SUMMARY: The American Cancer Society estimates that about 58,450 new cases of oral cavity and pharynx cancer will be diagnosed in the US in 2024 and about 12,230 patients will die of the disease. According to the CDC, about 46,711 Human PapillomaVirus (HPV)-associated cancers occur in the United States each year (25,689 among women, and 21,022 among men). Cervical cancer is the most common HPV-associated cancer among women, and Oropharyngeal cancers are the most common among men. There has been a significant increase in the incidence during the past several decades, due to changes in sexual practices.
HPV-positive Oropharyngeal Squamous Cell Carcinoma (OPSCC) is an entirely distinct disease entity from HPV-negative OPSCC. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV. The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC) when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in Head and Neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with Head and Neck cancer, and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.
HPV-positive OPSCC is more sensitive to chemotherapy and radiotherapy than is HPV-negative OPSCC, which translates to a much better prognosis and survival, when treated with a combination of platinum based chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. These tumors, typically being more responsive to therapy than their non-HPV counterparts, appear to benefit from reduced radiation doses, potentially minimizing the severe toxicities linked with conventional radiotherapy, without compromising oncologic outcomes.
Two pivotal studies presented at the 2024 Multidisciplinary Head and Neck Cancers Symposium have provided compelling evidence supporting the deintensification of radiotherapy in early-stage Oropharyngeal Squamous Cell Carcinomas associated with HPV. The approach for the first study was de-escalated postoperative adjuvant therapy, whereas the second study utilized mid-treatment FDG-PET response criteria to select patients eligible for de-escalated radiotherapy
Study by Washington University School of Medicine: De-escalation of Postoperative Adjuvant Therapy
The MINT trial (The Minimalist Trial) is a nonrandomized Phase II study which enrolled 58 patients with clinical Stage I–III HPV-positive Oropharyngeal Squamous Cell Carcinoma, or with a positive neck node with an unknown primary, who underwent surgery and selective neck dissection. Out of these, 54 patients were stratified post-surgery into three treatment groups based on pathologic risk:
Group 1: High-risk pathology patients (extracapsular extension or positive margin but not clinical or pathologic T4 or clinical N3 disease) received de-escalated postoperative adjuvant chemoradiotherapy with Cisplatin at 100 mg/m2 for one dose plus 42 Gy of radiotherapy in 21 daily fractions (N=20)
Group 2: Intermediate-risk pathology patients (lymphovascular invasion, perineural invasion, at least two positive nodes, at least one positive node 3 mm, T3 or N2 disease, but no extracapsular extension or positive margins, and not clinical or pathologic T4 or clinical N3 disease) received de-escalated postoperative adjuvant radiotherapy with 42 Gy in 21 daily fractions (N=30)
Group 3: Highest-risk pathology (Patients with clinical or pathologic T4 or clinical N3 disease) received standard-of-care treatment with higher doses of Cisplatin at 100 mg/m2 for three doses plus 60 Gy of radiotherapy delivered concurrently (N=4).
So, the experimental arms involved de-escalating postoperative chemoradiotherapy in Group 1 and de-escalating postoperative radiotherapy in Group 2. The Primary outcome measure was mean percent weight change starting at Day 1 and ending on the last day of radiation therapy (approximately 4 weeks). The hypothesis was that de-escalated treatment would result in less weight loss, which served as a quantitative surrogate for the severity of mucositis. Secondary outcome measures included disease Recurrence Rate, Progression Free Survival (PFS) and Overall Survival (OS).
It was noted that the de-escalated treatment resulted in significantly less weight loss. Specifically, the mean percent weight loss during de-escalated postoperative adjuvant chemoradiotherapy (Group 1) was 4.9%, compared to 7.4% in a historical cohort treated with conventional therapy (P=0.0003). For de-escalated radiotherapy alone (Group 2), the mean percent weight loss was 3.18%. The follow-up data of this study at a median of 50 months indicated low recurrence rates: 10% in Group 1 and 3.3% in Group 2. The 4-year PFS rates were 90.0% for Group 1 and 90.1% for Group 2, with OS rates of 100% and 94%, respectively. These results suggest that reduced radiation doses do not compromise the efficacy of treatment for patients with HPV-positive Oropharyngeal Squamous Cell Carcinoma.
Study by University of Michigan: FDG-PET-Guided Deintensification
The second study is a Phase II trial which enrolled 89 patients with Stage I–II HPV-positive Oropharyngeal Squamous Cell Carcinoma confirmed to have FDG-PET avidity. The treatment plan included an initial course of 70 Gy to gross disease and 56 Gy to elective nodal regions, administered concurrently with Carboplatin and Paclitaxel. Mid-treatment FDG-PET assessments were performed to evaluate metabolic tumor volume reduction. Patients with at least a 50% reduction in tumor volume had their radiotherapy de-escalated to 54 Gy, whereas the others completed the entire course of 70 Gy. The Primary endpoint was noninferiority of 2-year locoregional recurrence in the entire cohort, compared with an institutional historical control.
At a median follow-up of 32 months, the 2-year locoregional recurrence rate for the entire cohort was 6.8%. Patients continuing with the standard 70 Gy therapy had a 2-year locoregional recurrence rate of 4.6%, while those de-escalated to 54 Gy had a rate of 9.4%. These figures translate to two and three locoregional recurrences, respectively, which suggests overlapping confidence intervals and precludes definitive comparisons between the cohorts. The study also assessed other endpoints such as weight loss, swallowing function, and quality of life. Patients in the de-escalated group experienced significantly less weight loss (11 lbs versus 23 lbs in the standard-treatment group, P=0.001), and showed better maintenance of swallowing function and quality of life. The authors concluded that FDG-PET may be a reliable predictive biomarker to selectively de-escalate the radiation dose in early-stage HPV-positive disease.
The findings from these two studies underscore the feasibility and potential benefits of de-escalating radiotherapy in HPV-positive Oropharyngeal Squamous Cell Carcinoma. By tailoring treatment intensity, based on individual patient risk profiles and early responses to therapy, clinicians can achieve effective disease control while minimizing the severe side effects traditionally associated with high-dose radiation. This shift towards personalized, less intensive treatment protocols promises to enhance the quality of life and long-term outcomes for patients with this particular subset of Head and Neck cancers.
1. Long-term efficacy of risk-directed, de-escalated post-operative adjuvant therapy for surgically resected locally advanced, human papillomavirus-positive oropharynx squamous-cell carcinoma: A non-randomized, multi-arm phase 2 trial. Thorstad WL, Jackson RS, Oppelt P, et al.: 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 14. Presented March 1, 2024.
2. FDG-PET-based selective de-escalation of radiotherapy for HPV-related oropharynx cancer: Results from a phase II trial. Regan SN, Rosen BS, Suresh K, et al.: 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 16. Presented March 1, 2024.
