Cancer cachexia: towards integrated therapeutic interventions

Abstract

Biological treatments represent a novel approach to counteract cancer cachexia. Monoclonal antibodies targeting cytokines and molecules responsible for muscle wasting, with an anti-inflammatory effect, however, still have several limitations and need further clinical investigation. New research in this field will contribute to the better understanding of the multifactorial pathogenesis of cancer cachexia, while favoring the consolidation of multimodal preventive and therapeutic strategies encompassing nutritional and pharmacological treatments. New pharmacological therapies and conventional nutritional treatments will soon integrate in the ‘parallel pathway’, aimed at early recognition, prevention and treatment of the metabolic and nutritional derangements occurring in cancer. This will likely produce improvement in quality of life, tolerance to treatments and survival.

Keywords::

• biological therapies
• cachexia
• cancer
• nutritional intervention

In the recent years, the better understanding of the mechanisms underlying cancer cachexia revealed that inflammation is a key factor determining the cancer-associated metabolic derangements finally leading to the irreversible loss of muscle mass and function.

The paper by Ma JD et al. [1] published in the present issue of the journal describes novel biological agents for cancer cachexia that are currently under investigation. These molecules are effective in counteracting some of the mechanisms underlying muscle wasting occurring in cancer, especially systemic inflammation, which can contribute at central and peripheral levels to development of metabolic and nutritional modifications [2] and to reduced overall survival of cancer patients. Unfortunately, despite the significant advancement achieved during the last few years [3], one widely accepted operational definition of cancer cachexia is still lacking due to the complex multifactorial pathophysiology of this condition. This makes diagnosis of cachexia uncertain, its prevalence unclear and its possible prevention and treatment anecdotal, ultimately leading to poor cancer prognosis. Moreover, the multifactorial pathogenesis of cancer cachexia implies that its treatment should be based on multimodal strategies, which further complicates the therapeutic approach [4]. Besides, cachexia is still largely, although erroneously, considered as an ineluctable consequence of advanced cancer, making healthcare professionals reluctant to the implementation of active anticachexia strategies. In this scenario, it is evident how hard it can be to make a comparative evaluation of the different ongoing trials described in the article by Ma JD et al. [1]. Indeed, as the authors themselves recognise [1], these biological therapies have several limitations when used during refractory, that is advanced, cachexia [3], which is the stage of cachexia easier to clinically identify and diagnose, yet extremely difficult to treat with respect to the initial stage, namely, pre-cachexia [3].

The authors first analyze the ‘humanised’ monoclonal antibody targeting IL-6, named ALD518. A statistically significant improvement in hand grip strength and fatigue was reported after a single dose in a small group of cancer patients with cachexia, however with a lack of sustained response after 4 weeks of treatment [5]. In a larger group of patients with non-small cell lung cancer (NSCLC) who received ALD518, less fatigue and a non-statistically significant attenuation in lean body mass loss and at 12 weeks were observed compared with placebo [6].

A study (Phase III) testing MABp1, a fully humanised, monoclonal anti-IL-1α antibody, to reduce weight loss and to increase overall survival in patients with colorectal cancer in comparison with megestrol acetate is currently in progress [7]. Moreover, IP-1510 is a synthetic peptide IL-1 receptor antagonist currently studied in I/II Phase trial in patients with advanced cancer. The injection of 1 mg subcutaneous twice daily during a 28-day treatment period induced weight gain and improved self-reported appetite in the absence of significant side effects [8]. OHR/AVR118, a broad-spectrum peptide-nucleic acid immunomodulator, whose mechanism of action is still unknown, is now being tested in patients with different cancer with only preliminary results [9].

Previous studies in experimental and human cancer cachexia [10-12] have clarified the involvement of myostatin, a member of the TGF-β superfamily, as negative regulator of muscle growth by its binding to the activin type II (ActRII) B receptor. This led investigators to suggest the use of the fully human anti-ActRII monoclonal antibody bimagrumab (BYM338) [13]. So far, only experiments on animals with severe combined immunodeficiency and glucocorticoid-induced muscle wasting that showed dose-dependent recovery of skeletal muscle and increased body weight after 2 weekly doses are available in the literature. Studies investigating this effect are currently ongoing in humans affected by NSCLC Stage III/IV and pancreatic cancer associated with cachexia.

Besides the novel and promising role of the biological therapies that will represent a very important approach to cancer cachexia, nutritional and metabolic interventions appear nowadays essential to improve patients’ outcomes even if started in advanced cancer [14-16]. Recently, our group proposed the ‘parallel pathway’ as a preventative and therapeutic tool for cancer cachexia [17], aimed at the early recognition, prevention and treatment of the metabolic and nutritional derangements occurring in cancer. In particular, since the diagnosis of cancer is performed, patients should be constantly monitored by nutritionists in parallel with the oncologists, to early assess nutritional status and to diagnose metabolic modifications. In fact, in the absence of effective therapies for cancer cachexia, it appears mandatory to implement strategies to reduce involuntary weight loss and malnutrition since the early stage of the disease [17]. Evidence is accumulating that such early metabolic and nutritional monitoring and intervention encompassing nutritional and/or pharmacological interventions may positively affect quality of life and tolerance to treatments, supporting the view that preventative metabolic and nutritional interventions should become an integral part of the multimodal anticancer treatments [17].

Although the relevant role of increased inflammatory status in tumour progression and dissemination and on cancer-associated nutritional derangements is well recognised, experimental data indicate that pharmacologically interfering with myostatin in muscles of tumour cachectic animals improved cachexia and survival with no effect on the inflammatory status [18]. Therefore, these results, so far obtained only under controlled experimental conditions, are still a matter of controversy. In this light, nutrition in cancer patients can represent a multidimensional treatment not only intended to provide energy and protein requirements, but also to counteract inflammation and central and peripheral dysregulations. Some nutrients, such as fish-oil-derived fatty acids, hold anti-inflammatory properties when provided at sovranutritional doses (1.5 – 2 g/day). In particular, ω-3 fatty acids are the substrate of lipoxygenase and cyclooxygenase that catalyse the release of anti-inflammatory mediators, and their use in cachectic patients recently showed their efficacy to improve nutritional status [19]. It has been also suggested that the reduction of inflammation by ω-3 fatty acid administration might ameliorate immune response. Moreover, besides the role of specific nutrients, also including other specific substrates, the preservation of lean body mass might be achieved by physical activity in cancer patients that has been shown to present important anti-inflammatory properties and it was feasible and effective in reducing fatigue in advanced cancer.

Besides this, dietary intervention and physical activity should be considered to complement and not to replace the oncology schedules. In the ongoing study testing MABp1, this biological therapy is not given alone but, as it is clearly indicated by the authors, associated to the ‘best supportive care’ [7], which we assume to include nutritional intervention. Individualised early, nutritional counselling and support have been demonstrated to be effective in maintaining body weight and physical performance in cancer patients [19]. The key to the success of this ‘parallel pathway’ is the adherence to patients’ needs, which requires the coordinated and synergistic actions of specialised and well-trained physicians and dieticians, especially considering that energy intake in cancer patients should be not < 30 kcal/kg of body weight to counteract weight loss and malnutrition [19]. It is also demonstrated that nutritional support can contribute to reduce the number of complications and to shorten the recovery phase, and it can ameliorate the infection rates, with a better control of cancer-related symptoms, such as fatigue, and improve tolerance to anticancer treatments [17]. It is important to consider that nutritional intervention for cancer patients, focusing on drugs and nutrients able to modulate the pathogenic mechanisms underlying cachexia, especially inflammation, can improve response to therapy and improve overall quality of life [1,19]. Integration of nutritional and metabolic monitoring and support into the therapeutic programmes for cancer patients represents a new strategy, which is intended to go beyond its potential role in reversing cancer cachexia, attenuating body weight loss and ameliorating muscle performance. Clinically relevant data indicate that positive results may be observed in terms of enhanced efficacy of antineoplastic therapies, reduction of adverse events and better quality of life [17].

The complex and multifactorial pathogenesis of cancer-related metabolic and nutritional impairment requires multimodal preventative and therapeutic strategies [3,19]. Integration of novel biological treatments with metabolic and nutritional support appears to be the most scientifically sound and promising pathway to the future of cancer supportive therapies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.