75 Inflammation and post-tx sickness syndrome as an explanation for late effects

Abstract

The changing epidemiology of head and neck cancer, with an increase in HPV-positive oropharyngeal cancers and the refinement of a multidisciplinary approach, has led to an increase in the prevalence of long-term survivors after treatment. Consequently, a higher proportion of patients are suffering from late effects of the treatments, temporally defined as effects occurring or persisting more than 3 months after the end of the treatments. These late toxicities consist both of locoregional problems and systemic syndromes, with an impact on patients’ quality of life.There is still limited knowledge about the precise causes of these late toxicities, and at the same level, we lack predictive factors able to identify patients at higher risk of late effects. Treatment combinations with surgery followed by (chemo)radiation or with chemotherapy added to radiation with a radiosensitizing effect increase the probability of suffering from the late consequences of the same therapies. Pain, swallowing difficulties, trismus, osteonecrosis, dental disorders, mucositis, xerostomia or sticky saliva, hoarseness, lymphedema, and fibrosis are the most reported symptoms and signs, while fatigue, anxiety, depression, and cognitive impairment are the counterparts at the systemic level.There is growing evidence for the role of inflammation in the progression of cancer and treatment-related side effects. However, for head and neck cancer patients, there are still a lot of unanswered questions related to the role of inflammation as being both related to cancer disease and to the consequences of the intensive treatments carried out for this disease. In particular, it is well known that pro-inflammatory cytokines have been shown to be activated by malignant tumors and cancer treatment, and that their level during treatment is linked to higher acute toxicities. Also, the level of pro-inflammatory cytokines such as interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF) has been correlated to higher mucositis, dysphagia, and pain due to the acute toxic effect of chemoradiation. However, researchers have not yet proven the association between the level of proinflammatory cytokines in the acute phase of the treatment and the development of late toxicities. Even the role of the same pro-inflammatory mediators in the follow-up period has a conflicting correlation with the late toxicities reported by the patients. Chronic inflammation may cause fibrosis, one of the key pathological features of radiation-induced late effects such as dysphagia and transforming growth factor beta (TGF-β) and TNF are involved in the formation of fibrosis in irradiated tissue. There is even more debate about the cause of systemic symptoms after cancer treatment. Head and neck cancer patients may develop the post-treatment sickness syndrome, consisting of chronic fatigue, mood alteration, cognitive impairment, and sleep problems, among the most frequently reported symptoms. The neuro-behavioral sickness model recapitulates all these symptoms as being related to the stress induced by the treatment, causing alterations in mood, cognition, nutritional intake, and the neurovegetative system. One of the hypotheses is that activation of peripheral pro-inflammatory cytokine networks transmits signals to the brain, which promote sickness behavior. The tissue damage induced by the oncological treatments would result in a self-perpetuating activation of biological processes, leading to a persistent inflammation condition that results in worsening systemic late effects over time. However, this theory needs to be carefully validated with prospective studies exploring patient-reported outcomes and their correlation with inflammatory mediators. According to this model, if inflammation recapitulates the locoregional and systemic late toxicities induced by the treatments, research should lead efforts to find ways to counteract it. From one side, it is possible to define de-escalating treatments that could offer the same level of cancer control with a reduced burden of acute and late toxicities. This is particularly awaited in HPV-positive cancer patients, who are usually younger patients, obtaining higher survival rates and thus a higher impact of toxicities on quality of life. On the other hand, it is important to define specific protocols to reduce the impact of inflammation in the long-term. In this regard, the role of physical exercise has been clearly underestimated, and recent research has shown benefits for the survival and quality of life of head and neck cancer patients. Also, even with less scientific evidence, nutrition could offer a less inflamed systemic status that could help minimize the late effects of cancer treatment. It is clear that research in this field is in its infancy, and we need to put more efforts into defining the translational correlates of late toxicities and exploring new ways to counteract the post-treatment sickness syndrome.