Discoveries related to human papillomavirus (HPV) continue to generate new implications for head and neck oncology. HPV prevalence in oropharyngeal tumors increased from 16.3 percent during the 1980s to 72.7 percent during the 2000s, with increasing recognition that HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is a distinct entity from the tobacco-associated HPV-negative OPSCC seen so frequently in the past.
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“HPV-positive disease has a better overall survival, not just in terms of locoregional recurrence, but even after distant metastases have been found,” says Brian B. Burkey, MD, Vice Chairman of Cleveland Clinic’s Head & Neck Institute. “This is a different disease. It has a different, virally driven etiology, a different presentation and affects a different patient population, with very different outcomes upon treatment. So we have to treat it as a different disease.”
In a retrospective review of 291 OPSCC cases treated at Cleveland Clinic during an 18-year period, Dr. Burkey and colleagues found that HPV-positive disease was associated with a longer interval to distant metastases than HPV-negative disease, and that patients with HPV-positive disease tended to have distant metastases to sites that are atypical for OPSCC. The study was published in JAMA Otolaryngology – Head & Neck Surgery.
Focusing on patterns of recurrence
Investigators from the head and neck cancer multidisciplinary team noted that, although HPV-positive disease has a better prognosis, distant metastatic failure may now represent the most common cause of death in these patients, and yet knowledge about distant metastases remains limited.
Most studies have reported similar rates of distant metastases in patients with HPV-positive and HPV-negative OPSCC. However, some studies have suggested that HPV-positive disease may have a different pattern of spread, with metastases more often involving multiple organs and developing later than HPV-negative tumors.
The Cleveland Clinic and Rush University researchers thus sought to characterize the natural history of distant metastases in patients with HPV-positive as compared to HPV-negative OPSCC.
Patients, treatments and follow-up
In their single-institution retrospective cohort review, the investigators examined the rate, pattern and timing of distant metastatic failure in both subsets of advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy (CRT).
They identified patients using a tumor registry and electronic medical records. Patients included in the study were treated at Cleveland Clinic from 1996 through 2013 for nonmetastatic, locoregionally-advanced disease – i.e., American Joint Committee on Cancer stages III to IVB. HPV status was determined with genotyping and/or immunohistochemical analysis using the p16 protein as a surrogate marker. HPV status was determined retrospectively in patients treated prior to the 2007 institutional adoption of routine HPV testing.
During the study period, standard treatment generally consisted of radiotherapy with 70 Gy delivered in 35 fractions with once-daily fractionation for seven weeks Prior to 2008, the institutional approach was to administer concurrent chemotherapy with two cycles of cisplatin and fluorouracil, but high-dose bolus cisplatin or weekly cetuximab (Erbitux®) has become increasingly common in recent years.
Routine follow-up occurred every three months for the first two years after completing therapy, every four months for the third year, every six months during years four and five, and annually thereafter, with repeated imaging studies obtained approximately 12 weeks after completion of treatment and then subsequently as clinically indicated.
Differing patterns of distant metastases, different overall survival
Figure 1. Overall Survival After Distant Metastatic Failure in Patients
With Human Papillomavirus–Initiated (HPV+) and HPV- Oropharyngeal
Squamous Cell Carcinoma
Of the 291 patients who met inclusion criteria, 86.6 percent had HPV-positive disease and 13.4 percent had HPV-negative disease. There was no significant difference in the chemotherapeutic regimen or radiotherapy treatment between groups.
At a median follow-up of 3.1 years, 12.7 percent of the identified patients with OPSCC developed distant metastatic disease after definitive treatment; 28 were patients in the HPV-positive group and nine had HPV-negative disease. The Kaplan-Meier projected three-year distant control rate was significantly higher in patients with HPV-positive disease (88 percent versus 74 percent; p = .01).
All HPV-negative patients experienced treatment failure within 16 months, whereas those with HPV-positive disease developed distant metastases as late as six years after diagnosis. Thus, median time to distant failure was longer in patients with HPV-positive disease (16.4 versus 7.2 months; p = .008).
Metastases in the HPV-positive group also included several subsites and atypical sites of metastasis for OPSCC, including brain, kidney, skin, skeletal muscle, axillary and intra-abdominal lymph nodes.
Since this was a retrospective study reflecting the group’s experience, the findings were not entirely surprising. Dr. Burkey notes that the team’s experience was part of the impetus for pursuing this line of thought. “All of us were seeing these unusual recurrences with HPV-positive disease, far out from diagnosis and initial treatment,” he says.
Table 1. Metastatic Sites
HPV = Human papillomavirus; HPV+ = cancer is HPV-initiated; HPV- = cancer is not HPV-initiated
Implications for managing HPV-positive disease
The study’s results are part of an emerging framework that may support future clinical trials and advances in personalized medicine. Efforts to predict aggressive versus indolent p16-positive OPSCC have begun, and data on differing patterns of recurrence may present an opportunity to extend survival as well.
“What we are finding is that, in people with HPV-positive disease, we can treat them and gain significant long-term survival,” says Dr. Burkey. “In the HPV-positive patients, we have to be more vigilant about looking for distant metastases beyond two years. In addition to looking for them over a longer time frame, we have to be sensitive to looking for them in places we are not used to looking.”
When asked about an algorithm for post-treatment surveillance, Dr. Burkey acknowledges the complexity of the different clinical scenarios and the challenges of applying a single optimal standard for frequency and duration of follow-up.
“We can’t say get PET scans at three and five years – there’s not enough data for that,” he says. “I’m not sure that there’s a defined algorithm. Frequent clinical monitoring for locoregional disease every three months for the first two years, and then expanding out to maybe every six months by five years, is appropriate. Additionally, a PET scan at one year may be justified, followed by yearly chest X-rays, with more testing determined by patients’ symptoms. Anyone presenting with unusual symptoms should be worked up.”
With regard to initial therapy, some clinicians are considering whether less aggressive therapy — so-called deintensification — might be feasible for patients with HPV-positive disease, Dr. Burkey says. He notes, though, that available data in support of deintensification are limited.
Moving forward: A focus on prevention
Although uncommon, distant metastases represent the major form of disease recurrence in HPV-positive OPSCC and lead to poor outcome.
“We have to be thoughtful about how we do surveillance and how we treat distant recurrences, and do it differently than we have before,” Dr. Burkey says.
“The other thing is that all of us who treat this disease believe is that it is preventable. Very few men are currently vaccinated against HPV — certainly less than 30 percent in the target population of adolescents and early young adults, and that needs to be driven up. We ought to be thinking of how we prevent this in the first place.”
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