed a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Median progression‐free survival was 5.4 months (95% confidence interval: 0.0 – 14.2 months; range 2.7 months – 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients. Conclusions: Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion–positive NSCLC.

Complications of endoscopic ultrasound-guided needle aspiration

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and esophageal ultrasound-guided fi ne needle aspiration (EUSFNA) are minimally invasive techniques with established value in the diagnosis and staging of thoracic tumors as well as benign lung diseases. A linear ultrasound probe at the distal part of the endoscope enables puncture of mediastinal and hilar lesions, and the (left) adrenal gland under real-time guidance. Although mediastinoscopy has been considered the gold standard for mediastinal staging of lung cancer, the use of E(B)US-NA (EBUS-TBNA and/ or EUS-FNA) has increased substantially in recent years. Studies have shown that despite a lower negative predictive value than mediastinoscopy it nonetheless has high diagnostic accuracy and it does not routinely require general anesthesia [1,2]. In addition, most authors report an excellent safety profi le with E(B)US-NA [3 – 5]. Nonetheless, serious complications can occur and with the rapid diffusion into routine clinical practice, it is important that clinicians are aware of these. In this short report we describe six cases which were at some point managed in our institution in which signifi cant complications were clinically attributed to E(B)US-NA. We then briefl y review the relevant literature.

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

PURPOSE Next to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms. Here, we report on the clinical outcome of a series of patients with cMET-driven resistance to EGFR TKIs, treated with crizotinib. MATERIALS AND METHODS Eight patients with EGFR mutation positive NSCLC that acquired cMET amplification after EGFR TKI treatment were treated with crizotinib 250 mg twice daily, as monotherapy (n = 2) or in combination with an EGFR TKI (n = 6). RESULTS Four out of eight patients (50%) showed a partial response (PR) according to RECIST 1.1. Median progression-free survival (PFS) was 1.4 (95% CI 1.2-5.0) months. Responses were short-lasting with a median PFS of 3.5 (95% CI 1.4-5.2) months in patients with a PR. Median overall survival was 5.9 (95% CI 1.3-6.0) months and not statistically different between responders and non-responders (p = 0.37). All but one patient tolerated crizotinib treatment well. Heterogeneous responses were seen in patients with progressive disease as best response with a marked size decrease of the biopsied (cMET amplification positive) lesion and progression of other lesions. cMET amplification was not always mutually exclusive with other EGFR TKI resistance mechanisms. Post-progression biopsies were negative for cMET amplification. CONCLUSION Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI treatment results in short-lived and often heterogeneous responses, possibly due to subclonality of cMET-driven resistance and co-occurrence of other EGFR TKI resistance mechanisms.

Trastuzumab and paclitaxel in patients with EGFR mutated NSCLC that express HER2 after progression on EGFR TKI treatment

BackgroundHER2 expression and amplification are observed in ~15% of tumour biopsies from patients with a sensitising EGFR mutation who develop EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumour responses.MethodsA single arm phase II study was performed to study the safety and efficacy of trastuzumab and paclitaxel treatment in patients with a sensitising EGFR mutation who show HER2 expression in a tumour biopsy (IHC ≥ 1) after progression on EGFR TKI treatment. Trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) and paclitaxel (60 mg/m2) were dosed weekly until disease progression or unacceptable toxicity. The primary end-point was tumour response rate according to RECIST v1.1.ResultsTwenty-four patients were enrolled. Nine patients were exon 21 L858R positive and fifteen exon 19 del positive. Median HER2 IHC was 2+ (range 1–3). For 21 patients, gene copy number by in situ hybridisation could be calculated: 5 copies/nucleus (n = 9), 5–10 copies (n = 8), and >10 copies (n = 4). An objective response was observed in 11/24 (46%) patients. Highest response rates were seen for patients with 3+ HER2 IHC (12 patients, ORR 67%) or HER2 copy number ≥10 (4 patients, ORR 100%). Median tumour change in size was 42% decrease (range −100% to +53%). Median duration of response was 5.6 (95% confidence interval [CI], 3.8 to 7.3) months. Treatment toxicity was mild with four patients experiencing grade ≥3 toxicity, including fatigue, neuropathy, neutropaenia, urinary tract infection, and pneumonitis.ConclusionsTrastuzumab-paclitaxel induces objective tumour responses in 46% of EGFR TKI pretreated patients with an activating EGFR mutation and HER2 expression. The treatment was well tolerated. The relation between response rate and HER2 expression level and copy number suggests effective HER2 targeting by trastuzumab, although the combination with paclitaxel does not allow to determine the relative contribution of the individual drugs in terms of treatment efficacy.

Abstract 4584: High PD-1 expression on regulatory and effector T cells in lung cancer draining lymph nodes

The treatment of advanced non-small cell lung cancer (NSCLC) with PD-1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find biomarkers that will identify patients likely to benefit from this therapy. In this study we assessed the difference of T cell subsets and PD-1 expression levels on T cells in tumor-draining lymph nodes (TDLN), non-TDLN (NTDLN) and peripheral blood mononuclear cells (PBMC). To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine-needle aspirates (FNA) from TDLN and NTDLN of patients with NSCLC and compared to PBMC. Our data show that the frequency of PD-1+ CD4+ and CD8+ T cells, as well as the PD-1 expression level on activated regulatory T (aTreg) and CD4+ and CD8+ T cells, are higher in TDLNs as compared to NTDLNs or PBMC. These elevated PD-1 expression levels in TDLN may reflect tumor-specific T cell priming and may serve as a predictive or early response biomarker during PD-1 checkpoint blockade. Citation Format: Rieneke Van De Ven, Anna-Larissa N. Niemeijer, Anita G. Stam, Sayed M. Hashemi, Christian G. Slockers, Johannes M. Daniels, Erik Thunnissen, Egbert F. Smit, Tanja D. de Gruijl, Adrianus J. de Langen. High PD-1 expression on regulatory and effector T cells in lung cancer draining lymph nodes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4584. doi:10.1158/1538-7445.AM2017-4584

Pneumomediastinum and (bilateral) pneumothorax after high energy trauma: Indications for emergency bronchoscopy.

High energy trauma may cause injury to tracheobronchial structures. This is sometimes difficult to diagnose immediately. Pneumomediastinum and (bilateral) pneumothorax seen on a CT-scan of the thorax may suggest possible damage to central airways. Emergency bronchoscopy should be performed to detect and locate a possible tracheobronchial injury.