Randomized phase II trial of All-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer.
OBJECTIVE
This randomized phase II trial evaluated whether the combination of cisplatin and paclitaxel (PC) plus all-trans retinoic acid (ATRA) increases response rate (RR) and progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) with an acceptable toxicity profile and its association with the expression of retinoic acid receptor beta 2 (RAR-beta2) as a response biomarker.


METHODS
Patients with stages IIIB with pleural effusion and IV NSCLC were included to receive PC, and randomly assigned to receive ATRA 20 mg/m(2)/d (RA/PC) or placebo (P/PC) 1 week before treatment until two cycles were completed. RAR-beta2 expression was analyzed in tumor and adjacent lung tissue.


RESULTS
One hundred seven patients were included, 55 in the P/PC group and 52 in the RA/PC group. RR for RA/PC was 55.8% (95% CI, 46.6% to 64.9%) and for P/PC, 25.4% (95% CI, 21.3 to 29.5%; P = .001). The RA/PC group had a longer median PFS (8.9 v 6.0 months; P = .008). Multivariate analysis of PFS showed significant differences for the RA/PC group (hazard ratio, 0.62; 95% CI, 0.4 to 0.95). No significant differences in toxicity grade 3/4 were found between groups, except for hypertriglyceridemia (10% v 0%) in RA/PC (P = .05). Immunohistochemistry and reverse-transcriptase polymerase chain reaction assays showed expression of RAR-beta2 in normal tissues of all tumor samples, but only 10% of samples in the tumor tissue.


CONCLUSIONS
Adding ATRA to chemotherapy could increase RR and PFS in patients with advanced NSCLC with an acceptable toxicity profile. A phase III clinical trial is warranted to confirm these findings.
Arrieta
Oscar
O
Instituto Nacional de Cancerología, Universidad Autónoma Metropolitana, Mexico City, Mexico. ogar@servidor.unam.mx
González-De la Rosa
Claudia H
CH
Aréchaga-Ocampo
Elena
E
Villanueva-Rodríguez
Geraldine
G
Cerón-Lizárraga
Tania L
TL
Martínez-Barrera
Luis
L
Vázquez-Manríquez
María E
ME
Ríos-Trejo
Miguel Angel
MA
Alvarez-Avitia
Miguel A
MA
Hernández-Pedro
Norma
N
Rojas-Marín
Carlos
C
De la Garza
Jaime
J
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D018168:Receptors, Retinoic Acid / Q000032:analysis; D014212:Tretinoin / Q000008:administration & dosage
C533416:RARB2 protein, human; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D017239:Paclitaxel; D002945:Cisplatin