Source: OncologyStat
Author: Thomas F. Pajak

CHANDLER, Ariz. (EGMN) – Human papillomavirus infection is clearly a prognostic factor in patients with head and neck cancer. But whether HPV status can be used to guide treatment decisions is far from clear, according to speakers at a head and neck cancer symposium sponsored by the American Society for Radiation Oncology.

The Investigator’s Perspective

Across trials that tested different regimens in heterogeneous populations with head and neck cancer, patients with HPV-positive disease have had at least a one-half reduction in the risk of death, relative to their counterparts with HPV-negative disease, began Dr. Maura L. Gillison, a professor of medicine and epidemiology at Ohio State University in Columbus.

“Clearly, HPV tumor status is prognostic,” she said, citing multiple factors that might explain why HPV-positive patients have better survival outcomes.

Certain attributes that track with HPV positivity – better performance status, younger age, lower T stage, and absence of anemia – are also favorable prognostic factors, she noted. And HPV positivity confers a better response to both radiation therapy and induction chemotherapy.

In addition, data from the RTOG (Radiation Therapy Oncology Group) 0129 trial of chemoradiation show that HPV-positive patients are less likely than their HPV-negative peers to experience a locoregional failure and to develop second primaries, although rates of distant metastases are similar.

“What we can conclude at this point is that the relative survival for the HPV-positive patient appears independent of therapy, as long as that therapy is within the standard of care,” summarized Dr. Gillison. “But what we care about – and what the patient cares about – is the relationship between therapy and absolute survival, which is unknown.”

In balancing the risks and benefits of therapy in HPV-positive head and neck cancer, one might propose intensifying therapy with the aim of making it a fully curable disease, she observed. Alternatively, one might propose deintensifying therapy with the aim of reducing toxicity and improving patients’ quality of life.

But it is unclear whether intensification would in fact improve survival, or whether deintensification would be safe, especially given that metastasis remains equally problematic in HPV-positive disease.

“Until we have data, treatment decisions should be masked to HPV status,” Dr. Gillison recommended, while acknowledging that that is easier said than done.

Adding to the urgency, statistical modeling by her group suggests that the number of cases could reach 20,000 a year by 2020, she said, up from 5,200 in 2004.

“We need to immediately address the issues of care for these patients in cooperative groups, as we are currently experiencing the tip of the iceberg of this epidemic,” she concluded. “So the bottom line [is,] enroll patients in trials.”

The Statistician’s Perspective

The logistics of conducting a trial of deintensified therapy for HPV-positive head and neck cancer are challenging, asserted Thomas F. Pajak, Ph.D., a senior statistician with the RTOG in Philadelphia.

This as-yet hypothetical trial would likely enroll only HPV-positive patients, who also are likely to have an especially good prognosis because they have additional favorable characteristics, such as lower T stage, lower N stage, and fewer pack-years of smoking, he said.

The trial would compare standard therapy (chemoradiation) with deintensified therapy (reduced chemotherapy, reduced radiation therapy, or both) and would have a noninferiority design.

“An important question is, How long will the trial take?” Dr. Pajak commented. Under certain assumptions, including a 30% acceptable relative margin of inferiority in survival, conventional statistical parameters, and a required sample size of 700 patients, the time from trial opening to completion of the final analysis would be a staggering 20.2 years.

Hence, patient follow-up would be challenging. Moreover, patients would be required to come into the clinic for evaluation of quality of life and especially late effects. “When we are deintensifying, we think we are doing less harm, but we need the documentation,” he explained.

Results would have to be monitored throughout that duration as well, noted Dr. Pajak.

In addition, reporting of the trial’s results could be problematic, given that interim analyses are typically published only if the findings are highly significant (which he defined as P less than .001). “That means the chances are very unlikely that we will have results for dissemination before 20 years,” he said. “Yes, that’s unacceptable.”

“Here is the dilemma: We need somehow to release the results early to aid the investigators in making the treatment decisions without compromising the trial, because we want the patients out there and the doctors to have some comfort level while participating,” he commented.

To that end, he noted that new criteria have been proposed for reporting interim results of randomized noninferiority trials after patients have completed their treatment and some minimum duration of follow-up (J. Clin. Oncol. 2005;23:5831-6). This approach would allow earlier public dissemination of the data at meetings and in publications.

A final challenge is future relevance, according to Dr. Pajak. “Taking a long look, the critical question to me is, Is the favorable HPV trial’s answer even going to be relevant in 20 years?” he said. “That’s what we have to struggle with.”

The Patient’s Perspective

Receiving a diagnosis of HPV-related oral cancer has numerous life-altering ramifications for patients, according to Stephen Reynolds, a survivor of stage IV, HPV-positive, base-of-tongue cancer.

One issue is the shock of receiving an oral cancer diagnosis despite being at low risk for this disease by past criteria, he said, noting that he had always been athletic and never smoked. “One of my own doctors said, ‘This [cancer] used to be a VA hospital kind of thing,’ ” he commented. “It’s a bit of a struggle to get through that.”

Next is the impact on patients and on their interpersonal relationships of having a disease that is linked to a sexually transmitted virus, which may necessitate discussions with current partners and precipitate lingering questions about obligations to past partners.

“I had a great doctor, and I must say that we didn’t talk about this at all,” commented Mr. Reynolds, who works as a marketing executive in the software field and lives in New York City with his wife and young son.

In addition, in his case, testing has shown that HPV is still present. “It’s not threatening,” he commented. “But to know that the virus is in you, and that it’s lurking around in there, is pretty unsettling.”

When it came to treating his cancer, Mr. Reynolds said he was advised to be as aggressive as possible. “What was really emphasized to me was, look, you are young, you can take it, you have never been a smoker, so hit it as hard as you possibly can,” he said. Therefore, he chose to undergo surgery followed by concurrent chemoradiation.

About 2½ years after completing treatment, he is doing well, but has a number of lingering after-effects, he reported, including pain, diminished taste, loss of sensation, some difficulty with chewing and swallowing, reduced stamina, and – perhaps most importantly, given that his occupation requires frequent presentations – some speech issues.

“One has to wonder, if the road had been different,” he reflected, noting that in retrospect, he might have opted for less extensive treatment if it were known to be a safe alternative.

The understanding of HPV-related oral cancer has advanced considerably since his diagnosis, observed Mr. Reynolds, who applauded efforts to explore new treatment options for this disease.

“It sounds like … if I were to have this [cancer] in 2 more years, there might be some more choices presented to me, which I think I would welcome as a patient who tried to be informed,” he said.

Dr. Gillison reported that she has received research funding from Merck and Co. Dr. Pajak reported receiving consulting fees from Tragara Pharmaceuticals Inc. Mr. Reynolds reported having no conflicts of interest related to his talk.