A recent international multicenter study published in JAMA Otolaryngology–Head & Neck Surgery has shown that adding chemotherapy to adjuvant radiotherapy after surgery improves survival outcomes in patients with oral cavity squamous cell carcinoma. This is when there is major extranodal extension (ENE) of the disease. In contrast, in patients with minor ENE, chemotherapy does not appear to significantly improve clinical outcomes, which could prompt a reconsideration of current therapeutic recommendations.
The study, led by the Princess Margaret Cancer Centre in Toronto, included 755 patients treated between 2005 and 2018 at leading centers in Canada, the United States, and Australia. Among the authors is Dr. Cristina Valero, a researcher at the Sant Pau Research Institute (IR Sant Pau) and Memorial Sloan Kettering Cancer Center in New York, who was the only contributor affiliated with a Spanish institution.
Extranodal extension (ENE) is a pathological feature indicating that the tumor has spread to lymph nodes and breached their capsule, infiltrating surrounding tissues. This extension can be classified as minor (≤2 mm) or major (>2 mm), and its presence is generally associated with a poorer prognosis, including higher risk of recurrence and reduced survival.
ENE has long been considered a high-risk criterion justifying the use of concurrent chemotherapy with adjuvant radiotherapy following surgery. However, the findings of this new study challenge the need to add chemotherapy in all ENE cases, particularly those with minor extension.
“Currently, any degree of ENE is an indication for chemotherapy in combination with adjuvant radiotherapy, regardless of the extent of extranodal spread,” explains Dr. Valero. “The results of this study suggest that this approach may not be necessary for patients with minor ENE, thus avoiding treatments that do not provide clinical benefit and may lead to significant toxicities. More studies are needed to validate our findings before clinical protocols can be reconsidered.”
The findings of this study have important translational value. In patients with major ENE, chemoradiotherapy significantly improved both disease-free survival and overall survival. However, in patients with minor ENE, these improvements were not statistically significant, even after adjusting for age, tumor stage, surgical margins, or radiotherapy.
This evidence supports the need for a more refined risk stratification approach in the treatment of advanced oral cancer, aiming to personalize therapeutic decisions and reduce exposure to unnecessary aggressive treatments.
“Collaborative research of this kind is essential for advancing personalized medicine and for generalizing findings,” adds Dr. Valero. “It allows us to critically evaluate our clinical practices and make decisions based on the best available evidence.”
Leadership and Excellence in International Research
The study involved a large multidisciplinary team of oncologists, pathologists, surgeons, epidemiologists, and biostatisticians from top-tier institutions, including Memorial Sloan Kettering Cancer Center (U.S.), University Health Network in Toronto (Canada), Chris O’Brien Lifehouse (Australia), and the Medical University of South Carolina (U.S.). Dr. Valero is among the co-authors who contributed to data acquisition, analysis, and interpretation.
Her involvement highlights IR Sant Pau’s commitment to high-quality international clinical research and its active role in studies that have the potential to change clinical practice for the benefit of patients.
Manojlovic-Kolarski M, Su S, Weinreb I, Calvisi R, Perez-Ordonez B, Smith S, Patel S, Valero C, Xu B, Ghossein R, Katabi N, Clark J, Low T-HH, Gupta R, Graboyes E, Davies J, Richardson M, Goldstein D, Huang SH, O’Sullivan B, Xu W, Hansen A, de Almeida JR. Adjuvant chemoradiotherapy for oral cavity SCC with minor and major extranodal extension. JAMA Otolaryngol Head Neck Surg 2025. https://doi.org/10.1001/jamaoto.2025.1721.
