Cancer cachexia is the most common cancer-related syndrome. Cachectic patients show poor performance, lower treatment responses, and dismal prognosis [13, 22] . Indeed, cancer cachexia is present in different types of cancer and different stages and it is estimated that cachexia is responsible for around 20% of all cancer deaths [16, 23–27].
In this study, after a long-term clinical follow up, we detected a high prevalence of cachexia according to two standardized diagnostic criteria in disease-free patients post cisplatin-based chemoradiotherapy with curative intent. In addition, we demonstrated that cachectic patients presented lower muscle mass and strength. Cachexia present a trend to be associated with dysphagia when diagnosed according to Evans diagnostic criteria (p<0.06) and 73% of cachectic patients manifested dysphagia according to Fearon criteria.
In newly diagnosed HNSCC patients, cachexia frequency is at least 42% when diagnosed using Fearon criteria[27] and 6.1% when diagnosed using Evans criteria[19]. In our population, the percentage of cachexia was 20.7% and 8.6% according to Fearon and Evans, respectively, in disease-free HNSCC patients, after multimodal treatment. This distinction is important because there is a concept that cancer cachexia syndrome is associated with metabolic disturbances related to the tumor presence [15, 20]. Kwon and coworkers [19] showed that cachexia in HNSCC patients increases by 41% immediately after the end of the treatment as compared with pre-treatment values (6.1%). Nevertheless, according to the authors, the cachexia frequency decreases to 18% after 6 to 12 months post-treatment, approximately two times the frequency here observed two years after treatment completion.
In this context, we found a high percentage of dysphagia in our cohort. Dysphagia is correlated to body and muscle mass loss in cancer and non-cancer patients[28, 29], and this fact could explain at least part of our results. This data supports the idea that the cachexia in disease-free patients could be a side effect of cancer treatment and, as such, classified as a late toxicity. Indeed, around 50% of all head and neck cancer patients present dysphagia after treatment[30].
Cachexia in disease-free patients could be also attributed to a cisplatin side effect. This hypothesis is supported by recent data showing that cisplatin causes a muscle mass reduction. Damrauer et. al. showed in an animal model and cell cultures that cisplatin could regulate the proteolysis pathway leading to muscle wasting [31]. However, there are no clinical data to support this hypothesis.
Recently, Grossberg et al. showed that there is no correlation between body mass loss and survival in radiotherapy-treated HNSCC patients[32]. However, the authors described that pre- and post-radiotherapy muscle mass depletion was associated to shorter overall survival. Our data suggest that cachexia in disease-free patients has a muscle component, but we did not perform any survival or cancer recurrence analysis, so further studies are needed to better elucidate this question.
Our study demonstrated that severe weight loss was important in the diagnosis of cachexia, but muscle mass and strength alterations, hemoglobin and CRP are also important issues to evaluate metabolic dysfunction, which could be a trigger to weight loss. It is worth mentioning that cachectic patients in our cohort did not show a difference in metabolic markers when compared with non-cachectic patients. In fact, muscle mass and metabolic markers are mortality predictors in different types of cancer[33–35].
This study had some limitations. First, it was not possible to perform a more accurate analysis of muscle area using CT-scans images. Second, other late toxicities (e.g., xerostomia, hypothyroidism, esophageal toxicity, and others) could contribute to cachexia development in our patients, and these alterations could also have some impact on muscle mass, strength, biomarkers, and quality of life. Third, we did not evaluate the impact of the cachexia on disease recurrence and survival, and this long-term study is underway.
In conclusion, HNSCC patients treated with chemoradiotherapy after a minimum of 2-years of treatment completion presented cachexia, and cachectic patients presented impairment in muscle mass. Cachexia could be also associated with dysphagia and related to a worse muscle function. Cachexia and metabolic dysfunction should thus be better studied to elucidate its pathophysiology and prognostic impact on cancer HNSCC survivors in order to improve their outcomes.