The evidence supporting the use of this protocol comes from a phase 3 multicentre randomised trial involving 480 patients, comparing cisplatin plus gemcitabine followed by concurrent chemoradiation therapy (cisplatin) with concurrent chemoradiation therapy alone.r
Between December 2013 and September 2016, 242 patients were randomised to receive induction treatment with cisplatin (80 mg/m2 IV on day 1) and gemcitabine (1000 mg/m2 IV on days 1 and 8) for 3 cycles then concurrent chemoradiation therapy (cisplatin 100 mg/m2 day 1, 22, 43). 238 patients were randomised to receive concurrent chemoradiation therapy alone (cisplatin 100 mg/m2 day 1, 22 and 43).
The primary end point was recurrence free survival or death, secondary end points were overall survival (OS), distant and locoregional recurrence free survival, response rate, treatment adherence and safety.
Efficacy
After a median follow up of 42.7 months, the 3 year recurrence free survival was 85.3% (95% CI 80.0 to 89.3) in the induction chemotherapy group compared with 76.5% (95% CI 70.4 to 81.5) in the standard therapy group (HR for recurrence or death, 0.51; 95% CI 0.34 to 0.77; p=0.001).r
Patients in the induction chemotherapy group had a better 3-year OS compared to the standard therapy group 94.6% (95% CI 90.6 to 96.9) versus 90.3% (95% CI 85.6 to 93.5) with a stratified HR for death of 0.43 (95% CI 0.24 to 0.77).
Survival and response to treatmentr
© NEJM 2019
Kaplan-Meier curves (A) Recurrence-free survival (B) Overall survival (C) Distance recurrence-free survival (D) Locoregional recurrence free survivalr
© NEJM 2019
Toxicity
During induction chemotherapy, 38.9% of patients had acute adverse events of grade 3 or 4 with neutropenia being the most common. Over the entire treatment path 75.7% in the induction group had grade 3 or 4 adverse events compared to 55.7% in the standard therapy group. There were 0 deaths secondary to adverse events during the study, 6 patients discontinued induction treatment due to adverse events.r
The main grade 3/4 toxicities of the various treatments are summarised in the table below.r
Toxicityr |
Induction chemotherapy
(%) |
Standard therapy
(%) |
Grade 3 or 4 |
Grade 3 or 4 |
Leukopenia |
26.4 |
20.3 |
Neutropenia |
28 |
10.5 |
Anaemia |
9.6 |
0.8 |
Thrombocytopenia |
11.3 |
1.3 |
Mucositis |
28.9 |
32.1 |
Vomiting |
22.6 |
13.9 |
Nausea |
23 |
13.9 |