After years of radiating her patients post-surgery, Dr. Sana Karam, was determined to find a better approach to treating head and neck cancer, which strikes about 66,000 people in the United States every year.

The idea, explored in petri dishes and with mice by Karam’s team at the University of Colorado School of Medicine, was to target tumors with three presurgical sessions of hyperfocused radiation all in one week rather than the usual six or seven weeks of 30 to 35 post-surgery radiation sessions.

Unlike most radiation treatments, the aim wouldn’t be to kill the tumors directly but to wake up the patient’s immune system to get the job done. If it worked, patients might avoid the life-altering impacts of the standard of care: invasive surgeries for the removal of at-risk tissues and reconstruction surgery followed by extensive radiation treatments.

Karam is a radiation oncologist, and in 2018, launched a small, U.S. Food and Drug Administration phase 1 clinical trial at the UCHealth University of Colorado Hospital on the Anschutz Medical Campus. The primary goal at this stage was to test whether the new approach was safe. But the secondary aim was what really interested Karam: Could this sort of radiation prime the immune system in a way that would, with a little help from an immunotherapy drug called durvalumab, shrink tumors more effectively?

As Karam and her colleagues reported in a study that landed on the cover of the November 2022 issue of Nature Cancer, the answer looks like an emphatic “yes.”

Trial focused on head and neck cancer treatments produce ‘unheard of’ results

In cancer clinical trials, findings of marginal progress are common – a few weeks of added life expectancy, a few percentage points of greater drug efficacy. But in this case, the results were stunning. Once the team settled on a particular radiation dose, 88.9% of patients experienced total or near-total (95% or more) clearing of their tumors, Karam’s team found.

“We got close to 90% complete response or major pathologically complete response rates, which is outstanding,” Karam said. “It’s unheard of. I was shocked.”

Previous studies had cast doubt on the ability of immunotherapies to knock back non-HPV head and neck cancers. The problem has a couple of possible explanations, Karam said. In some cases, immune cells that initially target the tumors become “exhausted” from fighting the cancer. In others, if overstimulated, the body suppresses its initial immune response to the tumor by releasing a wave of immunosuppressive cells. It’s similar to when, after catching a cold, the immune system revs up for bit, but then calms itself back down, Karam said.

Karam’s lab work had led her to suspect that the immune system might generate a sustained response to these so-called “cold” tumors if coaxed to wake up to them. That wake-up call would come from chemical signals the tumor itself produced when heated up with radiation. At the same time, a shorter course of immunotherapy could avoid the immune system from overheating and then exhausting itself with respect to the cancer.

Her team recruited 21 patients over about three years, most with serious (stages 3 and 4) cases of head and neck cancer. Cory Rivers was one of them.

Surgery and radiation therapy for head and neck cancer

Rivers, now 47, was first diagnosed shortly after graduating from Southern Utah University with a degree in dance performance. The young professional dancer underwent radiation, chemotherapy, and surgery that removed one-third of his tongue. The cancer returned a couple of years later, prompting another round of chemotherapy and radiation, which he described as so brutal that it felt “like my ears were falling off.”

Radiation therapy for head and neck cancer has come a long way in the past two decades, Karam says. But the basic philosophy has remained unchanged.

“We treat the tumor and a huge field around it because we often think of where it could have migrated. So it’s an extensive volume,” Karam said.

The standard radiation treatment probably planted the seeds of the crisis that ended Rivers’ dancing career: He had a major stroke in late 2011, debilitating his left side and partially blinding his left eye.

Two decades later, at the height of the pandemic lockdowns in March 2020, Rivers’ cancer came back. Karam approached him about participating in the study.

“Will this help other people?” Rivers asked.

“Yes,” Karam said.

“Sign me up,” he said.

Rivers started on durvalumab and underwent three sessions of light-dose stereotactic radiosurgery to heat up the tumor so the immunotherapy drug and his immune system could get to work.  And work it did.

“You could see the tumor recede right before your eyes,” said Ryann Woodbury, Rivers’ daughter.

“It was unbelievable,” Rivers added.

Treatment plan: surgery, for now

Meanwhile, CU School of Medicine MD-PhD student Laurel Darragh was studying the blood of Rivers and other study volunteers. A member of the Karam lab, she observed major increases in immune-system T-cell infiltration as well as other biomarkers that showed the approach to be working at the cellular level.

But this was a phase 1 safety trial, and part of the trial’s approval hinged on patients undergoing surgery and standard radiation therapy regardless of how well things went. (As the trial progressed and the extent of the new approach’s effectiveness became clear, patients who entered the study after Rivers were allowed to skip the radiation treatment. Everyone, though, would undergo surgery.)

Rivers had all but a sliver of his tongue removed, the balance replaced by a flap of tissue harvested from his calf, which also supplied skin for the face. Much of the right side of his jaw was excised, replaced by a section of tibia. Skin from his thigh patched the opening on his calf; two and a half years later, it’s finally closing up.

“In my mind, I’ve always been lucky,” Rivers said. “I’ve always somehow beaten the odds. And when I went to sleep that day, I thought, ‘I’m going to wake up and it won’t be bad.’ But I woke up, and it was bad.”

Moving toward better treatment options + quality of life

He was in a UCH intensive care unit for two weeks and an inpatient for a few days after that. Woodbury drove in from her and fiancée Erik’s Wolff’s home in Salt Lake City to take care of him, and soon brought him back to live with them.

Rivers has now recovered and is disease free. But he remains on a soft-food diet, one supported by a soft-food blender that comes along to restaurants. Where he once spoke at a regular pace, he must now enunciate deliberately. His wit remains intact. When his daughter described him as “the strongest person I’ve ever met,” he didn’t miss a beat.

“You should see my biceps,” Rivers quipped.

His daughter wishes they could have avoided the surgery.

“Why do we have to take away a huge portion of his quality of life?” Woodbury said. “After we talked to Dr. Karam, I understood. But from my perspective, it was really frustrating to still have to go through with it.”

Karam agrees. She intends to further delineate her approach’s strengths – and weaknesses, because not all patients responded, and the team aims to learn from them, too – and move head and neck cancer treatments in the direction of breast cancer treatments. What might have been a radical bilateral mastectomy and chest-wall removal a half-century ago is today often a limited lumpectomy. Karam says she’s not retiring until the standard of care for head and neck cancer has taken a similarly big step.

No cancer is good. But head and neck cancer and its treatment attack not only tissues and bone but also one’s identity. A patient once told Karam that, had he known how he would look, how he couldn’t speak, eat, or taste, he would have rather died.

“It’s not just about prolonging life – it’s about the reduction of suffering,” Karam said. “We have to do better. It’s an obligation.”