HPV causes surge in oral cancer rates.
Kevin Pruyne knew he didn’t fit the stereotype of a hard drinker or heavy smoker who one day develops an oral cancer.
The 52-year-old mechanic had been working a three-week stint in a remote section of northern Alaska, repairing trucks on an oil field, when he noticed a hard lump beneath his jaw while shaving. For nearly three months, as Pruyne was prescribed antibiotics for a possible infection and then later shuttled between physician specialists, he kept hearing the same thing: the lump could not be cancer.
Pruyne only occasionally consumed alcohol and had never smoked. His wife, Kathy, began researching her husband’s symptoms, which included repetitive throat clearing, a nagging sensation that something was lodged in his throat and ringing in his ears. And the lump, which looked like the top half of an egg, felt solid to the touch.
This wasn’t some inflamed lymph node from a lingering head cold, Kathy Pruyne says. “He had every symptom [of cancer], but nobody would listen to me.”
For researchers and clinicians alike, determining appropriate treatment has taken on new urgency: HPV-positive oropharyngeal malignancies—most typically found on the tonsils or at the base of the tongue—increased 225 percent from 1988 to 2004. If current trends continue, HPV-positive oral cancer cases could soon surpass cervical cancer diagnoses, according to a 2011 study published in the Journal of Clinical Oncology.
As researchers have revisited data from prior oral cancer treatment studies, they’re realizing that patients with HPV-positive tumors respond better to chemotherapy and radiation. One study, which retrospectively analyzed treatment outcomes for stage 3 and stage 4 oropharyngeal patients based on their HPV status, found that the three-year overall survival rate was 82.4 percent in patients with HPV-positive tumors. Among those who tested negative, the three-year overall survival rate was 57.1 percent, according to the findings published in 2010 in The New England Journal of Medicine.
With that in mind, research trials are being launched to determine whether treatment can be modified in some way or even dialed back. The goal? To achieve the same survival with fewer of the swallowing difficulties, taste problems and other debilitating side effects.
“For a subset of patients, we’ve actually achieved a pretty high cure rate,” says James Rocco, MD, PhD, a head and neck surgeon at Massachusetts Eye and Ear Infirmary, and director of head and neck cancer research at Massachusetts General Hospital. “And the question is: Can we maintain that cure and reduce some of the major side effects of treatment?”
It’s very clear that HPV-positive oropharyngeal cancer is a completely different entity from HPV-negative.
But researchers and oncologists have only just begun to understand HPV-positive malignancies. “It’s very clear that HPV-positive oropharyngeal cancer is a completely different entity from HPV-negative,” says Stephen Liu, MD, a head and neck cancer specialist, and an assistant professor of medicine at the University of Southern California.
“We think that it’s going to impact treatment in the future,” Liu adds. But, he stresses, outside of a clinical trial, he “would really discourage anyone from receiving less treatment because their tumor is HPV-positive.”
Traditionally, tobacco and alcohol use have been the primary culprits for triggering cancers in the oropharynx and nearby areas of the mouth, as well as other structures in the throat, such as the larynx. Each year, nearly 40,000 Americans develop cancer of the oral cavity or pharynx. Men are more than twice as likely to receive a diagnosis.
But, until recent years, not someone like David Hastings. The certified public accountant was 58 years old, a lean cyclist who rode some 100 miles each week, when he learned six years ago that he had stage 4 oropharyngeal cancer located at the base of his tongue. Clinicians at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., also were puzzled, as the Gulfport resident tells it. “They said the typical oral cancer patient is a man in his 60s or 70s who sits in a bar all day and drinks and smokes.”
The association with HPV emerged from a perplexing conundrum, says Kian Ang, MD, PhD, a professor in the department of radiation oncology at M.D. Anderson Cancer Center in Houston. As cigarette smoking has declined in recent decades, so have head and neck cancers, with the exception of tumors in the oropharynx. (The region encompasses the middle section of the throat, along with the back portion of the tongue, the soft palate and the tonsils.) That statistical anomaly, Ang says, “gave us the first clue that something else might be going on.”
Cancers located in the tonsils or at the base of the tongue can sometimes spread undetected, not becoming visible until they’ve reached the nearby lymph nodes. Some early symptoms include swallowing difficulties or a sudden change or hoarseness in the voice. Like Pruyne, Hastings first became concerned when he felt a mysterious lump while shaving. “Totally painless, no sore throat—nothing,” he says.
Oropharyngeal tumors can be classified as stage 3 or 4 but still be considered localized, as long as they have not spread beyond lymph nodes and structures in the head and neck. Pruyne, whose cancer had migrated to numerous nodes on his neck’s right side, recalls how his oncologist hurried out of the room when his imaging test results became available.
The doctor had already warned Pruyne that he could offer relatively little help if the cancer had spread to his chest. “When he came back up, he was visibly relieved,” Pruyne recalls. “And he said, ‘Your lungs are clear.’”
Although radiation and chemotherapy can be difficult, some patients prefer to take that route, rather than run the risks of surgery, Rocco says. “For advanced local disease, removing the back of the tongue or the soft palate has huge consequences for people,” Rocco says. “They can’t eat. They don’t speak so well.”
But given that patients with HPV-positive tumors are typically diagnosed at a younger age, with potentially decades ahead of them to cope with long-term side effects, the aggressiveness of today’s chemotherapy and radiation regimens are also questionable, he says.
Clinical trials are recruiting patients to answer a question that’s relatively rare in cancer: Can treatment be ramped down? One closely watched phase 3 trial will assess whether Erbitux works as well in HPV-positive patients as the long-standing cisplatin-based chemotherapy regimen.
Cisplatin has been one of the standard drugs used in head and neck cancer, but it’s “very toxic,” says Andy Trotti III, MD, the study’s principal investigator and director of radiation oncology clinical research at Moffitt Cancer Center. The platinum-based drug can impact kidney function and sometimes damage hearing, among other side effects, he says.
Erbitux, which targets the epidermal growth factor receptor (EGFR), primarily affects the skin, Trotti says. In the phase 3 trial, now recruiting HPV-positive patients, the five-year overall survival of patients on Erbitux will be compared with those taking cisplatin. Both groups will receive IMRT.
Another ongoing trial is looking at whether the IMRT regimen can be shortened from six to five weeks, thereby delivering a lower dose of radiation in HPV-positive patients. The patients enrolled in that phase 2 trial, who also will receive cisplatin, paclitaxel and Erbitux, will be followed for two years.
The study represents a “first step” toward learning whether less radiation can be safely prescribed for HPV-positive patients, Liu says. Since radiation’s effects are cumulative, the extra week of radiation adds “a significant amount of toxicity.”
Meanwhile, the impact of HPV status on surgical decisions appears to be the subject of some unresolved debate. Given that HPV-positive oropharyngeal malignancies respond well to chemotherapy and radiation, Trotti says, “there has been a real trend away from surgery.”
But new surgical techniques are providing other options for HPV-positive patients who might prefer to limit the long-term side effects of chemotherapy and radiation, says Bert O’Malley, Jr., MD, chairman of the department of otorhinolaryngology of the University of Pennsylvania Health System.
Along with a physician colleague, O’Malley has developed a robotic surgery protocol called TransOral Robotic Surgery. With the assistance of tiny robotic arms and three-dimensional cameras, O’Malley operates through the patient’s mouth, enabling him to remove difficult-to-reach tumors.
A surgery that previously required between six and 16 hours might only take two, he says. Also the approach results in less scarring and fewer surgical complications than the traditional surgery, which may require the jaw to be split, he says.
It’s a new era in HPV-positive treatment, Rocco says. To make his point, he tells of a patient who recently walked in asking to be referred for robotic surgery. The gold standard is still to wait for clinical trial results, but that could take five-plus years, he adds.
There are people who are risk-takers. They’ll look at the data and they’ll make a decision, weighing cure and long-term side effects.
HPV-positive patients are frequently “savvy young professionals in the prime of life,” who sort through the latest research online, Rocco points out.
“There are people who are risk-takers,” he says. “They’ll look at the data, and they’ll make a decision, weighing cure and long-term side effects.”
Despite the rigors of treatment, Pruyne was able to resume his job near the Arctic Circle within a few months. He hopes to soon be telling a tale similar to Hastings’, who returned to his biking routine about a year after wrapping up treatment.
Hastings still copes with dry mouth and a reduced ability to taste. But the last time he visited Moffitt for an annual checkup, it felt more like a social call. After some chatting, he quips: “They said, ‘Get out of here. We need to spend more time with people who are sick.’”
Pruyne received a diagnosis of stage 4 oral cancer, which started with a tumor at the base of his tongue. He had already begun chemotherapy when he learned that researchers had discovered an association between the human papillomavirus (HPV) and increasing rates of oropharyngeal cancers. He asked that his tissue be tested; the results came back positive. Pruyne says he wanted to know whether his cancer was caused by HPV because “the prognosis is considerably better with HPV-positive cancer.” He adds he “wanted to hear that there was a better chance of a cure.”
But if there’s any concern, patients may receive six weeks of radiation for smaller tumors and seven weeks for larger ones, Ang says. Intensity-modulated radiation therapy (IMRT) is used because it better targets the radiation and thus can limit damage to the salivary glands, reducing dry mouth, as well as damage to other normal tissues, Ang says.
For larger and more aggressive tumors, adding chemotherapy to radiation therapy has been shown to extend survival. One meta-analysis published last year, based on 87 studies involving more than 16,000 patients, analyzed results by tumor location. Researchers found that the combination approach increased five-year overall survival by 8.1 percent in oropharyngeal patients compared with those who didn’t receive any chemotherapy.
The chemotherapy is believed to boost the effectiveness of the radiation, but at a cost—amplified side effects for the patient. The list of potential side effects is lengthy, with so many vulnerable structures and nerves packed into the head and neck area, Liu says. Patients can develop ulcers in their mouth and down their throat, he says. Their salivary glands can generate thick secretions that make it difficult to swallow and to eat.
“The ability to taste, to speak, to salivate,” says Liu, ticking off several more. “Dry mouth. These things can often be permanent. It’s a necessary evil right now because we do what we need to do to cure the cancer.”
Pruyne received two cycles of a cisplatin-based protocol that also included Taxotere (docetaxel) and 5-FU (fluorouracil). Then he started the biologic agent Erbitux (cetuximab) along with hefty doses of IMRT, delivered twice daily for six weeks.
Pruyne’s oncologist warned him that the treatment would be difficult, and it was. He endured radiation burns around the right side of his neck and had to use a feeding tube for two months.
Starting with a pivotal study published in 2000, researchers began honing in on the role of HPV. Of the 150-plus strains in the HPV family, more than 40 are believed to be transmitted through sexual contact, including anal, genital and oral, according to the National Cancer Institute. The body’s immune system typically eradicates the viruses in a few years before any symptoms emerge (but, in some cases, the cells remain molecularly altered forever). Several of the HPV strains to date, most frequently HPV type 16, have been linked to oral malignancies.
Increasingly, HPV-16 has become a major player in those oral malignancies, according to last year’s Journal of Clinical Oncology study, which projected an explosion in cases in the decades to come.
When researchers studied 271 tissue samples in previously diagnosed patients, HPV prevalence was identified in only 16.3 percent of those collected between 1984 and 1989. Between 2000 and 2004, 72.7 percent of specimens tested positive, a trend that also perhaps correlates with population-wide increases in oral sex, the researchers wrote.
The analysis also highlighted survival differences. If tumors tested HPV-positive, the median survival was nearly 11 years versus 1.6 years for people whose tumors didn’t carry the virus.
Some of the strides in oral cancer treatment that physicians thought they were achieving can at least be partially explained by the emergence of a less aggressive form of cancer, Ang says. “The other part of the improvement,” he says, “is really due to the addition of chemotherapy and the use of high-precision radiation.”
To thwart oropharyngeal malignancies, cancer specialists may incorporate a mix of treatments, including surgery, radiation and chemotherapy, depending upon the location and the aggressiveness of the tumor involved. Ang estimates that only about one-third of patients will undergo surgery. If the tumor can be removed and there’s no evidence that it’s spread to lymph nodes, radiation may not be needed, he says.