Commentary: Clinical Nodal Staging of Human Papillomavirus–Related Oropharyngeal Cancer

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The head and neck oncology program at the University of Virginia has published an article about the clinical nodal staging differences between human papillomavirus (HPV) (p16)-positive and human papillomavirus (HPV) (p16)-negative patients, which is timely and important. They demonstrated that patients whose primary tonsillar tumor stained positive for p16 had a 25% chance of contralateral lymph nodes, whereas patients whose tonsillar cancer did not stain positive for p16 did not demonstrate any contralateral lymph modes. This finding was statistically significant but is underpowered, a weakness that is acknowledged by the oncology group at University of Virginia (UVA). Previous literature has suggested that homolateral radiation of tonsil cancer is safe if the primary tumor does not involve the tongue base and does not spread along the palate to within 1 cm of the midline. The University of Toronto has presented large, thoughtfully analyzed, retrospective cohorts of patients whose disease was well controlled by a homolateral field.1 The authors from UVA highlighted that we now have a newly evolving disease, the patient with HPV-positive cancer, who may have different patterns of nodal involvement compared with HPV-negative patients. By choosing to study patients with small tonsil primaries confined to the tonsil site, they strengthen the assertion that the molecular biology of p16-positive tumors is driving the phenotype of contralateral metastasis. A weakness of the study is the fact that the contralateral nodes were involved according to the radiologic criteria but were not confirmed with a fine needle aspiration biopsy. Future work will have to better determine the proportion of contralateral nodes that are positive for carcinoma by prospective studies using positron emission tomography/computed tomography or fine needle aspiration biopsy. Nevertheless, this report corroborates the clinical experience with patients who are HPV positive: despite a better prognosis, these patients present with more extensive lymph node metastasis compared with patients whose oropharyngeal cancer is related to smoking and alcohol consumption. Bilateral disease, involvement of multiple nodal levels, and large metastatic nodal sizes may be more frequent in patients with HPV-positive oropharyngeal carcinoma. It is important that we characterize these differences and tailor treatment appropriately, so that patients are neither over nor undertreated.
The oncology group at UVA has suggested a bilateral treatment field based on these findings. This suggestion raises more questions than it answers (as most good research does). If there are contralateral nodes seen on imaging, what additional testing is required to justify an increase in the size of the treatment field or the extent of the treated targets? Should bilateral neck radiation be used for all p16-positive patients, all HPV-positive patients, or just patients who manifest contralateral neck disease? If the treatment fields or targets are designed to treat the neck bilaterally, what anatomic subsites of the oropharynx should also be treated bilaterally? Most interestingly, these research findings from UVA come at a time when there is a move by the National Cancer Institute and the Radiation Therapy Oncology Group to deescalate therapy. However, studies of deescalation of therapy that involve reducing the doses should not be mixed up with reducing the extent of the targets receiving prophylactic irradiation. Intensity-modulated radiation therapy has reduced the morbidity of the therapy for head and neck cancer by careful selection of the treated volume. For the design of treatment volumes, this study by the UVA group is a cautionary note about the need to take into account the biology of the tumor, rather than just its anatomic extent because the spread patterns of HPV-positive versus HPV-negative tumors may be different.
Demographic and behavioral differences between patients who are HPV positive and HPV negative have been demonstrated.
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