Maximiliano Van Kooten

A Randomized Phase 3 Trial Comparing Pemetrexed/Carboplatin and Docetaxel/Carboplatin as First-Line Treatment for Advanced, Nonsquamous Non-small Cell Lung Cancer

Introduction: This study compared survival without toxicity in patients with advanced, nonsquamous non-small cell lung cancer who were treated with first-line pemetrexed/carboplatin or docetaxel/carboplatin. Methods: This multicenter, open-label, parallel-group, phase 3 trial comprised patients randomized (1:1) to pemetrexed/carboplatin (n = 128) or docetaxel/carboplatin (n = 132). Patients received treatment on day 1 of each 21-day cycle (maximum of six cycles). Treatment included carboplatin (area under the curve = 5 mg/ml × min) and pemetrexed (500 mg/m2) or docetaxel (75 mg/m2). The primary outcome measure, survival without treatment-emergent grade 3/4 toxicity, was defined as the time from randomization to the first treatment-emergent grade 3/4 adverse event or death and was analyzed using a log-rank test. The analysis population included 106 patients in the pemetrexed/carboplatin (Pem/Carb) group and 105 patients in the docetaxel/carboplatin (Doc/Carb) group. Results: Survival without treatment-emergent grade 3/4 toxicity was significantly longer in the Pem/Carb versus the Doc/Carb group (log-rank p < 0.001; median survival without treatment-emergent grade 3/4 toxicity: 3.2 versus 0.7 months; adjusted hazard ratio = 0.45 [95% confidence interval: 0.34–0.61]). Overall survival was similar in the Pem/Carb versus the Doc/Carb group (log-rank p = 0.934; median survival: 14.9 versus 14.7 months; adjusted hazard ratio = 0.93 [95% confidence interval: 0.66–1.32]). Compared with the Doc/Carb group, fewer patients in the Pem/Carb group experienced grade 3/4 drug-related, treatment-emergent neutropenia, leukopenia, or febrile neutropenia, and more patients experienced anemia and thrombocytopenia. There were three study drug-related deaths during treatment in each group. Conclusions: The favorable benefit-to-risk profile of pemetrexed/carboplatin suggests that pemetrexed/carboplatin is an appropriate first-line treatment option for chemonaïve patients with advanced, nonsquamous non-small cell lung cancer.

Smoking history as a predictive factor of treatment response in advanced non-small-cell lung cancer: a systematic review.

Recent trials in patients with advanced non-small-cell lung cancer (NSCLC) suggest that nonsmokers may benefit more from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy than will smokers. The aim of this systematic review was to assess smoking history as a predictive factor for treatment outcomes in patients with NSCLC. Relevant published literature was identified through systematic searches of databases (MEDLINE, EMBASE, Cochrane Library), oncology and thoracic journals, and abstracts from major oncology conferences using prespecified criteria. Articles reporting treatment outcomes (overall survival [OS], progression-free survival [PFS], and/or response rate) in smoking history subgroups from randomized controlled trials of targeted therapy and/or chemotherapy were reviewed. Data from 30 trials (32 articles, 4 abstracts) were included. Of these, 23 trials tested first-line therapy. Treatment arms included EGFR TKIs (13 trials), EGFR monoclonal antibodies (2 trials), non-EGFR targeted treatments (9 trials), chemotherapy (27 trials), and placebo or best supportive care only (3 trials). Smoking history definitions and analyses of its effect on treatment outcomes varied widely. Only 11 trials reported testing for a treatment-by-smoking history interaction. The available evidence supports but does not confirm smoking history as a predictive factor for the response to TKIs, particularly in previously treated patients. The evidence does not support smoking history as a predictor of response to non-EGFR-targeted therapies or chemotherapy. Smoking history and its effect on treatment response are inadequately reported. More rigorous collection, analysis, and reporting may clarify whether smoking history is a predictor of treatment response in advanced NSCLC.

A Systematic Review of the Interobserver Variability for Histology in the Differentiation between Squamous and Nonsquamous Non-small Cell Lung Cancer

Introduction: The importance of identifying non-small cell lung cancer (NSCLC) histologic subtype has increased recently because of the development of target-specific chemotherapeutic agents. This systematic review was undertaken to examine the interobserver variability for histology in differentiating between subtypes of NSCLC, specifically the ability to differentiate squamous from nonsquamous histology. Methods: A systematic literature search was undertaken to identify studies that evaluated the reproducibility of histologic diagnosis by pathologists in their reporting of NSCLC subtypes. Studies were screened using a priori defined eligibility criteria. The National Health and Medical Research Council diagnostic levels of evidence were applied and quality assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Data were extracted and reanalyzed to permit comparison of agreement in nonsquamous and squamous cell carcinoma by 2 × 2 tables. Percentage agreement and kappa statistics were calculated for each included study. Results: Out of 1480 articles identified through the literature search, six were eligible for inclusion. The percentage agreement for all subtypes of NSCLC in the included studies ranged from 67.1 to 89.6% (&kgr;, 0.42–0.84). Based on the primary reanalysis of data (reanalysis 1), agreement between pathologists in differentiating nonsquamous and squamous histology ranged from 77.0 to 94.2% (&kgr; = 0.48–0.88) indicating a moderate to high level of agreement. Conclusion: The reasonably high agreement and kappa statistics for the included studies suggest that pathologists can reproducibly differentiate between nonsquamous and squamous NSCLC. This is clinically important in guiding oncologist decision making in choosing the most appropriate therapy for their patients.

Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer

AbstractPurpose. We studied cisplatin plusgemcitabine as induction (neoadjuvant)therapy in patients with stage IIInon-small cell lung cancer (NSCLC) toassess its objective remission rate,resectability, survival, and toxicity. Patients and methods. Patients with stageIII NSCLC received 2 cycles of gemcitabine1250 mg/m2 on days 1, 8, and 15,plus cisplatin 100 mg/m2 on day 2.Subsequently, patients were assigned tolocal therapy – surgery or radiotherapy. Results. Twenty-nine eligiblepatients (male/female: 21/8) with a medianage of 59 years (range, 43–71 years) wereenrolled between October 1996 and February1999. A total of 80 cycles were given,with a median of 3 per patient (range, 1–4cycles). Overall, toxicities were mild;only one patient had febrile neutropenia,and there were no grade 4 non-hematologicaltoxicities. There was one toxic deathfollowing afebrile grade 4 neutropenia.Overall clinical response rate (2 completeresponses [CRs] + 16 partial responses[PRs]) was 62% (95% CI, 45%–79%);10 patients had stable disease and noneprogressed; one patient was not evaluable.Eight of the 18 operated patients hadpathological response: 1 CR and 7downstagings to N(−); 14 patients wereresected. Median survival was 17 months(95% CI, 13–21 months), with 1-year and2-year actuarial survival rates of 61%and 29%, respectively. Conclusions. Gemcitabine pluscisplatin is a very active andwell-tolerated induction regimen in stageIII NSCLC. Comparative studies with otherstandard regimens are warranted.

Histology as a treatment effect modifier in advanced non-small cell lung cancer: a systematic review of the evidence.

Background and objective:  We conducted a systematic review of prospective, randomized, controlled trials (RCT) to examine whether histology had a treatment modifying effect (TME) on the efficacy outcomes of chemotherapeutic agents in patients with advanced (stage IIIB‐IV) non‐small cell lung cancer (NSCLC).

Influence of Apoptosis and Cell Cycle Regulator Proteins on Chemotherapy Response and Survival in Stage IIIA/IIIB NSCLC Patients

Background: Prognosis for non-small cell lung cancer (NSCLC) patients is very poor. Prediction of the response to treatment in individual patients may be possible using molecular biological alterations such as clinical biomarkers. We investigated the predictive value of apoptosis and cell cycle regulator proteins for neoadjuvant chemotherapy response in stage IIIA/IIIB NSCLC patients. Methods: We evaluated p53, bcl-2, p21WAF1/CIP1, p27Kip1, and Ki67 immunohistochemical expression and apoptotic index in mediastinal lymph node metastases from 23 IIIA and 10 IIIB NSCLC patients before treatment with neoadjuvant platinum-based chemotherapy. Univariate analysis was performed to evaluate the relationship between protein expression and survival or time to progression (TTP). Results: Median follow-up was 25 months (range, 4–112), median TTP was 11 months (range, 0–112), and median overall survival was 22 months (range, 4–112). Of 32 assessable patients, 18 (56%) had stable disease, 12 (38%) had a PR, and two (6%) had progressive disease. Of the 22 patients assessable for pN2 following chemotherapy, 16 (77%) were positive. Univariate analysis showed that shorter TTP correlated with progressive disease (p = 0.000), positive pN2 after chemotherapy (p = 0.026), high Ki67 (p = 0.022), and high p21WAF1/CIP1 (p = 0.038). Conclusion: Our results suggest that in IIIA/IIIB NSCLC patients, a high level of p21WAF1 expression in mediastinal lymph node metastases before neoadjuvant platinum-based chemotherapy is associated with a poor outcome. Our results suggest that expression of p21WAF1, which plays a role in preventing apoptosis, may be significant when selecting chemotherapy for NSCLC patients.