The addition of chemotherapy to adjuvant radiation is associated with inferior survival outcomes in intermediate‐risk HPV‐negative HNSCC

Abstract

Background Only high‐risk tumors with extranodal extension (ENE) and/or positive surgical margins (PSM) benefit from adjuvant therapy (AT) with concurrent chemoradiation (CRT) compared to radiation therapy (RT) in locally advanced head and neck squamous cell carcinoma (HNSCC). Optimal treatment for intermediate‐risk tumors remains controversial. We categorized patients based on their surgical pathologic risk factors and described AT treatment patterns and associated survival outcomes. Methods Patients were identified from CHANCE, a population‐based study, and risk was classified based on surgical pathology review. High‐risk patients (n = 204) required ENE and/or PSM. Intermediate‐risk (n = 186) patients had pathological T3/T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), or positive lymph nodes without ENE. Low‐risk patients (n = 226) had none of these features. Results We identified 616 HPV‐negative HNSCC patients who received primary surgical resection with neck dissection. High‐risk patients receiving AT had favorable OS (HR 0.50, p = 0.013) which was significantly improved with the addition of chemotherapy compared to RT alone (HR 0.47, p = 0.021). When stratified by node status, the survival benefit of AT in high‐risk patients persisted only among those who were node‐positive (HR: 0.17, p < 0.0005). On the contrary, intermediate‐risk patients did not benefit from AT (HR: 1.26, p = 0.380) and the addition of chemotherapy was associated with significantly worse OS compared to RT (HR: 1.76, p = 0.046). Conclusion In high‐risk patients, adjuvant chemoradiotherapy improved OS compared to RT alone. The greatest benefit was in node‐positive cases. In intermediate‐risk patients, the addition of chemotherapy to RT increased mortality risk and therefore should only be used cautiously in these patients.

Trends and Implications of Adjuvant Systemic Therapy for Head and Neck Cancer Without High‐Risk Features

“…While the use of aST in a highly selected subgroup of patients without ENE or positive margins is allowable within the NCCN guidelines and selected patients may still benefit, our results build on existing literature suggesting aST should be rarely utilized in this setting. 21,22 Additionally, our data does not support the supposition that systemic therapies are being used by highly specialized oncologists based on a nuanced reading of the available data, since these treatments were used more frequently in community facilities and when adjuvant therapy is given at an outside facility.…”

“…Our conclusion that aST in this setting is associated with inferior survival is supported by another related study using a different regional dataset. 22 All of these studies are retrospective in nature and so cannot conclude causality and do not exclude the concept that some patient or oncologic situations warrant postoperative chemoradiotherapy outside of ENE or positive margins.…”

“…Additionally, aST decreases the health‐related quality of life as compared to radiation alone 20 . Prior studies examining the real‐world use of aST in postoperative HNC have raised concern for inferior survival but relied primarily on registry data before key risk factors like ENE were available or have come from less generalizable datasets 21,22 . There also remains a need to understand the frequency and trends of aSTLR.…”

Adding Concomitant Chemotherapy to Postoperative Radiotherapy in Oral Cavity Carcinoma with Minor Risk Factors: Systematic Review of the Literature and Meta-Analysis

“…In the retrospective analysis by Fan [ 13 ] of patients with at least three minor risk factors, the multivariate analysis indicated that a tumor invasion depth ≥ 11 mm was an independent poor prognostic factor ( p < 0.05). In contrast, Tasoulas [ 86 ], in a mixed population of HNSCC patients (42 patients with OCC, 23% of total, intermediate-risk patients), found that the addition of chemotherapy to RT increased mortality risk. In the study by Chen MM [ 81 ], a wide analysis of the NCDB for HNSCC patients subjected to PORT or POCRT—of whom 1571 (62.2%) were treated with pRT and 956 (37.8%) with pCRT, respectively, with the presence of multiple positive lymph nodes and lymph vascular invasion in about 50% of patients in both groups—did not find differences in mortality with or without lymph vascular invasion.…”

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma

“…11 The clinical response rate was 93%, 30 of 39 (77%) patients avoided adjuvant radiotherapy, and quality of life results were favorable. 11,15 In this generally low risk population, the pathologic complete response rate was 35%. Immune checkpoint blockade (ICB) with anti-programmed cell death protein 1 (PD-1) antibodies improves survival in recurrent/ metastatic HNSCC.…”