The first randomised, controlled, phase III study to assess the efficacy and safety of the addition of adjuvant cisplatin-gemcitabine chemotherapy after concurrent chemoradiotherapy shows significant improvement in 3-year progression-free survival (PFS) compared with cisplatin-fluorouracil regimen in patients with locoregionally advanced nasopharyngeal carcinoma.
The study findings support the potential role of adjuvant cisplatin-gemcitabine; however, further studies are needed in more globally diverse populations to confirm these findings and to determine the optimal therapeutic dose, and haematological adverse events of the cisplatin-gemcitabine regimen should be carefully managed during treatment. The results are reported at 2023 ASCO Annual Meeting on 5 June in Chicago, IL, US by Dr. Lin-Quan Tang along with a simultaneous publication in The Lancet Oncology by Prof. Hai-Qiang Ma of the Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy in Guangzhou, China, and study colleagues.
Nasopharyngeal carcinoma, which is strongly associated with Epstein-Barr virus infection, is endemic in southeast Asia and southern China. Radiotherapy is the mainstay of treatment and early-stage nasopharyngeal carcinoma is usually treated with radiotherapy alone. However, locoregionally advanced nasopharyngeal carcinoma requires more intensive treatment; a significant treatment benefit with cisplatin-based concurrent chemoradiotherapy followed by adjuvant cisplatin-fluorouracil has been reported versus radiotherapy alone and concurrent chemoradiotherapy plus adjuvant chemotherapy has become the standard of care.
The authors explained in the background that patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. The NPC-9901 study has raised caution for the fact that the concurrent adjuvant cisplatin-fluorouracil regimen might not be adequate for distant control of N2-3 disease. Therefore, the optimal adjuvant chemotherapy regimen requires further investigation. The study team aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma.
The study team conducted an open-label, randomised, controlled, phase III study at 4 cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an ECOG performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 hours on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 hours) and cisplatin (80 mg/m2 intravenously for 4 hours on day 1) once every 4 weeks, for 3 cycles. Randomisation was stratified by treatment centre and nodal category.
The primary endpoint was 3-year PFS in the intention-to-treat population (i.e., all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. Patients are currently under follow-up.
From 30 October 2017 to 9 July 2020, 240 patients with a median age of 44 years and from whom 175 were male (73%) and 65 female (27%) were randomly assigned to the cisplatin-fluorouracil group (120 patients) or cisplatin-gemcitabine group (120 patients). As of data cut-off of 25 December 2022, median follow-up was 40 months (IQR 32–48). 3-year PFS was 83.9% (95% confidence interval [CI] 75.9–89.4) with 19 disease progressions and 11 deaths in the cisplatin-gemcitabine group and 71.5% (95% CI 62.5–78.7) with 34 disease progressions and 7 deaths in the cisplatin-fluorouracil group (stratified hazard ratio 0.54, 95% CI 0.32–0.93; log rank p = 0.023).
The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (52% in the cisplatin-gemcitabine group versus 29% in the cisplatin-fluorouracil group; p = 0.00039), neutropenia (32% versus 16%; p = 0.010), and mucositis (23% versus 28%; p = 0.43). The most common grade 3 or worse late adverse event occurring from 3 months after completion of radiotherapy was auditory or hearing loss (5% versus 9%). One patient (1%) in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths.
In an accompanied comment, Prof. Melvin L K Chua of the Department of Head and Neck and Thoracic Radiation Oncology and Division of Medical Sciences, National Cancer Centre Singapore, Oncology Academic Clinical Programme, Duke-NUS Medical School in Singapore and colleagues wrote that adjuvant cisplatin-gemcitabine was more poorly tolerated than cisplatin-fluorouracil with 62% of patients with cisplatin-gemcitabine versus 77% of patients with cisplatin-fluorouracil complied in completing 3 cycles of protocol adjuvant chemotherapy, which puts into question whether monotherapy capecitabine should be the preferred regimen for adjuvant chemotherapy, given the reported compliance rates of over 70%.
Long-term follow-up is required to support the 3-year overall survival advantage of adjuvant cisplatin-gemcitabine over cisplatin-fluorouracil. With induction chemotherapy now being a key treatment in locoregionally advanced nasopharyngeal carcinoma, the oncology field is faced with another conundrum on individualisation of treatment to either induction chemotherapy followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy upfront and adjuvant chemotherapy.
A plausible concept, which is being tested prospectively in NCT05517135, is the use of pretreatment Epstein-Barr virus DNA level for treatment stratification, in which patients with high levels are recommended for induction chemotherapy to target occult distant metastatic clones and those with low levels are recommended for upfront concurrent chemoradiotherapy. In this setting, adjuvant chemotherapy might be efficacious against chemoradiotherapy resistant tumour clones. And so, for these patients, the difficult choice remains of whether to choose between adjuvant cisplatin-gemcitabine or capecitabine alone.
This study was funded by grants from the National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.
References
- Liu L-T, Liu H, Huang Y, et al. Concurrent chemoradiotherapy followed by adjuvant cisplatin–gemcitabine versus cisplatin–fluorouracil chemotherapy for N2–3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial. The Lancet Oncology; Published online 5 June 2023: DOI: https://doi.org/10.1016/S1470-2045(23)00232-2
- Yip PL, Lee AWM, Chua MLK. Adjuvant chemotherapy in nasopharyngeal carcinoma. The Lancet Oncology; Published online 5 June 2023: DOI: https://doi.org/10.1016/S1470-2045(23)00266-8
- Tang L-Q, Liu L-T, Liu H, et al. Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-5-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: A multicentre, open-label, randomised, controlled, phase 3 trial. J Clin Oncol 41, 2023 (suppl 16; abstr 6000).