Aspects of palliative chemotherapy for lung cancer

Lung carcinoma is the main cause of cancer related deaths among the male population in The Netherlands. In females this carcinoma is only surpassed by breast and colon cancer. In The Netherlands in 1987, 8.500 persons died due to lung carcinoma (1). It is anticipated that despite government-installed preventive measures -including stop-smoking programs- the number of persons suffering from lung cancer will continue to rise in the near future (2,3). The results of all therapeutic modalities for lung cancer have reached a plateau for many years with about 10% overall cure (4). For therapeutic reasons, lung cancer is generally divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). For NSCLC surgery is the only curative modality for patients without demonstrable metastatic disease (5). For SCLC, which comprises 20-25% of all cases, combination chemotherapy forms the cornerstone of therapy with the vast majority of patients responding to therapy with prolonged survival and a small percentage of cures. While SCLC is responsive to chemotherapy, NSCLC is only moderately responsive to such therapy (6). Although much knowledge has been gathered on the biology of lung cancer, this basic research did not, however, result in improved survival of patients treated by chemotherapy for lung cancer (7). The failure of chemotherapy to cure lung cancer patients is basically a problem of drug resistance. Several resistance mechanisms have been discovered in the recent years. The most widely studied form is the so called pleiotropic drug resistance (PDR) (8). PDR has emerged as a consistent mechanism of resistance for several structurally unrelated cytotoxic agents in cancer cells. Resistance seems to be caused by a decreased intracellular drug concentration, caused by an increased efflux pump. This efflux pump can be antagonated in vitro by calcium antagonists. It has become clear that reversal of resistance mediated by the PDR-phenotype is in some cases possible in the clinic (9,lO). PDR however, seems to play little or no role in lung cancer (1 1). Resistance mechanisms which have been identified in vitro in lung cancer cell lines include enhanced DNA repair capacity and altered drug-topoisomerase interactions (12). For these and other drug resistance mechanisms it has by no means been elucidated whether they can be circumvented by sophisticated measures in the near future

Association of tumour and stroma PD-1, PD-L1, CD3, CD4 and CD8 expression with DCB and OS to nivolumab treatment in NSCLC patients pre-treated with chemotherapy

Background: Immune checkpoint inhibitors are most beneficial in patients with high tumour PD-L1 expression. However, the use of PD-L1 expression is not straightforward. We investigated PD-L1 expression and immune cell (IC) infiltrates in non-small-cell lung cancer (NSCLC) patients treated with nivolumab. Methods: Tumour tissue specimens of 139 NSCLC patients were scored for tumour/stromal PD-L1 and various IC expression markers, and associated with durable clinical benefit (DCB) and overall survival (OS). Results: Median OS was higher for patients with high stromal infiltration of CD8+ ICs (9.0 months) compared with patients with low and intermediate infiltration (both 5.0 months, p = 0.035) and for patients with high infiltration of stromal CD4+ ICs (9.0 months) compared with patients with low and intermediate infiltration (both 5.0 months, p = 0.010) and this was confirmed in the validation cohort. Post hoc analyses showed that biopsies taken after the last line of chemotherapy (ACT) were predictive for DCB and OS, whereas samples obtained before the last line of chemotherapy (BCT) were not. Conclusions: Stromal infiltration of ICs can predict response to PD-1-directed immunotherapy in NSCLC patients. Interestingly, we found differences in the predictive value of IC markers between the ACT and BCT biopsies, suggesting that chemotherapy might influence the immune microenvironment

Minimally invasive lobectomy versus stereotactic ablative radiotherapy for stage I non-small cell lung cancer

OBJECTIVES: A minimally invasive lobectomy (MIL) is the standard treatment for stage I non-small cell lung cancer (NSCLC) in medically operable patients. Stereotactic ablative radiotherapy (SABR) is recommended for inoperable patients and has been proposed as a potential alternative for operable patients as well. Here, we present the results of a feasibility study in preparation for a nationwide retrospective cohort study, comparing outcomes between both treatment modalities. METHODS: In this retrospective cohort study, data from patients with clinical stage I NSCLC treated with MIL or SABR in 2014-2015 were retrieved from databases from 12 Dutch hospitals. Progression-free survival (PFS), overall survival (OS) and lung cancer-specific survival (LCSS) were compared between MIL and SABR. RESULTS: A total of 597 patients with clinical stage I NSCLC treated with MIL (n = 356) or SABR (n = 241) were included. In total, 106 (30%) patients had died in the MIL group and 142 (59%) in the SABR group. After MIL and SABR, unadjusted 5-year PFS was 63% and 30%, OS was 72% and 38% and LCSS was 81% and 76%, respectively. Propensity score-weighted analyses did not show significant differences between MIL and SABR in OS [hazard ratios (HR) 0.74 (95% confidence interval (CI) 0.43-1.29)], PFS [HR 0.74 (95% CI 0.42-1.32)] or LCSS [HR 0.81 (95% CI 0.42-1.59)]. CONCLUSIONS: Unadjusted analyses revealed superior OS and PFS for MIL and similar LCSS, but this feasibility study was not sufficiently powered to demonstrate significant differences using propensity score methodology. Therefore, this study is currently being extended to include more than half of Dutch hospitals in order to enlarge the population to ≥1880 patients, not only to determine the best treatment for patients with stage I NSCLC overall, but also to assess the preferred treatment for patient groups with specific characteristics

A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer

PURPOSE: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Chemotherapy-naive patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. RESULTS: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. CONCLUSION: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted

Deletions of 11q22.3-q25 Are Associated with Atypical Lung Carcinoids and Poor Clinical Outcome

Carcinoids are slow-growing neuroendocrine tumors that, in the lung, can be subclassified as typical (TC) or atypical (AC). To identify genetic alterations that improve the prediction of prognosis, we investigated 34 carcinoid tumors of the lung (18 TCs, 15 ACs, and 1 unclassified) by using array comparative genomic hybridization (array CGH) on 3700 genomic bacterial artificial chromosome arrays (resolution = 1 Mb) and losses at 1p, 2q, 10q, and 11q; and iii) 11q deletions in 8 of 15 ACs versus 1 of 18 TCs = 0.004), which was confirmed via fluorescence in situ hybridization. The four critical regions of interest in 45% ACs or more comprised 11q14.1, 11q22.1-q22.3, 11q22.3-q23.2, and 11q24.2-q25, all telomeric of MEN1 at 11q13. Results were correlated with patient clinical data and long-term follow-up. Thus, there is a strong association of 11q223-q25 loss with poorer prognosis, alone or in combination with absence of 9q34.11 alterations (P = 0.0022 and P = 0.00026, respectively). (Am J Pathol 2011, 179:1129-1137; DOI: 10.1016/j.ajpath.2011.05.028