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Cachexia in NSCLC Patients Reversed With GSHR Agonist

Carlson, Robert H.

doi: 10.1097/01.COT.0000482921.53432.aa
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Cachexia is frustrating to oncologists who see patients wasting away, losing strength, muscle mass, and weight. Although drugs have been developed that at first appeared promising, there are currently no standard treatments. That may change in view of the latest results from the phase III ROMANA 1 and ROMANA 2 trials with anamorelin, an orally-active selective agonist of the growth hormone secretagogue receptor (GHSR) (Lancet Oncol 2016;17(4):519-31).

The trials appear to confirm GHSR's appetite-enhancing and anabolic effects. In the global, randomized, placebo-controlled trials, totaling 979 patients with advanced non-small cell lung cancer with cachexia, anamorelin significantly increased lean body mass—a co-primary endpoint—over a 12-week study period, while patients receiving placebo either maintained or lost weight.

Patients in ROMANA 1 receiving anamorelin had a median increase in weight of 0.99 kg over the 12-week period versus a median loss of 0.47 kg for placebo; in ROMANA 2, the median increase was 0.65 kg versus a median loss of 0.98 kg.

Patients receiving anamorelin also saw increases in muscle mass and had fewer symptoms of anorexia and cachexia based on questionnaires assessing quality of their life.

Importantly, survival was the same for the two study groups.

But treatment did not improve handgrip strength, also a co-primary endpoint and a marker of functional efficacy.

“Cachexia is part of the dying process—when patients have anorexia/cachexia it probably hastens their death,” said principal investigator Jennifer S. Temel, MD, Clinical Director of Thoracic Oncology, Department of Medicine, Massachusetts General Hospital, Boston, in a phone interview with OT.

Temel said cachexia studies have compared trial medications with megestrol acetate, a medication sometimes used but which is quite challenging in cancer patients.

“Cancer patients are at higher risk of blood clots to begin with, and megestrol acetate, a synthetic progesterone, can also cause them,” she noted. “I never give megesterol acetate to cancer patients; I'm too concerned about the side effects. In my daily practice, I don't give patients medications at all for cachexia, which is really frustrating for patients and their families because it is such a difficult symptom and we have to explain to them we have no safe and effective treatment.”

There were no significant side effects from anamorelin treatment, Temel said.

“This patient population was mostly on cancer chemotherapy or radiotherapy, so the side effects they experienced were mainly due to the underlying disease or its treatment,” Temel said. “There was a slightly higher risk of hyperglycemia, which could manifest itself as diabetes, and a few mild gastrointestinal complications, but in general the drug was extremely well-tolerated.”

Temel did acknowledge the study did not show an improvement in handgrip strength. “We cannot say we have functional improvement, but in medicine in general we don't have great functional measures. Handgrip strength is particularly challenging, although it has been used in healthy populations. Going forward we probably have to rethink our measure for functional status.”

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One Kilo the Tipping Point

Michael Sawyer, MD, Professor in the Departments of Oncology and Pharmacology at the Cross Cancer Institute, Edmonton, Alberta, Canada, was asked to comment on the ROMANA studies.

In a telephone interview with OT, Sawyer said it was very significant that patients in ROMANA 1 gained a median of one kilo of lean body mass.

“In an elderly or frail person, the loss of one kilo of lean body mass is enough to take that person from being active and at home to being institutionalized,” Sawyer said. “One kilo is considered the tipping point.”

Sawyer said a drug that could reverse muscle loss would potentially change the prognosis of cancer.

“The Holy Grail in cachexia in cancer is not just to reverse weight loss, but to have some of the significant proportion of that reversal in muscle,” he said. “Megesterol acetate can give you weight gain. but not the weight gain you want, which is muscle.”

Sawyer was asked whether hand strength is all that important if a patient's decrease in body mass is stopped or reversed by a treatment.

“I'm not sure it is,” he said. “An unresolved area in cachexia research is what the valid endpoints are. There is no drug approved for cachexia and one of the limitations for that is lack of functional outcomes. Many researchers believe the ultimate treatment for cancer cachexia will not be one drug but multiple modalities, the other modalities being exercise and nutrition.”

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Cachexia Cause of Cancer Death

Approximately 70 percent of cancer patients develop cachexia at some point, Sawyer said, and there is increasing understanding cachexia contributes directly to cancer mortality.

“While the most obvious muscles that develop wasting are those that are superficial and visible, the respiratory muscles, diaphragm and intercostal and even the heart, are also subject to cachexia.

“What may literally stop our cancer patients' hearts from beating in advanced cancer may be profound wasting of the heart itself.”

Why the body does this “is the million dollar question,” Sawyer said. “We know cachexia is not simply malnutrition. You can provide calories and supplements to the patient and that will not reverse the condition.”

Inflammation is thought to play a major role, he said. Interleukin-6 and other cytokines active in the tumor microenvironment also contribute substantially to cachexia and muscle wasting.

“Cachexia is a side effect of the cancer that the cancer is probably using to benefit itself.”

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New Hopes

An editorial accompanying the study concluded the ROMANA 1 and ROMANA 2 trials “offer new hopes” for more effective therapeutic strategies for cancer cachexia (Lancet Oncol 2016;17(4):414-15).

Maurizio Muscaritoli, MD, PhD, Professor in the Department of Clinical Medicine, Sapienza University of Rome, Italy, noted in the editorial that up to 50 percent of patients with cancer die with cachexia and up to 20 percent have cachexia as the cause of death (Crit Rev Oncol Hematol 2015;94:251-59).

“Although substantial progress on the pathogenic mechanisms, definition, and classification of cachexia has been achieved, such advancements have not yet translated into effective strategies that can prevent or treat this devastating disorder,” he wrote. “It is becoming increasingly clear that multimodal strategies, encompassing drugs, physical activity, and optimum nutritional support are required.

“The finding that anamorelin might attenuate the loss of muscle mass (sarcopenia), or even improve lean body mass during antineoplastic treatments might have major implications in clinical practice.”

Muscaritoli pointed out a weakness in the study, noting the authors did not measure actual food intake in patients. “That makes it difficult to ascertain whether improvement in anorexia translated into optimum nutritional intake, capable of effectively sustaining the anabolic boost of anamorelin.”

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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