The rise of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC), often referred to as throat cancer, has changed head and neck oncology. This cancer develops in the back of the throat, including the tonsils and base of the tongue, and is distinct from cancers caused primarily by tobacco and alcohol use. Patients diagnosed with HPV-positive OPC generally have a favorable prognosis and respond well to initial treatment, with substantially higher survival rates compared to those with HPV-negative disease. Despite these positive outcomes, the possibility of the cancer returning remains a serious concern. Understanding the frequency, pattern, and management of recurrence is crucial for long-term survivorship.
Overall Recurrence Rates
The likelihood of HPV-positive oropharyngeal cancer returning after successful initial treatment is low. Overall recurrence rates for HPV-positive OPC typically fall in the range of 9% to 25% over a five-year period. This figure represents a significant improvement, as recurrence rates for HPV-negative cases can be more than double this percentage.
Recurrence is categorized by location: local (original tumor site), regional (nearby lymph nodes), or distant (metastasis to other organs). For HPV-positive cases, locoregional recurrence occurs in about 9% to 17% of patients. Distant metastasis, where the cancer spreads to sites like the lungs or bones, is less common (4% to 6.5% of cases), but accounts for a significant portion of all relapses.
Distant recurrence is a more prevalent issue in HPV-positive disease than in HPV-negative disease, where local and regional failures dominate. The lungs are the most common site for distant spread. While most recurrences appear within the first two years, distant failure can occur later, sometimes years after initial therapy, necessitating long-term surveillance.
Factors That Affect Recurrence Risk
Several factors can elevate an individual’s risk of recurrence. Primary among these is the patient’s smoking history; ten or more pack-years of smoking is linked to a higher risk of the cancer returning. Smoking after diagnosis drives recurrence and second primary cancers, undermining the positive prognosis conferred by HPV status.
The initial extent of the disease is also a major predictor. Patients who presented with a greater initial tumor burden, such as a very large neck lymph node (over six centimeters) or involvement of multiple lymph nodes (five or more), face a higher risk of regional and distant recurrence. This burden is measured by the T and N categories of the tumor, which describe the size of the primary tumor and the extent of lymph node involvement, respectively.
If surgery was part of the initial treatment, the microscopic status of the tumor is crucial. Positive or close surgical margins, where cancer cells are found near the edge of the removed tissue, increase the risk of local recurrence. The presence of adverse pathologic features, such as cancer cells that have broken through the capsule of a lymph node (extracapsular spread), also indicates a higher risk that the cancer may return.
The presence of circulating tumor DNA (ctDNA) specific to the HPV virus in the bloodstream following treatment is a key predictor. If HPV ctDNA persists or reappears after therapy, it is highly associated with an increased risk of recurrence. This biological marker often signals the cancer’s return before it can be detected by traditional imaging, providing a real-time assessment of residual or recurring disease.
Surveillance and Follow-Up Protocols
A rigorous surveillance schedule is implemented to detect any recurrence early, as prompt intervention significantly improves the chance of a successful salvage treatment. The protocol involves frequent clinical visits, gradually decreasing in frequency over five years:
- Every one to three months in the first year.
- Every two to six months in the second year.
- Every four to eight months for years three through five.
Detection methods include a thorough physical examination of the head and neck, along with flexible laryngoscopy to inspect the original tumor site. Imaging, most commonly a Positron Emission Tomography-Computed Tomography (PET/CT) scan, is performed around three months after definitive therapy. Because HPV-positive patients are at risk for distant failure, some clinicians advocate for extended surveillance imaging beyond the first year.
Monitoring HPV ctDNA is beginning to supplement traditional surveillance. A rise in this blood-based biomarker can be the first sign of recurrence, appearing months before a tumor is visible on a scan or during a physical exam. Patient adherence to the prescribed schedule is paramount, as early detection is key to successfully treating relapsed disease.
Treatment Approaches for Relapsed Cancer
If a recurrence is confirmed, treatment, known as salvage therapy, depends on the location and extent of the returning cancer. For localized recurrences in the throat or neck, surgical removal, sometimes using minimally invasive techniques like transoral robotic surgery (TORS), is an option. If the initial treatment did not involve radiation, re-irradiation may be considered, though this carries a higher risk of side effects due to previous exposure.
If the cancer is metastatic or widespread, systemic treatments are necessary. Immunotherapy, using agents like pembrolizumab or nivolumab, has become a standard treatment for recurrent or metastatic HPV-positive OPC. These drugs harness the patient’s own immune system to target the cancer cells, and they are often used alone or combined with chemotherapy. Patients with a solitary recurrence or a low burden of disease at the time of relapse often have better outcomes with salvage therapy compared to those with more widespread recurrence.