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Open research questions in Head and Neck Cancer Studies

100 unresolved questions extracted from the limitations and future-work sections of 1,558 Head and Neck Cancer Studies papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although previous studies suggest that ELND omission may reduce postoperative complications, including pharyngocutaneous fistulas and deterioration in quality of life (QOL), its impact on prognosis remains controversial.

    A multicenter randomized phase III trial to evaluate the value of omission of elective neck dissection for T3–T4aN0 laryngeal cancer: JCOG2407 (JALNECK) · 2026 · DOI

  • Higher LNY with SSS technique was paradoxically associated with worse survival, and reliable LNY cut‐offs could not be established, while conventional pathological assessment with inspection and palpation showed greater consistency in defining LNY thresholds.

    Lymph Node Yield as A Quality Metric in the Treatment of Oral Cavity Squamous Cell Carcinoma: The Need for Centre‐Specific Thresholds · 2026 · DOI

  • ABSTRACT Recurrence limits survival in head and neck cancer (HNC), yet its annualized rate remains poorly defined due to heterogeneous follow‐up durations across studies.

    Global Annualized Recurrence Rates and Dynamic Risk Profiles in Head and Neck Cancer · 2026 · DOI

  • However, p16 overexpression does not invariably reflect transcriptionally active HPV infection, and the clinical significance of p16–HPV discordance remains incompletely defined, particularly in populations with high exposure to traditional carcinogens.

    Prognostic Implications of p16 Immunohistochemistry and Its Discordance with Transcriptionally Active HPV in Oropharyngeal Squamous Cell Carcinoma: A Taiwanese Cohort Study · 2026 · DOI

  • Conclusions: Externally validated ML models for predicting occult nodal metastasis in cN0 OCSCC show promise but remain insufficiently validated to guide END in routine practice.

    Performance of Machine Learning Models for Predicting Occult Nodal Metastasis in Oral Cavity Squamous Cell Carcinoma: A Systematic Review and Diagnostic Accuracy Meta-Analysis · 2026 · DOI

  • ABSTRACT Background The management of sublevel IIB during elective neck dissection (END) for clinically node‐negative (cN0) head and neck squamous cell carcinoma (HNSCC) remains debated.

    Is Level <scp>IIB</scp> Dissection Necessary in the Clinically <scp>N0</scp> Neck? A Systematic Review and Meta‐Analysis in Head and Neck Squamous Cell Carcinoma · 2026 · DOI

  • Furthermore, Stoicescu (2021) emphasized that frequently ocular underrecognized and that ophthalmologic evaluation should be integrated into standard oncology care.

    Correlation Between Duration of Docetaxel Administration and Epiphora Severity in Nasopharyngeal Carcinoma Patients · 2026 · DOI

  • While stage distribution and overall or disease-specific survival did not significantly differ between clusters, the present results support differences in the etiology and development of early-onset mobile tongue SCC, currently a poorly characterized clinical entity of increasing incidence.

    Mutational signature-based classification uncovers emerging oral cancer subtypes with distinct molecular patterns · 2026 · DOI

  • ABSTRACT Background The prognostic implications of regional lymph node metastases at the initiation of immune checkpoint inhibitor (ICI) therapy in oral cavity squamous cell carcinoma (OCSCC) are not well defined.

    Metastatic Lymph Node Status Is Associated With Progression‐Free Survival in Oral Cavity Squamous Cell Carcinoma Treated With Pembrolizumab · 2026 · DOI

  • However, owing to limited medical resources, continuous surveillance solely for early SPC detection remains challenging, highlighting the need for further research into practical and sustainable survivorship care for patients with HNSCC.

    Clinical Characteristics of Metachronous Second Primary Head and Neck Cancers Occurring 5 Years or More After Treatment for the First Primary Cancer · 2026 · DOI

  • Although adjuvant capecitabine has demonstrated efficacy in high-risk LA-NPC, whether intensifying adjuvant therapy by adding sintilimab, a highly selective, fully humanized monoclonal PD-1 inhibitor to capecitabine, can further improve survival outcomes remains unclear.

    Adjuvant sintilimab-capecitabine versus capecitabine alone in locoregionally advanced nasopharyngeal carcinoma with suboptimal response to induction chemotherapy: An open-label, randomized, controlled, phase 2 trial. · 2026 · DOI

  • The principal strength of this review lies in the integration of recent high-quality prospective evidence, particularly the ECOG-ACRIN E3311 trial, within the framework of the AJCC 8th edition staging system. This integration allows for a more accurate assessment of TORS in the era of risk- adapted treatment de-escalation. However, several limitations must be acknowledged. First, time restriction (2019–2025) was applied to prioritize studies aligned with contemporary surgical practice and AJCC 8th edition staging; however, this may have resulted in the exclusion of earlier studies with longer follow-up or large registry-based datasets, and is therefore acknowl- edged as a potential source of selection bias. Second, sub- stantial statistical heterogeneity was observed in survival outcomes, and the predominantly retrospective design of the included studies introduces potential selection bias, par- ticularly regarding smoking status. Furthermore, the lack of standardized reporting for smoking intensity (pack-years) across the included retrospective series limits our abil- ity to perform a definitive dose-response analysis, and our mechanical interpretations regarding the ‘hypoxia bypass’ Page 15 of 17 515 remain speculative until validated by prospective molecular studies. Third, while we performed subgroup analyses to mitigate the impact of combining primary and salvage cases, this mix- ture may have obscured distinct morbidity profiles. Nota- bly, the evidence for long-term feeding tube dependency in the salvage cohort remains limited, with this subgroup representing only 1% of the total meta-analysis weight, thus necessitating larger prospective studies to confirm these functional outcomes. Additionally, due to the limited follow-up duration in the included salvage cohorts, 5-year survival outcomes could not be pooled, and 2-year survival was utilized as the primary oncologic benchmark for this subgroup. Finally, inconsistent reporting of patient-reported quality-of-life (QoL) outcomes precluded a comprehensive quantitative synthesis of the patient’s perspective.

    Oncologic, functional, and economic outcomes of transoral robotic surgery for HPV-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of pathology and treatment strategies · 2026 · DOI

  • Despite rigorous methodology, this systematic review is subject to several inherent limitations. The decision to pool multiple selective COX-2 inhibitors and comparator types was necessary to achieve meaningful statistical power but constrained the ability to conduct subgroup analyses and explore heterogeneity in a robust manner. As a result, potential individual drug-specific effects may have been obscured. The systematic review process is also influenced by the construction of the search strategy, which relies on clinical knowledge and experience to capture all relevant terminology. Although this risk was mitigated through iterative search refinement, incomplete retrieval of relevant studies remains possible. Although database searches could identify non-English publications, indexing of titles and abstracts in English may limit retrieval of studies published in other languages. Additionally, studies are more likely to be conducted, published, and cited in high-income settings, potentially introducing geographic and socioeconomic publication bias.39 Overall, the certainty of evidence was rated as moderate to high for most outcomes. Downgrading typically occurred due to imprecision, particularly in subgroup analyses, or due to heterogeneity arising from the inclusion of multiple drugs and comparators. Importantly, the methodological quality of individual studies was generally good.

    The Safety of Selective COX-2 Inhibitors in Tonsillectomy Patients: a Systematic Review · 2026 · DOI

  • Taken together, these results suggest that the benefit of induction chemoimmunotherapy may vary by primary tumor subsite and primary tumor subsite may warrant further investigation in future prospective studies of induction chemoimmunotherapy in HPV-negative OPSCC.

    Subsite-specific benefit of induction chemoimmunotherapy in HPV-negative oropharyngeal squamous cell carcinoma · 2026 · DOI

  • statistical power and makes negative findings difficult to interpret with confidence. Moreover, treatment-by-subsite interaction analyses did not detect a statistically significant interaction for PFS or OS before or after PSM, although these analyses were limited by sparse events, including no PFS events in the non-BOT IC+ICI subgroup. Therefore, the observed non-BOT PFS signal should be interpreted as hypothesis- generating. Third, all patients in this cohort received induction-based treatment followed by definitive CCRT; therefore, we were unable to compare this strategy directly with upfront standard CCRT. In addition, detailed toxicity data were not consistently available from the retrospective medical records, and adverse events were not uni- formly graded according to CTCAE criteria. Therefore, safety out- comes were not included in the present analysis. Finally, key biologic correlates, including PD-L1 expression and other immune microenvironmental markers, were not available, which limits mech- anistic interpretation and prevents more refined biomarker-based patient selection. Future studies should incorporate prospective vali- dation, larger subsite-specific cohorts, and integrated translational profiling to better define which patients are most likely to benefit from induction chemoimmunotherapy.

    Subsite-specific benefit of induction chemoimmunotherapy in HPV-negative oropharyngeal squamous cell carcinoma · 2026 · DOI

  • R-CHOP remains the standard treatment for DLBCL. [17,18] All four NHL patients therapy, with received R-CHOP-based complete remission in two cases. In an 84- year-old patient, treatment was initial modified to R-CVP, reflecting geriatric oncology practice of adjusting therapy to age, comorbidity, and fitness. The VRD regimen used in the myeloma case produced VGPR after four cycles and may allow transplant consolidation. The CML case treated with imatinib showed molecular response but retained a guarded prognosis because blast crisis has poor outcomes, with allogeneic transplantation being the only potentially curative option.

    Hematolymphoid Tumors of the Oral and Oropharyngeal Region: A Retrospective Case Series from a Tertiary Care Centre · 2026 · DOI

  • Declarations Several limitations must be considered. The retrospective design introduces inherent selection bias, and depth of invasion was not available for all patients, necessitating a secondary model restricted to a subset of the cohort. Radiological assessments were based on routine clinical reports rather than centralized re-review, introducing potential interobserver variability but reflecting real-world clinical practice. Despite these limitations, this study benefits from a large, well-characterized cohort, detailed pathological nodal assessment, and the application of both three-level and dichotomous radiological classifications. By integrating quantitative nodal measures such as lymph node ratio with established biological risk factors, our analysis provides a detailed understanding of what radiological lymph node suspicion represents in clinical practice and highlights its role as an indicator of cumulative nodal tumor burden.

    Correlation of preoperative radiological lymph node assessment with pathological nodal and tumor findings in tongue and oral floor squamous cell carcinoma · 2026 · DOI

  • Future research should focus on prospective, multicentre investigations linking MDTB adoption with patient-level endpoints such as treatment timeliness, adherence to guide- lines, organ-preservation rates and survival.

    Predictors of multidisciplinary tumor board implementation in head and neck cancer: Global insights · 2026 · DOI

  • Several limitations of this study should be acknowledged. First, the study was conducted at a single tertiary care center, which may limit the generalizability of the findings to other settings with different patient populations or imaging protocols. Second, the inclusion of only surgically treated patients introduces potential selection bias, as patients with early-stage disease or those managed non- surgically were not represented. Third, although interobserver agreement was assessed independently, the use of consensus review in discrepant cases may have influenced the final diagnostic performance estimates. Additionally, other imaging modalities such as magnetic resonance imaging (MRI), cone-beam CT, or positron emission tomography (PET) were not evaluated, preventing direct comparison of diagnostic performance across modalities. Finally, potential confounding factors such as tumor size, histological grade, and artifact-related limitations were not systematically analyzed.

    Diagnostic Accuracy of Contrast-Enhanced Computed Tomography (CECT) in Detecting Mandibular Invasion in Oral Squamous Cell Carcinoma: A Prospective Study Using Histopathology as the Gold Standard · 2026 · DOI

  • This review has several strengths. The comprehensive search strategy across multiple databases minimizes the risk of missing relevant studies. The restriction to post- operative tongue carcinoma provides homogeneity and clinical applicability. The inclusion of RCTs alongside well-designed observational studies balances internal validity with representativeness. The assessment of multiple outcome domains (dosimetric, efficiency, clinical) provides a holistic comparison. Several limitations warrant acknowledgment. First, despite efforts to identify all relevant studies, the majority of included studies were observational, introducing potential for selection bias and confounding. While our sensitivity analyses restricted to RCTs yielded similar results, the relatively small number of randomized trials limits estimates. Second, heterogeneity in radiation dose-fractionation schemes, concurrent chemotherapy regimens, and outcome definitions across studies precluded formal meta-analysis for some outcomes and may limit generalizability. Third, most included studies had relatively short follow-up (median 24-36 months), limiting assessment of late toxicity and long-term survival. Fourth, the majority of studies originated from high-volume academic centers, potentially to community practice settings. Fifth, detailed information on treatment planning objectives, optimization algorithms, and quality assurance protocols was inconsistently reported, limiting our ability to identify technical factors that might influence comparative performance. Additionally, our review did not address cost- effectiveness formally, though the efficiency advantages of VMAT would likely translate to favorable economic profiles in most healthcare systems. Patient-reported outcome data, while supportive of VMAT benefits for xerostomia, were available in only a subset of studies, and standardized QoL assessment was not universal. Finally, subgroup analyses to identify patient populations who might derive particular benefit from VMAT were limited by inconsistent reporting of relevant baseline characteristics across studies. CONCLUSION This systematic review provides robust evidence that VMAT offers significant advantages over IMRT for post-operative radiotherapy in tongue carcinoma. The limiting generalizability IJDDT, Volume 16 Issue 7s, 2026 338 Intensity-Modulated Radiotherapy versus Volumetric Modulated Arc Therapy in Post-operative Carcinoma Tongue: A Systematic Review of Dosimetric Parameters, Treatment Efficiency, and Clinical Outcomes in 67% reduction in treatment delivery time and 35% represent substantial in monitor units reduction improvements efficiency without treatment compromising target coverage or oncological outcomes. The superior sparing of parotid glands and oral cavity translates to modest but clinically meaningful reductions in xerostomia and improved quality of life. Acute toxicity profiles are comparable, while late xerostomia shows favorable trends with VMAT. Based on the current evidence, VMAT should be considered the preferred radiation delivery technique for technical post-operative expertise and quality assurance infrastructure are available. The benefits are particularly compelling in high-volume centers where workflow efficiency gains can substantially improve patient access and resource utilization.

    Intensity-Modulated Radiotherapy versus Volumetric Modulated Arc Therapy in Post-operative Carcinoma Tongue: A Systematic Review of Dosimetric Parameters, Treatment Efficiency, and Clinical Outcomes · 2026 · DOI

  • To further advance the field and optimize radiation therapy for post-operative tongue carcinoma, future research should focus on: • Prospective randomized trials with adequate sample sizes and extended follow-up to definitively establish comparative effectiveness, particularly for late toxicity and long-term quality of life outcomes • Standardized patient-reported outcome assessment using validated instruments across all comparative studies to better capture patientcentered benefits • Cost-effectiveness incorporating treatment equipment costs, planning delivery efficiency, and long-term toxicity analyses time, • • management to inform resource allocation…

    Intensity-Modulated Radiotherapy versus Volumetric Modulated Arc Therapy in Post-operative Carcinoma Tongue: A Systematic Review of Dosimetric Parameters, Treatment Efficiency, and Clinical Outcomes · 2026 · DOI

  • 19 A limitation of this study, in part related to its early closure, is that we were unable to obtain robust estimates of treatment effects within subgroups due to small subsample sizes. Additionally, we could not determine whether p16 status influences the effectiveness of checkpoint inhibitors in this population.

    Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial · 2024 · DOI

  • ' Results: Multitudes of studies have been published recently stating the role of OMCT in head and neck squamous cell carcinoma (HNSCC), but the studies with the category of level of evidence required to advocate OMCT as a recognized therapy are still scarce.

    Oral Metronomic Chemotherapy in Advanced and Metastatic Oral Squamous Cell Carcinoma: A Need of the Hour · 2023 · DOI

  • Conclusion: Reviewed articles reported varied and contradictory results regarding the association of gene polymorphisms and HNSCC prognosis, which necessitates further studies along with meta-analysis on the results of such studies.

    Gene polymorphisms and prognosis of head and neck squamous cell carcinoma: a systematic review · 2022 · DOI

  • There are conflicting results regarding the association between polymorphisms such as ERCC2 A35931C , Asp312Asn , ERCC5 rs1047768 and rs17655 with HNSCC prognosis.

    Gene polymorphisms and prognosis of head and neck squamous cell carcinoma: a systematic review · 2022 · DOI

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100 open questions have been extracted from the limitations and future-work passages of 1,558 Head and Neck Cancer Studies papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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