The significance of retropharyngeal nodes in treatment deintensification

Treatmentdeintensificationof humanpapillomavirus (HPV) associated oropharyngeal squamous cell cancer (OPSCC) is a topic of active debate. It is well recognized that HPVassociated OPSCC has unique tumor biological characteristics, reflected by a high propensity fornodal involvement and yet more favorable outcomes compared with HPVnegative OPSCC, with significantly improved overall survival and a reduced risk of recurrence. Because patients with HPVassociatedOPSCCareoftenyounger (<60years), healthier, and more likely to outlive their disease than their historical counterparts, efforts to reduce the risk of severe late toxicity, primarily long-term dysphagia, have become a goal of treatment. The primary question now is, which of these patients are candidates for treatment deintensification? The best evidence suggests that patients with HPVassociated OPSCC with low-volume primary site tumors and limited nodal disease (N0-N2a) have lower rates of locoregional recurrence, distant metastatic disease, and improved overall survival.1 These observations have led to the suggestion that these low-risk patients can be targeted for deintensification strategies that omit chemotherapy. The addition of chemotherapy to radiation results in increased mucositis, long-term fibrosis, and late severe dysphagia.2 However, the primary determinant of severe late dysphagia seems to be the radiotherapydose to thesuperiorpharyngeal constrictors,with mean doses greater than 60 Gy to this site associated with a significantly increased risk of long-termdysphagia, aspiration, and gastrostomy dependence.3,4 The retropharyngeal nodes havebeen identifiedasanodalbasinat risk formetastases from OPSCCandareroutinely included inradiationtreatment fields.5 Because the retropharyngeal nodal basin is bound anteriorly by the pharyngeal constrictor muscles and posterior pharyngealwall,deintensificationstrategies that limit treatment tothis site may reduce long-term treatment-related toxicity. The incidence of retropharyngeal metastases from OPSCC is reported to range from10%to27%.6-11Most studies use pretreatment imaging to evaluate retropharyngeal adenopathy with criteria of size greater than 1 cm, central necrosis or cystic degeneration, or fluorodeoxyglucose F 18–avidity on positron emission tomography. The presence of retropharyngeal adenopathy is significantly more likely with advanced T stage, 3 or more involved nodes, contralateral cervical adenopathy, and tonsil or posterior pharyngeal wall subsites.7-9 Retropharyngealmetastases are theonly site ofnodal involvement in 2% to 7%of patients but are nearly always associated with posterior pharyngeal wall primary site involvement.6,10 In patients treated with primary surgery that includes retropharyngeal nodedissection, the incidenceof occult retropharyngealmetastasesnotdetectedby imaging is 7%,andstrongly correlateswithposterior pharyngealwall involvement and/or greater than stageN2adisease.9-11 These data suggest that patients with primary site posterior pharyngeal wall or posterior tonsillarpillar involvement,orwithmultiplecervicalnodes require treatment of the ipsilateral retropharyngeal node basin, whereas patients with low T stage sparing the posterior pharyngeal wall and limited nodal disease could potentially bespared radiation to the retropharyngealnodesandthus limit theeffectsof radiotherapy to thepharyngeal constrictors. This premise is incorporated in the Eastern Cooperative Oncology Group E3311 transoral surgery clinical trial schema, in which low-risk patientswithHPV-associatedOPSCC (<T3, <N2,with clear margins, 0-1 nodes, and no extracapsular spread) are spared radiation therapy. Thus, the findings of Spector et al12 in this issue are important but are not incongruous with the evidence to date. Deintensification strategies require the identification of lowrisk groups who may benefit from less intense therapies—in this case, patients at low risk for retropharyngeal node involvementwho couldbe spared conventional radiotherapy to the pharyngeal constrictors. Patients with clinically detectable retropharyngeal nodes are clearly not suitable for such a strategy. Risk stratification efforts to guide treatment deintensification in patients without clinically detectable retropharyngeal disease will benefit from the results of the E3311 surgical trial, which is actively accruing. Because retropharyngeal node dissection is not performed as part of neck dissection in this trial, thesurvival andrecurrencepatternsofboth low-risk patientswho are spared radiation, and intermediaterisk patients randomized to lower doses of radiation including retropharyngeal nodes, will allow us to better define risk groups and prospectively guide future deintensification efforts in HPV-associated OPSCC care.