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Page 6 of 11 Miller et al. J Cancer Metastasis Treat 2019;5:68 I http://dx.doi.org/10.20517/2394-4722.2019.001
[61]
molecules (e.g., VEGF) that are able to stimulate angiogenesis and promote tumour growth . Activated
neutrophils can move from the circulation to the tumour site to release reactive oxygen species that in turn
can lead to further DNA damage. They also have anti-tumour roles through antibody-mediated cytotoxicity
[62]
of tumour cells .
C-reactive protein is an acute phase non-specific inflammatory marker that can be elevated in response to
infection, surgery or malignancy. It is produced by the liver in response to increased levels of IL-6 released
[63]
by activated macrophages, as well as IL-1 and TNF-α . The Glasgow Prognostic Score utilises raised CRP
and hypalbuminaemia to predict those patients with systemic inflammation as part of cancer cachexia and
who have a poor outcome. It has been examined in more than 60,000 patients and has been shown to have
[64]
independent prognostic value .

IMMUNOTHERAPEUTIC AGENTS FOR CANCER CACHEXIA
Immunotherapeutic agents for cancer cachexia have yielded mixed results. The different forms of
immunotherapy are discussed in detail below.

TNFα inhibitors
There are currently several TNF inhibitors in use for the management of diseases such as rheumatoid
[65]
arthritis (RA), psoriasis and inflammatory bowel disease, namely etanercept, infliximab and adalimumab .
These drugs have revolutionised the treatment of RA but have also offered insights into the role that
TNF-α plays in cachexia. In RA patients, they attenuate the hepatic acute phase response and, importantly,
improve patients quality of life [65,66] . They have also been shown recently to prevent worsening of the disease
[67]
and restore fat free mass . These drugs are now used to treat many thousands of patients and have been
shown to be effective at blocking TNF-α, but are not effective in treating cancer-induced cachexia [62-64] . The
feature common to all of these diseases is chronic inflammation due to exaggerated production of pro-
inflammatory cytokines. Etanercept has showed some promising results in improving fatigue in a small
[68]
cohort of cancer patients . A phase I/II study was conducted on pancreatic cancer patients comparing
etanercept and gemcitabine with gemcitabine alone. A small increase in progression free survival was
seen associated with higher plasma IL-10 levels, but there was no significant improvement in 6 month
[68]
progression-free survival compared with gemcitabine alone . A placebo-controlled double-blind trial
was also undertaken in 63 patients with incurable malignancy and weight loss of > 2.27 kg over 2 months
or daily intake of < 20 calories/kg body weight. Weight gain was found to be minimal in both arms with
[69]
comparable survival times. Treatment was associated with higher neurotoxicity . In this trial, therefore,
etanercept was not effective in the treatment of cachexia in patients with advanced disease.

Infliximab has been used in a phase II placebo controlled randomised study in patients with stage II-IV
[70]
pancreatic cancer . Patients were given either 3 mg/kg or 5 mg/kg infliximab with gemcitabine or placebo
with gemcitabine. The mean change in lean body mass was + 0.4 kg for those on placebo, + 0.3 kg for those
receiving 3 mg/kg of infliximab, and + 1.7 kg for those receiving 5 mg/kg of infliximab. No statistically
[70]
significant differences were seen, however .
Another agent with anti-inflammatory activity is OHR/AVR118, a broad-spectrum peptide-nucleic acid
[71]
immune modulator that targets both TNF-α and IL-6 . A phase II study involving patients with advanced
[71]
cancer and cachexia showed an improvement in anorexia, dyspepsia, strength, and depression .
Anti-IFNg treatments
[29]
Anti IFNg treatments have been effective in reverting cachexia in the LLC mouse model . There have been
no trials undertaken in cancer patients, mainly due to the fact that this type of therapy requires a dose to
completely block the action of IFNg, and at present, such a treatment programme would be very expensive.
[72]
The only trial conducted in patients with cachexia due to sepsis showed no benefit .