Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non–Small-Cell Lung Cancer: The NVALT-4 Study

Groen, Harry J.M.; Sietsma, Hannie; Vincent, Andrew; Hochstenbag, Monique; Putten, John W. G. van; Berg, Anke van den; Dalesio, Otilia; Biesma, Bonne; Smit, Hans; Termeer, A.; Hiltermann, T Jeroen N; Borne, Ben E. E. M. van den; Schramel, Franz M.N.H.

doi:10.1200/jco.2011.35.5214

Cited by 99 publications

(83 citation statements)

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“…Two recent phase III trials (Table V) (21,22) that used a design identical or similar to that of our study, failed to demonstrate any survival benefit with the addition of a COX-2 inhibitor to chemotherapy in patients with advanced NSCLC. Groen et al (21) demonstrated no statistical difference regarding survival between NSCLC patients with tumors positive and those with tumors negative for COX-2 expression, as determined by IHC.…”

Section: Discussionmentioning

confidence: 70%

“…The frequencies of grade 3/4 myopathy (2.0%) and arthralgia (0.0%) were comparable to or lower compared to those reported by several phase II trials using carboplatin plus docetaxel without a COX-2 inhibitor (3.0-4.0 and 3.0%, respectively) (15,18). Two recent phase III trials (Table V) (21,22) that used a design identical or similar to that of our study, failed to demonstrate any survival benefit with the addition of a COX-2 inhibitor to chemotherapy in patients with advanced NSCLC. Groen et al (21) demonstrated no statistical difference regarding survival between NSCLC patients with tumors positive and those with tumors negative for COX-2 expression, as determined by IHC.…”

Section: Discussionmentioning

confidence: 91%

“…As shown in Table V, the OS in Asian patients with NSCLC appears to be longer compared to that in non-Asian patients (21)(22)(23)(24)35). Pharmacoethnic differences in the response of cancer patients to certain drugs was recently reported (36).…”

Section: Grade ------------------------------------------------------mentioning

confidence: 96%

“…Groen et al (21) investigated the association between COX-2 positivity and progression-free survival (PFS) and OS as a subgroup analysis. A phase II trial (23) demonstrated that prospectively defined subset analysis indicated a survival advantage with a COX-2 inhibitor and chemotherapy in patients with moderate-to-high COX-2 expression.…”

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confidence: 99%

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Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

Yokouchi

Kanazawa

Ishida

et al. 2014

Molecular and Clinical Oncology

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Abstract. Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg̸ml x min on day 1) and docetaxel (60 mg/m 2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high-and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration. IntroductionCyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins (PGs), is expressed in a number of solid tumors and is associated with carcinogenesis, tumor proliferation, infiltration, metastasis, angiogenesis and resistance to anticancer drugs (1). In lung cancer cells, COX-2, which is particularly overexpressed in adenocarcinoma (2), is considered to be a negative predictor of survival in this subpopulation (3-7). Based on these reports, several clinical trials have been conducted for the potentiation of targeting COX-2 in lung cancer (8).The cyclin-dependent kinase (Cdk) inhibitor p27 plays a critical role in cell cycle regulation from the G1 to the S phase by inhibiting Cdk4/6-cyclin D1 and Cdk2-cyclin E (9). Loss of p27 expression tends to be an unfavorable prognostic factor in patients with non-small-cell lung cancer (NSCLC) (10). Increased p27 expression is attributed to COX-2-independent mechanisms of G0/G1 arrest driven by COX-2 inhibitors (11). Thus, p27 expression may be another predictive factor of the response to COX-2 inhibitors.Taxanes, such as paclitaxel and docetaxel, are microtubule-stabilizing agents that act by interfering with spindle microtubule dynamics, causing cell cycle arrest and apoptosis through activating a number of molecular pathways (12,13). Taxanes are able to drive COX-2...

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 91%

Section: Grade ------------------------------------------------------mentioning

confidence: 96%

Section: Grade ------------------------------------------------------mentioning

confidence: 99%

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Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

Yokouchi

Kanazawa

Ishida

et al. 2014

Molecular and Clinical Oncology

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“…1,2 Two phase III studies investigating the effect on overall survival by adding celecoxib to chemotherapy in advanced NSCLC were, however, negative. 3,4 The negative overall results do not, however, exclude a clinical role of the compound in certain subpopulations. Since one of the mechanisms involved in the antineoplastic effect of COX-2 inhibitors appears to be inhibition of angiogenesis, [5][6][7] biomarkers related to angiogenesis might be useful as predictors of a positive clinical effect on survival by celecoxib.…”

Section: Introductionmentioning

confidence: 94%

Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy

Sörenson¹,

Fohlin²,

Lindgren³

et al. 2013

European Journal of Cancer

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Aim of the study: The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. Methods: In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400 mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. Results: VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR) = 0.64 [confidence interval (CI) 0.43-0.95], p = 0.028). Conclusion: Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.European Journal of Cancer (2012) xxx, xxx-xxx A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c

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Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non–Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants

Liang

Zhou

et al. 2019

JAMA Netw Open

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IMPORTANCE Treatment of locally advanced non-small cell lung cancer (NSCLC) remains challenging. The rationale of combining a cyclooxygenase 2 (COX-2) inhibitor with concurrent chemoradiation (CCRT) was based on results of preclinical research and prospective clinical studies; however, no randomized clinical trial has provided evidence of a direct comparison with CCRT alone. OBJECTIVE To determine the effect of combined selective COX-2 inhibition with standard CCRT on survival among patients with unresectable stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS A single-center, open-label, randomized phase 2 clinical trial was performed among 96 patients who had histologically and cytologically confirmed unresectable stage III NSCLC. Participants were enrolled from November 2011 to August 2015. Data were analyzed from February to October 2018. INTERVENTION Patients were randomized to receive thoracic radiation, 60 Gy, for 6 weeks concurrent with etoposide and cisplatin or the same regimen of CCRT combined with 200 mg of celecoxib, taken twice daily. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. The secondary end points were the proportion of patients with treatment-related toxic effects, progression-free survival, and overall survival in subgroups with and without the COX-2 genotype. RESULTS A total of 100 patients were randomized. Following the exclusion of 4 outliers, 96 participants (96.0%) were analyzed (51 randomized to CCRT alone and 45 randomized to CCRT with celecoxib; mean [SD] age, 60.0 [8.3] years; 73.0 [76.0%] male). The median overall survival time was 32.8 (95% CI, 17.0-48.5) months in the group that received CCRT with celecoxib and 35.5 (95% CI, 25.8-45.2) months in the group that received CCRT alone (P = .88). Celecoxib with CCRT was well tolerated; the incidence of symptomatic radiation pneumonitis was 6.6% (95% CI, 1.4%-18.0%) in the group that received CCRT with celecoxib and 11.8% (95% CI, 4.4%-23.9%) in the group that received CCRT alone (P = .49). Among patients with the high-risk genotype, celecoxib plus CCRT was not associated with higher progression-free survival (hazard ratio, 0.36; 95% CI, 0.13-1.04; P = .05) or overall survival (hazard ratio, 0.50; 95% CI, 0.15-1.72; P = .26) compared with CCRT alone. CONCLUSIONS AND RELEVANCE In unresectable stage III NSCLC, adding celecoxib to concurrent chemoradiation did not improve survival. A smaller, not statistically significant proportion of patients in the CCRT with celecoxib group compared with the CCRT alone group developed symptomatic (continued) Key Points Question Could selective cyclooxygenase 2 inhibition combined with standard concurrent chemoradiation therapy improve survival among patients with unresectable stage III non-small cell lung cancer? Findings In this phase 2 clinical trial of 96 patients, adding celecoxib to concurrent chemoradiation did not improve survival. Meaning Adding celecoxib to concurrent chemoradiation did not improve survival.

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Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non–Small-Cell Lung Cancer: The NVALT-4 Study

Abstract: In advanced NSCLC, celecoxib does not improve survival. In this study, COX-2 expression was not a prognostic biomarker and had no predictive value when celecoxib was added to chemotherapy.

Cited by 99 publications

References 19 publications

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy

Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non–Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants

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