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By D’Ann George, PhD, Medical Writer

Marie Langhorne, center, with her daughters.

When Marie Langhorne first felt pain in her right leg, in the fall of 2018, she was sitting in her office at Catawba College, in Salisbury, NC, where she has taught French since moving to North Carolina from New Orleans. Growing up in Normandy, France, Langhorne says she was taught to ignore pain.

In Europe, the threshold of pain there is slightly different from what the American system will allow,” she said. “European doctors would be kind of more, okay, you can do that. I know it hurts, but you keep going.” 

Langhorne said that her European stoicism, and a full teaching schedule, convinced her to ignore her pain and what it might mean for months, even though walking had become more difficult and she had grown thin from loss of appetite.

“Unusual for me, you know, because I’m French,” she said. 

And then came that day in her office, when she could ignore the pain no longer. She rose from her chair “and then just had to stop and scream because it was like the knife was inside and it was like somebody was moving that knife. That’s the best description I can give you. To this day, I’m like, I’ll do anything not to have that again,” she said. 

Though Langhorne knew that something was very wrong, she did not associate her leg pain with her leg bones.

At first I thought, it’s got to do with the muscle. The fact that it came from the bone . . . I don’t think I would have thought about it. It was low on my list.” 

Bone pain can mean cancer spread

Bone pain, especially in the arms and legs, can signal that a tumor has metastasized, or spread, to those areas. 

New bone metastases, and bone pain, can occur at any point in someone’s cancer journey. About 25% of patients with advanced renal cell carcinoma (RCC) will have bone metastases at some point. For Langhorne, the sharp increase in pain came nine years after her initial 2009 diagnosis of oncocytoma, a rare subtype of RCC. The pain prompted her to visit her primary physician and then Duke Cancer Center, but in retrospect, she wishes she had returned at the first sign of persistent pain.

Dr. Tian Zhang, a medical oncologist and kidney cancer expert at UT Southwestern Medical Center and member of the KCA’s Medical Steering Committee, said oncologists use a CT scan of the chest, abdomen, and pelvis to find RCC metastases. Most of the time, this is sufficient to spot metastatic sites, even in bones. 

However, if someone reports bone pain in the arms or legs, that indicates something amiss that the care team hasn’t found yet. In those cases, a long bone X-ray to look at arms and legs may help find the source of the bone pain. 

“X-rays are something that we don’t always do unless patients are symptomatic [with pain] or unless we see something weird on a CT,” Zhang said. 

Once Zhang hears that a patient is feeling something that sounds like bone pain, and confirms the existence of bone metastases through imaging, she begins “thinking about how this [bone metastatic] disease entity is a bit different than…lung-only metastases . . . or from patients who have lymph-node-only metastases.” 

Knowing where the metastatic site is helps Zhang choose which combination of immunotherapy to prescribe.

Because there are many options, choosing which therapy to use requires a nuanced analysis from an experienced physician. 

“Technically, all of the immunotherapy combinations approved for kidney cancer are approved for patients with bone mets,” Zhang said. “They can have ipilimumab/nivolumab. They can have axitinib/pembrolizumab. They can have cabozantinib with nivolumab, they can have lenvatinib with pembrolizumab.”

In 2017, the results of the CABOSUN trial revealed that cabozantinib (Cabometyx) delayed cancer progression longer than sunitinib (Sutent) in patients with newly diagnosed advanced RCC, and the delay in progression was specifically greater for those who had bone metastases. Since then, more recent research combining cabometyx with nivolumab (Opdivo) has demonstrated even greater benefits. 

For example, when Zhang first started treating Anna Fowler for bone metastases, she only had the data from the CABOSUN trial, so Fowler received only cabometyx. Even as a monotherapy, Fowler responded well for two and a half years. When Fowler’s cancer later progressed after another line of monotherapy, new data from the Checkmate-9ER study led Zhang to try a cabozantinib/nivolumab combination, which she said produced a “surprisingly beautiful response.”

Fowler’s experience underlines how cabozantinib is good for people with early metastases but also those who are not responding to treatment.  Fowler, diagnosed with metastatic RCC at age 78, survived for three more years.

“There can be some immune modulatory effects of cabozantinib [in a combination approach] that really enhances the immunotherapy response,” Zhang said. 

Some oncologists might stick to a particular combination for everyone who presents with bone metastases but Zhang takes a more bespoke approach. 

“I do think patients who have mets that go to different areas of their body – bone mets, brain mets, liver or lung mets – the [tumor] niches are not quite the same,” she said. “What makes a cancer take root in a bone is not the same as what makes a cancer take root in the lung and grow. The growth patterns, and what drives tumor growth in those areas, are different. So for me, it’s a matter of thinking through, well, which combination seems to be appropriate for this patient sitting in front of me? Distribution of mets is one thing I take into account.”

In addition to choosing among immunotherapy combinations, knowing that a person has bone pain, and confirmed bone metastases, helps physicians make another crucial treatment decision: when to begin therapies designed to prevent fractures and palliate bone pain.  

“I think one very important message is that patients with bone metastases who are symptomatic should have radiation [to relieve pain],” said Zhang.

Bone sparing agents like denosumab or the bisphosphonate zolendronic acid can help prevent fractures. 

CT scan of multiple skull bone metastases on the right side demonstrating both lytic (dark gray) and sclerotic (irregular white) components.

When aRCC metastasizes to the bones, it doesn’t just feel different, it looks different

“The interesting thing about kidney cancer in the bones,” said Zhang, “is that it has this lytic appearance.” 

On an imaging scan, lytic lesions in bones look like dark, roundish holes of various sizes as the body removes diseased bone tissue faster than it can be replenished. In contrast, solid tumor metastases from breast, lung, or prostate cancer, for example, look sclerotic, with calcium deposits to the marrow that results in fewer fractures. 

With effective treatment, lytic holes in bones can begin to fill up, making them appear like sclerotic lesions, which can be concerning for patients to see, Zhang said. However, in the setting of overall disease response, a sclerotic appearance likely indicates beneficial treatment response. 

Almost four years have passed since Marie Langhorne first felt excruciating pain in her leg and began treatment at Duke Cancer Center in Durham, NC, for both her cancer and her pain. At a recent zoom interview, she looked relaxed and radiant, with magnificent beaded earrings brushing the tops of her shoulders. On the wall behind her hung an equally colorful landscape that she commissioned from one of her French students, who is Haitian.

“This is actually a painting of my parent’s house in Normandy. I love it because of the way he made my mom and dad [in the painting]. My girls used to play there. They have lovely memories of the grandparents’ house in Normandy.” 

Marie is looking forward to returning to France for the 2024 Olympics. And to enjoying some French cheese, “the most delicious cheeses in the world,” she said.

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