A study of patients with metastatic lung cancer by researchers based in Brazil and the United States has found that their performance in simple physical tests such as sitting down, standing and walking can help physicians arrive at a prognosis and approach to treatment.

An article on the study is published in the European Journal of Clinical Investigation. 

The findings also included identification in the volunteers’ blood plasma of two substances – serine and M22G – with the potential to become biomarkers capable of indicating which patients are most likely to respond to chemotherapy.

The study was supported by FAPESP (projects 16/20187-6 and 19/17009-7), and was conducted by researchers at the University of São Paulo’s Medical School (FM-USP) in Brazil and Harvard Medical School in the US.

As explained by Willian das Neves Silva, first author of the article, cachexia anorexia syndrome, characterized by loss of skeletal muscle mass due to intense consumption of muscular and fatty tissue, is a common feature of advanced-stage cancer and is usually associated with loss of appetite, fatigue, and muscle weakness.

In the case of lung cancer, and specifically of non-small cell lung cancer (NSCLC), the most frequent form of lung cancer, the study showed that measuring muscle mass is not sufficient for prognostic purposes and that muscle function should also be taken into account.

“We saw that function is more important. Not just having muscles, but what the patient can do with them. The study showed that physical fitness matters more than muscle mass. Most patients were debilitated and suffering from some degree of cachexia [pronounced loss of weight and muscle mass]. Patients with better physical performance live longer, and this has nothing to do with their overall condition,” said Silva, who conducted the investigation for his PhD research, with three thesis advisors: Gilberto de Castro Junior, a professor at FM-USP; Patrícia Chakur Brum, a professor at the School of Physical Education and Sports (EEFE-USP); and Kathryn J. Swoboda, a researcher at Massachusetts General Hospital, Harvard Medical School’s largest teaching hospital.

According to the authors, the findings of the study can help oncologists manage chemotherapy more effectively and refer patients to palliative care or specialists in complementary disciplines if needed.

“We showed that patients who performed poorly in the simple physical tests also displayed impaired oxygen consumption, whereas patients who performed well were satisfactory in this item. We believe the inflammatory process associated with the tumor results in a set of metabolites circulating in the bloodstream with potentially negative effects on muscle cell metabolism. Somehow these cells are damaged by toxins that reduce oxygen consumption, making their overall condition worse,” Castro Junior said.

Lung cancer kills more men than any other type of cancer, and in women, it comes second, according to Brazil’s National Cancer Institute (INCA). Tumors are classified in accordance with the type of cell, and each develops differently. NSCLC is the most common, accounting for 80% of the total.

“It’s very frequent, and unfortunately median survival is very low – about ten months,” Castro Junior said, adding that lung cancer is associated with smoking in more than 90% of cases, and prevention is important. “We’re talking about patients aged 60-65 who were smokers for a long time.”

Methodology

The study sample comprised 55 NSCLC patients who attended the São Paulo State Cancer Institute (ICESP). Most were men, all of them smokers. They received treatment between April 2017 and September 2020 and were followed up for about three months on average during chemotherapy administered at the hospital.

Physical tests, collection of blood samples and CT scans took place in Brazil. In physical tests to assess capacity before the start of treatment, patients were asked to stand, walk three meters, return and sit down again; sit and stand ten times; and walk for a further six minutes. A group of 23 patients underwent an endurance test on a bicycle ergometer while wearing an oxygen mask and constantly increasing speed.

“Some of these patients had lost 30 kg in the previous six months and appeared debilitated, yet displayed adequate endurance nevertheless. From this, we concluded that there was no direct link between muscle mass and performance and that they would also be able to endure chemotherapy. Physical activity is important, in our view, even when performed in accordance with the capacity of each person, and can have a positive effect during treatment,” Silva said.

In Harvard, the blood samples and muscle cells collected in Brazil were submitted to metabolomic analysis to detect the intermediate or end-products of their metabolism in an attempt to identify molecules that could be used as markers of the disease.

As noted, serine and M22G were identified as potential biomarkers of a positive response to chemotherapy. Serine is a nonessential amino acid that takes part in several metabolic processes, such as protein synthesis, and is also necessary for the functioning of muscle cells. An excess of serine in cells is associated with tumor growth. Serine inhibition can help reduce tumors and has been suggested as a potential part of cancer treatment.

“We showed that both substances were linked to these patients’ performance, and could serve as markers of that performance in future. However, more research needs to be done on this,” Silva said.

Next steps will include reanalyzing all data for all patients with the aid of artificial intelligence in search of biomarkers that can help understand the mechanism of the disease, and investigating whether physical exercise during chemotherapy can improve the overall health of NSCLC patients. 

Muscle quality

More recent findings by the same research group, published in the journal JCSM Communications, show that inflammation, food aversion and intramuscular fat can all be used as predictors of prognosis in metastatic NSCLC patients.

“In this new analysis, we included another group of patients whose performance in physical tests was even worse than that of the previous study. We analyzed them as a single group and found that the patients with the worst inflammation, food aversion and intramuscular fat survived less. Intramuscular fat was an indication of poor-quality muscle, leading to poor performance in physical tests,” Silva said.

A long-term research goal is to understand how physical exercise could function as a kind of “remedy”, complementing the treatment. “We know patients with poor muscle function survive less. Could we somehow reverse this process by improving muscle function through exercise, making these cells more resistant to inflammation, breaking the vicious circle of cachexia and muscle loss, and boosting the antitumor effect of the treatment? This is what we aim to find out now,” Castro Junior said.

These studies are part of the Thematic Project “Cancer and heart: new paradigms of diagnosis and treatment”, led by Carlos Eduardo Negrão, full professor at both EEFE-USP and FM-USP.