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Treatment de-intensification and immunotherapy in human papillomavirus-related oropharyngeal squamous cell carcinoma – A review
*Corresponding author: Arthi Elango, Department of Medical Oncology, PSG Institute of Oncology, PSG IMSR, Tamil Nadu, India. drarthielango@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Elango A. Treatment de-intensification and immunotherapy in human papillomavirus-related oropharyngeal squamous cell carcinoma – A review. Int J Mol Immuno Oncol. doi: 10.25259/IJMIO_27_2025
Abstract
Human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is increasingly prevalent among younger patients, necessitating treatment strategies that balance effective oncological outcomes with reduced treatment-related toxicities. Traditional concurrent chemoradiation has been linked to significant adverse effects, prompting research into de-escalation strategies aimed at minimizing treatment intensity without compromising survival rates. This paper reviews various de-escalation approaches under investigation, including reduced radiotherapy doses, alteration or omission of concomitant chemotherapy, and the use of induction chemotherapy for patient selection. Notable clinical trials such as MC1273, ECOG 3311, and ORATOR have shown promising results in maintaining oncological control while enhancing quality of life; however, definitive recommendations are limited due to the absence of positive Phase III evidence. In addition, immunotherapy, particularly checkpoint inhibitors, presents a potential avenue for replacing toxic chemotherapy due to the unique immunogenic profile of HPV+ tumors. Despite the encouraging findings from Phase I and II trials, the current clinical guidelines do not endorse de-escalated treatments outside clinical trials, emphasizing the need for ongoing research to establish validated, personalized treatment protocols that optimize outcomes for patients with HPV+ OPSCC.
Keywords
Immunotherapy in human papillomavirus-related oropharyngeal carcinoma
Immunotherapy in oropharyngeal carcinoma
Oropharyngeal squamous cell carcinoma
Treatment de-intensification
Treatment de-intensification in oropharyngeal carcinoma
INTRODUCTION
Human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) affects younger patients and is an increasingly common malignancy. Traditional treatment with concurrent chemoradiation is associated with acute and chronic toxicities significantly affecting quality of life, considering the commendable oncological outcomes in patients with HPV+ OPSCC. The favorable prognosis and the burden of treatment-induced toxicities have driven extensive research into de-escalation strategies, aiming to reduce treatment intensity without compromising favorable survival outcomes.
RATIONALE FOR TREATMENT DE-ESCALATION
The improved oncological outcomes and prognosis of HPV + oropharyngeal tumors, due to their inherent radio and chemo-sensitivity, emphasises the need for de-escalation strategies. This increased sensitivity suggests that lower doses of radiation or less intensive chemotherapy might achieve similar oncologic results with reduced side effects.
DE-ESCALATION STRATEGIES UNDER INVESTIGATION
Several approaches are being explored in clinical trials to de-escalate treatment for HPV-positive OPSCC:
Radiotherapy dose and volume reduction
Retrospective analyses have suggested similar oncological outcomes for dose de-escalated radiotherapy in HPV-positive OPSCC when balancing for other prognostic factors, given the substantial evidence of dose–response relationship with toxicity to normal tissues. Trials have investigated various reduced radiation doses. The MC1273 trial was a Phase II study explored aggressive dose de-escalation for adjuvant chemoradiation to 30 Gy (or 36 Gy with extranodal extension) in HPV-positive OSCC patients after resection, showed excellent 2-year locoregional control, progression-free survival (PFS), and overall survival (OS) of 96.2%, 91.1%, and 98.7%, respectively, with improved quality of life and swallowing function.[1,2] The ECOG 3311 Phase II study utilized a risk-adapted de-escalation approach post-transoral resection. The study indicated that omitting post-operative radiation therapy (RT) for low-risk patients and using 50 Gy without chemotherapy for intermediate-risk patients may be appropriate.[3] High-risk patients were treated using concurrent therapy and radiation doses up to 66 Gy.[3] Other trials, such as the NRG HN002 and OPTIMA (Phase II) trials, are exploring dose de-escalation, including omission of concurrent chemotherapy and volume de-escalation strategies based on response to induction therapy, respectively.[4,5] However, despite promising Phase II results, no treatment de-escalation is currently recommended outside of clinical trials due to a lack of positive Phase III evidence.
Omission or modification of concomitant chemotherapy
Strategies used include replacing cisplatin, a highly toxic agent, with less toxic systemic agents such as cetuximab and the entire omission of systemic therapy in patients with clinically low-risk disease. Two pivotal Phase III de-escalation trials, De-ESCALaTE-HPV and RTOG 1016, failed to show the equivalence of cetuximab to cisplatin and showed increased recurrence rates for cetuximab compared to cisplatin.[6] These “negative” results tempered enthusiasm for this particular de-escalation approach. Therefore, cetuximab should not be used as a replacement for cisplatin for HPV/p16-positive and HPV/p16-negative oropharyngeal carcinomas without contraindications to cisplatin.[6] The approach exploring the omission of systemic therapy entirely for patients with clinically low-risk disease, treating them with radiation alone, is investigated in trials like NRG HN002.[4]
Usage of induction chemotherapy for patient selection
Induction chemotherapy is used to stratify risk and allows for reduced adjuvant RT in patients who respond well. The ECOG 1308, Quarterback, and OPTIMA trials used induction chemotherapy to guide subsequent reduced-dose radiation.[5,7,8] While promising, these Phase II studies generally have small patient numbers, and definitive recommendations cannot yet be derived.
Transoral robotic surgery (TORS) with de-escalated adjuvant therapy
Minimally invasive surgical techniques such as TORS have significantly reduced morbidity compared to traditional open surgery, making them an attractive option for primary tumor resection. De-escalation of adjuvant radiation and chemotherapy after TORS has been proposed, including reduced radiation dose/volume, reduced chemotherapy intensity, or complete omission of chemotherapy. The ORATOR trial compared transoral resection plus neck dissection (with post-operative chemo/radiation as needed) to definitive chemo/radiation for T1-2, N0-2, M0 OSCCs. While oncological outcomes were comparable, 1-year swallowing-related quality of life was significantly superior in the radiotherapy group.[9,10] Its follow-up, ORATOR II, is further investigating de-escalated definitive radiotherapy versus transoral surgery followed by de-escalated adjuvant radiotherapy for HPV-positive OSCC.[11] The PATHOS and ADEPT trials are also examining reduced-dose adjuvant RT or omission of chemotherapy after transoral resection, aiming to improve functional outcomes.[12,13]
Immunotherapy in HPV-related OPSCC
Immunotherapy, particularly with immune checkpoint inhibitors (ICIs) targeting PD-1/programmed death ligand-1 (PD-1/PD-L1), has emerged as a significant advancement in head-and-neck squamous cell carcinoma (HNSCC) treatment. Patients with HPV-related OPSCC are considered potential ideal candidates for immunotherapy for several reasons, including high immunogenicity due to viral antigens and an immune micro-environment. Viral antigens, E6 and E7 oncoproteins, act as immunogens, and the patient’s immune system can recognize them as foreign, potentially leading to a more robust immune response and activation. HPV-positive tumors often exhibit increased levels of PD-L1 and higher infiltration of CD8+ and PD-1 tumor-infiltrating lymphocytes, which are associated with a better response to PD-1 inhibitors such as nivolumab and pembrolizumab. While HPV-positive tumors can be more advanced, they generally have higher survival rates, possibly due to a better treatment response, including immunotherapy.
Current status of immunotherapy in HNSCC
PD-1 inhibitors (pembrolizumab and nivolumab) are approved for recurrent/metastatic HNSCC that progresses after chemotherapy, regardless of HPV status, although some studies suggest a more pronounced benefit in HPV-positive cases. Trials are investigating ICIs as replacements for cisplatin in combination with RT. NRG-HN005 (Phase II/III) compares standard cisplatin-based chemoradiation with cisplatin-based dose-deescalated chemoradiation and nivolumab-based radioimmunotherapy, aiming to show non-inferiority in PFS and superiority in quality of life.[14] However, recent large-scale randomized controlled studies, such as JAVELIN HN100 and KEYNOTE-412, evaluating the addition of PD-1/PD-L1 inhibitors to concurrent chemoradiation for locally advanced HNSCC (including some HPV-positive cases), have not shown an OS benefit for these combinations.[15,16] Neoadjuvant nivolumab has shown safety and induced pathological responses in HPV-positive tumors in trials such as CheckMate-358.[17] Ongoing studies, such as EA3161, are specifically enrolling patients with HPV-associated disease to understand the role of sequential immunotherapy (e.g., maintenance nivolumab after chemoradiotherapy).
CONCLUSION
Despite promising results from various Phase I and II de-escalation trials for HPV-related OPSCC, especially those incorporating surgery and personalized approaches, the current clinical guidelines do not recommend de-escalated treatment outside of formal clinical trials. Immunotherapy shows promising early results and could be a potential therapy replacing toxic chemotherapy as concurrent therapy. However, the failure of cetuximab to replace cisplatin highlights the critical importance of confirming all promising Phase II data with rigorous Phase III trials against current treatment standards. The field is actively evolving, with many ongoing studies anticipated to provide clearer guidance for individualized, risk-adapted treatment approaches that balance survival with quality of life for HPV-positive OPSCC patients.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that they have used artificial intelligence (AI)-assisted technology solely for language refinement and to improve the clarity of writing. No AI assistance was employed in the generation of scientific content, data analysis or interpretation.
Financial support and sponsorship: Nil.
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