When Cancer Treatments Stop Working: Is it the End of the Line?

In 2018, when Carol Brickell learned at the age of 60 that she had advanced non-small cell lung cancer, she was already sick. She’d had a stubborn cough for a couple months and felt weak and tired. Her oncologist in Dallas started her on a combination of chemotherapy and immunotherapy right away. The goal was for her to start feeling better while they awaited the results of biomarker tests that would tell them whether she was a candidate for targeted therapy.

Carol Brickell was diagnosed with advanced non-small cell lung cancer at age 60.

According to the tests, her tumors were ROS1 positive, which made Brickell eligible for a promising targeted therapy called Xalkori (crizotinib). But her disease was already responding well to her current treatment.

“I was feeling almost normal, so my oncologist and I decided to ride it out and keep doing chemotherapy,’” says Brickell, a certified professional career coach.

A year later, Brickell started having pain in her abdomen, and a scan showed swollen lymph nodes in the area. But she wasn’t very upset about the news. “I knew I had (Xalkori) in my back pocket,” she said.

Today, patients with different types of advanced cancers have several options to keep in their back pockets, so to speak, in case their first treatment stops working. When cancer becomes resistant to a particular therapy, that doesn’t mean it’s the end of the line.

“If the cancer is getting worse or if the therapy is too toxic for the patient, then it’s time to move on to a different treatment — so we look in our proverbial toolbox to see what will be the next-best tool,” says Dr. Erica Mayer, a senior physician in breast oncology at Dana-Farber Cancer Institute in Boston.

HOW CANCERS BECOME RESISTANT TO TREATMENT

Because of the many available therapies, people can live with different types of cancer, such as breast, lung and gastrointestinal, for many years by staying on treatment.

Carol Brickell found comfort in knowing she had other options when her cancer no longer responded to chemoimmunotherapy.

When a particular medicine stops working, “it’s just an expected part of the process and time to switch to something else,” says Dr. Arturo Loaiza-Bonilla, the National GI Program director and medical director of clinical research at Cancer Treatment Centers of America.

But why do treatments stop working?

“We believe that advanced cancer is always changing, mutating and trying to evade whatever treatment strategy we have directed toward it, no matter how effective that strategy might be,” Mayer says. Of most mutations or other changes that may develop in a cancer cell, only a small fraction might cause drug resistance by random chance, but it is those cells that will continue to grow in the presence of the drug and ultimately repopulate the tumor, which is now treatment resistant.

The form of treatment resistance depends on the type of treatment.

With chemotherapy, for example, one of the main ways cells become resistant is that proteins called drug transporters — their job is to protect healthy cells — start to flush chemotherapy agents out of cancer cells in a misguided attempt to protect the harmful cells from the toxic drugs. Then the chemotherapy can’t do its job.

Targeted therapy, on the other hand, attacks the specific gene in the tumor, called a driver mutation, that is causing the growth and spread of the cancer. It shuts down that gene so that it can no longer drive the advancement of the cancer. That works for a while, Loaiza-Bonilla says, “but eventually a co-pilot gene can take over and drive the cancer.”

When that happens, patients need to switch to or add a medication that targets that new driver.

Resistance to immunotherapy can happen in several ways. That’s because immunotherapy refers to many different drugs that work in distinct ways. But most people on immunotherapy take what’s called checkpoint inhibitors, such as Keytruda (pembrolizumab), Yervoy (ipilimumab), Opdivo (nivolumab) and Tecentriq (atezolizumab). These drugs prompt the immune system to recognize cancer cells and block the body’s built-in checkpoints.

“But then the cancer cells just change the way they look, and the T regulatory cells say, ‘Don’t attack these guys. They’re my friends,’” Loaiza-Bonilla explains.

Cancer cells may change to resist treatment in other ways too, including ways that researchers are still working to discover. Researchers also look for ways to thwart resistance.

“A tremendous amount of work that goes on in cancer biology labs is studying best ways to try to overcome and prevent further resistance,” Mayer says.

WHEN IT’S TIME TO CHANGE TREATMENTS

When a treatment stops working, the cancer resumes growing or begins cropping up in other places in the body as metastases. Doctors may find this through routine scans or tests that are typically done at scheduled intervals, or the patient may describe new symptoms, as Brickell did, that prompt the doctor to run tests.

In addition to Brickell’s abdominal pain, a lymph node in her neck started to grow. If scans showed it was the cancer coming back, she knew she had an effective option awaiting her in Xalkori.

“When you’re living with cancer, it’s like, ‘Well, there’s another one,’” she said of the enlarged lymph node in her neck. “And you just have to report it.”

She took Xalkori for 15 months, during which the spots on her lungs disappeared and the lymph nodes returned to normal size. “I had no evidence of disease,” she says.

Ed Russ found out that he had advanced colorectal cancer that spread to his lungs in 2016.

For Ed Russ it was different. The 64-year-old retired police detective from Homestead, Florida, was diagnosed in 2016 with advanced colorectal cancer that had spread to his lungs, but the lung metastases caused no symptoms at all.

“Honestly, I wouldn’t have even known it was there,” he said. But every time the doctors ordered a new round of scans after trying a different treatment, the images showed that the rectal tumor hadn’t budged and that more spots had appeared on his lungs.

For both Brickell and Russ, it was time to try something new, which can be nerve-racking.

“Patients with advanced disease, with some exceptions, are going to be on continuous treatment,” notes Dr. Patricia Ganz, director of cancer prevention and control research at Jonsson Comprehensive Cancer Center at UCLA Medical Center in Los Angeles. “When the disease is well controlled, they know the routine, they know what the side effects are, so if they have to face a change, it’s distressing,”

It also raises this question: Is this the end of the line?

“No,” says Loaiza-Bonilla. Patients with advanced cancers should be prepared for treatment changes from the start.

“I tell patients, ‘Sometimes advanced cancers are not curable, but they’re treatable, and that means that we have to try different options as we go along,’” he says. “When it is time to try a new treatment, patients just know that this is an expected part of the process.”

HOW TO CHOOSE THE NEXT MOVE

Oftentimes, doctors offer several options as a next treatment.

“Sometimes, there’s no single so-called best next step because we can’t predict the future. A treatment could work beautifully for patient A and then not work for patient B. There’s so much unknown,” says Dr. Xiuning Le, a thoracic oncologist at The University of Texas MD Anderson Cancer Center in Houston.

Ed Russ and his wife, Sandy, went to get a second opinion, and he learned more about his treatment options.

When a doctor offers multiple options, Le recommends that patients consider a few factors as they work with their doctor to decide.

“Gather as many options as possible, and then have your care team provide you with the benefit and toxicity data for each,” she says. “For example, treatment A could have a 30% response rate but cause kidney damage 50% of the time, while treatment B could have a 15% response rate but little risk of harming you in any way.”

If the benefits and efficacy of the different treatment options are similar, patients may choose based on possible side effects and other personal preferences. For example, logistics can figure in. Patients should consider whether a treatment, such as a clinical trial or an IV infusion, requires frequent travel to a faraway cancer center or multiple trips to an infusion center. In this case, a daily pill taken at home, for example, may be preferable.

WHEN TREATMENT OPTIONS INCLUDE A CLINICAL TRIAL

Sometimes a clinical trial is among the available treatment options. Although participation may require travel and more frequent doctor visits, many physicians consider these studies to be an extra level of care. But patients often have misconceptions about them.

“We thought clinical trials were the last resort, when you’re on your deathbed,” says Sandy Russ, Ed’s wife and his caregiver while he underwent treatment. “We were also afraid that in a clinical trial, somebody gets the drug and somebody gets the placebo. Who wants to take that chance?”

But the Russes learned that both are common misconceptions.

“Nowadays, there are lots of trials at all stages of care, even very early in the course of metastatic disease. So clinical trials are always an option,” Ganz says.

What’s more, cancer clinical trials are no longer placebo controlled unless standard-of- care treatment is given with the placebo. “No one gets a sugar pill or saline,” Loaiza-Bonilla says. “You either get the standard treatment or the standard of care plus the experimental drug.” But placebo is still needed in trials where the physicians and patients are providing information about response and side effects that might be biased by their knowing if the experimental drug is being given.

People might choose a clinical trial because the drug looks more promising than the other options, because they don’t have other options or because they want the extra care and heightened surveillance that come along with it.

Brickell chose a clinical trial after her disease stopped responding to Xalkori. She had the choice between Lorbrena (lorlatinib), a Food and Drug Administration (FDA)- approved targeted drug for ALK-positive non-small cell lung cancer, and a clinical trial of repotrectinib, a drug that targets genetic changes in ROS1, ALK and TRK, at UT Southwestern Medical Center in Dallas.

“The main reason I chose to go with the clinical trial was if I did the FDA-approved (Lorbrena) first and it didn’t work, that would be too many treatments and I would no longer qualify for that clinical trial,” Brickell said. “So I thought, ‘Let’s try the clinical trial first.’”

Brickell learned quickly that the drug wasn’t helping her. She stopped the trial, and her primary oncologist put her on chemotherapy with docetaxel, to which the cancer is responding very well.

When patients have several options, sometimes they can (like Brickell planned to) choose one now and the other later. Some oncologists like to plan well in advance and start discussing clinical trial options that are most suitable when the patient is still doing well on their current treatment in case the patient progresses in the future. They might even send tissue for testing ahead of time, as more trials now require specific protein or genetic characteristics to qualify, and this avoids the time crunch if a patient needs new therapy quickly.

Just as with standard treatment, patients should make sure they understand the risks of the clinical trial treatment.

“Medications in phase 2 or 3 trials have usually gone through a number of trials, so the safety and dosing have been established,” Le says. “Early-phase trials have detailed protocols in place to protect patients from harm. Overall, I encourage patients to consider enrolling in clinical trials.”

WHEN TO GET A SECOND OPINION

When a treatment stops working and it’s time to move on, it may also be a good time to get a second opinion.

When the clinical trial didn’t work for Brickell, she and her oncologist reached out to another oncologist, who is an expert in ROS1 gene changes, for a second opinion. He looked at the results of Brickell’s most recent biopsy and saw that a second gene change, called a RET fusion, was copiloting and helping the ROS1 gene drive the cancer. Based on this new information, the oncologist recommended that Brickell stay on chemotherapy. If the chemotherapy stopped working, Brickell would go back to a ROS1-targeted therapy and add a RET inhibitor such as Retevmo (selpercatinib) or Gavreto (pralsetinib).

“Getting a second opinion is always very helpful, both to confirm the recommendation of the primary oncologist and to also potentially be offered other options,” Ganz says.

Russ says a second opinion saved his life.

He had started his treatment at a local hospital in Florida near where he lives, and he had taken each of his doctor’s recommendations. First, he got radiation and the oral chemotherapy capecitabine. The radiation shrunk the rectal tumor by a whopping 80%. But the chemo didn’t affect the spots in his lungs. Next, Russ received the combination chemotherapy regimen known as FOLFOX (folinic acid, fluorouracil and oxaliplatin) via infusion for 24 weeks. The lung metastases, however, continued to grow and spread, and the rectal tumor was unchanged after the original dramatic response to radiation. Next, by then a year after receiving his diagnosis, Russ had surgery to remove the rectal tumor. It was a successful surgery, but the recovery was extremely difficult.

“I was at my lowest point after the surgery,” Russ recalls.

And he still needed to have yet another round of chemotherapy — this time, with FOLFIRI (folinic acid, fluorouracil and irinotecan) — to try, yet again, to get the cancer that continued to grow and spread in his lungs. His care team at the local hospital said his only other option was surgery to remove nearly half of the left lobe of his lung. They warned him that it would be a very difficult surgery. When Russ’ wife researched and presented other options to her husband’s doctors, they dismissed each one.

Things were bleak by that point. “Ed was in such bad shape. He was just existing,” says his wife, Sandy. “He wasn’t living. My biggest fear was that he would die, and I would find out that there was something else available that he could have tried.”

The Russes went to Cancer Treatment Centers of America for a second opinion. There, doctors confirmed that surgery was a good possible option for Russ but that if he didn’t want to undergo another procedure, there were alternatives.

A biopsy revealed that his lung tumors were HER2 positive, a common characteristic of breast tumors, making him eligible for targeted therapy. But because he would receive the targeted drug via IV infusion, like chemotherapy, he worried it would wipe him out in the same way. So he opted for surgery.

The surgeon removed the entire lower left lobe of his lung and all the cancer with it. When the cancer returned, Russ knew he had options. He started an experimental regimen of Herceptin (trastuzumab) and Perjeta (pertuzumab), FDA-approved drugs for HER2-positive breast cancers.

At Russ’ nine-week scan, the lesions on his lungs were notably smaller. At 18 weeks, they were gone.

In December 2020, Russ was able to stop the drugs. He had one small recurrence in his lungs, which was removed with surgery. His last two scans were clean, so Russ is currently cancer-free.

“Unlike when I started this process, I’m not afraid,” Russ said. “I know that if another one comes up, I have options.”

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