Risk stratification of EGFR+ lung cancer diagnosed with panel-based next-generation sequencing.

OBJECTIVE: Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. MATERIALS AND METHODS: To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). RESULTS: EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFR+NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (<5%) and not associated with clinical endpoints. Smoking did not affect outcome independently, but was associated with non-del19 EGFR mutations (p < 0.05) and comorbidities (p < 0.001). Laboratory parameters, like the blood lymphocyte-to-neutrophil ratio and serum LDH, correlated with the metastatic pattern (p < 0.01), but had no independent prognostic value. Reduced ECOG performance status (PS) was associated with comorbidities (p < 0.05) and shorter OS (p < 0.05), but preserved TKI efficacy. Non-adenocarcinoma histology was also associated with shorter OS (p < 0.05), but rare (2-3 %). The ECOG PS and non-adenocarcinoma histology could not be validated in our independent cohort, and did not increase the range of prognostication alongside the ENS. CONCLUSIONS: EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.

ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer.

BACKGROUND: Many patients with metastatic non-small-cell lung cancer (mNSCLC) experience disease progression after first- and second-line treatment; more treatment options are required for these patients. ARCTIC, a phase III, randomized, open-label study, assessed durvalumab ± tremelimumab versus standard of care (SoC) as ≥ third-line treatment of mNSCLC. PATIENTS AND METHODS: ARCTIC comprised two independent sub-studies. Study A: 126 patients with ≥25% of tumor cells (TCs) expressing programmed cell death ligand-1 (PD-L1) were randomized (1 : 1) to durvalumab [up to 12 months 10 mg/kg every 2 weeks (q2w)] or SoC. Study B: 469 patients with PD-L1 TC <25% were randomized (3 : 2 : 2 : 1) to durvalumab + tremelimumab (12 weeks durvalumab 20 mg/kg + tremelimumab 1 mg/kg q4w then 34 weeks durvalumab 10 mg/kg q2w), SoC, durvalumab (up to 12 months 10 mg/kg q2w), or tremelimumab (24 weeks 10 mg/kg q4w then 24 weeks q12w). Primary end points: overall survival (OS) and progression-free survival (PFS) for durvalumab versus SoC (study A; descriptive only) and durvalumab + tremelimumab versus SoC (study B). RESULTS: Study A: median OS 11.7 (durvalumab) versus 6.8 (SoC) months {hazard ratio (HR) 0.63 [95% confidence interval (CI), 0.42-0.93]}; median PFS 3.8 (durvalumab) versus 2.2 (SoC) months [HR 0.71 (95% CI, 0.49-1.04)]. Study B: median OS 11.5 (durvalumab + tremelimumab) versus 8.7 (SoC) months [HR 0.80 (95% CI, 0.61-1.05); P = 0.109]. Median PFS of 3.5 months for both groups [HR 0.77 (95% CI, 0.59-1.01); P = 0.056]. Treatment-related grade 3/4 adverse events: 9.7% (durvalumab) and 44.4% (SoC; study A) and 22.0% (durvalumab + tremelimumab) and 36.4% (SoC; study B). CONCLUSIONS: In heavily pretreated patients with mNSCLC, durvalumab demonstrated clinically meaningful improvements in OS and PFS versus SoC (patients with PD-L1 TC ≥25%); numerical improvements in OS and PFS for durvalumab + tremelimumab versus SoC were observed (patients with PD-L1 TC <25%). Safety profiles were consistent with previous studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02352948.

Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma.

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK+ lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.

SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. PATIENTS AND METHODS: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. RESULTS: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. CONCLUSION: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. TRIAL IDENTIFIER: Clinicaltrials.gov NCT01750281.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Complications in CT-Guided, Semi-Automatic Coaxial Core Biopsy of Potentially Malignant Pulmonary Lesions.

PURPOSE: Histological verification of pulmonary lesions is important to ensure correct treatment. Computed tomographic (CT) transthoracic core biopsy is a well-established procedure for this. Comparison of available studies is difficult though, as technical and patient characteristics vary. Using a standardized biopsy technique, we evaluated our results for CT-guided coaxial core biopsy in a semi-automatic technique. MATERIALS AND METHODS: Within 2 years, 664 consecutive transpulmonary biopsies were analyzed retrospectively. All interventions were performed using a 17/18G semi-automatic core biopsy system (4 to 8 specimens). The incidence of complications and technical and patient-dependent risk factors were evaluated. RESULTS: Comparing the histology with the final diagnosis, the sensitivity was 96.3%, and the specificity was 100%. 24 procedures were not diagnostic. In all others immunohistological staining was possible. The main complication was pneumothorax (PT, 21.7%), with chest tube insertion in 6% of the procedures (n = 40). Bleeding without therapeutic consequences was seen in 43 patients. There was no patient mortality. The rate of PT with chest tube insertion was 9.6% in emphysema patients and 2.8% without emphysema (p = 0.001). Smokers with emphysema had a 5 times higher risk of developing PT (p = 0.001). Correlation of tumor size or biopsy angle and the risk of PT was not significant. The risk of developing a PT was associated with an increasing intrapulmonary depth of the lesion (p = 0.001). CONCLUSION: CT-guided, semiautomatic coaxial core biopsy of the lung is a safe diagnostic procedure. The rate of major complications is low, and the sensitivity and specificity of the procedure are high. Smokers with emphysema are at a significantly higher risk of developing pneumothorax and should be monitored accordingly. KEY POINTS: Using an 18G core biopsy system with 6 specimens will allow immunohistological staining with high sensitivity and specificity. Smokers with emphysema are at a significantly higher risk of developing a pneumothorax.

[Infiltration of the superior vena cava in NSCLC: results of surgical intervention]. / Ergebnisse des chirurgischen Vorgehens bei NSCLC und Infiltration der Vena cava superior.

The benefits of surgical therapy of locally advanced non-small cell lung cancer (NSCLC) with infiltration of the superior vena cava (SVC) remains controversial. Here we describe our therapeutic approach and results of our intervention.A retrospective analysis of 22 patients with NSCLC who underwent SVC replacement (n = 17) or reconstruction (n = 5) between 1998 and 2013 was performed. Pneumonectomy was necessary in 16 patients, lobectomy in 8. Preoperative chemotherapy was administered to 3 patients, 16 received postoperative radiation treatment. The clinical course and survival were analyzed.Major postoperative morbidities were found in 13 patients. Graft thrombosis did not occur. Thirty-day mortality was 7 % in pneumonectomy patients and 0 % following lobectomy. Local recurrence was found in 4.5 %, distant metastases developed in 54.5 % of the patients (p = 0.0008). One- and five-year survival probabilities for all patients were 63.6 and 27.9 %. Five-year survival probability was 33 % for patients with SVC reconstruction and 25 % for patients with SVC replacement (p = 0.22). Five-year survival rates after pneumonectomy and lobectomy were 21.4 % and 37.5 %, respectively (p = 0.18).Radical resection involving the SVC in carefully selected patients with NSCLC results in excellent local tumor control. Due to the high rate of distant metastases, application of induction and adjuvant chemotherapy should be carefully assessed.

Open, randomized, multi-center phase II study comparing efficacy and tolerability of Erlotinib vs. Carboplatin/Vinorelbin in elderly patients (>70 years of age) with untreated non-small cell lung cancer.

BACKGROUND: Targeting the epidermal-growth-factor-receptor (EGFR) in non-small cell lung cancer (NSCLC) is an established treatment option with less toxicity compared to conventional chemotherapy. This study was undertaken to determine whether Erlotinib is non-inferior compared to chemotherapy as a first-line therapy in unselected elderly patients. MATERIALS AND METHODS: Patients ≥ 70 years with untreated, metastatic NSCLC were randomized to Erlotinib (E), 150 mg/day or Carboplatin (AUC5) plus Vinorelbine (25mg/m(2) on days 1 and 8) every three weeks (CV). Primary endpoint was progression-free survival (PFS). After progression, crossover was strongly recommended. Secondary endpoints were duration of response, 1-year survival, overall survival (OS), response rate (RR), quality of life (FACT-L), assessment of comorbidities by simplified comorbidity score (SCS) and Charlsons' comorbidity score, safety and assessment of molecular markers. RESULTS: Between June 2006 and August 2008 284 pts were randomized to E (144) and CV (140). PFS was significantly inferior with E (median PFS 2.4 versus 4.6 months [HR 1.6, 75% CI 1.22-2.09, p: 0.0005]) as well as RR (7.8% v 28.3%, p: 0.0001). No significant difference in OS appeared (median E: 7.3 months versus CV: 8.4 months, HR: 1.24 [75% CI 0.9-1.71]). In never smokers PFS (median PFS: 3.7 v 4.3 m, E v CV, HR 0.72, 75% CI 0.35-1.48) and OS (median: 16.5 versus 17 months, HR 0.99 [75% CI 0.38-2.57]) were comparable. More skin toxicity and diarrhea was seen with E compared to more myelotoxicity, neurotoxicity and constipation with CV. Less severe adverse events were observed with E (81 v 102, E v CV). CONCLUSION: CV had an increased efficacy compared with E in an unselected population of elderly patients with advanced NSCLC.

Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study.

BACKGROUND: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement. PATIENTS AND METHODS: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m(2) day (d)1 + 8) and vinorelbine (V: 25 mg/m(2) d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m(2) d1) and pemetrexed (Px: 500 mg/m(2) d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. RESULTS: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P < 0.001). CONCLUSION: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb.

Third CECOG consensus on the systemic treatment of non-small-cell lung cancer.

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options.

Docetaxel-carboplatin chemotherapy combined with cetuximab in patients with locally advanced or metastatic non small-cell lung cancer (NSCLC)--results of the nonrandomised phase II study TaxErb.

This open label, single arm phase II study was designed to evaluate the efficacy and safety of the addition of cetuximab to first line chemotherapy with carboplatin and weekly docetaxel in patients with advanced non small-cell lung cancer (NSCLC). From February 2007 to December 2008 74 patients with NSCLC (stage IIIB and IV), ECOG PS ≤2 and no prior systemic chemotherapy were enrolled and treated with carboplatin (area under the curve=5 on day 1) and docetaxel (35 mg/m(2) on days 1, 8, and 15). Cycles were repeated every 4 weeks for a minimum of 4 and a maximum of 6 cycles. Cetuximab (400mg/m(2) on day 1 with subsequent doses of 250 mg/m(2) weekly) was administered until progression or intolerable toxicity up to a maximum treatment duration of 12 months. The primary endpoint was the overall response rate (CR+PR) according to RECIST. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Patients received a median of 4 cycles of docetaxel-carboplatin-chemotherapy. The median number of administrations of cetuximab was 14. Sixty-seven patients were evaluable for response. Partial response was seen in 29/67 patients corresponding to an overall response rate (ORR) of 43.3% (95%CI, 28.5-53.7). No patient experienced complete response. The clinical benefit rate (PR+SD) was 79.1%. The 1-year rates for PFS and OS were 11.2% and 64.4%, respectively. Median PFS was 4.8 months (95%CI, 3.70-5.31) and median OS 12.9 months (95%CI 8.26-∞). Adverse events were mainly grades 1-2. Skin toxicity (76% of pts), dyspnea (36.5%) and anemia (31.1%) were most frequent. Results from this phase II study suggest that the addition of cetuximab to first-line doublet carboplatin and weekly docetaxel results in a considerable clinical efficacy with an acceptable toxicity profile for patients with advanced or metastatic NSCLC.

A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer.

BACKGROUND: This trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin area under the curve 5 mg x min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1-3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity. RESULTS: Of 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0-7.0] in the IP arm and 6.0 months (95% CI 5.2-6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4-11.6) and 9.0 months (95% CI 7.6-10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96-1.73, P = 0.095) and 1.34 (95% CI 0.97-1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. CONCLUSION: This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.

Single nucleotide polymorphisms in matrix metalloproteinase genes and lung cancer chemotherapy response and prognosis.

The prognosis for lung cancer patients treated with chemotherapy is poor. Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes could influence treatment outcome by altering apoptotic pathways. Eight SNPs with known or suspected phenotypic effect in six genes (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP12) were investigated. For 349 Caucasian patients with primary lung cancer, receiving first-line chemotherapy, three different endpoints were analysed: response after the second cycle, progression free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analysed using multiple logistic regression for all patients and histology-, stage- and treatment-specific subgroups. Hazard ratio estimates for PFS and OS were calculated using Cox regression methods. None of the investigated polymorphisms modified response significantly in the whole patient population. However, tumour stage IIIB variant allele carriers of MMP2 C-735T showed a significantly worse response. PFS was significantly prolonged in MMP1 G-1607GG variant allele carriers and OS in small cell lung cancer patients carrying the MMP12 A-82G variant allele. In conclusion, this study identified SNPs in MMP1, MMP2, MMP7 and MMP12 for further investigation as possible predictors of chemotherapy outcome in lung cancer patients.

A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: This phase III randomized trial compared pemetrexed 500 mg/m(2) (P500) with pemetrexed 900 mg/m(2) (P900) to determine whether higher dosing benefits non-small-cell lung cancer (NSCLC) patients as second-line therapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week. RESULTS: Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837-1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817-1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories. CONCLUSIONS: P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

[Successful individualized and targeted therapy of an NSCLC patient with Gefitinib based on a predictive assessment of the EGF-receptor mutation status]. / Erfolgreiche individualisierte zielgerichtete Gefitinib-Therapie beim NSCLC nach prädiktiver Mutationsanalyse des EGF Rezeptors.

BACKGROUND: Molecular alterations in the tyrosine kinase (TK) domain of the human epidermal growth factor receptor (EGFR) have been correlated with tumour remission upon treatment with the TK inhibitor Gefitinib in non-small cell lung cancer (NSCLC). We have retrospectively investigated the correlation of point mutations with clinical response and, based on our retrospective results, used predictive molecular assessment as the basis for treatment in one patient. METHODS: Mutational analysis was performed in 11 NSCLC-patients (10 responders, 1 non-responder) among 62 patients treated with Gefitinib within an expanded access program. RESULTS: Activating molecular alterations were found in 8/11 investigated samples (point mutations in exons 18 and 21, deletions in exon 19). All molecular changes were found in adenocarcinoma or bronchioloalveolar carcinoma. The tumours of two male responders with squamous cell carcinoma showed either a wild-type sequence or carried a nonsense mutation. In one patient treatment with Gefitinib after prospective assessment of mutations resulted in tumour remission and thus proved to be predictive. CONCLUSIONS: Mutations in the EGFR TK domain correlate with the clinical response to Gefitinib. The predictive assessment of molecular alterations may thus be helpful for treatment decisions in selected cases. A clinical response to Gefitinib is nevertheless also found in patients with wild-type EGFR.

[Non-small-cell lung cancer third-line therapy with gefitinib]. / Drittlinientherapie mit Gefitinib beim nicht-kleinzelligen Bronchialkarzinom.

The EGFR-inhibition via tyrosine-kinase-inhibitor gefitinib (Iressa) constitutes a new way to treat non-small-cell lung cancer. Recent research results enable us to better understand the basics of molecular targeted therapy (MTT). These results are helpful to re-interpret the clinical results obtained so far for gefitinib and to consider for the first time in a predictive manner factors for the selection of patients suitable for therapy. Three case reports are presented in this paper which illustrate that -- with view to the results from translational research -- the use of gefitinib offers an efficient new therapeutic modality for the treatment of chemotherapy-resistant non-small-cell lung cancer.

The role of wildlife in emerging and re-emerging zoonoses.

There are huge numbers of wild animals distributed throughout the world and the diversity of wildlife species is immense. Each landscape and habitat has a kaleidoscope of niches supporting an enormous variety of vertebrate and invertebrate species, and each species or taxon supports an even more impressive array of macro- and micro-parasites. Infectious pathogens that originate in wild animals have become increasingly important throughout the world in recent decades, as they have had substantial impacts on human health, agricultural production, wildlife-based economies and wildlife conservation. The emergence of these pathogens as significant health issues is associated with a range of causal factors, most of them linked to the sharp and exponential rise of global human activity. Among these causal factors are the burgeoning human population, the increased frequency and speed of local and international travel, the increase in human-assisted movement of animals and animal products, changing agricultural practices that favour the transfer of pathogens between wild and domestic animals, and a range of environmental changes that alter the distribution of wild hosts and vectors and thus facilitate the transmission of infectious agents. Two different patterns of transmission of pathogens from wild animals to humans are evident among these emerging zoonotic diseases. In one pattern, actual transmission of the pathogen to humans is a rare event but, once it has occurred, human-to-human transmission maintains the infection for some period of time or permanently. Some examples of pathogens with this pattern of transmission are human immunodeficiency virus/acquired immune deficiency syndrome, influenza A, Ebola virus and severe acute respiratory syndrome. In the second pattern, direct or vector-mediated animal-to-human transmission is the usual source of human infection. Wild animal populations are the principal reservoirs of the pathogen and human-to-human disease transmission is rare. Examples of pathogens with this pattern of transmission include rabies and other lyssaviruses, Nipah virus, West Nile virus, Hantavirus, and the agents of Lyme borreliosis, plague, tularemia, leptospirosis and ehrlichiosis. These zoonotic diseases from wild animal sources all have trends that are rising sharply upwards. In this paper, the authors discuss the causal factors associated with the emergence or re-emergence of these zoonoses, and highlight a selection to provide a composite view of their range, variety and origins. However, most of these diseases are covered in more detail in dedicated papers elsewhere in this Review.

Prognostic significance of cytokine modulation in non-small cell lung cancer.

Increased production of immunosuppressive interleukin-10 (IL-10) by non-small cell lung cancer (NSCLC) and increased serum IL-10 concentrations in NSCLC-patients have recently been correlated to reduced survival. We earlier demonstrated suppression of IL-2 secretion in whole blood cell cultures of NSCLC-patients. We now analyzed the influence of IL-2 secretion on survival in NSCLC-patients and the influence of IL-10 on IL-2 secretion. The correlation of the IL-2 producing ability of whole blood cells in response to PHA in 90 NSCLC-patients at the time of diagnosis to survival was calculated by Crit-level, the Kaplan-Meier method and the log-rank test. With a cut-off value of IL-2 production of 1,100 pg/ml by whole blood cells the difference in survival was significant with a p-value of 0.014. In the group with high and low IL-2, median survival was 14.1 and 9.7 months, respectively. In the subgroup of 33 surgically-treated patients the difference in survival was significant with a p-value of 0.011. In 14 patients with surgical resection of the tumor and high IL-2 at diagnosis and 19 patients with surgical resection, but low IL-2 at diagnosis, median survival was 86.2 and 11.3 months, respectively. Secretion of IL-2 in whole blood cell cultures from healthy individuals was inhibited in a dose-dependent manner upon addition of IL-10. Taken together, suppression of IL-2 secretion has prognostic significance for survival of NSCLC-patients and may be mediated by tumor-derived IL-10.