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Many of us may remember?The Incredible Hulk?television show in the late 1970s and early 1980s. But how many remember what made the scientist David Banner turn into the Incredible Hulk? knows. In fact, he was captivated with the information¡ªBanner bombards himself with gamma radiation. ¡°I loved that character,¡± Iyengar says. ¡°The show told me that there was something interesting going on with radiation.¡±

Many years and a few degrees later, Iyengar is now a radiation oncologist at UT Southwestern Medical Center in Dallas. He uses radiation therapy to treat people with lung cancer. Iyengar also works in a lab, where he does cancer biology research to learn how to help his patients even more.

¡°Radiation works best when there is a single large tumor,¡± Iyengar says. But that¡¯s not the case for most people with lung cancer because they don¡¯t find out they have it until it¡¯s spread to other parts of the body.

For lung cancer that¡¯s spread, the standard treatments typically include some combination of surgery, chemotherapy, and radiation. And for certain types of lung cancer, doctors might use targeted therapy or immunotherapy.

But for many of Iyengar¡¯s lung cancer patients, radiation is the only treatment they can have. Surgery and chemotherapy often aren't good choices for them because of another problem they have¡ªcachexia (kuh-KEK-see-uh).?

How Cachexia Affects a Lung Patient's Life: Radiation oncologist Puneeth Iyengar, MD, PhD, explains the reason cachexia is so harmful to people with lung cancer.

How Cachexia Affects Treatment Choices

Also known as wasting syndrome, cachexia occurs in the last stages of many diseases including heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and cancer. The condition causes extreme loss of fat and muscle, leading to dramatic weight loss. It can lead to such weakness that even routine activities can become difficult. ¡°When a patient with one of these illnesses appears gaunt and emaciated, he or she may be suffering from cachexia,¡± Iyengar says.

Up to 50% of all cancer patients may have some degree of cancer cachexia. It¡¯s especially common in people with colorectal, gastrointestinal, lung, or pancreatic cancer. It may be responsible for 20 to 30% of all deaths related to cancer.

Lung cancer patients with cachexia tend to die sooner than those without it. That¡¯s largely because of its effect on their treatment options, not because it occurs during the late stages of disease as people once thought, Iyengar explains. Fat wasting, which occurs before muscle wasting, can occur even in early stages of disease before the cancer¡¯s spread.

¡°Patients with cancer cachexia have really limited treatment options,¡± he says. ¡°A patient with early- stage lung cancer would normally have surgery if it's possible because it¡¯s a potentially curative treatment. But if they have cachexia, they can¡¯t have surgery.¡± Plus, these patients are too weak to endure chemotherapy, and if they are strong enough for it, they don¡¯t respond as well to it as a lung cancer patient who doesn't have cachexia.

¡°This means that even these early-stage patients have already lost the opportunity to get the standard care of treatment,¡± Iyengar says. ¡°Plus, if a patient¡¯s lost too much weight or has cachexia-associated fat and muscle wasting, they won¡¯t be eligible for advanced clinical trials. Again, they¡¯ve lost out on the opportunity to have the most effective treatment modalities.¡±

What patients with cancer cachexia are left with is often radiation alone. ¡°A patient can be wasting away, but we can still treat a tumor,¡± Iyengar says. ¡°And hopefully by treating it, we can slow down the wasting process.¡±

Looking for Answers in the Lab

Iyengar wasn¡¯t satisfied with the care his lung cancer patients with cachexia were able to get, so he¡¯s looking for solutions in his lab with financial support through a grant from the American Cancer Society.

Previously, most researchers focused on how to reverse muscle loss from cachexia, he says. But his research team, ¡°fundamentally shifts the emphasis of cachexia to the fat changes and losses.¡±

With other types of disease, cachexia is thought to be related to the immune system, Iyengar says. But with cancer cachexia, the cause seems to be something in the tumor.

¡°The tumor needs nutrition as a fuel support, and it doesn¡¯t have the normal means of generating fuel that a noncachectic tumor has. So, it breaks down fat to use as its fuel,¡± he says.?

Working with mice that have a cancer wasting syndrome, Iyengar and his research team have tried several things to suppress the tumor¡¯s ability to cause fat and muscle loss. For instance, they¡¯ve tried:

• Feeding the mice a high-fat diet, thinking that such a diet might limit the tumor's "need" to break down fat. The results are promising.
• Giving mice a chemical that removes all their body fat before injecting cancer cells that cause cachexia. Their thinking was that the tumors won't grow as much without? their fuel source, fat. And they don't.
• Genetically altering the mice to remove a molecule that a tumor needs to be able to break down fat. This resulted in the tumor growing half as big as the tumor in mice who weren't genetically altered.
• Using the anti-diabetic drug pioglitazone (pye oh GLI ta zone), which is known to affect fat storage, to see how it reprograms fat. The research team also wanted to know if this drug could block the tumor¡¯s ability to break down fat. ?¡°We found that it limited the growth of the tumor, preserved the fat mass, and promoted the mice¡¯s overall survival,¡± Iyengar says.
  

¡°We¡¯ve definitely found ways to manipulate the tumors to make it less beneficial for them to break down fat,¡± Iyengar says. ¡°We¡¯re still early in the evolution of our understanding of this wasting syndrome, but we certainly have identified molecules and factors in a patient¡¯s blood that can actually help us determine whether a patient will be heading toward cachexia.¡±?

Giving Lung Cancer Patients With Cachexia More Options

¡°I want my future lung cancer patients with cachexia to have the same new and improved treatment choices as my patients who don¡¯t have cachexia,¡± Iyengar says. The treatments in development, he says, will change the whole concept of treating lung cancer. ¡°The idea is to turn lung cancer into a chronic illness.¡±

Here¡¯s the way Iyengar envisions the future of lung cancer care: Patients will get a combination of treatments. They¡¯ll stay on systemic treatment that kills cancer cells throughout the body, like chemotherapy, targeted therapy, or immunotherapy. ¡°If 1 or 2 cancerous spots pop up, we¡¯ll treat them with very focused radiation,¡± he says. Then they go back to systemic therapy. If other spots develop, they would get radiation again.

Even if this type of treatment plan was available today, lung cancer patients with cachexia wouldn¡¯t be able to tolerate it. ¡°If we get cachexia under control, though,¡± Iyengar says, ¡°they might have the chance to get the newest treatments and live longer.¡±

Before that can happen, Iyengar says, other researchers need to find the most effective systemic therapies for all cancer patients. He hopes to test specific drugs in early phase clinical trials in cachexia based on his team¡¯s promising results in mice. He estimates both will take about 3 years.