ASCO 2010-HPV STATUS PROGNOSTIC IN OROPHARYNGEAL CANCER

June 16, 2010 (Chicago, Illinois) — The human papillomavirus (HPV) status of a tumor is a "strong and independent" prognostic factor for survival in patients with oropharyngeal cancer.

This was the conclusion of a new study presented here at the American Society of Clinical Oncology 2010 Annual Meeting and simultaneously published online June 7 in the New England Journal of Medicine.

The median 3-year rate of overall survival was 82.4% for patients with HPV-positive tumors (n = 206) and 57.1% for patients with HPV-negative tumors (n = 117; P < .001).

The patients all had stage 3 or 4 oropharyngeal squamous cell carcinoma and were randomized to 2 different radiotherapies, each combined with cisplatin therapy. There was no significant difference in survival between the 2 radiotherapy groups.

The American investigators found that the HPV-positive patients had a 58% reduction in the risk for death (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.27 - 0.66); the hazard ratio was calculated after controlling for age, race, tumor and nodal stage, tobacco exposure, and which radiotherapy a patient underwent in the trial.

As an outgrowth of their study, the investigators developed a novel risk model for oropharyngeal cancer patients.

"A combination of tumor HPV status, pack-years of tobacco smoking, and cancer stage may be used to classify patients as having a low, intermediate, or high risk of death," write the study authors, including senior author Maura Gillison, MD, PhD, from the Ohio State University Comprehensive Cancer Center in Columbus.

They also ask a provocative question about low-risk patients and their need for chemoradiotherapy — given the enduring adverse effects such as xerostomia and dysphagia.

"Whether patients with HPV-positive tumors who are considered to be in the low-risk category can be spared the long-term complications of intensive, multimodal therapy without compromising their survival is now a highly relevant clinical question," the authors write.

A More Definitive Finding

Previous studies have shown that, in this setting, patients with HPV-positive tumors have better survival than those with HPV-negative tumors, write Dr. Gillison and her coauthors.

However, because of small study samples in those studies, "other favorable prognostic factors associated with tumor HPV status (e.g., early tumor stage or young age) could not be ruled out as an explanation for the observed difference in survival," they write.

The size of the study, with its 323 patients, "enable the authors to control for many variables and to conclude that HPV status was a critical independent prognostic determinant," notes Douglas Lowy, MD, and Karl Munger, MD, in an editorial that accompanies the study.

Dr. Lowy is from the Center for Cancer Research of the National Institutes of Health and Dr. Munger is from Harvard Medical School in Boston, Massachusetts.

The new study is an analysis performed within a randomized clinical trial conducted by the Radiation Therapy Oncology Group (RTOG 0129), which examined whether accelerated fractionation radiotherapy is superior to standard fractionation radiotherapy when each therapy is combined with concurrent cisplatin.

To be eligible in the trial, which enrolled 743 patients from 2002 to 2005, patients had to have had a squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. The analysis focused only on the patients with oropharyngeal cancers.

Same But Different

In their editorial, Drs. Lowy and Munger observe that the 2 classes of oropharyngeal squamous cell carcinoma seem to have "distinct causes."

The HPV-positive cases are associated with sex-related risk factors (increased likelihood of orogenital activity) and the HPV-negative cases are associated with tobacco and alcohol consumption, they write.

However, data from the study suggest that smoking has a negative effect on prognosis in both HPV-positive and HPV-negative cases, Drs. Lowy and Munger point out.

The editorialists also note that "clear cut molecular differences" between the 2 classes of carcinoma have been identified.

Nearly all HPV-positive cases express the viral E6 and E7 oncoproteins, which "may render the HPV-positive tumors more immunogenic than the HPV-negative tumors," they write.

Serologic assays detect anti-E6 or anti-E7 antibodies in many patients with HPV-positive tumors, note the editorialists. Also, a higher proportion of patients with HPV-positive tumors have partial or complete responses to treatment.

In summary, it seems clear that HPV-positive and the HPV-negative oropharyngeal squamous cell carcinomas are "distinct entities."

The study authors believe that this means that future clinical trials "should be designed specifically for patients with HPV-positive or HPV-negative squamous cell carcinoma of the head and neck."

Reanalysis of existing clinical trial data is also in order, say Dr. Gillison and colleagues, because it might uncover some "therapeutic implications" for patients with the different HPV types.

Different Levels of Risks: Can Some Patients Forgo Treatment?

The investigators report that HPV status was the major determinant of survival, followed by pack-years of tobacco smoking (<10 vs >10), then nodal stage (n0 to N2a vs N2b to N3) for HPV-positive tumors and tumor stage (T2 or T3 vs T4) for HPV-negative tumors.

Using a recursive partitioning analysis, they classified the patients in the study into 3 categories with respect to risk for death:

* Low risk had a 3-year survival rate of 93%
* Intermediate risk had a 3-year survival rate of 70.8% (HR for the comparison with low risk, 3.54; 95% CI, 1.91 - 6.57)
* High risk had a 3-year survival rate of 46.2% (HR for the comparison with low risk, 7.16; 95% CI, 3.97 - 12.93).

All HPV-positive patients were considered low risk unless they were smokers with a high nodal stage (N2b to N3) — then they were considered intermediate risk.

All HPV-negative patients were considered high risk unless they were nonsmokers with stage T2 or T3 tumors — then they were considered intermediate risk.

Currently, there is no evidence to guide treatment decisions for individual patients on the basis of HPV status, note the study authors. However, they see their study as a basis for future clinical research, including the possibility, as noted above, that low-risk patients might not receive radiotherapy, given its serious adverse effects.

Dr. Gillison has disclosed no relevant financial relationships. Dr. Lowy reports receiving royalties from Merck and GlaxoSmithKline for technology related to the HPV vaccine licensed by the National Institutes of Health to the companies. Dr. Munger reports being a consultant to Arbor Vita and on the Merck speakers bureau.

N Engl J Med. Published online June 7,2010. Abstract, Abstract