Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Johnson, David H.; Fehrenbacher, Louis; Novotny, William; Herbst, Roy S.; Nemunaitis, John; Jablons, David M.; Langer, Corey J.; DeVore, Ronald A.; Gaudreault, Jacques; Damico, Lisa A.; Holmgren, Eric; Kabbinavar, Fairooz

doi:10.1200/jco.2004.11.022

Cited by 1,830 publications

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“…The observed better response rate and survival in adenocarcinoma compared to squamous-cell carcinoma recently reported with cisplatin and pemetrexed, as opposed to a better response and survival of squamous-cell carcinoma to cisplatin and gemcitabine, 4 and the proven benefit of adding bevacizumab to carboplatin and paclitaxel to improve the outcome of non-squamous cancer patients 5,6 indicate the clinical need to fine-tune the tailored approach in undifferentiated lung carcinomas. Owing to their rarity and also the recent subclassification (large-cell variants and sarcomatoid carcinoma variants), a molecular or immunochemical profiling would be very useful, in the absence of specific data about their clinical response to chemotherapy, to understand if at least part of LCCs is more closely related to adenocarcinoma or squamous-cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6] The recognition that some chemotherapeutic regimes were more effective in squamous-cell carcinomas, whereas other drug combinations were apparently better active in nonsquamous histological types (eg antifolate drugs), brought up the issue of accurately defining the histotypes in both preoperative and surgical materials. The responsiveness of large-cell lung cancers to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, possibly due to the heterogeneous tumor types entered in this group along the years and by different pathologists.…”

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confidence: 99%

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Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno-and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno-and large-cell types. Modern Pathology ( Keywords: large-cell carcinoma; squamous differentiation; desmocollin-3; diagnosis Lung cancer is subdivided into four histotypes, including small-cell carcinoma (SCLC) on the one side, and carcinomas of squamous-, adeno-and large-cell types on the other. These latter tumor groups have different pathological features, but have generally been treated so far according to similar strategies, so that a clear-cut distinction among these types (except for SCLC) was not considered clinically relevant. 1 Indeed, the WHO classifications of lung carcinoma have always kept the different histological types separate and proposed individual categories for squamous carcinoma, adenocarcinoma and large-cell (anaplastic) carcinoma (LCC). 2 The latter category underwent major changes in the last classification scheme, 3 having undifferentiated pleomorphic and/or sarcomatoid variants been moved to a new group o...

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Section: Discussionmentioning

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Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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“…In a first‐line setting, the addition of bevacizumab to chemotherapy significantly improved the clinical outcome with overall survival (OS) of 12.3 months in a Western population and 24.3 months in a Chinese population 8, 9. However, increased toxicity was observed during bevacizumab treatment and class‐related adverse events including hypertension, proteinuria, febrile neutropenia and life‐threatening pulmonary hemorrhage, particularly in squamous NSCLC 8, 9, 10. The approval of ramucirumab and nintedanib has provided new options for NSCLC patients who progressed on initial treatment, with improved OS and tolerable toxicity when combined with standard second‐line chemotherapy 11, 12, 13.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of rh‐endostatin (Endostar) combined with pemetrexed/cisplatin followed by rh‐endostatin plus pemetrexed maintenance in non‐small cell lung cancer: A retrospective comparison with standard chemotherapy

Zhou

Zuo²,

et al. 2018

Thoracic Cancer

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BackgroundRecombinant human endostatin (rh‐endostatin) plus standard chemotherapy in advanced non‐small cell lung cancer (NSCLC) patients has shown improved efficacy; however, it is unclear whether it is effective and safe when added to pemetrexed/cisplatin and used as maintenance therapy.MethodsWe retrospectively evaluated the data of untreated NSCLC patients administered rh‐endostatin plus pemetrexed/cisplatin or pemetrexed/cisplatin. The primary endpoint was progression‐free survival (PFS).ResultsFifty‐six and 39 patients received rh‐endostatin plus pemetrexed/cisplatin and pemetrexed/cisplatin, and 34 and 29 underwent maintenance treatment, respectively. The median PFS was 10 months (95% confidence interval [CI] 5.85–14.15) in the rh‐endostatin and 8.2 months (4.04–12.36) in the chemotherapy group, but the difference was not statistically significant (P = 0.13). In patients administered maintenance treatment, rh‐endostatin plus pemetrexed was associated with prolonged PFS compared to single‐agent pemetrexed when PFS was calculated from first dosing (13.7 [9.41–17.99] vs. 8.2 [4.16–12.24]; P = 0.032); however, PFS did not differ between the groups (hazard ratio 0.618; 95% CI 0.368–1.038; P = 0.069) after adjusting for clinical factors. No difference was observed in the objective response rate between the groups (48.2% vs. 38.5%; P = 0.346), with the exception of men (62.1% vs. 33.3%; P = 0.032) or in the incidence of drug‐related or grade 3–4 adverse events.ConclusionIn previously untreated, advanced‐stage NSCLC patients, first‐line treatment with pemetrexed/cisplatin plus rh‐endostatin did not prolong PFS or overall survival when compared to pemetrexed/cisplatin, but a trend of improved PFS was observed in patients administered maintenance rh‐endostatin plus pemetrexed.

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“…Thus, the development of highly specific and responsive sensitivity tests for anticancer agents is important to be able to predict the response to an anticancer agent before using it for treatment. Recent experimental and clinical studies have reported several molecular targeted therapies, such as 5-fluorouracil (5-FU)-derived agents against thymidylate synthase (TS) (Rustum et al, 1997), Gefitinib or Erlotinib against epidermal growth factor receptor (Mitsudomi et al, 2005), and Bevacizumab against vascular endothelial growth factor-A (Johnson et al, 2004).…”

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Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

et al. 2006

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The sensitivity to 5-fluorouracil (5-FU) has been reported to be associated with target molecule thymidylate synthase (TS), fluoropyrimidine-metabolising enzymes such as orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD). We performed an immunohistochemical study on the clinical significance of TS, OPRT, and DPD expression using 151 resected non-small-cell lung cancer (NSCLC) patients postoperatively treated with a combination of tegafur and uracil (UFT). Eightytwo carcinomas were TS-positive, 105 carcinomas were OPRT-positive, 68 carcinomas were DPD-positive. No correlation was observed in the HSCORE between the TS and OPRT expression (r ¼ 0.203), between the TS and DPD expression (r ¼ 0.098), or between the OPRT and DPD expression (r ¼ 0.074). Regarding the survival of NSCLC patients treated with UFT, the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours (P ¼ 0.0133). The 5-year survival rate of patients with OPRT-positive stage II to III tumours was significantly higher than that with OPRT-negative stage II to III tumours (P ¼ 0.0145). In addition, the 5-year survival rate of patients with DPD-negative tumours was also significantly higher than that with DPD-positive tumours (P ¼ 0.0004). A Cox multivariate regression analysis revealed the TS status (hazard ratio 2.663; P ¼ 0.0003), OPRT status (hazard ratio 2.543; P ¼ 0.0005), and DPD status (hazard ratio 2.840; Po0.0001) to all be significant prognostic factors for the survival of resected NSCLC patients postoperatively treated with UFT.

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Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Cited by 1,830 publications

References 22 publications

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

Efficacy and safety of rh‐endostatin (Endostar) combined with pemetrexed/cisplatin followed by rh‐endostatin plus pemetrexed maintenance in non‐small cell lung cancer: A retrospective comparison with standard chemotherapy

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

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