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

Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management

Edema; Nausea; Non-small cell lung cancerEdema; Náuseas; Cáncer de pulmón de células no pequeñasEdema; Nàusees; Càncer de pulmó de cèl·lules no petitesIntroduction The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. Patients and Methods Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. Results Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. Conclusion Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population

Encorafenib plus binimetinib in patients with BRAFV600-mutant non-small cell lung cancer: phase II PHAROS study design

BRAF V600 mutation; Binimetinib; EncorafenibMutació de BRAF V600; Binimetinib; EncorafenibMutación de BRAF V600; Binimetinib; EncorafenibBRAFV600 oncogenic driver mutations occur in 1–2% of non-small-cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAFV600-mutant NSCLC, as first- or second-line treatment. The primary end point is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy end points and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAFV600-mutant NSCLC

The embryonic genes Dkk3, Hoxd8, Hoxd9 and Tbx1 identify muscle types in a diet-independent and fiber-type unrelated way

<p>Abstract</p> <p>Background</p> <p>The mouse skeletal muscle is composed of four distinct fiber types that differ in contractile function, number of mitochondria and metabolism. Every muscle type has a specific composition and distribution of the four fiber types. To find novel genes involved in specifying muscle types, we used microarray analysis to compare the gastrocnemius with the quadriceps from mice fed a low fat diet (LFD) or high fat diet (HFD) for 8 weeks. Additional qPCR analysis were performed in the gastrocnemius, quadriceps and soleus muscle from mice fed an LFD or HFD for 20 weeks.</p> <p>Results</p> <p>In mice fed the 8-week LFD 162 genes were differentially expressed in the gastrocnemius <it>vs</it>. the quadriceps. Genes with the strongest differences in expression were markers for oxidative fiber types (e.g. <it>Tnni1</it>) and genes which are known to be involved in embryogenesis (<it>Dkk3</it>, <it>Hoxd8</it>,<it>Hoxd9 </it>and <it>Tbx1</it>). Also <it>Dkk2, Hoxa5, Hoxa10, Hoxc9, Hoxc10, Hoxc6 </it>and <it>Tbx15 </it>were detectably, but not differentially expressed in adult muscle tissue. Expression of differentially expressed genes was not influenced by an 8-week or 20-week HFD. Comparing gastrocnemius, quadriceps and soleus, expression of <it>Hoxd8 </it>and <it>Hoxd9 </it>was not related with expression of markers for the four different fiber types. We found that the expression of both <it>Hoxd8 </it>and <it>Hoxd9 </it>was much higher in the gastrocnemius than in the quadriceps or soleus, whereas the expression of <it>Dkk3 </it>was high in quadriceps, but low in both gastrocnemius and soleus. Finally, expression of <it>Tbx1 </it>was high in quadriceps, intermediate in soleus and low in gastrocnemius.</p> <p>Conclusions</p> <p>We found that genes from the Dkk family, Hox family and Tbx family are detectably expressed in adult mouse muscle. Interestingly, expression of <it>Dkk3</it>, <it>Hoxd8, Hoxd9 </it>and <it>Tbx1 </it>was highly different between gastrocnemius, quadriceps and soleus. In fact, every muscle type showed a unique combination of expression of these four genes which was not influenced by diet. Altogether, we conclude that genes important for embryogenesis identify mouse muscle types in a diet-independent and fiber type-unrelated manner.</p

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study

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