Hypofractionated concurrent chemoradiotherapy in locally advanced oral tongue cancer: Approaching surgical outcomes

Squamous cell carcinoma of the oral tongue (OSCC) remains a significant oncologic challenge, particularly in inoperable locally advanced cases. While surgery with adjuvant radiotherapy (RT) forms the standard of care, non-surgical cases experience markedly poorer outcomes.[1,2] Conventionally, in inoperable cases, definitive chemoradiotherapy (CRT) is delivered using fractionation schedules of 66-70 Gy in 1.8-2.0 Gy per fraction, achieving only borderline curative outcomes.[2] Despite all these attempts, 2-year survival rates are below 30%, unlike patients with operable oral tongue, where even 5-year survival rates approach 50%.[2,3] Emerging approaches, such as hypofractionation and concurrent low-dose chemotherapy, are being investigated to improve local control and survival in this unfavorable subgroup. STUDY OVERVIEW Venkataraman et al.,[4] conducted a single-arm pilot study investigating the feasibility and toxicity of accelerated hypofractionated radiotherapy (HFRT) using a simultaneous integrated boost (SIB) technique, delivering 55 Gy in 20 fractions with weekly low-dose cisplatin (35 mg/m2) in patients with unresectable oral tongue carcinoma. Most participants presented with extensive lesions involving the anterior tongue and base of tongue (BOT), often extending to the floor of mouth or valleculae-features commonly rendering tumors inoperable in resource-limited settings. Such presentations frequently lead to dysphagia, aspiration risk, and malnutrition, necessitating tailored interventions that consider both oncologic control and functional preservation.[5] METHODOLOGICAL CONSIDERATIONS Although only 10 patients were included, the selection of inoperable cases remains appropriate given the advanced local disease burden. However, clarification regarding inclusion criteria would enhance reproducibility. The extension of the primary tumor into the BOT is not, by itself, a contraindication for surgery; thus, factors such as proximity to the hyoid bone or infiltration of critical musculature should be explicitly documented to justify unresectability. The radiation protocol involved differential dosing, 55 Gy, 48 Gy, and 44 Gy to high, intermediate, and low-risk planning target volumes (PTV), respectively, over 20 fractions. This regimen was adapted from Jacinto et al.,[6], who provided radiobiological justification for hypofractionation in head-and-neck cancer. Importantly, no volumetric data were provided for PTVs or nodal involvement, a limitation when evaluating organ-at-risk (OAR) sparing and potential late effects. TOXICITY AND COMPLIANCE Treatment compliance was encouraging, with all ten patients completing RT and 90% (n = 9) receiving at least four cycles of cisplatin. Acute toxicity included Grade 3 mucositis in 50% (n = 5) and dysphagia in 20% (n = 2) of patients, aligning with existing HFRT studies. However, the absence of data on feeding tube placement, onset of toxicities, or time to resolution limits the utility of these findings for clinical translation. Previous reports suggest HFRT may cause temporally distinct toxicity peaks compared to conventional fractionation, which warrants further study. RADIOBIOLOGICAL AND CLINICAL IMPLICATIONS In head-and-neck oncology, fraction size strongly influences late toxicity profiles. While this study did not report late effects, their evaluation is essential, particularly for complications like osteoradionecrosis, xerostomia, fibrosis, and radiation myelopathy. Large-scale studies, such as the HYPNO trial[7] have designated late Grade ≥3 toxicity as a co-primary endpoint. The results of HFRT in other sites have well-established dose per fraction as one of the greatest determinants of late radiation morbidity.[8] The absence of such data in this pilot study limits its implications for widespread HFRT adoption. A further limitation is the ambiguity around dose-volume histogram (DVH) data. The authors reference QUANTEC guidelines;[9] but it remains unclear whether the reported DVH metrics were planned or achieved values. This is a crucial distinction given that aggressive SIB plans in anatomically constrained areas like the oral cavity and oropharynx challenge OAR sparing. RATIONALE FOR HYPOFRACTIONATION The impetus for exploring HFRT in OSCC stems from the limitations of conventional schedules, especially in inoperable cases. Prolonged overall treatment time (OTT) in conventional RT is associated with accelerated tumor repopulation, reducing local control by approximately 1.4% per day or 11% per week. Hypofractionation shortens OTT and increases biological effective dose (BED), potentially overcoming repopulation dynamics.[10] Theoretical radiobiological modeling supports this approach, although clinical validation remains sparse in head-and-neck cancer. Nevertheless, the head-and-neck region encompasses multiple critical OARs, necessitating cautious dose escalation. While HFRT in prostate and breast cancers has been widely accepted,[8] its application in OSCC must account for unique toxicity risks due to the complex anatomy and dense clustering of radiosensitive tissues. COMPARISON WITH EXISTING LITERATURE Jacinto et al.,[6] demonstrated the feasibility of concurrent cisplatin with HFRT in head-and-neck squamous cell carcinoma (HNSCC), though with high feeding tube dependency (~75%). While Venkataraman et al.,[4] reported favorable compliance, absence of enteral nutrition data limits the assessment of real-world tolerability. The HYPNO trial and CompARE[11] platform study offer promising frameworks for HFRT evaluation in HNSCC. Their comparative arms, stratified endpoints, and larger cohorts are likely to yield definitive guidance. Until such results are published, HFRT should be viewed as investigational outside of clinical trials. FUTURE DIRECTIONS Longitudinal data on late toxicity and durable response rates are urgently needed to establish HFRT as a standard for inoperable OSCC. Given that both Venkataraman et al.,[4] and Jacinto et al.,[6] assessed local-regional control (LRC) at eight weeks post-RT, longer follow-up intervals (≥12 weeks) should be standard for response assessment. Moreover, studies should report on feeding tube rates, toxicity timelines, and quality-of-life measures. Prospective randomized trials comparing HFRT with standard fractionation, using endpoints such as LRC, progression-free survival, late toxicities, and quality-of-life indices, are warranted. The ongoing HYPNO and CompARE studies may provide such clarity. Hence, we conclude that this pilot study affirms the feasibility and tolerability of hypofractionated RT with concurrent low-dose cisplatin in unresectable oral tongue cancer.[4] While preliminary findings are promising, the absence of long-term outcomes and late toxicity data necessitates caution. Larger, controlled trials are essential to validate this approach and potentially redefine standards for managing inoperable OSCC.