What is the recommended treatment approach for a patient with human papillomavirus (HPV)-associated cancer?

Treatment of HPV-Associated Cancer

For HPV-associated oropharyngeal cancer, treatment is based on TNM stage: early stage (I-II) disease should receive single-modality therapy with either surgery or radiotherapy achieving 80-90% remission rates, while advanced stage (III-IVa-IVb) disease requires multimodal therapy combining surgery, radiotherapy, and chemotherapy, with treatment sequencing determined by tumor location, stage, and anticipated functional outcomes. 1

Treatment Algorithm by Stage

Early Stage Disease (Stage I-II)

• Single modality treatment is standard, selecting between surgery or radiotherapy based on:

  • Tumor location and extent 1
  • Anticipated cure rate (80-90% remission expected) 1
  • Functional and esthetic outcomes 1

• For T1-T2 N0-N1 HPV-positive oropharyngeal cancer, transoral robotic surgery (TORS) is recommended when the tumor is lateralized with high probability of R0 resection and no radiologic evidence of extranodal extension or matted nodes 2

Advanced Stage Disease (Stage III, IVa, IVb)

• Multimodal therapy is required, combining surgery, radiotherapy, and chemotherapy 1

• For locally advanced (T3-T4a or N2-N3) disease, concurrent chemoradiotherapy is the preferred primary treatment with cisplatin 100 mg/m² on days 1,22, and 43, plus concurrent radiation therapy to 70 Gy 2

• Treatment sequencing and combination are determined by:

  • TNM stage 1
  • Tumor location 1
  • Expertise of treating physicians 1
  • Patient preference 1

Adjuvant Therapy Following Surgery

• Radiation therapy alone (50-60 Gy) is indicated for: close surgical margins (1-3 mm), perineural invasion, or lymphovascular invasion 2

• Chemoradiotherapy (radiation plus concurrent platinum-based chemotherapy) is indicated for: positive margins, ≥5 positive lymph nodes, or >1 mm extranodal extension 2

Recurrent or Metastatic Disease

Platinum-Refractory Disease

• Nivolumab is the category 1 recommendation for patients with recurrent or metastatic squamous cell head and neck cancer progressing on or after platinum-based chemotherapy 1

• Pembrolizumab is a category 2A alternative for the same indication 1

• For patients with CPS ≥1, pembrolizumab monotherapy demonstrated median OS of 12.3 months versus 10.3 months with cetuximab/platinum/5-FU (HR 0.78, p=0.0171) 3

• For patients with CPS ≥20, pembrolizumab showed even greater benefit with median OS of 14.9 months versus 10.7 months (HR 0.61, p=0.0015) 3

PD-L1 Testing Considerations

• PD-L1 expression (≥1%) is associated with significantly better response rates to pembrolizumab (22% vs 4% in PD-L1 negative, p=0.021) 1

• Responses occur in both HPV-associated and non-HPV-associated disease 1

Critical Prognostic Factors

HPV Status Impact

• HPV-related head and neck cancer is biologically and clinically distinct from tobacco-related disease, with significantly better prognosis even in stage IV disease 1

• Cure rates for HPV-related disease approach 90% in some large studies, particularly in never smokers 1

• Smoking history negatively impacts prognosis even in HPV-positive disease 2

Current Research Focus

• Much current research focuses on reducing radiation dose or volume in HPV-related disease to decrease acute and chronic toxicities while maintaining efficacy 1

• De-intensified chemoradiotherapy (60 Gy with weekly cisplatin 30 mg/m²) has shown favorable patient-reported outcomes with early recovery of quality of life and continued improvement of xerostomia and dysphagia beyond 1 year post-treatment 4

Important Caveats

• Despite better prognosis, there is currently insufficient data to recommend less-intense treatment for HPV-positive oropharyngeal cancers relative to HPV-negative cancers outside of clinical trials 1

• HPV status should be considered a prognostic factor, and patients with HPV-related cancers should be enrolled in clinical trials evaluating treatment de-intensification 1

• Cure rates for advanced stage disease remain limited primarily due to locoregional recurrence, despite aggressive multimodal treatment 1

Psychosocial Communication

• Oncologists must be prepared to discuss HPV transmission, sexual behavior, and address feelings of guilt and anxiety that patients may experience regarding the sexually transmitted nature of their cancer 1

• Communication should remain neutral and non-stigmatizing, with progressive information disclosure adapted to patient literacy and culture 1

• Patients may have concerns about sexual intimacy, transmission to partners, and sometimes infidelity issues that require sensitive discussion 1