Cancer Cachexia (Unintended Weight Loss and Appetite Loss)

July 18, 2023 • By Fight CRC

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Manju

This month Maia and I will focus on cancer cachexia, unintended weight loss and appetite loss. For those who are unfamiliar with the term, here’s a great blog post on cachexia.

In simple terms, cachexia is a complex, life-threatening metabolic condition that can cause unintentional weight loss, loss of appetite, muscle wasting, and fatigue. Cachexia may be seen in patients with advanced cancer, and this is because of cancer. 

While cachexia is not heavily studied, there is a great deal of misunderstanding and confusion around this condition. Cachexia often prompts caregivers to encourage cancer patients to eat more since they believe that cachexia is happening because the patients aren’t eating enough. But this thinking and behavior is often unhelpful and, worse, can add to the patients’ distress.

Here’s a nice article from the NCI that describes cachexia and some new advances in the field.

For colorectal cancer patients and caregivers, here are a few points to keep in mind about cancer cachexia:

  1. Cancer cachexia can lead to appetite loss and body weight and muscle loss and is a consequence of cancer. Treating the underlying cancer can help alleviate cancer cachexia in non-metastatic CRC patients. For stage IV patients with cachexia, it is important to understand that this is a clinical condition that needs medical attention. Seeing your loved ones not eat and progressively lose weight can be distressing to caregivers. Understanding that cachexia is a clinical condition can help caregivers modify their behavior and stop adding additional stress to patients who may be struggling to eat.
  2. Cancer cachexia can lead to wasting or severe loss of fat and muscle and interfere with daily activities, which can be distressing to patients and families. Unfortunately, there is a lot of confusion about this topic. There are no standardized ways to measure or identify cancer cachexia, and different approaches, including loss of more than 5% body weight in the previous six months, are currently used to estimate if it has set in. There are no effective treatments for a cachexia diagnosis, but recently published ASCO Cancer Cachexia Guidelines, which Maia will discuss below, has some information that’s useful for patients to know.
  3. Even though there aren’t many treatments available currently for cachexia, dietary counseling and physical therapy are often suggested to patients, and now some cancer centers have programs specifically directed at cancer cachexia.
  4. General inflammation due to cancer and altered metabolic balance that results in faster breakdown of fat and muscle than what can be replenished by diet is what is thought to lead to wasting.

In the next section below, Maia will discuss a few ongoing trials on cancer cachexia and a rapid guideline update on management of cachexia issued by ASCO just a couple of weeks ago (June 2023).

Maia

A Dose Escalation Study of AV-380 in Metastatic Cancer Patients with Cachexia

NCT05865535

The first trial I’d like to highlight is one that is very new. It is not yet recruiting at the moment of writing. It uses a novel agent, AV-380, to see how well it works to improve weight gain and muscle mass in people with cachexia – and it will also look at if AV-380 is safe.

The study is open to people with metastatic cancer, colorectal cancer included, who have cachexia. In addition to chemotherapy, participants will receive AV-380.

AV-380 is a humanized inhibitory IgG1 antibody targeting growth differentiation factor 15 (GDF-15). We will see GDF-15 mentioned often when talking about cachexia.

GDF-15 is a pro-inflammatory cytokine whose elevated circulating levels have been correlated with cachexia. This has been observed in actual patients and also in several animal models of cancer cachexia. The evidence suggests that a pro-inflammatory state may be responsible for many of the symptoms associated with cachexia. 

Preclinical data show that inhibition of GDF-15 results in a switch from catabolism to anabolism, suggesting that GDF-15 inhibition with AV-380 may reverse the effects of cachexia. Catabolism is the mechanism that breaks down muscle and fat for energy in the absence of enough nutrients (food). Anabolism is the opposite of catabolism: It is the mechanism that takes smaller units like nutrients, cells, or amino acids, and bonds them together to create bigger structures (it is the process involved in the healing of an injury, the growth of children, and building muscles). That is the process that must be favored when dealing with cachexia.

ACTO: A Phase II, Randomized, Placebo-Controlled Study Evaluating Olanzapine in the Management of Cancer Cachexia

NCT05705492

This trial will take place at Portland, Oregon, and it is also a new one, not yet recruiting at the moment of writing this blog. In this case, the study doesn’t use a novel agent but one that is already approved for other indications: olanzapine.Even more, while writing this blog, ASCO issued a Rapid Guideline Update on the management of cachexia, that allows oncologists to offer daily low-dose olanzapine for adults with advanced cancer (colorectal cancer is included) to improve weight gain and appetite.

ASCO Guidelines Cancer Cachexia Rapid Recommendation Update for adults with advanced cancer

Olanzapine is an antipsychotic drug that is already approved for the treatment of schizophrenia and bipolar disorder. It is also being studied for other conditions, including cancer cachexia. As an atypical antipsychotic, olanzapine works by blocking the activity of certain proteins in the brain. Also, it is thought to have some effects on metabolism. This is why it is being studied for the treatment of cancer cachexia. The drug is taken orally, as a pill.

Recently, researchers at an Indian single-center study reported in the Journal of Clinical Oncology that olanzapine was associated with weight gain and improved appetite vs. placebo in patients receiving chemotherapy for newly diagnosed locally advanced or metastatic gastric, hepatopancreaticobiliary, or lung cancers.

The purpose of this study for 44 participants in Oregon is to explore if olanzapine can help to improve weight gain and muscle mass in people with cachexia. The study will also look at the safety of olanzapine. The findings of this clinical trial will probably offer more evidence to support this recent Rapid Recommendation Update by ASCO, regarding the management of cachexia.

Frequency of Cachexia in Ambulatory Cancer Patients and Psychological Burden in Patients and Their Primary Caregivers

NCT04090619

This is an observational trial being conducted at the University of Texas MD Anderson Cancer Center. Patients with advanced cancer and their primary caregiver can participate.

The study is not for the direct treatment of cachexia but to gather data about the frequency of cachexia in cancer patients and the psychological burden it can have on them and also on their loved ones.

Participants will need to complete eight questionnaires about appetite, quality of life, symptoms, history of weight loss, nutritional status, body image, and nutritional support over 30 minutes.

Even if this study won’t immediately change the treatment or care received, your participation could help to improve the lives of other cancer patients in the future by helping doctors to provide better support and treatments.

Study of the Efficacy and Safety of Ponsegromab in Patients with Cancer, Cachexia and Elevated GDF-15 (PROACC-1)

NCT05546476

This phase II clinical trial, ongoing at several locations nationwide and worldwide, started last year, and it is recruiting.

The study is open to people with non-small cell lung, pancreatic, or colorectal cancer who are also dealing with cancer cachexia. Patients will be tested for serum GDF-15 concentrations, since GDF-15 is a protein that is thought to play a role in the development of cachexia. Persons with cancer and those with elevated levels of GDF-15 will be eligible. Participants will be randomly assigned to receive either ponsegromab or a placebo, as a low dose subcutaneous injection every four weeks.

Ponsegromab (also called PF-0694686) is a monoclonal antibody that targets GDF-15. By targeting GDF-15, ponsegromab is thought to help to prevent or improve weight loss and muscle mass loss. This drug is still in clinical development, and it has not yet been approved by the FDA for any indication.

This is a phase II trial; results from a phase I trial have been reported: “ponsegromab was well tolerated and suppressed serum GDF-15 concentrations to below the median concentration seen in healthy subjects. Preliminary evidence of efficacy, including a mean observed weight gain of approximately 6.5% at 12 weeks, supports continued development of ponsegromab for the treatment of cancer cachexia.”

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