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A prospective analysis of a phase II Eastern Cooperative Oncology Group study confirms what has up to now been reported only in retrospective, single-institution studies—that head and neck squamous cell cancer patients infected with the human papilloma virus have significantly better survival than do their counterparts without the virus.
Human papilloma virus (HPV) positivity conferred a 79% lower risk of death in the multicenter ECOG 2399 study, Dr. Carole Fakhry reported. She said HPV status should now be considered a biomarker for prognosis in head and neck squamous cell cancer (HNSCC).
Moreover, these results may necessitate a reinterpretation of survival rates in previous trials to determine whether survival differences were in fact due to HPV status, rather than to the actual therapy that was used, according to Dr. Fakhry of the Johns Hopkins Medical Institutions in Baltimore.
The primary objective of ECOG 2399 was to assess organ preservation with taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III and IV larynx and oropharyngeal cancer patients.
The trial also sought to estimate disease-free survival and patterns of failure.
Dr. Fakhry and associates evaluated pathologic tissue samples from 96 study participants for the presence of HPV infection, and then went on to determine prognostic factors, treatment response, and survival outcomes in terms of HPV status.
HPV status—in particular HPV-16, which is the dominant viral isolate known to be responsible for a subset of HNSCC—was assessed with in situ hybridization, polymerase chain reaction, and line blot tests.
These tests also screened for HPV-31, 33, and 35, which are the other isolates that have been linked to HNSCC.
A total of 40% of patients (38) were found to be HPV-positive, and all had oropharyngeal tumors. They were more likely to have a better ECOG performance status, and lower cumulative lifetime exposure to smoking than were HPV-negative patients.
They were also more likely to be male, have less weight loss on presentation, and present with a stage T2 tumor, Dr. Fakhry reported.
HPV-positive patients had a higher response to induction and chemoradiation therapy. Response rates after induction chemotherapy were 82% for HPV-positive patients vs. 55% for HPV-negative patients (P = 0.01). After chemoradiotherapy, they were 84% vs. 57%, respectively, (P = 0.07).
At a median follow-up of 39 months, the risk of progression was 72% lower and risk of death was 79% lower in HPV-positive patients, compared with HPV-negative patients. These figures were derived from a Cox proportional hazards model, Dr. Fakhry said.
Discussant Thomas F. Pajak, Ph.D., of the Radiation Therapy Oncology Group in Philadelphia said these results are impressive at first glance, but that he was troubled by the Cox analysis in the trial.
He proposed that the investigators generate a new Cox model, restrict it only to oropharyngeal patients, and compare HPV status to no more than three other factors in order to obtain a new, and more reliable, estimate of the risk of death.
"A Cox model with too many variables in it is unreliable," Dr. Pajak remarked.
In another presentation that looked at HPV-associated HNSCC, Dr. Anil K. Chaturvedi, of the National Cancer Institute in Rockville, Md., reported that HPV-related HNSCC has increased in the United States during the last 3 decades, particularly among white men between the ages of 40 and 59 years.
Using data from the Surveillance, Epidemiology, and End Results (SEER) registry for the period 1973-2003, Dr. Chaturvedi and co-investigators also found that HPV-related HNSCCs were being diagnosed at more advanced stages and at significantly younger ages. These trends became apparent in the early 1990s. Meanwhile, the incidence of cancers not related to HPV decreased in both men and women, especially in those over the age of 40.
He concluded that the increasing incidence of HPV-linked HNSCC could be due to changes in sexual behavior, and that the decreasing incidence of cancers not related to HPV could be due to the decreased prevalence of smoking.
Fakhry C. et al. Prognostic significance of human papillomavirus (HPV) tumor status for patients with head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-center phase II clinical trial. Abstract 6000.
Chaturvedi A. et al. Incidence trends for human papillomavirus-related (HPV-R) and unrelated (HPV-U) head and neck squamous cell carcinomas (HNSCC) in the United States (US). Abstract 6001.
Commentary |
These studies on HPV represent a critically important topic, since HPV-related oropharynx carcinoma is beginning to constitute a significant portion of the oncologist's practice in head and neck cancer. In our experience at the Dana-Farber Cancer Institute, HPV is a factor in almost 50% of the patients we see. As many as 25% of patients in the community are HPV-positive, young, nonsmoking, and nondrinking individuals. Their life expectancy is higher, but they often present with more advanced disease. I believe this "epidemic" of HPV-related disease is going to change the demographic and the urgency of treatment in this cancer. The fact that HPV-positive tumors have a better prognosis than oropharynx cancer caused by smoking is extremely important. Curing these patients will mean dealing with long-term sequelae in a young population living longer after treatment—living with scarring and fibrosis, as well as other complications from radiation, including a risk for second cancers. The prevalence of HPV-related oropharynx cancer also raises other issues. Because this is a sexually transmitted disease in which sexual practices increase risk, we must ask whether the patient's significant other or sexual partners should be vaccinated or tested. Do they need surveillance? And what about children? It is possible that HPV is transmitted by saliva. We don't have these answers yet. ECOG 2399, which showed survival to be better in patients with HPV-positive tumors, involved a very aggressive sequential treatment plan of induction chemotherapy followed by chemoradiotherapy. We do not have data showing that we can reduce aggressive curative treatment with these patients; i.e., use less intensive chemotherapy or radiotherapy and achieve the same effect. At Dana-Farber, we have seen distant metastases in patients presenting initially with HPV-related oropharynx cancers and in those treated with chemoradiotherapy without systemic therapy. Our experience suggests we must take this report with a grain of salt. The HPV-positive patients had better overall survival, but they also had better performance status, were less likely to smoke, were healthier, and were better able to tolerate treatment. We need to know more about these factors, particularly, treatment tolerability. These are prognostic factors that significantly affect outcome. Looking at future treatments, HPV-induced oropharynx carcinoma is a poster child for targeted therapy. The HPV E6 and E7 viral gene products are necessary for tumor cell survival, and they can serve as specific targets for gene therapy, immunotherapy, siRNA, antisense, and other targeted approaches. We should look intensively at these possibilities; hopefully, there will be new funding for research in these novel approaches. As we move into the next decade, this should be a major effort on the part of our colleagues in translational research. Using targeted agents, I believe that within 5 years we can cure this group of patients without resorting to chemotherapy or radiation therapy. — Marshall R. Posner, M.D.
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