Induction Versus Adjuvant Gemcitabine/Cisplatin in Locally Advanced Non-metastatic Nasopharyngeal Carcinoma

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Background Nasopharyngeal carcinoma (NPC) is one of the cancers which shows significant geographic prevalence variation. Worldwide, there were 130,000 new cases in 2018.As a non-endemic region, only 35 new cases were diagnosed in Kuwait in the same year. Nevertheless, it accounts for 1.3% of cancer ...

Background Nasopharyngeal carcinoma (NPC) is one of the cancers which shows significant geographic prevalence variation. Worldwide, there were 130,000 new cases in 2018.As a non-endemic region, only 35 new cases were diagnosed in Kuwait in the same year. Nevertheless, it accounts for 1.3% of cancer related mortality in Kuwait. Radical radiotherapy (RT) is the mainstay treatment of NPC for decades. A high cure rate can be achieved for patients with early-stage. The breakthrough in the management of NPC came with the intergroup study 009 which showed significant improved progression free survival with adding chemotherapy (CTH) to the radiation. As compared to RT alone, concurrent chemoradiation (CRT), showed significant improvement in 10-year overall survival and progression free survival in meta-analysis of nasopharyngeal carcinoma (MAC-NPC) collaborative group. Addition of systemic therapy to concurrent CRT was the proposed solution to treatment failures; whether in the induction (ICT) or adjuvant (ACT) settings. However, ICT or ACT in NPC remains controversial; largely due to inconsistent results of several prospective randomized trials. The above-mentioned MAC-NPC group reviewed six clinical trials in which CRT followed by ACT was compared with RT alone (administrated without concurrent or adjuvant chemotherapy). Overall survival (OS) was significantly improved compared with RT alone (10-year overall survival 57% versus 43.1%, HR 0.65, 95% CI 0.56-0.76), as well as 10-year progression-free survival; PFS (53.2% versus 38.5%). However, this was not consistent in endemic areas with high prevalence of Epstein-Barr virus (EBV); which is known causative for NPC. Chen et al reported in a Chinese phase III trial 508 patients with advanced NPC randomized to ACT (cisplatin plus fluorouracil) vs observation following CRT with weekly cisplatin. There was no improvement in the five-year failure-free rate with ACT compared with CRT alone (five-year rate 75% versus 71%, HR 0.88, 95% CI 0.64-1.22) Later, from the same endemic region, Sun Yat-sen university conducted a multi center phase III clinical trial in which 480 patients, stage III to IVB, node-positive NPC were randomly assigned to ICT followed by CRT versus CRT alone. This study showed improvement of recurrence-free survival (RFS) and distant RFS. Another reason for reluctancy to adopt ICT or ACT in the management of advanced NPC, is the morbidity of current chemotherapy regimens. The high toxicity profile with some of these regimens was the real obstacle toward the use of them. In previous studies, the back bone for adjuvant or induction chemotherapy in NPC has been platinum and 5-fluoruracil, with or without a taxane. This regimen was poorly tolerated, with only 40-60 % of patients could complete their preplanned course of treatment in many trials. Recently, in multicenter randomized trial, Zhang and his group compared gemcitabine and cisplatin as ICT plus CRT with CRT alone. The 3-year RFS was 85.3% in the induction group and 76.5% in the standard-therapy group (HR 0.51; 95% CI, 0.34 to 0.77; P=0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (HR 0.43; 95% CI, 0.24 to 0.77). What is more important is that 96.7% of the experimental arm completed 3 cycles of ICT. On behalf of the Nasopharyngeal Cancer Portal Group of Investigators, Bossi colleagues from Europe, Kuwait, Jordan, Turkey and USA, assessed the impact of treatment intensity within a large retrospective multicenter cohort, nasopharyngeal cancer in non-endemic areas. Our group shared in this pooled analysis and the data showed a higher rate of death and recurrence with non-intensive treatment, (defined as no "added" systemic treatment to CRT). Ongoing Phase 3 Trials exploring ICT or ACT in NPC: There are multiple phase 3 trials ongoing to refine the ICT or ACT approach. Sun Yat-sen University is conducting a study comparing TPF with PF as ICT regimen in stage IVa-b NPC (NCT02940925). They also explore the effect of triple combination of ICT, CRT and ACT in high risk NPC (NCT02621970). Another comparison between induction TPF vs adjuvant PF is recruiting (NCT03306121). Fudan University also from China exploring maintenance gemcitabine after radical treatment in N3 disease (NCT03403829). Jiangxi Provincial Cancer Hospital testing adding neoadjuvant and adjuvant PD-1 inhibitor to ICT-CRT (NCT04557020) Another promising strategy to control the distant failures in locally advanced NPC, is to employ immunotherapy in the primary treatment. There are many ongoing trials exploring this strategy, mainly in China. However, the validity in endemic vs non-endemic regions should be taken with caution. Aim of the study In our proposal we are trying to compare the efficacy and tolerability of ICT followed by CRT with CRT followed ACT in locally advanced NPC

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