Novel Cancer Weight-loss Drugs Needed to Improve Outcomes

Liam Davenport

July 04, 2016

BARCELONA — Novel drugs that reflect the recently discovered underlying mechanisms of body mass and muscle loss in cancer are required if clinicians are to have an impact on outcomes, say experts in palliative care.

Current therapies are either ineffective or have intolerable adverse effects, meaning that "new drugs are needed" to optimize care for this "multidimensional problem," commented Florian Strasser, MD, head of oncological palliative medicine, Cantonal Hospital, St Gallen, Switzerland.

He was speaking here at the 18th World Congress on Gastrointestinal Cancer (WCGC).

In a separate presentation, Dileep Lobo, MD, Professor of Gastrointestinal Surgery, University of Nottingham, UK, pointed out that the field is hampered by a lack of good quality evidence because of the heterogeneity of studies and the use of different endpoints.

One promising pathway for novel interventions in cachexia, he noted, is to target inflammation, as recent studies have shown that levels of a number of inflammatory markers are raised in cachexia, and Dr Strasser called for future clinical trials in gastrointestinal cancer to include variables related to cachexia.

Approached for comment, Eric Van Cutsem, MD, PhD, congress co-chair and professor of internal medicine at the University of Leuven, Belgium, said that the relevance of cachexia and sarcopenia is well understood, noting: "We know that it's a bad prognostic factor for patients and that during the disease also it correlates closely with poorer outcome."

Speaking to Medscape Medical News, he added that "we are starting to understand the underlying mechanism of cachexia and sarcopenia." The important thing, he emphasized, is having different pharmacological ways to intervene, "but we are not there yet," he said.

"The next step is to have the proof of it [underlying mechanisms] from clinical trials," he continued. However, there are studies of potential drugs for cachexia and sarcopenia that "have yet to report," he pointed out, observing: "Some of them will be successful, probably, but like anything in medicine, not all will be successful. But it's a start."

Multifactorial Syndrome

In a state-of-the-art presentation, Dr Strasser explained that cachexia is a multifactorial syndrome characterized by ongoing loss of skeletal muscle mass that cannot be fully reversed and leads to progressive functional impairment.

Cachexia is typically defined as weight loss greater than 5% of body weight, but for individuals with a body mass index less than 20 kg/m2, it is defined as a weight loss greater than 2%.

Sarcopenia is the loss of muscle mass and can be because of hypogonadism, physical inactivity, corticosteroids, thyroid dysfunction, and the aging process, as well as cachexia.

Dr Strasser pointed out that cachexia is common in cancer patients and is associated with reduced survival. Moreover, increasing cachexia grade, as defined recently by Martin and colleagues, is associated with worsening survival. Sarcopenia is also linked to an increased risk of postoperative complications and worse survival, as well as anticancer treatment toxicity.

Dr Strasser noted recent studies that point to inflammation being involved in cachexia. As shown recently by Mueller and colleagues in animal studies, “the two major drivers of cachexia are inflammation, via the TNF-receptor adaptor protein, but also muscle problems.” He noted, however, that it is not clear the extent to which the findings are translatable to humans.

Another study showed that patients with cachexia have, compared with controls, a significantly higher ratio of neutrophils to lymphocytes (P = .02), higher C-reactive protein levels (P < .0001), and lower albumin levels (P = .0027).

Other biomarkers of inflammation associated with cachexia were interleukin (IL) -8 and IL-6, and transforming growth factor beta 1, prompting Dr Strasser to observe that "measuring inflammation is relevant in clinical practice."

Prevention of, or improvements in, cancer cachexia or sarcopenia must begin, he said, by identifying patients through routine monitoring of nutritional disturbances at every stage of the patient's disease.

The patient should then be assessed on a series of domains; specifically, the depletion of both fat and muscle reserves; nutritional intake and appetite; inflammation, tumor dynamics, and hypoanabolism; and neuromuscular and emotional/cognitive function. Other causes of weight loss and inflammation should also be ruled out.

Dr Strasser emphasized that treatment of "cachexia requires multidimensional interventions delivered by multi-professional teams," and includes nutritional counseling to, for example, eat lots of small meals that contain proteins and fat, alongside changes to eating habits and the use of oral supplements.

Although he said that the evidence for parenteral nutrition is "poor," Dr Strasser noted that sip feeding has been shown in pancreatic cancer patients with cachexia to have a positive impact on protein kinetics by decreasing protein breakdown.

Crucially, cachexia is improved by effective anticancer treatment. He also noted that exercise has the potential "to impact positively on muscle mass and strength," as well as inflammatory markers and physical function, and has been shown in a mouse model of cachexia to improve muscle mass and fiber size.

In terms of drug therapy, the currently available medications are typically hampered either by a lack of efficacy or prohibitive adverse effects. For example, there is insufficient evidence in support of cannabinoids, non-steroidal anti-inflammatory drugs, amino acids, and androgens.

Moreover, corticosteroids should be used only for 1 to 2 weeks to relieve short-term distress because of the accumulation of adverse effects, while fish oil or eicosapentanoic acid are often poorly tolerated. Prokinetic agents only affect satiety, while progestins only improve fluid or fat mass and have limiting adverse effects, including thromboembolism and mortality.

A number of emerging drugs have consequently been examined recently, including melanocortin receptor 4 antagonists, ghrelin and its analogues, androgen and beta2-mimetics, drugs affecting muscle pathways, and anti-inflammatory agents such anti-IL-1 and anti-IL-6 products, among others.

Although some are "promising," Dr Strasser took the ghrelin analogue anamorelin as an example, showing that it improved muscle and fat mass but had no impact on survival or handgrip, while its effect on cancer treatment toxicity and physical activity has not been assessed. The initial results from clinical trials with anamorelin have previously been reported by Medscape Medical News (here and here).

Nutritional Support

In the second presentation, Dr Lobo examined whether perioperative nutritional support improves outcomes in cancer surgery patients, noting that undernutrition is not only associated with increased morbidity and mortality and reduced quality of life, but also with more intensive treatment, longer hospital stays and higher costs of care.

Assessment for undernutrition should begin 2 to 3 weeks before surgery, with preoperative nutrition, if needed, started 7 to 14 days before the procedure. Dr Lobo also said that prolonged starvation 12 hours beforehand is no longer considered necessary.

He noted that both enteral and parenteral nutrition are associated with a number of pros and cons, but that the surgeon should start from the premise that "if the gut works, use it."

On the question of what to give, he said that nutrition should consist of macro- and micronutrients, alongside electrolytes and elements such as iron, zinc, and selenium.

However, Dr Lobo agreed with Dr Strasser that currently available medications to treat undernutrition were shown either to be ineffective or to have adverse effects that limited their utility.

After noting some palliative measures to deal with, for example, intestinal obstructions, Dr Lobo pointed out that he had not backed up many of his claims during his presentation, asking, "Where is the evidence?"

The reason, he said, is that "there is very little good quality evidence." For example, a recent meta-analysis of 15 studies with over 3000 patients failed to demonstrate any benefit from routine enteral or parenteral feeding after pancreatoduodenectomy.

"You may say, 'This doesn't make sense,'" said Dr Lobo. "But it does make sense, because the problem with these studies is that everyone has different endpoints, some of them physical endpoints, some of them nutritional endpoints, and very few of these endpoints are related to outcomes."

He continued, "There's a lot of heterogeneity in these studies, and the nutritional status of the patients at the start is completely different, so we cannot make firm conclusions."

No relevant financial relationships were reported.

18th World Congress on Gastrointestinal Cancer (WCGC). Presented 29 June 2016.

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