Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small cell lung cancer (NSCLC): A feasibility study

Background: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy. Patients and Methods: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m(2)). This was to be followed by 2 cycles of cisplatin/vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment. Results: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%. Conclusion: Oral vinorelbine 50 mg/m(2) (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy

A pooled analysis of concurrent chemoradiotherapy (CCRT) for patients with stage III non-small cell lung cancer (NSCLC) who participated in U.S. Cooperative Group Trials: comparing the outcomes of elderly to younger patients (pts)

Poster Discussion Session: Lung Cancer-Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers: abstract 8508BACKGROUND: CCRT is the standard treatment (TRT) for stage 3 NSCLC. Elderly pts are common and may have increased toxicity and poorer results from CCRT. METHODS: We collected individual patient data (IPD) of pts who participated in cooperative group phase 2/3 trials of CCRT for stage 3A/3B pts from 1990-2012. We compared the overall survival (OS), progression-free survival (PFS), and adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted and adjusted Hazard Ratios (HRs) for survival time and their confidence intervals (CIs) were ...postprin

Accelerated high-dose radiotherapy alone or combined with either concomitant or sequential chemotherapy; treatments of choice in patients with Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Results of high-dose chemo-radiotherapy (CRT), using the treatment schedules of EORTC study 08972/22973 or radiotherapy (RT) alone were analyzed among all patients (pts) with Non Small Cell Lung Cancer (NSCLC) treated with curative intent in our department from 1995–2004.</p> <p>Material</p> <p>Included are 131 pts with medically inoperable or with irresectable NSCLC (TNM stage I:15 pts, IIB:15 pts, IIIA:57 pts, IIIB:43 pts, X:1 pt).</p> <p>Treatment</p> <p>Group I: Concomitant CRT: 66 Gy/2.75 Gy/24 fractions (fx)/33 days combined with daily administration of cisplatin 6 mg/m²: 56 pts (standard).</p> <p>Group II: Sequential CRT: two courses of a 21-day schedule of chemotherapy (gemcitabin 1250 mg/m²d1, cisplatin 75 mg/m2 d2) followed by 66 Gy/2.75 Gy/24 fx/33 days without daily cisplatin: 26 pts.</p> <p>Group III: RT: 66 Gy/2.75 Gy/24 fx/33 days or 60 Gy/3 Gy/20 fx/26 days: 49 pts.</p> <p>Results</p> <p>The 1, 2, and 5 year actuarial overall survival (OS) were 46%, 24%, and 15%, respectively.</p> <p>At multivariate analysis the only factor with a significantly positive influence on OS was treatment with chemo-radiation (P = 0.024) (1-, 2-, and 5-yr OS 56%, 30% and 22% respectively). The incidence of local recurrence was 36%, the incidence of distant metastases 46%.</p> <p>Late complications grade 3 were seen in 21 pts and grade 4 in 4 patients. One patient had a lethal complication (oesophageal). For 32 patients insufficient data were available to assess late complications.</p> <p>Conclusion</p> <p>In this study we were able to reproduce the results of EORTC trial 08972/22973 in a non-selected patient population outside of the setting of a randomised trial. Radiotherapy (66 Gy/24 fx/33 days) combined with either concomitant daily low dose cisplatin or with two neo-adjuvant courses of gemcitabin and cisplatin are effective treatments for patients with locally advanced Non-Small Cell Lung Cancer. The concomitant schedule is also suitable for elderly people with co-morbidity.</p

Platinum drugs in the treatment of non-small-cell lung cancer

The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours

Glial ER and GAP junction mediated Ca 2+ waves are crucial to maintain normal brain excitability

Astrocytes play key roles in regulating multiple aspects of neuronal function from invertebrates to humans and display Ca2+ fluctuations that are heterogeneously distributed throughout different cellular microdomains. Changes in Ca2+ dynamics represent a key mechanism for how astrocytes modulate neuronal activity. An unresolved issue is the origin and contribution of specific glial Ca2+ signaling components at distinct astrocytic domains to neuronal physiology and brain function. The Drosophila model system offers a simple nervous system that is highly amenable to cell-specific genetic manipulations to characterize the role of glial Ca2+ signaling. Here we identify a role for ER store-operated Ca2+ entry (SOCE) pathway in perineurial glia (PG), a glial population that contributes to the Drosophila blood-brain barrier. We show that PG cells display diverse Ca2+ activity that varies based on their locale within the brain. Ca2+ signaling in PG cells does not require extracellular Ca2+ and is blocked by inhibition of SOCE, Ryanodine receptors, or gap junctions. Disruption of these components triggers stimuli-induced seizure-like episodes. These findings indicate that Ca2+ release from internal stores and its propagation between neighboring glial cells via gap junctions are essential for maintaining normal nervous system function