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Introduction Despite intensive investigation, 70 Gy of chemoradiation (CRT) with cisplatin remains the standard for HPV-positive oropharyngeal cancer (OPC). The recent NRG-HN005 trial reported impressive 2-year locoregional control (LRC) and progression-free survival (PFS) rates in the control arm of 100% and 98.1%, respectively, creating an exceptionally high benchmark for future studies, which had been previously designed based on a historical control rate of 85%–90%. 1 Meanwhile, real-world ‘off-trial’ de-escalation has increased and is associated with inferior OS and PFS.2 3 As such, both the American Society for Radiation Oncology (ASTRO) and the American Society of Clinical Oncology (ASCO) have emphasised that phase II data are insufficient to change the standard of care and de-escalation outside clinical trials is not recommended.4 5Historical data from Radiation Therapy Oncology Group (RTOG) trials using older radiotherapy techniques reported a 43% risk of severe late toxicity, including fistula formation, feeding tube dependence and treatment-related mortality.6 With more modern intensity-modulated radiation therapy (IMRT), late grade 3 and 4 toxicities have ranged from 13% and 9%, respectively, with early experiences in RTOG 0022, to 9% and 0%, respectively, in the more recent TROG 12.01.7 8 Most patients experience significant acute toxicities, including fatigue, xerostomia, dysgeusia, dysphagia, dermatitis, mucositis and weight loss, predominantly grade 2 or higher.8For patients with locally advanced HPV-positive OPC, definitive CRT remains the standard of care. This usually consists of 70 Gy of conventionally fractionated radiotherapy, typically delivered 5 days a week over 7 weeks concurrently with cisplatin, a regimen established through multiple randomised trials, demonstrating excellent LRC and overall survival. In the postoperative setting, generally adjuvant radiotherapy to 60–66 Gy, with the addition of cisplatin for high-risk pathologic features such as positive margins or extranodal extension (ENE), remains the accepted standard.Given the excellent oncologic outcomes and long life expectancy of many patients with HPV-positive OPC, attention has increasingly shifted toward reducing treatment-related morbidity while preserving cure. This tension between cure and function has driven sustained interest in treatment deintensification strategies across surgical, radiation and systemic therapy domains.As treatment strategies for HPV-positive OPC continue to evolve, a multidisciplinary lens is crucial for navigating the integration and cross-disciplinary impacts of deintensification across surgical, medical and radiation oncology disciplines. This review examines the emerging evidence from prospective trials, evaluates novel multimodality approaches and discusses the shifting landscape of clinical trials. By bridging data across specialties, we aim to provide clinicians with a comprehensive perspective on the present state of the field and future directions for optimising oncologic outcomes and quality of life in patients with low-risk and intermediate-risk HPV-associated OPC. Across these approaches, careful assessment of functional outcomes and patient-reported outcome measures (PROMs) has become central to evaluating the true impact of de-intensification.Transoral surgical approaches and risk-adapted treatment Over the last decade, de-escalation has spanned systemic therapy alteration or omission, 9–12 incorporation of transoral surgery (TOS) approaches, including transoral robotic surgery (TORS)13–18 and deintensification of radiotherapy dose or volumes.19–21 Increasingly, clinical trials have assessed treatment-related outcomes from the perspective of the patient using validated PROMs.22 Although many patient-reported instruments and outcomes are available, swallowing-related quality of life (swQOL) has emerged as the focal point for comparative clinical trials. Global QoL measures have already been proven to be poor candidates for assessing the impact of deintensification given the typical U-shaped trajectory and recovery to baseline scores 6–12 months after completion of treatment, presumably due to post-treatment adaptation of how patients assess their QoL (response shift).23 Of the swQOL instruments available, the MD Anderson Dysphagia Inventory (MDADI) has emerged as one of the most widely used PROM tools in HPV OPC deintensification trials although its sensitivity to mild or early changes remains in question.10 11 16 24 25Historically, radical resection of oropharyngeal primaries required invasive open surgery involving mandibulotomy and extensive soft tissue manipulation, leading to significant morbidity and mortality compared with definitive radiotherapy.26 Following FDA approval of TORS in 2009, significant interest arose regarding whether upfront surgical approaches could improve toxicity and quality of life compared with primary (chemo)radiation. Several studies have shown that TORS is associated with decreased operative time, hospital stay, postsurgical quality of life and improved survival compared with open approaches.27 28 Although there was limited evidence from randomised trials supporting an improvement in survival or toxicity compared with primary (chemo)radiotherapy, use of TORS grew rapidly.29TOS approaches, including TORS and transoral laser microscopy (TLM), have emerged as an alternative treatment platform for selected patients with OPC. Rather than representing deintensification per se, TOS enables a risk-adapted postoperative strategy, with the potential to omit chemotherapy, and in some cases, reduce adjuvant radiation dose and/or volumes based on pathologic findings. This programme, which essentially substitutes surgery for other interventions, has been evaluated both as a comparator to definitive CRT and as a foundation for subsequent deintensification strategies.Trials comparing upfront TORS against primary (chemo)radiation The Oropharynx: Radiotherapy Versus Trans-Oral Robotic Surgery (ORATOR) randomised phase II trial compared TORS plus risk-adapted adjuvant therapy with definitive CRT using MDADI as its single primary endpoint, demonstrating comparable oncologic outcomes but different toxicity profiles for HPV-positive or HPV-negative OPC (American Joint Committee on Cancer (AJCC) 7th T1-T2, N0-N2, nodes ≤4 cm). 25 Adjuvant radiation (60 Gy) was given for pT3–4, margins <2 mm, nodal involvement or lymphovascular invasion (LVI) and CRT (64 Gy) for positive margins or ENE. The primary endpoint was the total MDADI score at 12 months. Only 29% avoided adjuvant therapy, with 53% requiring radiotherapy and 18% requiring chemoradiotherapy. MDADI scores statistically favoured primary radiotherapy at 12 months for the total and composite scores, and the global and emotional subscales; however scores did not exceed the predefined minimal clinically important difference. Longitudinal modelling of the subscales and total scores up to 3 years after treatment, using linear mixed models, favoured primary radiotherapy for the total and composite scores, and the physical and emotional subscales. Base-of-tongue (but not tonsil) cancers had superior MDADI total scores with upfront CRT at 3 years. Notably, dry mouth was worse with CRT (p=0.032), whereas pain was worse after TORS (p=0.002). Grade 2–5 adverse events were similar between the arms (91% surgery vs 97% radiotherapy, p=0.61); however, CRT patients experienced higher neutropenia and hearing loss, while TORS patients had increased dysphagia and pain. Five-year OS (84% RT vs 85.1% TORS) and PFS (84% RT vs 82.2% TORS) rates were comparable.30 These rates can be interpreted as representative of the general OPC population, as the eligibility was not restricted to HPV-positive patients only.The subsequent ORATOR2 trial randomised only HPV-positive OPC (AJCC 8th T1–T2, N0–N2) patients to either primary de-escalated radiotherapy (60 Gy±weekly cisplatin 40 mg/m² for node-positive patients) or TOS with adjuvant radiotherapy (50 Gy, or 60 Gy for positive margins or ENE), reserving trimodality for R2 resections.13 31 The trial was terminated early due to safety concerns following two deaths in the surgery arm (oropharyngeal haemorrhage and cervical spine osteomyelitis) and additional PFS events, including a myocardial infarction-related death and local recurrence. Two-year PFS was inferior with surgery (83.5% vs 100%, p=0.04) and OS similarly favoured radiotherapy (90% surgery vs 100% RT, p=0.04). While the surgery arm results have been highly controversial, it can be stated that the RT arm confirms the outstanding outcomes demonstrated in NRG-HN005. MDADI scores were comparable overall at 2 years, except in the physical domain, which favoured primary radiotherapy (90.2 vs 78.6, p=0.008). The ORATOR studies underscore the need for caution with surgical or other deintensification and reinforce the need for robust comparative randomised data. Ongoing European trials continue to evaluate TORS against primary radiotherapy (table 1).Table 1Comparative trials between transoral surgery with risk-adaptive adjuvant therapy and primary radiotherapy in OPCStudyPhase and designPopulationSurgery armRT armPrimary endpointKey outcomesORATOR14 25 30Randomised phase II (open-label, n=68)AJCC 7th T1-2 N0-2TORS+ND ± adjuvant RT/CRTCRT 70 GyQuality of life 1-year post treatmentRT arm had superior MDADI at 12 mo; 5-year OS: 84% (RT) vs 85.1% (TORS); AE rates similarORATOR213 31Randomised phase II (open-label, n=61)AJCC 8th T1-2 N0-2TORS+ND ± adjuvant RT/CRTDe-intensified RT (60 Gy+weekly cisplatin)2-year OSTrial stopped early due to toxicity in TORS arm; 2-year OS 100% (RT) vs 90% (TORS)TopROC97Prospective, two-arm, open-label, multicentre randomised controlled comparative effectiveness study, registered as phase IV (n=280)T1-3 N0-2c amenable to resectionTOS+ND ± adjuvant RT/CRTCRT 70–72 Gy SIBTime to local or locoregional failure or death from any causeOngoingQoLATI (NCT04124198)Randomised phase III (n=112)AJCC 8th T1-2, N0-1TORS+NDHF (76 Gy/56#), Acc RT 66 Gy/33#) + cisplatin + nimorazole (66–76 Gy)MDADI scores at 3 and 12 months after treatmentOngoingBest of (NCT02984410)98Randomised phase III (n=112)T1–T2 N0–N1 OPC and supraglottic, T1 hypopharynxTOS+ND± adjuvant RT/CRTRT 66–70 Gy over 6 weeksMDADI at 4.5 and 12 months after randomisationOngoingAE, adverse event; AJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy; MDADI, MD Anderson Dysphagia Inventory; ND, neck dissection; OPC, oropharyngeal cancer; RT, radiotherapy; SIB, Simultaneous Integrated Boost; TORS, transoral robotic surgery.Studies evaluating TORS with deintensified adjuvant therapy ECOG-ACRIN 3311, a randomised phase II trial primarily designed to assess the feasibility of TOS with risk adapted adjuvant therapy, enrolled patients with HPV-positive OPC (AJCC 7th stage III–IV) suitable for TOS. Patients were assigned to one of four adjuvant arms based on their pathology. Low-risk patients (pT1–2, N0–1, ≥3 mm margins, no ENE, PNI or LVI) received no further treatment (arm A). High-risk patients (positive margins, >1 mm ENE, or ≥5 involved lymph nodes) received trimodality therapy (66 Gy with weekly cisplatin; arm D). Intermediate-risk patients (margins <3 mm, PNI, LVI, N2a–N2b, or ≤1 mm ENE) were randomised to standard-dose (60 Gy, Arm B) or de-escalated (50 Gy, arm C) adjuvant radiation therapy. Updated results with longer follow-up showed encouraging 54-month PFS rates of 93.2% (low-risk), 90.2% (60 Gy), 94.9% (50 Gy) and 85.5% (trimodality). 32 33 Notably, among the four recurrences in the observation arm, three occurred beyond 40 months, highlighting the importance of long-term follow-up even in low-risk cohorts. Only 10.6% of patients on trial avoided all adjuvant therapy, whereas 31.5% received trimodality. Dose reduction did not clearly improve global or swQOL; MDADI 2-year composites were 92.8, 82.3, 80.7 and 75.6, respectively. Postsurgical questionnaire compliance was low, especially in arm A (31% at 1–2 years). Consequently, the NCCN34 and ASTRO5 guidances recommend awaiting PATHOS phase III results35 testing similar comparisons.Trimodality therapy is generally discouraged, with lower long-term MDADI scores compared with single-modality or bimodality approaches (table 2).24 Real-world practice shows almost 59% of patients with T1-T2, N1-N2b undergoing surgery receive trimodality therapy, highlighting the need for careful patient selection.36 The MC1273 (primary endpoint 2-year LRC) and the subsequent MC1675 (primary endpoint grade ≥3 long-term toxicity) trials tested marked postoperative radiation dose reduction following TORS, using 30–36 Gy twice daily adjuvant RT with docetaxel in select patients. These studies reported excellent LRC and PFS overall and low feeding-tube dependence, but a cautionary note was that patients had notably worse 2-year PFS if they had ENE (79% in MC1273) or pN2 (43·8% in MC1675). Importantly, these results suggest that pathologic risk stratification may permit meaningful reductions in postoperative radiation dose without compromising oncologic outcomes; however, applicability remains limited to select patients, and those with ENE or pN2 may not be suited for de-escalation.17 18 The ongoing phase II ADAPT trial (NCT03875716) seeks to test omission of chemotherapy in pT1-T4, N0-N2 disease with positive margins or >1 mm ENE, in addition to RT reduction to 46 Gy or RT omission in lower risk patients guided by postoperative circulating tumour HPV DNA. Meanwhile, the PATHOS phase II/III trial is treating T1-T3 N0-N2b patients after TOS+ND to 3 groups based on pathology. Group C with positive margins or ENE will be randomised to 60 Gy RT or CRT; group B with T3, N2a-N2b, PNI, LVI or close margins will be randomised to 60 vs 50 Gy RT; group A with no adverse risk factors on pathology will receive no adjuvant treatment. A preplanned analysis in the PATHOS trial favoured TLM over TORS in nasogastric tube insertion rates, mean MDADI domains and H&N35 swallowing item at 4 weeks after surgery. Longer term functional outcomes are awaited.37Table 2Composite MDADI scores and compliance from contemporary HPV-associated OPC studiesNumberBaseline (mean, SD)Baseline PRO compliance (n, %)12 months (mean, SD)12-month PRO compliance (n, %)24 months (mean, SD)24-month PRO compliance (n, %)ECOG 331116 32 Arm A (TORS alone)3889.135/38 (92%)94.711/38 (29%)92.811/38 (29%) Arm B (50 Gy)10090.291/100 (91%)79.171/100 (71%)82.342/100 (42%) Arm C (60 Gy)10887.499/108 (92%)78.864/108 (59%)80.760/108 (56%) Arm D (CRT)11388.2102/113 (90%)73.370/102 (69%)75.654/102 (53%)NRG-HN00211 CRT arm15790.8 (10.0)132/157 (84%)85.3 (15.4)121/157 (77%)–– RT arm14987.9 (12.8)134/149 (90%)81.8 (14.4)106/149 (71%)––ORATOR14 25 30 CRT/RT arm3491.4 (14.5)NR86.7 (11.4)27/34 (79%)86.0 (13.5)NR TORS arm3488.2 (12.8)NR80.2 (13.1)27/34 (79%)84.4 (12.6)NRORATOR213 31 CRT/RT arm30NRNR85.7 (15.6)NR–– TORS arm31NRNR84.5 (14.5)NR––De-ESCALaTE HPV10 Cisplatin arm16281.1 (19.8)155/162 (95.7%)NR129/162 (79.6%) Cetuximab arm16583.9 (16.3)153/165 (92.7%)NR129/165 (78.2%)NECTORS99 Single arm: induction chemo+TORS6777.6 (20.6)67/67 (100%)83.0 (17.3)53/67 (79.1%)86.6 (11.7)38/67 (56.7%)CRT, chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; HPV, human papillomavirus; MDADI, MD Anderson Dysphagia Inventory; NR, Not reported; OPC, oropharyngeal cancer; PRO, patient-reported outcome; RT, radiotherapy; TORS, transoral robotic surgery.Omitting adjuvant treatment to the primary site Decoupling the treatment of primary and nodal sites offers an intriguing option, explored in several studies ( online supplemental table 1).38–40 The FIND trial omitted radiation to the pharynx if primary was excised with clear (≥ 3 mm) or if no primary was found post-TORS in patients presenting with p16-positive unknown primary cancers. Pharynx radiation was avoided in 50% of patients, with 2-year LRC and disease-free survival rates of 100% and 95%, respectively. Similarly, the Alternative Volumes of Oropharyngeal Irradiation for De-intensification trial omitted primary site radiation in pT1-pT2 N1-N3 patients treated with TORS+ND if margins ≥2 mm, no LVI and no PNI and received only neck RT.39 The 2-year local recurrence-free survival was 97.9%, with one patient developing a regional neck recurrence and no long-term feeding tube dependence in any patient. It should be noted that the mean RT dose to the primary site was 36.9 Gy and this could have contributed to oncologic control. Typical criteria used to guide primary omission in trial settings have included pT1-2 tumours, negative margins (≥2–3 mm), no LVI or PNI, and ≤5 positive lymph nodes (without bulky nodal disease or ENE), and tumour >1 cm from midline.SP110.1136/bmjonc-2025-000758.supp1Supplementary dataCaution is warranted with postoperative plasma circulating HPV tumour DNA (ctHPVDNA)-guided omission strategies. A prospective pilot study enrolling 12 patients after surgery reported early locoregional recurrences that were not predicted by postoperative ctHPVDNA clearance, leading to early trial closure and underscoring the current sensitivity and accuracy questions in relying on molecular surveillance alone to omit adjuvant radiotherapy.41ASCO multidisciplinary guidelines for TOS in HPV-positive OPC ASCO has recommended that when TORS is used, it should be done in experienced multidisciplinary teams to provide a risk-adapted approach for T1-T2 OPC with a high probability of R0 resection and low probability of ENE based on preoperative radiological assessment. 42 Lateralised tumours with low ipsilateral nodal burden and clinically negative contralateral neck are considered optimal candidates for TORS, and a margin of 1–3 mm may be considered adequate. Adjuvant RT should be offered for close margins, 2–4 positive nodes or ≤1 mm ENE; concurrent platinum-based chemotherapy should be added for positive margins, 5 or more nodes or >1 mm ENE. It should be noted that various guidelines’ recommendations differ regarding management of ENE, with the ASTRO clinical practice guideline recommending postoperative CRT for any ENE.5 These relatively sparse guiding criteria are primarily based on the high-quality dataset available from ECOG 3311 but could evolve further with the publication of PATHOS or other trials in the future.Deintensification with primary (chemo)radiation While modern IMRT has reduced morbidity, significant acute and chronic side effects from standard 70 Gy with cisplatin persist. Various strategies for deintensification of definitive chemoradiation have emerged, including definitive radiation dose reduction, elective dose and volume reduction, proton therapy utilization, and cisplatin omission or modification. Each strategy targets specific toxicities: lowering definitive RT dose reduces mucosal injury and dysphagia; elective dose and volume reductions may mitigate severe lymphopenia associated with poorer survival 43 44; proton radiotherapy can offer improved normal tissue sparing; and cisplatin omission or alteration would increase treatment tolerability.Primary chemo(radiation) dose de-escalation Several phase II studies evaluated 60 Gy to gross disease in combination with weekly cisplatin. The UNC/UF trial offered a lower dose of cisplatin weekly (30 mg/m²) with 60 Gy IMRT for select T3 or N2 patients, yielding an 86% 2-year PFS. 45 46 The LCCC1612 study evaluating 60 Gy IMRT or proton therapy with weekly cisplatin (30 mg/m²) reported favourable 1-year PFS (92%–93%).47 NRG-HN002 reported a 90.5% 2-year PFS rate with 60 Gy RT (five fractions/week) with weekly (40 mg/ m²) cisplatin in T1–T3, N0–N2 patients with ≤10 pack year smoking history.11 Despite promising results from these trials, the interim futility analysis of NRG-HN005 was a sobering reminder of the validity of defining the standard of care from phase II studies. This was a randomised phase II/III non-inferiority trial of p16-positive OPC (T1-2N1 or T3N0-N1), closed early after interim analysis failed to demonstrate non-inferiority for either of the reduced radiation dose experimental arms.1 The trial randomised patients to 70 Gy of accelerated IMRT over 6 weeks+100 mg/m2 cisplatin every 3 weeks (two cycles) versus 60 Gy IMRT over 6 weeks+100 mg/m2 cisplatin every 3 weeks versus 60 Gy accelerated IMRT over 5 weeks with 6 cycles of nivolumab. The two experimental arms approximately reproduced what had been seen in earlier phase 2 trials, but the control arm was successful in an unprecedented manner in control over gross disease, resulting in an LRC rate of 100% at 2 years unattained by either experimental de-escalated approach, though longer-term follow-up is needed in this favourable population. The 2-year PFS rates were 98.1% vs 88.6% vs 90.3% respectively, and 2-year OS results were 99% versus 98% versus 96.1% respectively. Ultimately, despite over a decade of clinical trial research, 70 Gy with concurrent cisplatin remains the standard of care in the setting of definitive chemoradiation. While the control arm of NRG-HN005 has been noted to have cisplatin every 3 weeks as opposed to weekly and used a mildly accelerated radiation therapy schedule, the extremely similar results from the ORATOR2 trial indicate that these interventions probably did not alter the fundamental conclusions.Response-adapted (chemo)radiation therapy following induction therapy Induction-based response-adapted strategies aim to identify biologically favourable tumours early in the treatment course, allowing subsequent deintensification in responders while preserving standard treatment for higher-risk disease. Proposed advantages to induction include signalling early tumour responsiveness, treating occult micrometastases, providing cytoreduction to aid a negative-margin resection, and selecting patients suitable for reduced radiation dose or volume. However, these approaches add systemic toxicity, treatment complexity and duration, and risk overtreatment in patients who have excellent outcomes with standard therapy. The Quarterback single-institution phase II trials 48 demonstrated the feasibility of induction chemotherapy by testing three cycles of induction docetaxel, cisplatin, and 5-fluorouracil (5-FU), with sequential reduction of 5-FU doses across the three trials, followed by 56 Gy RT with weekly carboplatin in HPV-positive OPC patients qualifying due to radiographic ECE, T4, ≥N2 c disease or non-HPV16 subtype. The 3-year LRC, PFS and OS were 88%, 86% and 93% respectively. In contrast, ECOG-ACRIN E1308, a multicentre cooperative group phase II study, provided broader insight into response-adapted de-escalation. Patients with HPV16 and/or p16 positive OPC stage III–IV were treated with three cycles of induction cisplatin, paclitaxel and cetuximab, and 54 Gy RT with cetuximab if they had a complete clinical response at the primary site, otherwise receiving a standard dose of 69.3 Gy. The 2-year PFS and OS rates were 80% and 94%, respectively, with patterns of failure showing inferior outcomes in patients with significant smoking history or bulky disease. Similarly, Chen et al reported a phase II trial 44 patients with HPV-positive OPC treated with induction carboplatin/paclitaxel followed by response-adapted reduced-dose chemoradiotherapy (54–60 Gy with weekly paclitaxel), achieving a 2-year PFS 92%, with three locoregional recurrences and one distant metastasis.49OPTIMA II was a phase II trial evaluating response-adapted de-escalation using deep response (≥50% tumor shrinkage) rate following induction therapy as its primary endpoint, for patients with HPV-positive OPC (AJCC 7th T3–T4 and/or N2–N3) who were initially treated with induction nivolumab, nab-paclitaxel and carboplatin and then had tailored radiation volumes.50 High risk was defined as T4, N2c–N3, >20 pack-year smoking, or non-HPV16 subtype. Radiation volumes were based on the preinduction GTV, with CTV1 equal to GTV+1 cm, and CTV2 including CTV1 plus the next echelon of uninvolved but at-risk lymph nodes as outlined in the protocol. PTVs were 5 mm expansions; in the single-modality de-escalation arm, there was no PTV2. Patients were stratified by risk and induction response. Group A (low risk, ≥50% shrinkage) received TORS or 50 Gy RT to PTV1. Group B (low-risk with 30%–50% shrinkage or high-risk with ≥50%) received intermediate-dose CRT (50 Gy with cisplatin to PTV1 with reduced or omitted PTV2 or 45 Gy two times per day with paclitaxel, 5-FU, hydroxyurea). Group C (low-risk <30% or high risk <50%) received standard-dose CRT 70–75 Gy to PTV1 and 50 Gy to PTV2. Of 73 patients, 97% responded to induction, with 71% achieving >50% shrinkage. Nine of 28 in group A had TORS. Two-year PFS and OS were 90% and 91.4%, with OS by group at 96.4% (A), 91.0% (B) and 87.5% (C).Elective nodal dose and volume de-escalation While the reduction of definitive RT dose has proved challenging, mounting evidence points to some success in lowering doses to elective nodal irradiation (ENI) regions, with potential implications for reduction in toxicity, immunosuppression and lymphopenia ( table 3).51 A phase II trial from Montreal showed 100% 5-year LRC and OS in lateralised p16-positive OPC who were given 43.2 Gy in 24 fractions of ENI.20 Deschuymer et al randomised patients to 50 Gy versus 40 Gy (EQD2) of ENI, showing no significant differences in 5-year regional recurrences (RR) (7.5% vs 14.0%, p=0.1) or overall survival (49.6% vs 56.5%, p=0.56), with most failures arising within the high-dose volume rather than in the elective region.52 The phase II INFIELD trial treated 72 patients with OPC (n=51) and larynx cancer (except T1-2 N0) with only involved and adjacent nodal stations to 40 Gy, with boosts to involved/suspicious nodes to 70/64 Gy and concurrent chemotherapy in 90%.53 At a median follow-up of 24.7 months, there were no solitary elective nodal recurrences, 2-year OS/PFS rates were 89%/79% overall, and PROMs were stable or improved by 12 months except for saliva and taste. More recently, the phase III randomised UPGRADE-RT trial (n=295) compared reduced-dose ENI (43 Gy) versus standard dose (50 Gy) in cT2-4N0-2M0 HNC and found non-inferior control: 2-year elective nodal recurrence rates were 4.9% and 4.3%, respectively, with most of these recurrences occurring synchronously with recurrence within gross disease. Exploratory analyses showed less acute grade ≥3 dysphagia (10.7% vs 19.2%, p=0.046) and better xerostomia-related quality of life (46% vs 60%, p=0.025) in the reduced-dose arm.54Table 3Studies evaluating reduced elective neck doses/volumes with corresponding outcomesStudy namePhase and designPatients, nPopulationENI approachPrimary endpointKey outcomesBahig et al20Single arm phase II29Lateralised p16+OPC43.2 Gy in 24 fractions2-year LRC100% 5-year LRC and OSCCTG HN-10 Evader21Single arm phase II99 (eligible)T1-3 N0-1 HPV+OPCReduced volume: ipsilateral VII, II-Va; contralateral II; omitted in lateralised tonsil2-year event-free survival91.8% 2-year EFS, 94.7% OS; 1 out-of-field regional eventINRT-AIR58Single arm phase II67Head and neck SCCEliminated ENI; treated suspicious nodes to 66.5 GySolitary elective volume recurrence0% 2-year solitary elective nodal recurrence; stable MDADITsai et al60Retrospective276HPV+OPC, including cT3-T4 and cN2-N3ENI 30 Gy, omitted levels IB and VLocoregional control97% 2-year LRC, 95.1% OS; 8 LRR, 7 in 70 Gy regionINFIELD53Single arm phase II72All stages OPC and larynx cancer except T1-2 N040 Gy to primary and nodal regions, second course boost gross disease only to 70 Gy (64 Gy if suspicious)Solitary elective volume recurrence2-year OS 89%, PFS 79%, 7 nodal failures, 5 in PTV70, 1 with PTV70 and elective failureENID100Single arm phase II12HPV-related OPC T1-3 N1-2 M0, excluding active smokers40 Gy to the known disease and elective lymph nodes, and a subsequent boost was delivered to the PET defined gross disease for an additional 30 Gy in 15 fractionsQuality of life and feeding tube ratesInitial analysis of 12 patients; 100% 1-year RFS, 0 Gr2+toxicities at 3 monthsDeschuymer et al52Randomised phase III200Non-metastatic HNSCC (oral cavity, oropharynx, hypopharynx, larynx, CUP), all stages with bilateral ENI, age>18, KPS≥70%Bilateral ENI: 40 Gy (experimental) vs 50 Gy (standard)Rate of dysphagia at 6 months of follow-up5-year OS: 56.5% vs 49.6%, p=0.56; RR: 14.0% vs 7.5%, p=0.10; RR in PTVelect: 2 in each armUPGRADE-RT54Randomised phase III300 randomised, 295 analysedcT2-4 N0-2 M0 SCC OPC (51% vs 64% HPV-positive), larynx, hypopharynx treated with chemoRTENI 50 Gy vs 43 Gy, intermediate-risk nodes boosted to 60 Gy in dose reduction groupNormalcy of diet at 1 year2-year elective nodal recurrence 4.9% vs 4.3%; less acute grade≥3 dysphagia, improved xerostomia QoLSAVER101Single arm phase II52p16+OPC without contralateral nodal involvement treated with primary proton or photon-based (chemo)radiation or adjuvant (chemo)radiation following transoral robotic surgery (TORS)Reduced elective nodal irradiation to the contralateral neck, with selective coverage limited to levels II–IIIElective out-of-field contralateral nodal failureNo contralateral failures at mean f/u of 15 months. Ongoing.SELECT57Randomised phase III510 (target accrual)Lateralised OPC candidates for bilateral neck RTLymphatic mapping-guided contralateral neck management (omission or inclusion) vs bilateral neck RTDisease-free survivalOngoing CUP, carcinoma of unknown primary; EFS, event-free survival; ENI, elective nodal irradiation; HNSCC, head and neck SCC; HPV, human papillomavirus; KPS, Karnofsky performance score; LRC, locoregional control; LRR, locoregional recurrence; OPC, oropharyngeal cancer; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; QoL, quality of life; RFS, recurrence-free survival; RT, radiotherapy; SCC, squamous cell carcinoma.Omission of neck levels represents another avenue to reduce toxicity. For example, omitting level 1B decreases the oral cavity dose and xerostomia,55 while omitting level VII decreases the mucosal, constrictor and parotid doses; both practices are endorsed by the DAHANCA guidelines unless there is oral cavity and posterior pharyngeal wall involvement, respectively.56 The CCTG HN-10 Elective Volume Adjusted De-Escalation Radiotherapy (EVADER) trial enrolled T1-3 N0-1 HPV-positive OPC to reduced volume ENI with ipsilateral levels VII, II-Va with lower border ≥2 cm below inferior extent of high-dose nodal 70 Gy volume, and contralateral level II. In lateralised tonsil cases, contralateral ENI was omitted. With 99 eligible patients, the 2-year event-free survival and OS were 91.8% and 94.7%, respectively, and there was 1 out-of-field regional control event.21 The ongoing Selective Avoidance of Nodal VolumEs at Minimal Risk (SAVER) trial (NCT04609280) similarly is investigating reduced contralateral ENI in HPV-positive OPC, while SPECT-CT Guided ELEctive Contralateral Neck Treatment (SELECT) (NCT05451004) is an ongoing international phase III non-inferiority trial (n=510) comparing lymphatic-mapping-guided contralateral neck management with standard bilateral neck RT in lateralised OPC.57Novel strategies are also under investigation. The Involved Nodal Radiotherapy using AI-Based Radiomics (INRT-AIR) trial took a different approach and eliminated ENI entirely, with an artificial intelligence-assisted classification model determining whether to treat suspicious lymph nodes to 66.5 Gy without ENI. The 2-year risk of solitary elective nodal recurrence was 0% with no significant decline in composite MDADI scores after treatment at 2 years.58 At Memorial Sloan Kettering Cancer Center, a cohort of 276 HPV-positive OPC patients (including 31.5% AJCC 8th cT3-T4 and 23.5% cN2-N3) treated with ENI 30 Gy, omission of levels IB/V, and 0 mm CTV70 margin achieved 2-year LRC and OS of 97% and 95.1%. There were eight locoregional recurrence events, seven of them within the high dose 70 Gy regions and one in the elective region, which in retrospect should have been considered gross disease and treated to 70 Gy.59,60Intensity-modulated proton therapy Intensity-modulated proton therapy (IMPT) takes advantage of the unique properties of proton beams and enables highly conformal dose distributions with minimal exit dose beyond the target. This characteristic reduces normal tissue radiation exposure, which could be particularly beneficial in head and neck cancers given the proximity to critical structures. A recent meta-analysis reported improved survival with IMPT (HR for 2-year OS=0.44, p<0.01) and reduced side effects such as dysphagia, dysgeusia, mucositis, fatigue and weight loss. 61 The recently published phase III randomised trial comparing IMRT with IMPT in USA centres suggested IMPT may be associated with lower gastrostomy tube dependence rates and posited superior OS emerging at several years of follow-up.62 In contrast, results from the UK-based TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer randomised trial provide an important counterpoint. In this rigorously controlled trial that only involved two national proton centres with support for patients’ lodging and travel to them, contemporary IMPT and locally administered IMRT achieved similar OS rates and similarly low rates of long-term feeding tube dependence and comparable PROMs, including MDADI scores at 1 year, despite favourable dosimetric sparing with protons.63 64 These divergent findings between two sets of randomised data from different countries remain incompletely understood and have prompted substantial discussion within the field. Potential issues to consider include ongoing advances in IMRT delivery, different endpoint selection, and timing of toxicity assessments and patient eligibility and dropout, but these remain speculative, and no single explanation can reconcile the results. A comprehensive analysis of these trials is beyond the scope of this review, and the reader is referred to continuing dedicated analyses.65 66 Other randomised trials of proton therapy are in progress. Longer follow-up and additional data will be important to define patient subsets most likely to benefit from IMPT.Cisplatin omission Multiple randomised phase III trials have demonstrated that substitution of cisplatin with cetuximab in HPV-associated OPC results in inferior LRC and overall survival, without meaningful reduction in treatment-related toxicity. Cetuximab substitution demonstrated inferior survival without significant toxicity reduction compared with cisplatin, 8–10 67 while omission of chemotherapy in the 60 Gy accelerated RT arm in NRG-HN002 failed to meet the criteria for PFS acceptability.11 Radiation with cetuximab should not be considered a deintensification strategy, and cisplatin remains the standard concurrent systemic agent when patients are eligible. Importantly, these results do not imply that cetuximab has no role in clinical practice. For patients who are cisplatin-ineligible, cetuximab remains an accepted alternative, although with consideration of its inferior oncologic efficacy in an HPV-positive population more free of competing risks. In such cases, treatment decisions should prioritise patient safety with emphasis on the potential for trade-offs in disease control.With no immediate replacement for cisplatin on the horizon, there is interest in optimising its schedule and dose. A meta-analysis comparing high-dose 100 mg/m2 cisplatin every 3 weeks to weekly low-dose 40 mg/m2 showed no difference, but this should be interpreted with caution.68 Several trials have used weekly cisplatin with 60–70 Gy RT with favourable results (online supplemental table 2).8 11 31 45 46 67 69 The ongoing phase III NRG-HN009 (NCT05050162), which includes HPV-positive and HPV-negative cohorts, compared these two cisplatin schedules using a non-inferiority design supplemented by PROM data. In results reported only in abstract form at the time of this publication, this team reported that the phase III study would not proceed in HPV-positive patients due to failure to establish lower toxicity from weekly cisplatin in phase II. The preliminary oncologic outcomes reported in this abstract were similar between arms.Integrating biomarkers for personalised treatment selection A large body of evidence supports HPV-positive and HPV-negative OPC as biologically distinct entities with different aetiologies, genetic profiles, 70 presenting symptoms, imaging characteristics,71 treatment responsiveness, and prognosis.72 However, as recent trials have shown, not all HPV-positive OPC can be safely de-escalated.1 11 Investigators are keen to explore novel biomarkers incorporating clinical, radiological, and biological information that may aid in risk-stratification and improved patient selection for deintensification, with some incorporating intratreatment information as biologically-based adaptive strategies.73–75 Early evidence supports the promise of several biomarker categories: ctHPVDNA, functional and hypoxia imaging, tumour microenvironment and immune profiling (figure 1).Figure 1De-escalation paradigms in HPV-associated oropharyngeal cancer, stratified by primary surgical and definitive chemoradiotherapy approaches. ctHPVDNA, circulating human papillomavirus tumour DNA; CRT, chemoradiotherapy; ENI, elective nodal irradiation; FDG PET, fluorodeoxyglucose positron emission tomography; FMISO PET, 18F-fluoromisonidazole positron emission tomography; RT, radiotherapy; UWO3, University of Western Ontario 3.Early assays of plasma ctHPVDNA have demonstrated strong prognostic value when assessed during treatment: in NRG-HN002, undetectable plasma tumour tissue modified viral HPV DNA (TTMV) at week 4 of RT had negative predictive value (NPV) of 95.0% for 2-year locoregional failure and 93.3% for 2-year PFS,76 while next-generation sequencing-based assays yielded NPVs of 96.6% for LRC and 95.4% for PFS at the same timepoint.77 Prospective longitudinal monitoring studies have confirmed increasing predictive accuracy over time, with an NPV of 100% and PPV of 94% after two consecutive positive TTMV tests months apart.78 While post-treatment ctHPVDNA surveillance has shown high sensitivity and specificity for recurrence detection, its primary value at this time remains in monitoring rather than treatment selection. Accordingly, ongoing de-escalation trials have increasingly focused on integrating baseline and on-treatment ctHPVDNA kinetics with clinical and imaging response to guide real-time treatment adaptation. These include varying strategies to omit adjuvant therapy, reduce RT dose, or dynamically adapt to individual patients based on their mid-treatment clearance (table 4). While these studies are ongoing, the early results highlight both the promise and caution of ctHPVDNA-guided de-escalation. The phase II two-cohort Risk-adapted Adaptive therapy in HPV-positive Cancer using circulating Tumor DNA profiling (ReACT) 1.0 trial screened 143 HPV-positive OPC patients and enrolled 102 qualifying with baseline TTMV levels of >200 copies/mL; these were classed as low risk or intermediate (T4 disease or >10 pack-year smokers) risk. All low-risk and those intermediate-risk patients achieving undetectability by week 4 of RT received deintensified CRT (54–66 Gy with reduced dose platinum or RT alone). Of 89 (60 low-risk and 29 reclassified) patients meeting criteria for de-escalation, the 2-year PFS estimate was 93% (95% CI 85 to 100) and OS was 100%. These results were obtained from a single centre using individualised selection, assessment and treatment assignment, and despite its prognostic significance, the robustness of TTMV to predict ultimate PFS remains unclear.79Table 4Overview of select ongoing ctDNA-guided de-escalation studiesStudyDesignTarget accrual, nPopulationDe-intensification strategyPrimary endpointStatusReACT (NCT04900623)Phase II145HPV+OPCRisk- and ctHPVDNA-adapted RT dose (5–6 weeks vs 7–8 weeks); optional concurrent chemo2-year PFSOngoingDART 2.0 (NCT05541016)Phase II455HPV+OPCFour arms based on ctHPVDNA and clinical/pathologic risk: observation, DART (30–36 Gy twice daily) with concurrent docetaxel, standard CRT (60–70 Gy), or adaptive CRT (dose based on week 4 ctHPVDNA)PFS up to 5 years across cohortsOngoingSIRS 2.0 (NCT05419089)102Phase II83HPV+OPSCC, AJCC 7th T1–T2N0–2b, postoperative ctHPVDNA undetectable, ≤20 pack-yearsLow to intermediate risk groups: TORS only, no adjuvant therapyHigh risk group: 46 Gy of adjuvant RT and weekly cisplatin2-year local and/or regional disease recurrenceOngoingNCT05307939103Prospective, 2-arm30Postoperative HPV+OPC with risk factors and undetectable ctHPVDNAArm A: Active surveillance with delayed RT on ctDNA detectionArm B: De-escalated adjuvant CRT (30 Gy+chemo)Pathologically confirmed PFS at 2 yearsCohort A closed early due to recurrence; cohort B ongoingNCT0457210075Prospective50Locoregionally advanced HPV16/18 OPCRisk- and response-adapted de-escalation: 50 Gy RT±cisplatin or TORS for responders; 70 Gy CRT for poor respondersCorrelation of quantitative ctHPVDNA with radiographic responseOngoingAJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy; ctDNA, circulating tumor DNA; ctHPVDNA, circulating human papillomavirus tumour DNA; HPV, human papillomavirus; OPC, oropharyngeal cancer; OPSCC, Oropharyngeal squamous cell carcinoma; PFS, progression-free survival; RT, radiotherapy; TORS, transoral robotic surgery.Among functional imaging approaches, 18F-Fluoromisonidazole positron emission tomography (FMISO PET) has the most mature data. In the 30 Reduction in Radiation for Oropharyngeal Cancer (30 ROC) trial pretreatment and intra-treatment FMISO PET were used to select appropriate T0-T2, N1-N2c HPV-positive OPC patients for major CRT de-escalation to a definitive dose of 30 Gy after primary tumour resection (without neck dissection), if they had no pre-RT hypoxia or early resolution after 1–2 weeks of RT. Of 152 patients, 128 (84%) were able to meet these criteria, with the remainder receiving 70 Gy, with 2-year PFS and OS rates of 94% and 100%, respectively, and no late grade 3–4 events in the 30 Gy arm.73 80 Locoregional failure was defined as any recurrence at the primary site at any time or neck recurrence >140 days from end of CRT. In the 30 Gy arm, eight patients developed nodal recurrences, and an additional four had persistent nodal disease for <140 days, compared with 0 nodal failures in the 70 Gy arm. Higher pretreatment nodal volume and smoking status were correlated with hypoxia or non-resolution of hypoxia.81 Subsequent abstract-level data have shown this paradigm may be extended to definitive treatment of the primary site at 30 Gy in selected patients, with similarly encouraging outcomes; mature results are awaited.82 Ongoing trials include a phase II study for locally advanced T3-T4 HPV-positive OPC receiving 30 ROC postinduction therapy (NCT05491512)83 a phase II trial in HPV-negative OPC (NCT05544136), and a phase III randomised double-blinded trial of FMISO PET guided deintensification versus standard of care CRT in HPV-positive OPC (NCT06563479). Despite promising outcomes, FMISO-based strategies currently face practical limitations, including restricted radiotracer availability, additional cost, and lack of standardisation of F-MISO reporting beyond single-institution experiences. Earlier studies using 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) response to guide treatment adaptation have also suggested prognostic value, though these data derive from smaller cohorts with shorter follow-up and remain less mature than hypoxia-guided strategies.84 85Emerging molecular and immune-based classifiers, including alterations in TNF/NF-κB signalling, immune microenvironment-derived scores, and intratumoral immune cell density, have shown prognostic associations in retrospective and translational analyses of HPV-positive OPC.86–90 Classification of HPV-positive OPC using a three-gene immune score, the UWO3 score, to distinguish three classes, immune-rich, mixed and immune desert, based on the tumour immune microenvironment characteristics, has been shown to predict OS across six independent cohorts.91 In addition, using data from MC127317 and 30 ROC73 trials, the UWO3 score was able to further refine selection by predicting recurrence. Seven out of 9 patients (77.8%) in the immune desert group had recurrence, while 4 out of 24 (16.6%) in the immune-rich and mixed groups recurred. Separately, comparing CD103+high versus low patients from the TROG 12.01 and Determination of Epidermal growth factor receptor-inhibitor (cetuximab) versus Standard Chemotherapy (cisplatin) (De-ESCALaTE) trials showed that high CD103+expression was associated with 100% 3-year OS compared with 86% in low CD103 treated with cetuximab and radiotherapy. This difference was not seen in the cisplatin and radiotherapy group.92 While these biomarkers could further refine risk stratification beyond clinical staging, they remain exploratory and are not yet suitable for prospective treatment selection outside of clinical trials.Balancing cure and function: patients as part of the multidisciplinary decision-making team Enrolling patients on deintensification studies offers the potential to reduce treatment-related morbidity but inherently accepts a higher risk of recurrence for a minority of patients. The consequences of misjudging this balance are well illustrated by phase III trials substituting cetuximab for cisplatin, which were initially viewed as relatively conservative de-escalation strategies. Allocation to the cetuximab arm resulted in higher treatment failure and death (an estimated 1 in 11 patients in the cetuximab died due to treatment allocation) without quantifiable improvement in the metrics used to gauge toxicity or quality of life. Considering the impressive results of the NRG-HN005 control arm, we must tread carefully, aligning what matters to patients with clinical trial design. It should be stated and perhaps made clear to patients in the informed consent process, that no de-escalation approach in this patient population has clearly achieved results on par with the NRG-HN005 control arm.In studies where patient preferences have been elicited, cure remains the most prized outcome for most patients before and after treatment, both in unselected HNC and HPV OPC cohorts.93 94 When thresholds were tested for omitting chemotherapy in CRT-treated patients with OPC (not all HPV-positive), the majority (35/51, 69%) would forgo the additional morbidity of chemotherapy only after being assured of a low difference in survival of <5%.95 A recent study compared patient priorities before and 12 months after CRT and found cure (93%/91%) and survival (69%/66%) were top priorities of patients, whereas 56% of patients considered swallowing a top priority.94This demonstrates that for some patients, de-escalation is not a priority. Those patients with a low tolerance for risk are not ideal candidates for de-escalation studies. Even among those patients consenting to de-escalation, incorporating patient-centred perspectives into clinical trial design remains essential.96 This would ensure that the evidence resulting from clinical trials is more likely to translate into clinical practice if it aligns with the values of those it aims to benefit.However, patient preference alone does not resolve the broader therapeutic dilemma. Even with moderately de-escalated regimens such as 60 Gy with concurrent cisplatin, most patients are cured, raising the question of whether incremental gains in LRC or even PFS from higher-intensity regimens justify exposing all patients to this higher toxicity to prevent recurrence in a small proportion. This trade-off is further complicated by numerous factors, such as the potential for successful salvage in selected patients, substantial heterogeneity in how toxicity is measured and experienced, and the qualitative differences between modest dose reductions and more aggressive approaches such as the 30 ROC regimen. As de-escalation strategies move towards increasingly divergent therapeutic ratios, defining appropriate endpoints beyond PROMs, including durability of functional outcomes, late toxicity, and salvage feasibility, will be critical. Addressing these questions may require trials comparing competing therapeutic ratios rather than assuming a single continuum of risk and benefit.Conclusion After more than a decade of intensive research, definitive CRT to 70 Gy with concurrent cisplatin remains the standard of care for HPV-positive OPC. However, substantial multidisciplinary evidence now demonstrates that many patients have undergone treatment deintensification on clinical trials without sacrificing oncologic outcomes. Thus, identification of those patients who can safely have deintensified treatment is a critical next step. Promising data have emerged from surgical deintensification with TORS, radiation dose and elective volume reduction strategies, and tailored modifications to systemic therapy. Novel biomarkers including circulating HPV DNA, functional hypoxia imaging, and immune profiling and characterisation of the tumour microenvironment offer precision tools to refine risk stratification and guide individualised strategies beyond traditional staging and HPV status alone. Effective implementation of these strategies into the standard of care will depend on multidisciplinary collaboration and careful incorporation of patient values, preferences, and patient-reported outcomes into future clinical trials.