Cytokines levels, Severity of acute mucositis and the need of PEG tube installation during chemo-radiation for head and neck cancer - a prospective pilot study

Meirovitz, Amichay; Kuten, Michal; Billan, Salem; Abdah-Bortnyak, Roxolyana; Sharon, Anat; Peretz, Tamar; Sela, M.; Schaffer, Moshe; Barak, Vivian

doi:10.1186/1748-717x-5-16

Cited by 66 publications

(71 citation statements)

References 24 publications

(39 reference statements)

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“…Previous studies have shown IL6 upregulation to be one of the earliest detected responses to radiation-induced tissue injury (33)(34)(35). Our above findings suggested that IL6 is also linked to the later expression of senescence-associated markers in the irradiated salivary glands.…”

Section: Il6 Signaling Enhances Radiation-induced Senescence In the Ssupporting

confidence: 58%

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Marmary¹,

Adar²,

Gaska³

et al. 2016

Cancer Research

106

111

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Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiationinduced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (gH2AX and 53BP1) and the expression of senescence-associated markers (SA-bgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. Cancer Res; 76(5); 1170-80. Ó2016 AACR.

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Section: Il6 Signaling Enhances Radiation-induced Senescence In the Ssupporting

confidence: 58%

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Marmary¹,

Adar²,

Gaska³

et al. 2016

Cancer Research

106

111

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“…In addition to our previous findings with 58 patients [4] and current findings in this study, Hart et al also reported that low IL-8 was correlated with increased risk of RILT in NSCLC [20]. Meirovitz et al found that low IL-8 was associated with the need for percutaneous endoscopic gastrostomy (PEG) tube installation due to mucositis during RT of head and neck squamous cell cancers [21]. Though there are few reports on the role of IL-8 in predicting radiation induced toxicity, these findings were consistent with our findings in that the lower the baseline IL-8 level, the higher the toxicity.…”

Section: Discussionsupporting

confidence: 78%

“…IL-8 is interesting, as it has chemotactic activity for leukocytes and induces collagen synthesis and cell proliferation [19] in animal studies but it has been consistently found to have anti-inflammatory effect in humans [20] [21]. In addition to our previous findings with 58 patients [4] and current findings in this study, Hart et al also reported that low IL-8 was correlated with increased risk of RILT in NSCLC [20].…”

Section: Discussionsupporting

confidence: 71%

Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Wang

Campbell

Stenmark

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

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Purpose/Objectives We previously reported that combination of mean lung dose (MLD), and inflammatory cytokines (IL-8 and TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and explore new models with more cytokines. Materials/Methods 142 patients with stage I–III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT, 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the Receiver Operating Characteristic (ROC) curves was used for model assessment. Results Sixteen of 65 patients (24.6%) developed RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8 and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) developed grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8 and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone. Conclusions We validated that a combination of mean lung dose, pre IL-8 level and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared to MLD alone.

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“…Elevations in cancer-related and treatment-induced circulating inflammatory cytokines may be partially responsible for the development of clusters of symptoms (e.g., pain, fatigue, distress, and disturbed sleep; the symptom equivalent of tumor burden that is often referred to as ‘symptom burden’) during RT. For example, a positive correlation was found between IL-6 serum levels and severity of mucositis and dysphagia in head and neck cancer patients receiving combined chemoradiation therapy [13]. Also, pro-inflammatory cytokines (IL-6, -10 and TNFR1) are over-expressed in non-small cell lung cancer patients undergoing chemoradiation therapy [188].…”

Section: Targeting Pro-inflammatory Response To Reduce the Side-efmentioning

confidence: 99%

Targeting inflammatory pathways for tumor radiosensitization

Deorukhkar

Krishnan

2010

Biochemical Pharmacology

131

112

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Although radiation therapy (RT) is an integral component of treatment of patients with many types of cancer, inherent and/or acquired resistance to the cytotoxic effects of RT is increasingly recognized as a significant impediment to effective cancer treatment. Inherent resistance is mediated by constitutively activated oncogenic, proliferative and anti-apoptotic proteins/pathways whereas acquired resistance refers to transient induction of proteins/pathways following radiation exposure. To realize the full potential of RT, it is essential to understand the signaling pathways that mediate inducible radiation resistance, a poorly characterized phenomenon, and identify druggable targets for radiosensitization. Ionizing radiation induces a multi-layered signaling response in mammalian cells by activating many pro-survival pathways that converge to transiently activate a few important transcription factors (TFs), including nuclear factor kappa B (NF-κB) and signal transducers and activators of transcription (STATs), the central mediators of inflammatory and carcinogenic signaling. Together, these TFs activate a wide spectrum of pro-survival genes regulating inflammation, anti-apoptosis, invasion and angiogenesis pathways, which confer tumor cell radioresistance. Equally, radiation-induced activation of pro-inflammatory cytokine network (including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α) has been shown to mediate symptom burden (pain, fatigue, local inflammation) in cancer patients. Thus, targeting radiation-induced inflammatory pathways may exert a dual effect of accentuating the tumor radioresponse and reducing normal tissue side-effects, thereby increasing the therapeutic window of cancer treatment. We review recent data demonstrating the pivotal role played by inflammatory pathways in cancer progression and modulation of radiation response.

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Cytokines levels, Severity of acute mucositis and the need of PEG tube installation during chemo-radiation for head and neck cancer - a prospective pilot study

Cited by 66 publications

References 24 publications

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Targeting inflammatory pathways for tumor radiosensitization

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