Abstract
Purpose:
Patients with p16/human papilloma virus (HPV)–associated oropharyngeal squamous cell carcinoma have a favorable outcome after treatment. In this group of patients who could have a long life expectancy, the optimal surveillance strategy and modality is not well established. We aim to determine the ability of a negative postradiation positron emission tomography (PET)/computed tomography scan to predict the risk of subsequent relapse in these patients.
Materials and Methods:
A retrospective analysis of patients with p16/HPV-associated oropharyngeal squamous cell carcinoma who completed definitive (chemo)radiation therapy and had a posttreatment PET/computed tomography scan from 2006 to 2013 was performed. Patient, tumor, and treatment characteristics and clinical outcomes were recorded. Tumors were considered HPV/p16 positive if either HPV (by in situ hybridization) or p16 (by immunohistochemistry) was positive. Disease-free survival and overall survival rates were estimated using the Kaplan-Meier method.
Results:
In our study, 327 patients were evaluated. The median age was 57 years. The most common primary sites were base of tongue (50%) and tonsil (48%). Of the patients evaluated, 291 (89%) had a negative posttreatment PET scan. For these 291 patients who had a complete metabolic response after treatment, the 5-year disease-free survival and overall survival rates were 91% and 89%, respectively. The median time to development of recurrence was 16 months. Of the 291 patients, 24 patients (8%) had disease recurrence; 13 recurrences were locoregional, and 13 were distant. Eleven (4%) patients with recurrence had further surgery or radiation, and 8 patients (3%) were without disease as of the last follow-up.
Conclusions:
Patients who achieve a complete metabolic response on posttreatment PET imaging have an excellent prognosis, and the risk of developing a recurrence in the future is very low. Therefore, a more cost effective surveillance program should be considered for this subgroup of patients.
Summary
Patients with human papillomavirus–associated oropharyngeal cancer have a favorable outcome after treatment. The optimal surveillance strategy and modality is not well established. We conducted a retrospective analysis of 327 patients with HPV–associated oropharyngeal cancer who received definitive (chemo)radiation therapy and who had post-treatment positron emission tomography/computed tomography scans. This study showed that patients who achieve a complete metabolic response on post-treatment positron emission tomography imaging have an excellent prognosis, and the risk of developing a recurrence in the future is very low (8%).
Introduction
The human papillomavirus (HPV) has been established as a cause of oropharyngeal cancers (1, 2), and data suggest its incidence is rising (3, 4). Furthermore, it has been observed that patients with HPV-associated oropharyngeal cancer have relatively favorable disease control rates and overall survival rates (5–7). For example, in an update of the Radiation Therapy Oncology Group 0129 trial, Nguyen-Tan et al reported 8-year overall survival and progression-free survival rates of 71% and 64%, respectively, for patients whose tumor contained p16 (used as a surrogate marker for HPV association) (7).
Although guidelines for treatment of patients with head and neck cancer are established, the specifics of surveillance are nebulous for patients rendered in a no evidence of disease status. Most cooperative group trials use a schedule of re-evaluation every 3 months, with imaging—typically anatomically based, such as computed tomography (CT) (8)—for the first 2 years after treatment and a schedule of decreasing frequency over the subsequent years (5). These schedules are empirically based and primarily designed for increased diligent surveillance in the first 2 years because most patients develop disease recurrence during that period. Although recurrences outside this 2-year window have been observed for patients with HPV-associated cancer (9, 10), most patients develop recurrent disease within the first 2 years after treatment. However, fewer patients with HPV-associated cancer develop recurrence compared with those patients with non-HPV-associated cancers, and thus the likelihood of detecting a recurrence at a routine surveillance visit will be low.
The vast majority of patients who develop HPV-positive oropharyngeal cancer present with malignant cervical adenopathy (11). Although it is not universally established, many oncologists who treat patients with adenopathy using nonsurgical approaches obtain a positron emission tomography (PET) (often with CT) scan after radiation to determine whether there is residual disease in the neck that should be managed with surgery.
Recognizing that the likelihood of detection of recurrent disease at a routine surveillance visit is low, we were interested in determining how the initial negative restaging imaging, specifically with PET/CT, would predict subsequent recurrence. To this end, we report the performance of a posttreatment PET scan in detecting residual disease after treatment and the subsequent long-term outcomes in patients with p16/HPV-positive oropharyngeal cancer with negative posttreatment PET scan.
Materials and Methods
Eligible cases with histologically confirmed squamous cell carcinoma of the oropharynx with positive p16 or HPV status were identified from an institutional board review–approved study. All patients had localized disease, received curative-intent radiation therapy (between 2006 and 2013), and had posttreatment combined PET/CT imaging within 26 weeks upon completion of radiation therapy. Our general practice has been to restage patients initially with contrast-enhanced CT scans at approximately 8 weeks postradiation. Dependent on the findings, a PET/CT scan was generally requested between 4 and 12 weeks after the initial follow-up visit. Patients with (1) evidence of distant metastatic disease at presentation, (2) previous irradiation to the head and neck region, and (3) PET/CT performed for nonsurveillance purposes (eg, to investigate a suspicious finding on conventional imaging, such as CT, or a concerning patient-reported symptom or clinical finding) were excluded. Patient demographic characteristics, smoking status, disease characteristics (primary subsite, HPV and p16 status, primary tumor [T] and nodal [N] stage), treatment characteristics (total dose and fraction, neck dissection after radiation therapy), and treatment outcomes were recorded. The American Joint Committee on Cancer staging manual, seventh edition, was used. Patients with positive posttreatment PET result or with residual disease confirmed histologically were subsequently excluded from clinical outcomes analysis.
PET/CT imaging
The fluorodeoxyglucose (FDG) PET/CT was performed using various General Electric PET/CT platforms with bismuth germinate and cerium-doped lutetium yttrium orthosilicate detectors, all without time-of-flight and point-spread-function reconstruction. Data acquisition was done with a mixture of 2-dimensional (until 2008) and 3-dimensional modes (2008 onward). Patients were asked to fast for at least 6 hours and had a fasting blood glucose less than 180 before imaging. The FDG dose was calculated according to patient’s weight and administered intravenously 1 hour before scanning. Sequential PET and CT images were obtained from the eyes to midthighs, with the patient in a supine position with both arms raised. A separate sequential PET and CT acquisition was then performed from the vertex through the upper neck with the arms by the sides. PET and CT images were coregistered and interpreted by a neuroradiologist with institutional PET credentialing or by a board-certified nuclear medicine physician. PET imaging therapy response was interpreted according to the Hopkins Criteria (12). A score of 1 was interpreted as complete metabolic response (negative PET), 2 to 4 was reported as equivocal response, and 5 was active or persistent disease (positive PET).
P16 and HPV status determination
The institutional pathology department reviewed all tissue samples. The p16 status was determined via immunohistochemistry on paraffin-embedded tumor samples. Positive p16 expression was defined as ≥70% tumor cells with strong and diffuse staining. HPV status was determined via in situ hybridization. Both p16 and HPV status were recorded. If a patient only had HPV or p16 status, the overall status was determined according to that single entity. However, if both p16 and HPV testing were performed and there was a discordant result, both results were recorded (p16 status followed by HPV status).
Statistical analysis
The clinical outcomes of patients who had true negative posttreatment PET scans were analyzed. Disease-free survival was defined as months of survival without a recurrence, calculated from the end of radiation therapy. The Kaplan Meier method was used to estimate disease-free survival and overall survival. P ≤ .05 was considered statistically significant. Multivariate analysis using Cox proportional hazards methodology was performed to analyze variables of interest. Statistical analyses were conducted using JMP v12.1.0 (SAS Institute, Cary, NC).
Results
Patient characteristics
Postradiation PET/CT imaging was performed for 327 patients treated between 2006 and 2013 for p16/HPV-associated cancer. Thirty-six patients (11%) had positive PET results. Patients with positive PET results had either surgical intervention (a neck dissection or biopsy of primary site) or repeat imaging 2 to 3 months later.
Sixteen patients (44%) had a false positive PET scan. Eight had a negative neck dissection, 2 had subsequent negative fine needle aspiration of neck nodes, and 6 had a subsequent negative scan suggesting resolution of treatment-related inflammation.
Of the 36 patients, 20 (56%) had a true positive PET scan: 5 had persistent or progressive local disease, 7 had persistent regional nodal disease, 1 had persistent local and regional disease, and 7 had distant metastatic disease.
In addition, 291 patients (89%) had a negative posttreatment PET scan. Table 1 summarizes the patient, tumor, and treatment characteristics of these 291 patients. The median age at diagnosis was 57 years (range, 35–84 years). Primary sites included base of tongue (51.5%), tonsil (47.8%), and soft palate (0.7%). HPV and p16 status were both available for 232 patients (79.3%); 45 patients (15.5%) had HPV status and 14 (4.8%) had p16 status only. Most patients had T1 to T2 primary disease and N2b clinical nodes (Table 2).
Table 1.
Patient, tumor, and treatment characteristics
| n | % | |
|---|---|---|
| Age (y) | Median, 57 | Range, 35–84 |
| Subsite | ||
| Base of tongue | 146 | 50.2 |
| Tonsil | 139 | 47.8 |
| Glossopharyngeal sulcus | 4 | 1.4 |
| Soft palate | 2 | 0.7 |
| Smoking status at diagnosis | ||
| Current | 47 | 16.2 |
| Previous (≥10 pack-years) | 81 | 27.8 |
| Previous (<10 pack-years) | 38 | 13.1 |
| Never | 125 | 43.0 |
| T stage | ||
| T1 | 95 | 32.7 |
| T2 | 111 | 38.1 |
| T3 | 48 | 16.5 |
| T4 | 35 | 12.0 |
| Tx | 2 | 0.7 |
| N stage | ||
| N0 | 3 | 1.0 |
| N1 | 36 | 12.4 |
| N2a | 25 | 8.6 |
| N2b | 148 | 50.9 |
| N2c | 68 | 23.4 |
| N3 | 10 | 3.4 |
| Nx | 1 | 0.3 |
| Overall stage | ||
| I | 1 | 0.3 |
| II | 0 | 0 |
| III | 35 | 12.0 |
| IVa | 245 | 84.2 |
| IVb | 10 | 3.4 |
| ICON-S stage | ||
| I | 31 | 10.7 |
| II | 216 | 74.2 |
| III | 44 | 15.1 |
| p16 status | ||
| Positive | 245 | 84.2 |
| Negative | 1 | 0.3 |
| Unknown | 45 | 15.5 |
| HPV status | ||
| Positive | 220 | 75.6 |
| Negative | 48 | 16.5 |
| Equivocal | 9 | 3.1 |
| Unknown | 14 | 4.8 |
| Overall p16/HPV status | ||
| Positive | 234 | 80.4 |
| Positive/negative | 57 | 19.6 |
| Induction chemotherapy | ||
| Yes | 133 | 45.7 |
| No | 158 | 54.3 |
Abbreviations: HPV = human papillomavirus; ICON-S = International Collaboration on Oropharyngeal Cancer Network for Staging.
Table 2.
T and N categories of patients with postradiation negative positron emission tomography/computed tomography scans
| N0 | N1 | N2a | N2b | N2c | N3 | Nx | Total | |
|---|---|---|---|---|---|---|---|---|
| T1 | 1 | 15 | 12 | 47 | 15 | 4 | 1 | 95 |
| T2 | 0 | 13 | 11 | 62 | 21 | 4 | 0 | 111 |
| T3 | 0 | 5 | 1 | 25 | 16 | 1 | 0 | 48 |
| T4 | 2 | 2 | 1 | 13 | 16 | 1 | 0 | 35 |
| Tx | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 |
| Total | 3 | 36 | 25 | 148 | 68 | 10 | 1 | 291 |
Of these 291 patients, 26 (9%) had a likely negative PET result initially, whereby the imaging report suggested further follow-up on low-grade FDG avidity, which was thought to be treatment-related inflammation. These patients had subsequent imaging to establish complete response. Despite a negative posttreatment PET scan, 22 patients (8%) had neck dissections; 21 had surgery for residual nodal remnants noted on CT imaging, and 1 patient had pre–radiation therapy planned neck dissection for N3 disease. Nodal remnants measured 5 to 29 mm. No viable tumor was found in the dissections of all 22 patients.
Clinical outcomes for patients with negative PET scan results
Of the 291 patients, 24 patients (8.2%) subsequently developed disease recurrence. The 5-year overall survival and disease-free survival rates were 89% and 91%, respectively. Freedom from local, regional, and distant recurrences are depicted in Figure 1. The median follow-up time was 54 months for the remaining 267 patients who did not have recurrence. Only 6 of these patients (2%) were alive with less than 2 years of follow-up.
Fig. 1.
Kaplan-Meier curves depicting freedom from local, regional, and distant recurrences for patients with negative posttreatment positron emission tomography scan.
To assess for time bias (ie, the greater the time interval between treatment and PET, the less likely a patient would have recurrence), we sorted patients into 3 groups based on the treatment–PET time interval (TPTI). These groups were (1) 8 patients with <8 weeks’ TPTI, (2) 234 patients with 8 to 16 weeks’ TPTI, and (3) 49 patients with >16 weeks’ TPTI. There were no significant differences in recurrence rates, neither when comparing all 3 groups together (P = .87) nor with pairwise comparisons (1 vs 2, P = .65; 2 vs 3, P = .99).
The pattern of failure was evenly divided between locoregional and distant (13 events each; 2 patients had both locoregional and distant recurrence). Local recurrence was rare, developing in only 3 patients and isolated in only 1 patient. Isolated regional recurrence developed in 9 patients. The median time to recurrence was 16 months (range, 7–37 months), with events evenly spread through the 30-month range. Eleven patients (46%) had salvage treatments, with 8 patients (33%) successfully salvaged. Sites of recurrence and salvage are summarized in Table 3. Therefore, in the cohort of 291 patients, only 4% developed a salvageable recurrence, and 3% were successfully salvaged.
Table 3.
Sites of recurrence and salvage therapy
| Site of recurrence | Patients (n = 24) | Salvage treatment | Successful salvage* |
|---|---|---|---|
| Local | 1 | 1 | 1 |
| Regional | 9 | 6 | 5 |
| Local and regional | 1 | 1 | 0 |
| Distant | 11 | 3† | 2 |
| Regional and distant | 1 | 0 | - |
| Local, regional, and distant | 1 | 0 | - |
Successful salvage defined as alive or dead without evidence of disease.
Solitary lung metastasis salvaged with surgery or radiation therapy.
When the mode of presentation or detection of relapse was reviewed, 10 patients were symptomatic and 14 had asymptomatic disease detected via surveillance imaging alone. Sites of relapse in the clinical- and imaging-detected groups are summarized in Table 4. The 8 patients who were asymptomatic and found to have distant disease all had lung metastases. Three patients had disease detected on an abnormal chest x-ray, 3 had lung nodules detected on a restaging CT of the head and neck, 1 was being followed for an abnormal CT scan chest at diagnosis (with findings not consistent with metastasis), and 1 patient was restaged after presenting with a suspicious finding at the primary site that proved to be false. Of the 11 patients who underwent salvage therapy, 4 had clinical symptoms and 7 were asymptomatic.
Table 4.
Site(s) of recurrence by presentation
| Mode of detection/presentation | Site of recurrence | n | Salvage treatment |
|---|---|---|---|
| Clinical | Regional | 4 | 2 |
| Local and regional | 1 | 1 | |
| Distant | 3 | 1 | |
| Regional and distant | 1 | 0 | |
| Local, regional, and distant | 1 | 0 | |
| Imaging | Local | 1 | 1 |
| Regional | 5 | 4 | |
| Distant | 8 | 2 |
Univariate and multivariate analysis
On univariate analysis, there was no correlation between primary tumor (T) stage (P = .5910), nodal (N) stage (P = .1996), p16/HPV status (double positive vs positive p16-negative HPV, P = .5044), overall American Joint Committee on Cancer stage (P = .15), International Collaboration on Oropharyngeal cancer Network stage (P = .1864), and smoking status at diagnosis (P = .8108) and the development of subsequent relapse. There was a higher incidence of relapse among patients who received induction chemotherapy, with crude rates of 12% versus 5% for those who did and did not receive neoadjuvant chemotherapy (P = .031). However, in multivariable analysis, this finding was not statistically significant (hazard ratio, 2.4; 95% confidence interval, 0.97–6.34; P = .08).
Discussion
Our study highlights that, for patients with HPV-associated squamous cell carcinoma of the oropharynx, a negative posttreatment PET scan had a negative predictive value of 92% with regard to predicting subsequent recurrence. Of those patients for whom recurrence was detected, salvage therapy was performed in less than half. Finally, limiting the analysis to asymptomatic patients, only 7 patients (2%) had detected disease amenable to salvage therapy.
A large body of literature has evaluated the role of PET as a tool for postradiation residual disease. The principal focus has been to determine the necessity of surgery for suspected residual disease, with the main conclusion being that the negative predictive value of PET is extremely high and that surgery can be avoided (13–16). Few studies have comprehensively assessed the ultimate negative predictive value of a posttreatment negative PET. In 2009, Yao et al (17) reported on 149 patients with head and neck cancer with a median follow-up of 32 months; these patients had an initial posttreatment PET scan. The 3-year disease free survival was 70.5%. Despite the limitation to head and neck cancer, the cohort was quite diverse: <42% of the initial cohort had oropharyngeal cancer, HPV status was not included, and 32% were treated with postoperative radiation. Patterns of disease recurrence were not described.
More recently, 2 groups have reported on the long-term outcomes of patients with posttreatment negative PET scans and have done subgroup analyses of their HPV-associated cohorts. Koshkareva et al (18) reported a negative predictive value of disease recurrence at 2 years of 93% in 40 patients. Other than treatment given with curative intent, details of therapy, particularly if patients had surgery, were not provided. Vainshtein et al (8) reported a negative predictivevalue of 91% to 98% in 98 patients with negative or near-negative postradiation PET scans. A range was reported because the analysis focused on primary site and neck recurrences separately, and the group did not report distant recurrence.
Several investigators have evaluated the role of subsequent PET/CT staging for patients with an initial (3-month) posttreatment negative scan and have suggested that the negative predictive rates are close to 98% on these repeat studies (8, 15, 17–20). In a cohort of 512 patients, Mcdermott et al (19) identified 214 patients treated for head and neck cancer (of whom about one-third had oropharyngeal carcinoma); these 214 patients had a negative posttreatment PET scan. Of these patients, 137 had a subsequent PET scan within 6 months, of which 114 were negative. The negative predictive value was 2%, but the false positive rate was 19%. An addition 8% had recurrences that developed before subsequent imaging.
In a smaller study than ours but with a similar population (HPV-positive oropharyngeal cancer treated with definitive radiation), Vainshtein et al (8) also found a 98% negative predictive value in subsequent scans but a 9% locoregional recurrence rate overall in those with subsequent scans.
Although hypothesis generating, it remains unclear if repeat PET/CT is cost-effective or the most efficacious mode of surveillance. Although our recurrence rates seem similar to those of other reports (18–20), several features were distinct. First, contrary to these other reports, the most common mode of recurrence in our series was distant. Some patients with oligometastatic lung disease in our series underwent successful salvage and demonstrated a protracted disease course. Systemic therapies, particularly newer novel agents, may prolong survival without cure in selected patients with distant disease. Thus, the rigor required for surveillance to detect distant disease is moot.
The other mode of recurrence that was fairly common was regional, occurring in 50% of the patients, with isolated recurrence in 38%. The salvage rate was relatively high (46%) in this subgroup, suggesting that of the 3 modes of recurrence (local, regional, and distant), identification of early regional recurrence may benefit the patient most. It remains unclear if functional imaging or anatomic imaging is better, although integrating sonography of the neck in lieu of CT or magnetic resonance imaging may be both more practical and cost efficient (21, 22).
Our data suggest that, in an asymptomatic patient, identification of recurrence was only half the overall rate. What is less clear from our observations is whether the symptomatic patients presented on an unscheduled visit because of their concerns or whether symptoms were noted on a history obtained during a scheduled appointment. The latter would suggest that routine surveillance should still be performed at the appropriate recommended intervals, with imaging selected based on the presence or absence of findings on the history and physical examination. Recognizing that the yield of subsequent routine imaging for this large subset of patients with HPV-associated oropharyngeal cancers with a posttreatment negative PET/CT will be low, the economic implications of how many imaging tests are acceptable in a population to detect a curable or noncurable recurrence is beyond the scope of this discussion.
Conclusions
The negative predictive value of any recurrence in nearly 300 patients with HPV-associated oropharyngeal cancer and a post-(chemo)radiation negative PET/CT scan is 92%. Asymptomatic patients with a negative posttreatment PET/CT scan have a 1.4% chance of having a local recurrence, a 4.1% chance of having a regional recurrence, and 5.5% chance of a distant recurrence. The utility of finding a potentially salvageable local, regional, and distant recurrence was 1%, 2.4%, and 1.7%, respectively. Therefore, for cost-effective follow-up, for patients with an initial negative posttreatment PET scan, we recommend regular clinical surveillance with imaging selected based on history and physical examination findings. Nodal recurrences, when isolated, were often successfully salvaged, suggesting that a surveillance program that has the greatest focus on the neck will be of more value.
Acknowledgments
S.P.N. is funded by the Australian Postgraduate Award, the Royal Australian, the New Zealand College of Radiologists Research Grant, and the Radiological Society of North America Fellow Grant. C.D.F. receives funding support from the National Institutes of Health, the National Cancer Institute Paul Calabresi Clinical Oncology Program Award, the MD Anderson Institutional Research Grant Program, and the Andrew Sabin Family Fellowship. C.D.F. received speaker travel funding from Elekta AB.
Footnotes
Abstract was presented at the 2018 Multidisciplinary Head and Neck Cancers Symposium, Feb 15–17, 2018, Scottsdale, Arizona.
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