Managing side effects from lung cancer treatment with dose reductions is an approach experts have been using more, even though some patients voice concerns about lowering a drug’s impact on the disease.
In 2015, Michele Altizer developed a persistent cough and shortness of breath, eventually receiving her first diagnosis of stage 3 adenocarcinoma, leading to a variety of side effects.
"I thought the surgery was bad and very painful, but (chemotherapy) was equally as bad," Altizer says. "There were a lot of side effects (from surgery and chemotherapy) ... I have nerve damage from the surgery, like in my ribcage. I have hearing damage from the chemo burning the nerves in my ears. ... My taste isn’t right. ... I don’t have (a) good memory anymore. I have to write everything down now, and it just goes from there.”
Three years later, the cancer returned, but now in both of her lungs, making this stage 4 metastatic cancer. Altizer underwent next-generation sequencing of the tumor, which determined that she had the KRAS mutation, making her a fit for a clinical trial assessing Lumakras (sotorasib), a biological drug that targets the mutant form of certain KRAS mutations.
She started with the highest dose of Lumakras — 960 milligrams — which left her feeling very fatigued; so tired, in fact, that she said that she was sleeping 18 hours a day and could barely lift her toothbrush.
“ ‘That’s not how I want to live my life,’ was how it was brought up to (my doctor),” she recalls. “I want to be able to do stuff before I do die. So, is there anything we can do to where I can stand the drug, (and) my cancer’s still gone, but have a life as well? And that’s when they started talking about the dose reduction.”
This involved a process of stopping Lumakras altogether for one 21-day cycle, then starting again at a 480-milligram dose. Altizer took that for a while and was still really tired. She ended up stopping the drug again for a week before starting a 240-milligram dose, when she noticed an improvement in her side effect.
Now, at 61 years old, the mother of three sons resides in Madison Heights, Michigan and is “doing great” on her reduced dose of treatment.
Altizer is one of many patients whose cancer teams adjusted the dose of a drug to address side effects like fatigue. This decision may leave patients with anxiety while wondering if a lower dose may lead to other effects like the cancer spreading. Close monitoring by the patient’s cancer team allows them to keep a close eye on the disease while managing side effects.
Treatment de-escalation in lung cancer can pertain to several. approaches, all of which are aimed to reducing exposure to a given therapy. What most patients with lung cancer are accustomed to as treatment de-escalation refers to adjusting the intensity of a therapy to potentially manage any side effects from that treatment. For most cancer drugs, there is a set regimen with specified changes in the doses and schedule that is used for first, second or beyond de-escalations due to side effects.
“For patients with advanced disease, if they start to have side effects that become intolerable, we lower the dose or we deescalate the intensity of the treatment, in an attempt to preserve or maximize quality of life while still keeping cancer in control,” explains Dr. Ryan Gentzler, associate professor in the division of hematology and oncology in the department of medicine at the University of Virginia in Charlottesville.
That’s what happened with Altizer; after her dose was decreased, she felt better, despite still feeling a little tired, she says, which she believes could be something else.
Dose de-escalation may also be linked to purposely omitting a component of treatment from the outset in hopes that it is not as critical, and that the patient with lung cancer can achieve the same results.
A focused radiation approach may be beneficial to patients with lung cancer that has metastasized (or spread) to the brain. The traditional paradigm for patients with meta- static lung cancer is whole-brain radiation, which is associated with a lot of toxicity. Researchers have developed new treatment with stereotactic radiosurgery, allowing cancer teams to just treat focal spots (limited to a specific area) in the brain compared with the whole brain, especially in patients with oncogene-driven mutations like ALK, EGFR and ROS1. This approach has been found to have the same results, if not better, with fewer side effects for eligible patients.
In April of this year, Dr. Jacob Langston, chief resident PGY-5 in the department of radiation oncology at the University of Colorado Anschutz Medical Campus Aurora, and his colleagues published results from a study in the journal Lung Cancer, in which 12 patients with non-small cell lung cancer (NSCLC) were treated with tyrosine kinase inhibitors first before they proceeded to stereotactic radiotherapy.
“All these patients, ... who would always be a candidate for whole- brain radiation, we converted them into stereotactic radiosurgery patients at that point,” Langston explains. “So that was a pretty significant thing that we were able to do, was spare the toxicity of whole brain and just treat them focally.”
Even with lowering the dose or using a different tactic to minimize the burden of side effects, there is still a chance that treatment may not go the way a patient expected it to, Langston adds. That’s not to say that there are no other options.
“That’s always a risk,” he notes. “The downside would be potentially not getting a response ... or having progression. ... But I think that’s where the component of monitoring those people very closely comes in. That way, if they start to show that they’re not having a response, you can switch lines of therapy, think about new systemic therapies to introduce.”
Many studies assessing treatment de-escalation have been conducted with retrospective data, meaning that researchers have assessed either events that have already happened or trials with established data. In these instances, statistical models are used to predict certain scenarios.
An example of this is a study published in the European Journal of Cancer in August 2022, in which researchers analyzed data from 1,006 patients with stage 3 NSCLC previously treated with chemoradiotherapy followed by at least one dose of Imfinzi (durvalumab).
The patients treated with immunotherapy certainly lived longer and had a longer time without their cancer recurring, says Dr. Nithya Ramnath, professor of medicine and Marylou Kennedy Research Professor of Thoracic Oncology at the University of Michigan in Ann Arbor and section chief of oncology at the VA Ann Arbor Healthcare System in Michigan. Despite this benefit, patients in this study had significant side effects such as inflammation of the lungs (pneumonitis). Side effects like these led to 15% of patients to discontinue the treatment for immune-related side effects and 6% for non-immune-related side effects.
Ramnath and her colleagues delved deeper into the data to learn more about which duration of immunotherapy would provide patients with the most improved survival: three months, six months, nine months or 12 months. The “sweet spot,” as Ramnath calls it, seemed to be in the six-month range, which demonstrated that there may be patients in the real world that may be receiving immunotherapy for longer than they may benefit from it.
“There is a possibility that some patients can have a de-escalation of therapy and still obtain the same degree of benefit,” she says. “But who these patients are and how we do this sort of a study becomes the big question.”
The type of studies needed to potentially change the standard of care are large prospective, randomized clinical trials. The challenge is that these trials are difficult to do, Gentzler explains, because they require both a lot of time and patients to conduct. Until those trials emerge that show that de-escalation is equally effective or even more effective than standard of care, cancer teams proceed with knowledge from retrospective studies and real-world experience.
Jordan Meyerson, a 59-year-old Long Island native living in Boca Raton, Florida, received a diagnosis of stage 4 metastatic, ALK-positive lung cancer in September 2016. He was treated with several tyrosine kinase inhibitors — three, to be exact, over a two-year period — before his cancer no longer reacted to the therapy. His cancer team switched him to chemotherapy, which he underwent from 2018 to 2019.
In December 2019, his treatment changed to Lorbrena (lorlatinib), an ALK inhibitor indicated for patients with ALK-positive metastatic NSCLC, when his team discovered that the disease spread to his liver. Meyerson first started with a 100-milligram dose, but after six to eight weeks of the treatment, his wife noticed some side effects.
“My wife noticed that I was having mood swings, cognitive issues, anger issues, so she asked me to speak with a doctor,” he says. “And they reduced me down to 75 milligrams.”
That approach helped address Meyerson’s side effects, and by May 2020, he was considered having no evidence of disease.
He continued with the 75-milligram dose of Lorbrena until November 2021, when he developed severe neuropathy in his hands and feet. His team recommended dropping the dose from 75 milligrams to 50 milligrams, which made him anxious at first.
“Needless to say, I was petrified,” Meyerson explains. “Going from 100 (milligrams) to 75 (milligrams) wasn’t so bad, but (from) 100 (milligrams), being no evidence of disease, and now I’m down to 50 (milligrams) to see if it would take away my neuropathy. ... The doctor assured me that ‘It’s OK, we’ll monitor you, we’ll scan you. And if something comes up, we can always put (your dose) back up. Don’t worry about it.’ ”
He proceeded with the 50-milligram dose, which eliminated his neuropathy. Three months later, his scans showed that there was no evidence of disease, which remains his status today.
Even with the limited prospective trials in this space, this approach of dose reductions is still being applied in clinical practice to help patients address their side effects.
“I do this in my practice,” Gentzler says. “I think there’s always how people practice compared to what the data show. And patients (proceed with) informed decision-making and discussions about risks and benefits of treatments, and we make a joint decision to de-escalate therapy in that individual patient.”
Even with the information needed to make this decision, patients may still have anxiety, as Altizer recalls having, despite having knowledge from her experience being a pharmacy tech. She says her husband was also nervous about this approach.
“My husband was very edgy when they discussed taking me off (Lumakras) just to recover myself for a while,” she says. “(He’d say,) ‘Well, what if it comes back? And what if the drug doesn’t work now because you went off it?’ ”
Meyerson remembers a similar anxiety of the disease coming back, especially with the second dose reduction.
“The fear factor, it’s like taking a teddy bear away from a baby,” he says.
Several sources are available for patients with lung cancer including advocacy groups, which allow patients to potentially speak with others who have experienced a similar situation. Patients with lung cancer may also benefit through online resources, with the caveat that they discuss findings with their care teams to ensure they obtain the most accurate information.
Experts also urge patients to make sure there’s a plan in place with their care team.
“What does the surveillance period look like? How often is your physician going to be getting scans? What is that interval? That’s an important question to ask, how often the follow up is, how often you’ll be seen by your physician,” Langston says.
Ramnath says that patients know their bodies best, so listening to it can be very helpful in making a decision about treatment de-escalation.
“(Patients) know how something is affecting them,” she explains. “And if they have seen certain side effects, they’re going to say, ‘You know what, I’m actually comfortable with this approach. ... And (when) something happens, we go back to treatments.’”
Altizer emphasizes the importance of trusting the care team when it comes to decisions like reducing the dose.
“That would be my No. 1 thing, is just trust the team you’re with,” she says. “And if you’re not, if you don’t trust what’s happening, find somebody else. That’s the biggest part right there.”
Meyerson also advises patients listen to their doctor’s suggestions, as the course of treatment can change if any negative effects occur with a dose reduction.
“With de-escalation, if your doctor feels that you could do it, try it,”
he says. “You can also go back up (in dose). That’s a real possibility. I know a lot of people that have been on a different drug than myself that were feeling lethargic on one dosage, their (dose) went down, they didn’t feel right, and they had a little bit of progression. They went back up (in dose), and the progression went away.”
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