Cure. In the context of cancer, the word is everywhere in news headlines recently. But it’s often lacking from the one place it counts — the oncologist’s office.
Is there (or will there ever be) a time when cancer patients can realistically expect to hear the term applied to them?
“I do not like that word,” said Miggie Olsson, a pancreatic cancer survivor, of the word cure. “It’s very frustrating for patients to be coping with that word, because that’s what you want, but once you get the [cancer] diagnosis you’re kind of stuck with it for the rest of your life.”
For Olsson, the term is especially confusing. She’s more than 10 years out from a diagnosis — advanced pancreatic cancer — that most people survive by less than a year. Is Olsson cured? Her doctors never used that word with her, she said.
There’s a stark contrast between the abundance of cure-talk in some settings, like the media buzz around promising but still experimental new immunotherapies and the National Cancer Moonshot, and the lack of the word in others. Navigating that contrast can be difficult for survivors like Olsson — and the current cancer patients she meets regularly as a patient volunteer at Seattle Cancer Care Alliance. They long for a defined stopping point to their cancer, Olsson said. But they end up with more clinical terms like partial remission, complete remission or “no evidence of disease" (see definitions sidebar below), terms that reflect medicine’s imprecise ability to pinpoint whether cancer is ever truly, completely, gone.
That imprecision is reflected in the fact that an individual patient may not hear the word “cure” on their oncologist’s lips. But that doesn’t mean the word has no meaning to doctors and scientists, said Dr. Fred Appelbaum, transplantation researcher and deputy director and executive vice president of Fred Hutchinson Cancer Research Center. It’s just that it’s very difficult to apply it to a single person because it comes down to data — and time.
“When [scientists] say cure, we mean that the person is off of therapy and that their chance of dying of that disease is no greater than someone in the general population. Now, you need large numbers of patients in a certain category to ever determine that,” Appelbaum said. “You get closer and closer to cure as you go further out from therapy, but to say you’re truly cured — it’s always something of a guess for any one individual.”
Olsson, who is now 67, finds “cure” especially troubling because the word represents the hope she so desperately wanted in 2006, when she was first diagnosed with stage 4 pancreatic cancer. But her doctors didn’t have much optimism to offer. Her first doctor told her she wasn’t eligible for surgery and was facing a life expectancy of mere months. Olsson didn’t accept that answer and found an oncologist at SCCA who was willing to try more aggressive treatments, treatments that eventually worked for her.
But she still found herself looking for a finish line that never came. Her last day of chemo was late in 2007. Every other patient she knew got a little party thrown by the nurses on their last day, but not Olsson. They didn’t believe she’d ever be done with treatment, she said.
At every major milestone — ending treatment, two years cancer-free, five years cancer-free — she’d ask her doctors when they could stop worrying, when she’d be out of the woods. At her five-year follow-up appointment, she asked her doctor (a different oncologist than had originally treated her), “Do I get to say cure?” she said. “He looked at me and said, ‘No, I’m not going to give you the cure word. I’m not even going to give you complete remission.’ And I was so angry.”
That shifting path to “cure” in Olsson’s case had to do with data. In a later conversation with her oncologist, he clarified, she said. He told her: “With a lot of cancers, there’s a well-paved road and there are signs on the road … With you, not only are there no signs, there’s no paved road. There’s no data,” she said.
After that discussion, Olsson realized she had to make her own milestones. These days, she leaves the worrying to her medical team, she said.
Appelbaum said he and his oncologist colleagues have to be truthful with their patients, first and foremost.
“We don’t use the term cure loosely. Whenever we talk to a patient about the concept of a cure, we try to be very clear that we can never be absolute, but we can say that your chances are extremely favorable when you get to a certain point,” he said. “You want people to go back and live their lives the way they would normally live them, but you can’t make false promises.”
That said, Appelbaum and his colleagues are optimistic cures for many cancers may be coming in the form of new immunotherapies. They’re basing that optimism not just on the therapies’ early successes, but on the long track record of data on immunotherapy’s predecessor: bone marrow transplantation, a technique that’s more than proved its worth as a curative therapy for certain blood cancers.
There’s reason to believe immunotherapy may spawn new cures, Appelbaum said, because it’s based on the same general principles as transplantation. Bone marrow transplants were developed by the late Dr. E. Donnall Thomas in the 1960s and 70s — and formed the bedrock for the creation of Fred Hutch itself in 1975 — but the technique’s roots go back much farther.
In a general sense, the original idea of transplantation was to eliminate a leukemia or lymphoma patient’s cancerous cells — the bone marrow cells — through a massive amount of total body irradiation, and then to replace those cells with healthy, donated bone marrow. The concept was relatively simple, if brutal, in its execution.
But animal experiments and very early human transplants performed in France clued researchers into the fact that something else was going on. The donated bone marrow cells, which included the donor’s immune cells, were attacking and killing remaining cancer cells left in the body in a phenomenon the French researcher Dr. Georges Mathé dubbed “graft-vs.-leukemia.” Mathé performed the first more or less successful bone marrow transplant in 1960 — that patient died of an infection two years after transplant, but his leukemia never came back.
So the Seattle transplant team had hints that the immune system had the power to eliminate cancer when they first set out to really get transplantation off the ground, said Dr. Rainer Storb, a Fred Hutch transplantation researcher who was a member of Thomas’ original transplant group.
“We knew when we started transplantation that we couldn’t rely entirely on the irradiation, but also had to rely on this … graft-vs.-leukemia effect,” Storb said.
Even when the team had worked out some of the kinks in transplantation, most of their patients still died, Storb said. Many of them relapsed or died of infections, in that era before good antimicrobial drugs were developed. But for those who survived a year or two past transplant, something special seemed to be happening.
In 1977, the transplant team published a paper describing the fate of their first 100 transplant patients. In the paper, there’s a simple-looking statistical chart, what is known as a Kaplan-Meier curve, plotting the survival of those 100 patients over five years. The line plunges sharply between the time of transplant and year two — 83 of those patients died — but then it levels off. And stays level: When the transplant worked, it seemed to really work.
“I knew, for the patients that we could get through, that their chance was being able to be cured,” said Dr. Jean Sanders, a Fred Hutch pediatric transplant specialist who was also part of Thomas’ team. “That Kaplan-Meier survival curve, Don [Thomas] had to be convinced by the statisticians that this was the definition of cure.”
In the decades since, researchers at Fred Hutch and around the world have made refinements both to transplantation itself and to the supportive care that surrounds it that have significantly improved that survival rate and made the treatment less toxic. But they knew they were starting from an exciting point, Storb said.
“We considered [curing patients] an achievement, and now it’s sort of almost routine,” he said.
Those twin discoveries — the existence of graft-vs.-leukemia and the Seattle team’s work showing transplantation could actually cure patients of cancer — laid the groundwork for today’s immunotherapies, including promising new T-cell therapies that extract and re-engineer a patient’s own immune cells to recognize and attack their cancer.
It’s too early to determine whether such immunotherapies are truly curative, said Fred Hutch immunotherapy researcher and oncologist Dr. Stanley Riddell, who has led the development of an engineered immunotherapy, known as CAR T-cell therapy, now being tested in a clinical trial for patients with advanced acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma or chronic lymphocytic leukemia.
“It depends on the cancer you are treating, but in general we don’t like to use the word cure until patients are several years out from their treatment,” Riddell said. “We know that many times, cancers can come back years later.”
Again, it’s all about the numbers. About 120 patients total (with the different types of blood cancers) have been treated on the Fred Hutch CAR T-cell trial, but many of them quite recently — the average time since treatment on the trial is nine months, although some of the patients are more than two years past receiving their T cells.
Terms oncologists may use when cancer is responding to treatment:
Definitions according to the National Cancer Institute.
Early results are promising: 93 percent of the ALL patients and a smaller majority of the lymphoma patients achieved remission after T-cell therapy. Some of the leukemia patients have since gone on to have traditional blood stem cell transplants. That’s a case-by-case decision, Riddell said, but until researchers have more data on the T-cell therapy, a traditional transplant still represents the best chance for cure for many of these patients.
Researchers know that when it comes to leukemia, if a patient is going to relapse, it’s highly likely it will happen in the first two to three years after treatment, Riddell said. That’s in contrast to some cancers like breast cancer, where a 10- or 15-year remission before relapse is not unheard of.
But the patients receiving treatment on the CAR T-cell trial are different from the average leukemia patient — they’ve been through many prior treatments that didn’t work against their cancers. These patients are likely to relapse within a few months after treatment, Riddell said. And, unlike in the 1970s when transplantation’s curative powers were being realized, today’s researchers are able to detect remaining cancerous cells at very low levels in the body — about one in a million cells.
Using those techniques, the researchers know that many of the patients on the trial are in what’s known as a “molecular remission,” Riddell said, “which is a really, really deep remission, probably remissions that are deeper than anything they’ve ever had with any prior treatment.
“Does that mean [we know if] they’re cured?” he asked. “Absolutely not. We just have to wait.”
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Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.