Radiotherapy comparable to concurrent chemoradiotherapy in nasopharyngeal cancer subset
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CHICAGO — Intensity-modulated radiotherapy conferred disease control and survival outcomes comparable to concurrent chemoradiotherapy but with less toxicity among patients with low-risk nasopharyngeal carcinoma, according to study results.
The findings of the randomized phase 3 noninferiority trial, presented at ASCO Annual Meeting, suggested concurrent chemoradiotherapy (CCRT) could be safely omitted for patients who receive intensity-modulated radiotherapy (IMRT).
“As we know, concurrent chemoradiotherapy with or without induction or adjuvant chemotherapy has been the standard modality for stage II [nasopharyngeal carcinoma],” Jun Ma, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, said during a presentation. “High-level evidence regarding the role of chemotherapy for this population in the intensity-modulated radiation therapy era is lacking.”
Background and methods
Ma acknowledged the controversy surrounding the benefit of concurrent chemotherapy for low-risk nasopharyngeal carcinoma, which the researchers defined as stage II and T3N0M0 disease without adverse features such as large lymph nodes (3 cm or larger), level IV or higher lymph nodes, presence of extranodal extension and Epstein-Barr virus DNA level of 4,000 copies per mL or greater.
Ma cited studies that showed cisplatin-based CCRT increased incidence of severe acute adverse effects and late toxicities, as well as risk for treatment-related mortality, while failing to confer a significant survival benefit in the IMRT era. The researchers hypothesized IMRT alone provides noninferior 3-year failure-free survival with less toxicity compared with CCRT among patients with low-risk nasopharyngeal carcinoma.
The multicenter, open-label study conducted at four hospitals in China included 338 patients aged 18 to 65 years with histologically confirmed, stage T1-2N1/T2-3N0M0 nasopharyngeal carcinoma and a Karnofsky score of 70 or higher. Researchers randomly assigned patients between Nov. 11, 2015, and Aug. 4, 2020, to intensity-modulated radiotherapy alone, which consisted of five daily fractions of 2 to 2.2 Gy per fraction per week for a total of more than 66 Gy (n = 169), or with concurrent chemotherapy, which consisted of 100 mg/m2 cisplatin on days 1, 22 and 43 (n = 169). The groups had similar characteristics, including patient age (median, 48 years in both groups) and percentages of men (68% vs. 72.2%) and patients with stage II disease (75% vs, 74%). They stratified randomization by treatment center and stage.
Most patients in the CCRT group (60.4%) completed at least three cycles of CCRT.
Failure-free survival (FFS) served as the primary endpoint. Secondary endpoints included OS, locoregional RFS, distant metastasis-free survival, toxicity and health-related quality of life.
Median follow-up was 41 months.
Key findings, implications
Results showed 3-year FFS rates of 90.6% with IMRT alone and 91.9% with CCRT (HR = 1.35; 95% CI, 0.69-2.64), for a difference of 1.3 percentage points (one-sided 95% CI, 7.3 to 4.7), which met significance for noninferiority (P = .001).
Researchers observed no differences between the IMRT and CCRT groups in 3-year OS (98.2% vs. 97.6%; HR = 3.22; 95% CI, 0.65-15.98), 3-year distant metastases-free survival (HR = 2.11; 95% CI, 0.63-7.02) and 3-year locoregional RFS (HR = 1.27; 95% CI, 0.57-2.8).
Grade 3 to grade 4 adverse events occurred significantly more often in the CCRT group and included vomiting (14.8% vs. 1.2% in IMRT group) anorexia (29% vs. 4.8%), mucositis (18.9% vs. 9.7%) and weight loss (4.7% vs. 0.6%). No patients died due to causes related to treatment.
Patients in the IMRT group demonstrated significantly improved quality of life and lower symptom burden, Ma said.
“Our trial supports IMRT alone as a valid option to be the future treatment for patients with low-risk T1-2N1 and T3N0 nasopharyngeal carcinoma,” he said.
Perspective
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Shlomo Koyfman, MD
These data are compelling and underscore the importance of risk stratification in locally advanced nasopharyngeal cancer. There is a tendency — especially in the United States — to treat all patients with more than stage I nasopharyngeal cancer with an intensive paradigm of concurrent chemoradiation plus either induction or adjuvant high-dose chemotherapy. This study appropriately questions the need for such intensive approaches and provides strong evidence that — for patients without adverse features, such as large lymph nodes (3 cm or larger), level IV or higher lymph nodes, presence of extranodal extension and Epstein-Barr virus (EBV) DNA level of 4,000 copies per mL or greater — de-intensified approaches should be strongly considered.
However, several cautionary notes are in order. First, the EBV DNA assays can be quite variable across institutions, and this cutoff may not be reliable from center to center. Harmonization of this assay is sorely needed. Perhaps more importantly, this trial includes endemic EBV-related disease only and should not be extrapolated to the growing proportion of patients in parts of the U.S. with non-EBV-related nasopharyngeal cancer who are known to have worse outcomes. These patients need their own studies to optimize their treatment paradigms as they have a distinct biology.
Finally, although morbidity was increased with chemotherapy, the incidence and severity of toxicity was only modestly worsened and the late effects in the two groups were similar. This finding underscores the need to identify clinically meaningful endpoints that should guide future de-intensification efforts that will translate into substantial improvements in the outcomes that matter most.
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Ma J, et al. Abstract 6000. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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