Purpose
Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact ...quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition.
Methods
A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords “Radiation-Induced Fibrosis,” “Radiotherapy Complications,” “Fibrosis Therapy,” and other closely related terms.
Results
RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways.
Conclusion
Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.
Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated ...fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression.
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•Prediction of occult nodal metastasis can be used to guide surgical treatment.•Improved predictive methods may personalize treatment of early oral cancers.•Predictive performance of depth of ...invasion and machine learning was compared.•Machine learning outperformed depth of invasion in predicting nodal metastasis.
To develop and validate an algorithm to predict occult nodal metastasis in clinically node negative oral cavity squamous cell carcinoma (OCSCC) using machine learning. To compare algorithm performance to a model based on tumor depth of invasion (DOI).
Patients who underwent primary tumor extirpation and elective neck dissection from 2007 to 2013 for clinical T1-2N0 OCSCC were identified from the National Cancer Database (NCDB). Multiple machine learning algorithms were developed to predict pathologic nodal metastasis using clinicopathologic data from 782 patients.The algorithm was internally validated using test data from 654 patients in NCDB and was then externally validated using data from 71 patients treated at a single academic institution. Performance was measured using area under the receiver operating characteristic (ROC) curve (AUC). Machine learning and DOI model performance were compared using Delong’s test for two correlated ROC curves.
The best classification performance was achieved with a decision forest algorithm (AUC = 0.840). When applied to the single-institution data, the predictive performance of machine learning exceeded that of the DOI model (AUC = 0.657, p = 0.007). Compared to the DOI model, machine learning reduced the number of neck dissections recommended while simultaneously improving sensitivity and specificity.
Machine learning improves prediction of pathologic nodal metastasis in patients with clinical T1-2N0 OCSCC compared to methods based on DOI. Improved predictive algorithms are needed to ensure that patients with occult nodal disease are adequately treated while avoiding the cost and morbidity of neck dissection in patients without pathologic nodal disease.
Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% ...cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth
and
(
< 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.
HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs.
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This study was performed to identify treatment related toxicities in older adults undergoing concurrent chemoradiotherapy for head and neck cancer and nutritional and skeletal muscle measures that ...might identify frailty. Imaging analysis was done with the following skeletal muscle measurements: skeletal muscle index (SMI), skeletal muscle density (SMD), and skeletal muscle gauge (SMG). Patients were dichotomized by age into younger (<70 years old, 221 patients) and older age groups (≥70 years old, 51 patients). Low SMI was more common in older patients (86.7%) compared to younger patients (51.7%, p < 0.01), as were low SMD (57.8% vs. 37.3%, p = 0.012) and low SMG (76.1% vs. 44.2%, p < 0.01), despite having similar BMIs (27.3 kg/m2 versus 27.7 kg/m2, p = 0.71). Older patients were significantly more likely to experience chemotherapy toxicity than younger patients (54.9% versus 32.3%, p < 0.01). On multivariate analysis age (p < 0.01), current smoking status (p < 0.01), and low SMI (p < 0.01) remained as significant predictors for missed chemotherapy cycles or discontinuation. Older patients were more likely to require ≥5-day radiation breaks than younger patients (27.5% versus 8.6%, p < 0.01). On multivariate analysis, age (p < 0.01), low albumin status (p = 0.03), and low SMI (p = 0.04) were identified as predictors of prolonged radiation treatment breaks. Based on the results of our study, sarcopenia may be used as an additional marker for frailty alongside traditional performance status scales.
Social determinants of health (SDoH) and rurality are known factors that may influence outcomes in head and neck squamous cell carcinoma (HNSCC). Patients residing in remote locations or those with ...multiple SDoH may encounter barriers to initial diagnosis, adherence to multidisciplinary treatments, and posttreatment surveillance, which may impact their overall survival. However, previous studies have shown mixed results associated with rural residence. The aim of this study is to identify the impact of rurality and SDoH on 2‐year survival in HNSCC. The study was conducted using a Head and Neck Cancer Registry at a single institution from June 2018 through July 2022. Rurality, defined by US census scores, and individual measures of SDoH were used. Our results indicate that each additional adverse SDoH factor results in 1.5 times the odds of mortality at 2 years. Individualized measures of SDoH, rather than rurality alone, better reflect patient prognosis in HNSCC.
Abstract Purpose Head and neck surgery and radiation cause tissue fibrosis that leads to functional limitations and lymphedema. The objective of this study was to determine whether lymphedema therapy ...after surgery and radiation for head and neck cancer decreases neck circumference, increases cervical range of motion, and improves pain scores. Methods and materials A retrospective review of all patients with squamous cell carcinoma of the oral cavity, oropharynx, or larynx who were treated with high-dose radiation therapy at a single center between 2011 and 2012 was performed. Patients received definitive or postoperative radiation for squamous cell carcinoma of the oral cavity, oropharynx, or larynx. Patients were referred to a single, certified, lymphedema therapist with specialty training in head and neck cancer after completion of radiation treatment and healing of acute toxicity (typically 1-3 months). Patients underwent at least 3 months of manual lymphatic decongestion and skilled fibrotic techniques. Circumferential neck measurements and cervical range of motion were measured clinically at 1, 3, 6, 9, and 12 months after completion of radiation therapy. Pain scores were also recorded. Results Thirty-four consecutive patients were eligible and underwent a median of 6 months of lymphedema therapy (Range, 3-12 months). Clinically measured total neck circumference decreased in all patients with 1 month of treatment. Cervical rotation increased by 30.2% on the left and 27.9% on the right at 1 month and continued to improve up to 44.6% and 55.3%, respectively, at 12 months. Patients undergoing therapy had improved pain scores from 4.3 at baseline to 2.0 after 1 month. Conclusions Lymphedema therapy is associated with objective improvements in range of motion, neck circumference, and pain scores in the majority of patients.
Abstract
Background: Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the ...development of HA-based carriers for anti-cancer therapeutics.
Purpose: The objective of this study was to determine whether HA conjugation of anticancer drugs impacts CD44-specific HA-drug uptake and disposition by human head and neck cancer cells.
Methods: The internalization and cellular disposition of hyaluronan-doxorubicin (HA-DOX), hyaluronan-cisplatin (HA-Pt), and hyaluronan-cyanine7 (HA-Cy7) conjugates were investigated by inhibiting endocytosis pathways, and by inhibiting the CD44-mediated internalization pathways that are known to mediate hyaluronan uptake in vitro.
Results: Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drugs.
Discussion: The results suggested that the main mechanism of HA-based conjugate uptake may be active transport via CD44 in conjunction with a clathrin-dependent endocytic pathway. Other HA receptors, hyaluronan-mediated motility receptor (RHAMM) and lymphatic vessel endothelial hyaluronan receptor (LYVE-1), did not play a significant role in conjugate uptake.
Conclusions: HA conjugation significantly increased CD44-mediated drug uptake and extended the residence time of drugs in tumor cells.
Introduction
Head and neck malignancy treatment often involves invasive surgeries, necessitating effective postoperative pain control. However, chronic reliance on opioid medications remains a ...challenge for many patients after surgery. Multimodal analgesia (MMA) within enhanced recovery after surgery protocols has shown success in limiting narcotic pain medications for other cancer types. In a prior study, MMA comprising acetaminophen, ketorolac, gabapentin, and a neurogenic block reduced opioid use in the 7‐day postoperative period for major head and neck reconstructive surgery. This study investigates the impact of multimodal analgesia on opioid prescription and pain during the 6‐week postoperative period for patients undergoing major head and neck oncologic surgeries, aiming to understand the longer‐term effects of narcotic use.
Methods
The study retrospectively examined participants in a hybrid type 1 effectiveness‐implementation pragmatic trial to assess multimodal analgesia's long‐term effectiveness in head and neck free flap surgery. Arm A received scheduled acetaminophen and as‐needed opioids, while Arm B received scheduled gabapentin, ketorolac, a regional nerve block at the donor site, scheduled acetaminophen, and as‐needed opioids. Retrospective data collection included opioid prescription use and pain scores up to 6 weeks after surgery, gathered from the Kansas prescription drug monitoring program, K‐TRACS.
Results
Thirty patients participated, 14 in Arm A and 16 in Arm B. The average morphine milligram equivalents per day of filled prescriptions were not significantly different between Arm A and Arm B (7.23 vs. 7.88, p = .845). Additionally, average pain scores at 6 weeks showed no significant difference between the two groups (1.4 vs. 1.9, p = .612).
Conclusion
Patients with head and neck cancer treated with multimodal analgesia during the perioperative period did not exhibit significant differences in opioid use and pain within 6 weeks after discharge. To confirm these findings, a re‐examination with strict measures of opioid use and scheduled pain assessments in a prospective manner is warranted.
Level of Evidence
4.
This study explores the impact of multimodal analgesia on opioid use and pain in the 6 weeks following head and neck free flap surgery. This study found no significant differences in opioid prescriptions filled or pain level at follow‐up visits between the multimodal and usual care groups. Further investigation through prospective assessments with stricter measures of opioid use and scheduled pain evaluations is recommended to validate these results.
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