Optimizing the therapeutic ratio: a narrative review of de-escalation and response-adapted strategies in series including human papillomavirus negative head and neck cancer

Introduction

The past decade has witnessed a transformative shift in the management of head and neck squamous cell carcinoma (HNSCC), particularly driven by the emergence of human papillomavirus (HPV)-positive oropharyngeal HNSCC as a distinct disease entity recognized in 2012 by the International Agency for Research on Cancer (1). Characterized by a more favorable prognosis, increased chemosensitivity, and heightened radiosensitivity compared to its HPV-negative counterpart, HPV-positive disease has become the cornerstone for the development of treatment de-escalation strategies (2,3). Phase II and retrospective clinical trials have demonstrated that tailored reductions in treatment intensity—encompassing lower radiation doses, de-intensified chemotherapy, or targeted reductions in treatment volumes—may effectively maintain excellent oncologic control while significantly mitigating the burden of acute and long-term toxicities, thereby profoundly enhancing patients’ quality of life. This paradigm of “less is more” in HPV-positive HNSCC has set a crucial precedent, proving that treatment efficacy need not always come at the cost of severe life-altering side effects (4-6).

However, despite these advancements, the conventional multidisciplinary treatments for other aggressive head and neck malignancies, including HPV-negative HNSCC and nasopharyngeal carcinoma (NPC), continue to impose a substantial burden of morbidity on patients. Standard approaches, often involving intensive chemoradiotherapy (CRT), lead to a cascade of debilitating acute and late toxicities such as severe dysphagia, xerostomia, hearing impairment, hypothyroidism, and permanent changes to the skin and tissues (7-10). These side effects compromise essential functions, impair social interaction, and diminish overall well-being, often persisting for years beyond treatment completion. The imperative to improve the therapeutic ratio—maximizing disease control while minimizing treatment-related harm—remains a paramount challenge for these patient populations.

Building upon the partially successful de-escalation models established in HPV-positive HNSCC, a critical clinical question has emerged: can similar principles of reduced treatment intensity be safely and effectively applied to HPV-negative HNSCC and NPC? HPV-negative HNSCC, often associated with a more aggressive biological profile and less favorable outcomes, presents unique challenges for de-escalation, yet the need to reduce treatment-induced suffering is equally pressing. Likewise, NPC, given its deep-seated anatomical location near numerous critical organs and its typically extensive nodal involvement, necessitates high-dose radiotherapy (RT) that frequently results in severe and chronic late effects. Any strategic reduction in treatment intensity in these settings demands meticulous evaluation to ensure that oncologic control is not jeopardized.

This narrative review aims to comprehensively synthesize and critically appraise the current evidence regarding dose and/or volume de-escalation strategies specifically implemented in the treatment of HPV-negative HNSCC and NPC. We will investigate novel strategies, such as enhanced elective nodal irradiation (ENI) methods and response-adapted therapies after neoadjuvant immunochemotherapy. This review looks at how they affect important oncologic outcomes, acute and late toxicity profiles, and patients’ quality of life in an effort to find promising avenues for a more accurate, customized, and bearable treatment environment for people with these difficult head and neck cancers (HNCs). We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1656/rc).

Methods

Search strategy

A comprehensive systematic search (Table 1) was executed across two electronic databases: PubMed and Scopus. The search was performed on June 30^th, 2025, and included a time span from January 1^st, 2010 to June 29^th, 2025. The following search string was applied to both databases: (radiotherapy) AND (“head neck cancer” OR “head and neck cancer”) AND (HPV-negative) AND (“de-escalation” OR “deescalation” OR “deintensification” OR “de-intensification” OR “reduced dose” OR “reduced volume”).

All retrieved records were systematically exported to reference management software (EndNote) to facilitate efficient deduplication. To be included the study should include adult patients (≥18 years) diagnosed with locoregionally advanced HPV-negative HNSCC or NPC. The intervention should include treatment de-escalation strategies involving RT dose reduction, RT volume reduction (for example, ENI de-escalation, response-adapted RT), or the integration of novel systemic therapies (for example, immunotherapy, targeted therapy) to enable RT de-escalation. Studies should include as comparator standard-of-care RT or CRT for the respective cancer types, or other de-escalation approaches. Studies without a direct comparator were included if they provided novel insights into safety or efficacy of de-escalated treatments. Primary outcomes included locoregional control (LRC), overall survival (OS), progression-free survival (PFS), distant metastases (DMs), regional recurrences (RRs) and specific acute and late toxicities (for example, dysphagia, xerostomia, hypothyroidism, radiation dermatitis).

After the first search was completed and duplicate records were eliminated, a thorough two-phase screening procedure was applied to the remaining unique citations. Titles and abstracts were simultaneously screened by two independent reviewers (I.T.d.C. and S.L.F.) according to the predetermined eligibility criteria in the first phase. Records that at least one reviewer thought might be pertinent were moved on to the following stage.

The same two reviewers independently evaluated the full-text articles of all eligible records in the second phase, comparing them to the entire set of eligibility requirements. Any disagreements about inclusion or exclusion at any point during the screening procedure were settled by means of productive dialogue. A third senior reviewer (A.C.P.d.R.) was consulted if agreement could not be reached.

One reviewer (I.T.d.C.) extracted pertinent data for each of the included studies using a standardized, pre-piloted data extraction form, and a second reviewer (S.L.F.) independently verified the data. Study characteristics, patient demographics, specifics of the detailed intervention, and all reported outcomes related to efficacy and toxicity were among the key data points extracted. Attempts were made to precisely estimate data when it was displayed graphically without numerical values.

Two reviewers independently evaluated each included study’s risk of bias (I.T.d.C. and S.L.F.). The Cochrane Risk of Bias tool for Randomized Trials [Risk of Bias 2 (RoB 2)] was intended to be used for randomized controlled trials. The Risk Of Bias In Non-randomized Studies Of Interventions (ROBINS-I) tool was used for non-randomized research. Discussions or, if required, consultation with a third reviewer (A.C.P.d.R.) were used to settle any disputes that arose between the reviewers during the assessment. The results of the risk of bias evaluation will be presented narratively in the results section and thoroughly condensed in a special table.

A formal quantitative meta-analysis was considered neither appropriate nor feasible due to the small number of included studies and the expected heterogeneity in study designs, patient populations, particular de-escalation strategies, and outcome reporting. Rather, the results will be presented and interpreted using a thorough narrative synthesis approach.

Results

The initial search yielded 90 results from PubMed and 716 results from Scopus; 529 distinct records were left after extensive deduplication; 22 full-text articles were obtained for a thorough evaluation in accordance with the predetermined eligibility criteria after the title and abstract screening stage. For a variety of reasons, 16 of these articles were disqualified (for example, lack of primary data, review articles, incorrect patient population, and lack of focus on de-escalation). Six primary research articles (see Table 2) were eventually included in the final systematic review as a result of this stringent selection process. The flow diagram shows the entire study selection process, from identification to inclusion (see Figure 1). The combined results of these six included studies offer support for the idea that de-escalation techniques can lessen treatment burden while preserving oncologic efficacy in HPV-negative HNSCC and NPC.

Figure 1 Flow diagram. HNC, head and neck cancer; HPV, human papillomavirus.

HPV-negative HNSCC de-escalation

Rosenberg et al. (11) investigated a response-adapted de-escalation strategy in HPV-negative HNSCC, in which neoadjuvant nivolumab combined with carboplatin and paclitaxel achieved a 53% deep response rate and enabled stratification into de-escalated versus standard chemoradiation. In their cohort, HPV-negative status was confirmed by p16 immunohistochemistry for oropharyngeal primaries, although for non-oropharynx sites the article does not specify the exact HPV testing method. Beyond HPV status, key disease characteristics, including tumor stage distribution (predominantly T3–T4), primary site, and substantial tobacco exposure, underscore the biologic aggressiveness of this population and contextualize the feasibility of de-escalation. Patients achieving ≥50% reduction by Response Evaluation Criteria in Solid Tumors (RECIST) received 66 Gy with omission of elective nodal volumes, whereas non-responders received standard 70–75 Gy CRT. At 2 years, OS was 73% and PFS was 66%, with no significant differences between de-escalated and standard CRT arms (OS: 74% vs. 79%; PFS: 69% vs. 69%). Tumor-related outcomes, including objective response rate (86%), LRC (89% vs. 93%), and distant control (94% vs. 90%), remained high in both groups. Toxicity outcomes, reported using the Common Terminology Criteria for Adverse Events (CTCAE) criteria, also favored the de-escalated arm, in which the most common adverse events were mucositis (74% vs. 94%), radiation dermatitis (68% vs. 88%), and dry mouth (37% vs. 63%). Importantly, the assignment to de-escalated CRT was non-randomized and based on response—a strong prognostic factor—which limits the ability to isolate the causal impact of de-escalation. Still, the findings suggest that response-guided dose and volume reduction may be feasible in selected HPV-negative patients, providing a potential framework for future biomarker-driven de-escalation strategies.

For ENI in HNSCC, Murthy et al. (12) contrasted 60 and 50 Gy equivalent doses in 97 patients with primary neoplasms in the oropharynx, larynx, and hypopharynx with clinical staging between T1–T4a N0–N2b M0, excluding T1–2 laryngeal tumors. Three-year LRC did not differ significantly, according to their matched-pair analysis (78.7% vs. 77%, P=0.93). Crucially, neither dose was associated with any isolated RRs in the ENI regions. Clinically significant toxicity reductions were observed in the 50 Gy ENI group, including significantly lower biochemical hypothyroidism (26.5% vs. 54%, P=0.007) and a lower mean ipsilateral parotid dose (35.7 vs. 42 Gy, P=0.03), which resulted in a faster recovery of salivary function. The risk of bias in this study is increased by the non-randomized design, notable variations in RT delivery platforms, and insufficient reporting of patient-reported outcomes. Furthermore, information related to patients’ HPV status or smoking habits is not described in the study.

Deschuymer et al. (13) compared ENI doses of 40 vs. 50 Gy in patients with non-metastatic HNSCC. The two treatment arms were well balanced with respect to tumor site, stage, HPV status, and smoking history. Five-year RR rates did not differ significantly between groups (14.0% with 40 Gy vs. 7.5% with 50 Gy), and only two recurrences in each arm occurred within the elective nodal volume. OS was likewise comparable (56.5% vs. 49.6%). Importantly, earlier reports from the same cohort demonstrated a reduction in grade ≥3 dysphagia at three months with the lower ENI dose (7% vs. 18%), supporting a clinically relevant decrease in acute swallowing toxicity. HPV status for oropharyngeal tumors was assessed using combined p16 immunohistochemistry and HPV-DNA polymerase chain reaction (PCR), but subgroup analyses for HPV-negative disease were limited by sample size. Although the trial lacked statistical power to establish non-inferiority, the low incidence of elective-field failures, coupled with the observed toxicity benefit, suggests that a 40 Gy ENI dose can be used safely in appropriately selected patients.

Zakeri et al. (14) evaluated outcomes in 73 patients with laryngeal, hypopharyngeal, p16-negative oropharyngeal, and unknown-primary squamous cell carcinomas treated with ENI of 40 Gy. HPV status was assessed by p16 immunohistochemistry (the only method reported); all oropharyngeal and unknown-primary tumors were p16-negative, while p16 testing in laryngeal and hypopharyngeal cancers was performed when available. Apart from HPV/p16 status, the cohort represented a high-risk population with predominantly T3–T4 tumors (64.4%), node-positive disease (68.5%), and classically aggressive primary sites; smoking history was not quantified. De-escalation consisted specifically of reducing elective nodal dose to 40 Gy with intensity modulated radiotherapy (IMRT), maintaining full-dose (70 Gy) coverage of gross disease and selectively boosting indeterminate nodes. With a median follow-up of 23.3 months, all locoregional recurrences occurred within the 70 Gy volume, and no isolated elective nodal failures were observed, including among the entirely p16-negative oropharyngeal subgroup. The 24-month cumulative incidence of locoregional and distant recurrence was 9.8% and 13.1%, respectively. Toxicity was assessed through the Gothenburg Trismus Questionnaire rather than CTCAE grading; all symptom domains showed improved scores at 24 months compared with baseline, reflecting favorable functional outcomes with reduced elective-dose irradiation.

In the INRT-AIR phase II trial, Sher et al. (15) evaluated an aggressive de-escalation strategy in a mixed HNSCC population. HPV status was determined solely by p16 immunohistochemistry; the study did not report outcomes separately for HPV-negative patients. Key prognostic factors, such as tumor site, stage, and smoking history, were captured at baseline, reflecting a clinically heterogeneous and generally high-risk cohort. The intervention consisted of complete omission of ENI, using an AI-assisted and radiologic model to treat only involved or suspicious lymph nodes. Gross disease received standard curative doses. Tumor-related outcomes were excellent: the 2-year isolated elective nodal failure rate was 0%, with one out-of-field nodal recurrence occurring only at the time of DM. Toxicity was low, with stable MD Anderson Dysphagia Inventory (MDADI) scores (89.1 at 12 months; 92.6 at 24 months) and only Grade I–II dermatitis and minimal gastrostomy use. By avoiding ENI, the trial achieved substantially lower normal tissue doses, likely contributing to improved patient-reported outcomes. The absence of a control arm remains the main limitation.

De-escalation of advanced locoregional NPC

Long-term data on target volume reduction in NPC was supplied by Xiang et al. (16) after evaluating 212 patients with stage III–IVB disease. According to their randomized trial, pre-induction chemotherapy (IC) delineation was not inferior to delineating the nodal gross tumor volume (GTVn) based on post-IC tumor extent (a reduced volume). The 5-year OS (83.3% vs. 78.2%, P=0.67) and PFS (78.1% vs. 72.0%, P=0.40) rates were similar, and the 5-year LRRFS rates were 93.5% (post-IC) vs. 90.2% (pre-IC) (P=0.63). Notably, the incidence of late toxicities such as hearing loss (P=0.045) and xerostomia (P=0.028) was lower in the post-IC group. Additionally, patients in this group reported reduced symptoms like dry mouth (P=0.004) and improved long-term quality of life, particularly cognitive function (P=0.045). Even with a robust randomized design and a good follow-up period, bias is introduced by a problematic LRRFS calculation method and a lack of blinding for both personnel and outcome assessment. HPV status or tobacco use are not mentioned by the authors.

Risk of bias

Each included study’s risk of bias was evaluated using these instruments: the ROBINS-I for non-randomized studies and the RoB 2 for randomized controlled trials. Table 3 summarizes the risk of bias.

Discussion

To our knowledge, this is the first narrative review to evaluate de-escalation and response-adapted strategies in HPV-negative HNC. When compared to HPV-positive populations, de-escalation trials have demonstrated excellent nodal control even with reduced elective doses.

RT de-escalation has emerged as a key approach in modern oncology, aiming to preserve tumor control while minimizing toxicity. Advances in imaging, radiation delivery, and molecular characterization have enabled more precise patient selection for dose or volume reduction, mitigating acute and late toxicities, particularly in anatomically and functionally critical regions.

Lowering the amount or dosage of ENI is probably associated with fewer swallowing-related side effects, based on biological and dosimetric factors. Smaller elective targets and reduced ENI doses usually result in less radiation exposure to the pharyngeal constrictors, supraglottic larynx, epiglottis, and cervical esophageal inlet. This decrease corresponds with established dose-volume relationships for these structures and is anticipated to lessen mucosal inflammation, edema, and fibrosis, which are major contributors to clinically significant dysphagia, aspiration, and long-term feeding tube reliance. Clinically, ENI de-escalation may result in fewer high-grade swallowing incidents both during and after treatment, such as lower rates of percutaneous endoscopic gastrostomy (PEG) or nasogastric (NG) tube placement during treatment and less frequent use of feeding tubes. De-escalated ENI can enhance both acute and late functional outcomes by reducing mean and partial-volume doses to swallowing-critical structures. It may also improve patient-reported swallowing measures and reduce clinician-graded toxicity.

Sher et al. (15) demonstrated no isolated elective nodal failures at 24 months after 40 Gy ENI in HPV-positive disease, paralleling findings from HPV-negative cohorts and suggesting that lower elective doses may suffice for microscopic disease control. However, the phase II/III NRG-HN005 trial (17) failed to show non-inferiority for reduced doses to the gross tumor volume, emphasizing the need for further phase III validation.

In HPV-negative disease, Rosenberg et al. (11) reported significantly lower rates of dermatitis and mucositis with de-escalated CRT, while Murthy et al. and Deschuymer et al. (12,13) showed reductions in biochemical hypothyroidism and improved salivary recovery with lower ENI doses. Zakeri et al. (14) confirmed that 40 Gy ENI maintained LRC and improved quality of life, and Sher et al. demonstrated minimal toxicity when ENI was completely omitted (15). In NPC, Xiang et al. (16) found fewer late toxicities—particularly xerostomia and hearing loss—with reduced target volumes. Collectively, these data indicate that dose and volume de-escalation can meaningfully lessen morbidity while maintaining efficacy.

This review has limitations, including potential selection and reporting biases, small sample sizes, and significant heterogeneity among included studies. Most trials were phase II with relatively short follow-up, limiting conclusions about long-term safety and durability of tumor control. Extended follow-up from ongoing prospective trials is required to confirm whether reduced toxicity can be achieved without compromising oncologic outcomes.

The included studies comprise heterogeneous populations of HPV-positive, HPV-negative, and unknown-status cases. Given the historically poorer prognosis of HPV-negative tumors, de-escalation in this subgroup should be applied cautiously. While reductions in dose or volume may decrease morbidity, they must be balanced against potential risks to tumor control. Future prospective research should establish clear, evidence-based criteria to safely guide de-escalation, acknowledging that both tumor biology and site-specific factors influence outcomes and toxicity profiles.

Conclusions

Although the available evidence indicates that dose and volume de-escalation may reduce treatment-related morbidity while maintaining acceptable oncologic outcomes, the concept of de-escalation in HPV-negative HNSCC remains at an early stage of clinical development. The studies identified in this review are limited by small sample sizes, heterogeneous patient populations, and the predominance of phase II, single-arm or non-randomized designs. These constraints reduce the certainty with which safety and efficacy can be inferred, since HPV-negative tumor biology are more aggressive and therapeutic margins are narrower. For this reason, while preliminary data are encouraging, the current literature is not sufficiently robust to support definitive changes in standard treatment paradigms. Larger, methodologically rigorous prospective trials, with adequate statistical power, longer follow-up, and stratified reporting for HPV-negative cases, are essential to determine whether de-escalation can be safely and broadly implemented in this population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1656/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1656/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1656/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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