Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer

University of California, Davis, Davis, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2008; 26(21):3543-51. DOI: 10.1200/JCO.2007.15.0375
Source: PubMed

ABSTRACT Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.
This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles.
Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P <or= .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

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    • "Bevacizumab , a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), was approved in 2006 in combination with carboplatin and paclitaxel, specifically excluding patients with squamous carcinomas (SQC) because of an unacceptably high rate of severe hemoptysis [6]. Similarly, the survival benefit of pemetrexed, initially approved in 2004 for sec- J Cancer Res 2015;5(7):2229-2240 ond-line treatment, proved to be restricted to non-squamous histology [7]. "
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    ABSTRACT: Erlotinib, bevacizumab, and pemetrexed improved survival of metastatic non-small cell lung cancer (mN-SCLC) in clinical trials, but their benefits are restricted to non-squamous histology. We studied recent survival trends in mNSCLC subpopulations defined by histology and associated clinical factors correlating with adenocarcinoma or endothelial growth factor receptor mutations. Using the Surveillance, Epidemiology and End Results database, we calculated relative survival at 1 year from diagnosis for mNSCLC cases diagnosed in 2000-2011. Trends by histol-ogy, age, sex, race, prevalence of smoking or poverty, expressed as annual percent change (APC) using joinpoint regression, were compared by test of slope parallelism (P par). Among 226,446 cases, 47% had adenocarcinoma, 20% squamous carcinoma, 6% other, and 27% unspecified histology. The proportion of cases designated as ad-enocarcinoma significantly increased after 2005. One-year survival increased from 23.5% in 2000 to 30.5% in 2010, significantly more for adenocarcinoma (APC, 3.3%) than squamous carcinoma (APC, 2.1%, P par =0.0018). For patients with adenocarcinoma, these trends were significantly better for Asians than Whites (P par =0.012) and for areas with fewer smokers (P par =0.014). Such differences were not observed for squamous carcinoma (P par =0.87 and 0.14, respectively). The absolute disparity in one-year survival between adenocarcinoma and squamous carcinoma increased from 1.6% in 2000 to 5.5% in 2010. The disparity between Asians and Whites increased from 5.2% to 13.1%, respectively. These data demonstrate that improvement in survival of mNSCLC since 2000 is now evident on a population scale. The superior increment for patients with adenocarcinoma, particularly among Asians and in communities with fewer smokers, suggests impact of the newly introduced, histology-specific agents, rather than better supportive care alone. Growing disparities between adenocarcinoma and squamous carcinoma highlight the needs to intensify research on treatment for subgroups that did not benefit from recent advances.
    American Journal of Cancer Research 07/2015; 5(7):2229-2240. · 3.97 Impact Factor
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    • "Apart from the entirely undifferentiated LCC, the current 2004-WHO classification recognizes five different variants of LCC, namely clear cell carcinoma (CCC), lymphoepithelioma-like carcinoma (LELC), LCC with rhabdoid phenotype (LCC-R), basaloid carcinoma (BC) and large cell neuroendocrine carcinoma (LCNEC) [1]. In our and others' views [5] [6] [7] [8] [9] [10] [11] [12], this sub-classification of LCC is a source of confusion, because BC shows a SQC lineage and should be classified accordingly, LELC should be restricted to Epstein–Barr virus-related neoplasms with SQC lineage (as seen in the relevant head & neck tumors), most LCC-R and at least two third of CCC are definitely poorly-differentiated ADC, and LCNEC belongs to the spectrum of NET. A rare subset of LCC do not react with any of the specific lineage markers ( " null phenotype " ) or shows immunohistochemistry (IHC) negativity for ADC markers in the presence of only focal positivity for squamous or NE markers ( " unclear phenotype " ) and remain part of the LCC- NOS category when dealing with surgical specimens, and of the NSCLC-NOS group in the case of cytology/biopsy samples, provided that metastatic or other uncommon pulmonary tumors (e.g., sarcomatoid or NUT midline carcinomas) have been reasonably excluded (Fig. 2). "
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    ABSTRACT: Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question-answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time).
    Lung Cancer 01/2015; 87(3). DOI:10.1016/j.lungcan.2015.01.008 · 3.74 Impact Factor
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    • "Several European studies also found higher frequencies than our study, but (unconscious) selection for testing based on clinical factors may have played a role in these findings. As a reminder and for comparison, in the hitherto largest – predominantly European – study in advanced NSCLC [2], there were 30% female patients and 14% never-smokers. In the more recent Spanish findings in the context of a randomised controlled trial, occurrence of exon 19 or 21 mutations was 16.6% [19]. "
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    ABSTRACT: Background ESMO consensus recommends EGFR mutation testing in never/former light smokers (<15 pack-years) or patients with non-squamous NSCLC. The aim of this work was to determine the frequency and clinical predictors of EGFR mutations, and the role of specimen sampling tests, in Caucasian standard practice setting. Methods We screened 297 patients according to this consensus. Mutational analysis of EGFR was performed using the Therascreen EGFR RGQ PCR mutation kit. Clinical and pathological correlative data were collected. Results An EGFR activating mutation was found in 32 patients (11%), twelve exon 19 deletions, two exon 18 and eighteen exon 21 point mutations. Most were in females, but half were in smokers. Negative TTF-1 staining had a very strong negative predictive value (all except one patient had TTF-1 positive adenocarcinoma). Both biopsies as well as cytology specimens (mainly EBUS-TBNA) did well: 24 mutations in 213 biopsy samples (11.2%) and 8 in 84 cytology samples (9.5%), respectively. The Therascreen acted as a sensitive test in all types of samples: 7 activating mutations were found in samples rated to have <5% of tumour cells, and there were only 4 test failures in the whole series. Conclusion In this Caucasian standard practice NSCLC cohort, tested according to the ESMO consensus, activating EGFR mutation occurred in 11% of the patients. Half of these were in former/current smokers. With our sampling technique and use of the Therascreen kit, EBUS-TBNA cell blocks performed as good as biopsies.
    12/2014; 2(1):9. DOI:10.1186/s40247-014-0009-0
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