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 + .

Health-related quality of life after prophylactic cranial irradiation for stage III non-small cell lung cancer patients: Results from the NVALT-11/DLCRG-02 phase III study.

BACKGROUND AND PURPOSE: The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL. MATERIALS AND METHODS: Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores. RESULTS: In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39-54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914). CONCLUSION: No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed.

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype.

INTRODUCTION: Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small-cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small-cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up. METHODS: Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next-generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1). RESULTS: All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5-18.5 months). Mean Ki-67 PI was 59% (range 15-100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11-23 months) vs 5 months (95% CI 0.7-9 months), P = 0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified, and both SCLC-like (n = 6) and NSCLC-like (n = 2) subtypes were present. No MEN1 mutation was found. CONCLUSION: Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

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.

A randomized phase II study comparing paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)†.

BACKGROUND: Nitroglycerin (NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia-inducible-factor (HIF)-1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/cisplatin in patients with advanced nonsmall-cell lung cancer (NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF-1 inhibitors increases antitumor activity. PATIENTS AND METHODS: In this randomized phase II trial, chemo-naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin (area under the curve 6)-paclitaxel (200 mg/m(2))-bevacizumab 15 mg/kg on day 1 every 3 weeks with or without NTG patches 15 mg (day -2 to +2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression-free survival (PFS). The study was powered (80%) to detect a decrease in the hazard of tumor progression of 33% at α = 0.05 with a two-sided log-rank test when 222 patients were enrolled and followed until 195 events were observed. RESULTS: Between 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [95% confidence interval (CI)] PFS in control arm was 6.8 months (5.6-7.3) and 5.1 months (4.2-5.8) in experimental arm, hazard ratio (HR) 1.27 (95% CI 0.96-1.67). Overall survival (OS) was 11.6 months (8.8-13.6) in control arm and 9.4 months (7.8-11.3) in experimental arm, HR 1.02 (95% CI 0.71-1.46). In the experimental arm, no additional toxicity was observed except headache (6% versus 52% in patients treated with NTG). CONCLUSION: Adding NTG to first-line carboplatin-paclitaxel-bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.

Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study.

BACKGROUND: Elderly patients with advanced non-small-cell lung cancer (NSCLC) may derive similar benefit from platinum-based chemotherapy as younger patients. Quality of life (QoL) and comprehensive geriatric assessment (CGA) is often advocated to assess benefits and risks. PATIENTS AND METHODS: A total of 181 chemotherapy-naive patients [≥70 years, performance score (PS) of 0-2] with stage III-IV NSCLC received carboplatin and gemcitabine (CG) (n = 90) or carboplatin and paclitaxel (CP) (n = 91) every 3 weeks for up to four cycles. Primary end point was change in global QoL from baseline compared with week 18. Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken. A principal component (PC) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival. RESULTS: There were no changes in QoL after treatment. The number of QoL responders (CG arm, 12%; CP arm, 5%) was not significantly different. CGA items were only associated with neuropsychiatric toxicity. Quality-adjusted survival was not different between treatment arms. The PC analysis derived from nine CGA, six QoL and one PS score indicated only one dominant dimension. This dimension was strongly prognostic, and physical and role functioning, Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors. CONCLUSIONS: Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner. CGA and QoL items measure one underlying dimension, which is highly prognostic.

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.

Thyroid carcinoma as first manifestation of familial adenomatous polyposis.

A 22-year-old female member of a family with familial adenomatous polyposis (FAP) presented with a thyroid nodule. Histology revealed a follicular carcinoma. The patient was on regular follow-up as part of the FAP screening program; 1.5 years after the thyroidectomy she appeared to have multiple adenomatous polyps in her colon and FAP was diagnosed. Thyroid-carcinoma is one of the extraintestinal manifestations of FAP and particularly women in the age of 25-35 years are at risk according to the literature.