Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: Results of a phase III randomised controlled trial.

AIM: To determine equivalence of modified gemcitabine and oxaliplatin compared with gemcitabine and cisplatin in unresectable gallbladder cancer (GBC). Primary end-point was overall survival (OS). METHODS: Open label, prospective, randomised phase III equivalence study. Inclusion criteria included histologically proven unresectable GBC, 18 years or older, adequate organ functions and Eastern Cooperative Oncology Group ≤2. SAMPLE SIZE: 108 patients were required in each arm to have an equivalence margin of ±2 months with power of 80%. TREATMENT: Modified gemcitabine and oxaliplatin (mGemOx)-gemcitabine 900 mg/m2, oxaliplatin 80 mg/m2, maximum 6 cycles; gemcitabine + cisplatin (CisGem)-gemcitabine 1000 mg/m2, cisplatin 25 mg/m2, maximum 8 cycles, all day 1 and 8 every 3 weeks. RESULTS: Two hundred sixty subjects were recruited between February 2011 and July 2015. Two hundred forty-three patients (119, mGemOx and 124, CisGem) received at least 1 dose and analysed for safety and efficacy (modified intention to treat). Median OS was 8·5 months for whole group (95% confidence interval [CI]: 7·9-9·1). Median OS in mGemOx was 9 months and 8·3 months in CisGem; p = 0·057 (hazard ratio = 0·78; 95% CI = 0·60-1·02). Restricted mean OS for follow-up limited to 30 months was 11·2 months (95% CI: 9·8-12·6) in mGemOx and 10·4 months (95% CI: 9·1-11·7) in CisGem. Difference of the mean was 0·8 months with 95% CI, exceeding 2 months (-1·1 to 2·7), hence rejecting equivalence. Peripheral neuropathy, thrombocytopaenia in mGemOx and nephrotoxicity was higher with CisGem. CONCLUSION: This trial failed to show equivalence of eight cycles of CisGem to six cycles of mGemOx. Numerically OS was better with mGemOx. Toxicities were different. The trial was not powered to answer superiority. CLINICAL TRIAL REGISTRATION: CTRI/2010/091/001406.

Retinoic acid receptor-alpha as a prognostic indicator in oral squamous cell carcinoma.

Retinoids reverse potentially malignant lesions and inhibit the development of second primary tumors in oral cancer patients by binding to nuclear retinoid receptors. Alterations in the expression of retinoid receptor-alpha are implicated in tumor progression. Herein, we hypothesized that increased expression of RARalpha protein in oral squamous cell carcinoma (SCC) is associated with a poor clinical outcome and thus may serve as a prognostic factor. Retrospective immunohistochemical analysis of RARalpha protein expression was carried out in paraffin-embedded tissue sections from 115 patients with completely resected oral SCCs for whom clinical follow-up data were available. Increased expression of RARalpha protein was observed in 67/115 (58%) oral SCCs (weakly positive in 38 patients and strongly positive in 29 patients). Kaplan-Meier analysis showed that patients with RARalpha positivity had significantly shorter disease-free survival time (median time 40 months vs. 86 months, p = 0.0229). Furthermore, disease-free survival time of the 29 patients with strongly positive RARalpha was significantly worse than for the 86 patients with weak or undetectable levels of RARalpha (p = 0.0328). Strong RARalpha expression in oral SCCs was associated with a significantly worse disease-free survival, suggesting that RARalpha may serve as a prognostic indicator of poor clinical outcome. Further studies are warranted to determine its utility in identifying the subset of patients who would benefit from use of retinoids as adjuvant in chemotherapy or chemopreventive approaches.