Patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experienced improved failure-free survival (FFS) and other survival outcomes with metronomic capecitabine as compared with patients receiving observation, according to phase III study data presented at the 2021 ASCO Annual Meeting (4-8 June). These findings were simultaneously published in the Lancet.
While presenting results on behalf of colleagues, Jun Ma of the Sun Yat-sen University Cancer Center in Guangzhou, China explained that metronomic chemotherapy refers to frequent and regular administration over long time periods of chemotherapeutic drugs at substantially lower doses than typically prescribed, and is a strategy that delivers low toxicity and good compliance.
The study investigators noted that disease recurrence is common in patients with loco-regional advanced NPC achieving remission following first-line treatment with the standard of care, concurrent cisplatin-radiotherapy with or without induction chemotherapy. Therefore, they conducted this phase III, multicentre, randomised, controlled study which enrolled 406 patients with high-risk locoregionally advanced NPC (stage III to IVA, excluding T3-4N0 and T3N1). Eligible patients had no loco-regional disease or distant metastasis after definitive chemoradiotherapy.
Following 1:1 randomisation (204 patients in metronomic capecitabine and 202 in standard observation group), 201 patients were treated with metronomic capecitabine at 650 mg/m2 twice daily for 1 year and 200 patients received standard-therapy consisting of observation. Treatments began at a median of 14 (interquartile range [IQR] 13-15) weeks after the last radiation dose in the capecitabine arm and median 15 (IQR 13-15) in the observation arm.
The study primary endpoint of FFS at 3 years, which was defined as loco-regional recurrence/distant metastatic recurrence and/or death from any cause, was met in the capecitabine group where the 3-year FFS rate was 85.3% (95% confidence interval [CI] 80.4–90.6) compared to 75.7% in the standard therapy/observation group (95% CI 69.9–81.9). In this comparison, the stratified hazard ratio (sHR) for recurrence or death was 0.50 (95% CI 0.32–0.79; p = 0.0023).
In terms of secondary endpoints, the 3-year overall survival (OS) rate was 93.3% (95% CI 89.7–97.1) with capecitabine compared to 88.6% (95% CI 84.2–93.2) with observation (sHRdeath 0.44: 95% CI 0.22–0.88 p = 0.018); the 3-year distant FFS rates were 89.4% versus 82.1% (sHRdeath or distant recurrence 0.52; p = 0.014) and the rates of 3-year locoregional FFS were 92.6% versus 87.8% (sHRlocal regional recurrence or death 0.50; p = 0.041), respectively.
Overall, 82 (20%) patients on capecitabine had a disease recurrence or death event; of these, 29 (14%) events were in the metronomic capecitabine group and 53 (26%) events were in the standard therapy group.
The median follow-up was 38 (IQR 33–42) months, which represented 45 (IQR 40–49) months from the start of standard therapy.
The median duration of capecitabine treatment was 12.1 months (IQR 10.4–12.2) and the median relative dose intensity for capecitabine was 98.1% (IQR 72·0–100).
During treatment 37 (18%) patients required dose reduction; the capecitabine dose was reduced by one level (75% of starting dose) in 28 (14%) patients and by two levels (50% of starting dose) in 9 (4%) patients. Dose interruptions and dose reductions due to adverse events (AEs) occurred in 52 (26%) patients and 28 (14%) patients, respectively. Ten (5%) patients discontinued capecitabine due to AEs and 4 (2%) patients discontinued due to disease recurrence.
In contrast, 18 patients discontinued observation within one year; of these 15 had disease recurrence and 3 discontinued for other reasons.
The safety analysis included 201 patients receiving capecitabine and 200 patients receiving observation for the one-year treatment period. With capecitabine the most commonly reported any grade AE was hand and foot syndrome (HFS) in 58% of patients. The most commonly reported grade 3-4 AEs with capecitabine versus observation included HFS (9% versus 0), neutropaenia (4% versus 3%), and leukopenia (3% each arm).
Twelve (6%) patients receiving capecitabine and 25 (12%) receiving standard observation died; however, no deaths were determined to be treatment-related.
Conclusions
The investigators wrote that, to their knowledge, this is the first randomised phase III study to assess the efficacy and safety of adding metronomic capecitabine as an adjuvant therapy to chemoradiotherapy in patients with high-risk locoregionally advanced NPC.
They concluded that metronomic capecitabine was less toxic than other adjuvant therapies and that these results show adjuvant metronomic capecitabine significantly improved failure-free survival compared with observation.
Furthermore, excepting hand-foot syndrome, the incidence of grade 3 or 4 adverse events was similar between the groups and quality of life was not compromised.
The authors concluded that these findings suggest that the addition of metronomic capecitabine to chemotherapy as an adjuvant therapy could improve survival in patients with high-risk locoregionally advanced NPC.
The editorialists commented in an accompanied article published in the Lancet that this study has the potential to change clinical practice, and if so, would be of particular benefit to patients receiving intensive definitive chemoradiotherapy and in those living in low- and middle-income countries (LMICs). For now, this study of metronomic chemotherapy paves the way for improving access to so-called new and affordable cancer therapies in LMICs, and will allow adaptation to local constraints beyond cost, such as patients needing to travel long distances to oncology centres in the absence of public transportation, the incidence of side effects, the treatment of frail patients, advanced disease due to delayed diagnosis, and the use of central catheters.
This was investigator-initiated study supported by national government funds. Chia Tai Tianqing Pharmaceutical provided capecitabine free of charge for this study.
References
- Chen Y-P, Liu X, Zhou Q, et al. Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. The Lancet, Published online 7 June 2021. https://doi.org/10.1016/S0140-6736(21)01123-5
- Kerbel RS, Andre N. Adjuvant metronomic chemotherapy for locoregionally advanced nasopharyngeal carcinoma. The Lancet, Published online 7 June 2021. https://doi.org/10.1016/S0140-6736(21)01240-X
- Ma J, Chen Y-P, Zhou Q, et al. Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: A phase 3, multicenter, randomized controlled trial. J Clin Oncol 2021;39(suppl 15; abstr 6003). DOI: 10.1200/JCO.2021.39.15_suppl.6003