Doublet induction chemo + CRT yields favourable benefits for NPC
Adding induction chemotherapy (IC) with gemcitabine and cisplatin (GP) to a backbone of cisplatin-based chemoradiotherapy (CRT) generated favourable recurrence-free survival (RFS) and overall survival (OS) rates and toxicity profile in patients with locoregionally advanced nasopharyngeal carcinoma (NPC), according to data presented at ASCO 2019.
“In this subgroup of patients with unfavourable prognosis, concurrent CRT with a platinum-based agent constitutes the backbone of treatment, with chemotherapy sensitizing the tumour to the toxic effects of RT,” said the researchers. “[Our findings showed that] IC + CRT significantly improved RFS and OS compared with CRT alone [in this setting].”
A total of 480 individuals (median age 45.5 years, 72.0 percent male) were randomized 1:1 to receive CRT (three cycles of cisplatin 100 mg/m2 Q3W plus intensity-modulated RT) – either alone (standard) or in combination with three cycles of IC with gemcitabine 1 g/m2 and cisplatin 80 mg/m2 Q3W. [ASCO 2019, abstract 6003; N Engl J Med 2019;doi:10.1056/NEJMoa1905287]
After a median follow-up of 42.7 months, the 3-year RFS rate was improved with IC vs standard therapy (85.3 percent vs 76.5 percent), corresponding to a stratified hazard ratio (sHR) for recurrence or death of 0.51 (95 percent confidence interval [CI], 0.34–0.77; p=0.001).
The 3-year OS rate was similarly better with IC vs standard therapy (94.6 percent vs 90.3 percent, sHR for death, 0.43, 95 percent CI, 0.24–0.77), as was distant RFS rate (91.1 percent vs 84.4 percent, sHR for distant recurrence or death, 0.43, 95 percent CI, 0.25–0.73).
“Upfront GP targets occult distant metastasis in high-risk NPC, reduces risk of distant metastasis, and improves RFS,” said study author Dr Jun Ma from the Sun Yat-sen University Cancer Center in Guangzhou, China. The early OS advantage could also be due to the reduced distant metastatic recurrence rate in the IC arm, added the researchers.
However, IC generated a higher incidence of acute grade 3/4 adverse events (AEs) than standard therapy (75.7 percent vs 55.7 percent), the most common being mucositis (28.9 percent vs 32.1 percent), neutropenia (28.0 percent vs 10.5 percent), and leukopenia (26.4 percent vs 20.3 percent). Conversely, the incidence of grade 3/4 late AEs was lower with IC vs standard therapy (9.2 percent vs 11.4 percent), the most common being deafness or otitis (5.4 percent vs 6.8 percent).
Despite the toxicity associated with systemic therapy after CRT, [Ann Oncol 2018;29:1972-1979; J Clin Oncol 2018;doi:10.1200/JCO.2018.77.7847; Int J Cancer 2019;145:295-305] systemic intensification strategies are critical in targeting distant metastatic relapses, said Ma. Given the lack of comparative data, the choice of a gemcitabine- or taxane-based IC regimen may be based on the anticipated AEs matched against patients’ comorbidities, said the researchers.
Previous trials have shown conflicting outcomes with gemcitabine-based IC, with evidence showing favourable clinical responses and another showing a lack of survival benefit. [Head Neck 2006;28:880-887; Int J Radiat Oncol Biol Phys 2015;91:952-960] Researchers attributed these differences to the more favourable characteristics of participants in the latter trial, coupled with the low-dose carboplatin used which might have influenced its interaction with gemcitabine.
Despite these contrasts, there are studies corroborating the efficacy of GP in NPC and establishing this doublet regimen as a first-line treatment alternative to cisplatin + fluorouracil in recurrent or metastatic disease. [Eur Arch Otorhinolaryngol 2012;269:1027-1033; Lancet 2016;388:1883-1892]
Although the majority of participants had unfavourable prognostic features (N2 or N3 disease) or bulky primary tumours (T3 or T4) which are all surrogates for occult metastasis, [J Natl Compr Canc Netw 2017;15:913-919] the findings translate to a 4.3–percentage-point survival advantage over standard therapy at 3 years, at the cost of a higher incidence of acute AEs, said the researchers. “This trial establishes [IC + CRT] as the standard of care in locally advanced NPC. [This combination] can be an option for first-line treatment in this high-risk subgroup,” they concluded.