Inverse planning optimization with lead block effectively suppresses dose to the mandible in high-dose-rate brachytherapy for tongue cancer.

PURPOSE: In this study, we developed in-house software to evaluate the effect of the lead block (LB)-inserted spacer on the mandibular dose in interstitial brachytherapy (ISBT) for tongue cancer. In addition, an inverse planning algorithm for LB attenuation was developed, and its performance in mandibular dose reduction was evaluated. METHODS: Treatment plans of 30 patients with tongue cancer treated with ISBT were evaluated. The prescribed dose was 54 Gy/9 fractions. An in-house software was developed to calculate the dose distribution based on the American Association of Physicists in Medicine (AAPM) Task Group No.43 (TG-43) formalism. The mandibular dose was calculated with consideration of the LB attenuation. The attenuation coefficient of the lead was computed using the PHITS Monte Carlo simulation. The software further optimized the treatment plans using an attraction-repulsion model (ARM) to account for the LB attenuation. RESULTS: Compared to the calculation in water, the D2 cc of the mandible changed by - 2.4 ± 2.3 Gy (range, - 8.6 to - 0.1 Gy) when the LB attenuation was considered. The ARM optimization with consideration of the LB resulted in a - 2.4 ± 2.4 Gy (range, - 8.2 to 0.0 Gy) change in mandibular D2 cc. CONCLUSIONS: This study enabled the evaluation of the dose distribution with consideration of the LB attenuation. The ARM optimization with lead attenuation further reduced the mandibular dose.

Research on the role of cellular autophagy in the sensitivity of human tongue cancer cells to radiotherapy and chemotherapy.

OBJECTIVE: This paper aims to investigate the role of cisplatin-induced autophagy in human tongue squamous carcinoma Tca8113 cells. METHODS: After inhibiting the expression of autophagic proteins with different autophagy inhibitors (3-methyladenine, chloroquine), the sensitivity of human tongue squamous cell carcinoma (Tca8113) cells to killing by gradient concentrations of cisplatin and gradient doses of radiation was detected using a colony formation assay. Further, the changes of autophagy expression in Tca8113 cells that had been treated with cisplatin and radiation were detected using western immunoblot, GFP-LC3 fluorescence and transmission electron microscopy. RESULTS: The sensitivity of Tca8113 cells to cisplatin and radiation was significantly increased (P < 0.05) after reducing autophagy expression using different autophagy inhibitors. Meanwhile, the expression of autophagy in the cells was significantly increased by cisplatin and radiation treatment. CONCLUSION: Tca8113 cells upregulated autophagy under the effect of either radiation or cisplatin, and the sensitivity of Tca8113 cells to cisplatin and radiation could be improved by inhibiting autophagy using multiple pathways.

Twelve Years of Establishing the Strategies for Tongue Reconstruction.

BACKGROUND: Reconstruction after resection of malignant tongue tumors remains one of the most difficult problems in head and neck oncology. Recent trends in tongue reconstruction have focused on optimizing speech and swallowing functions and maximizing quality of life. In the recent literature, several reconstructive strategies including regional flaps and free flaps have been described. PATIENTS AND METHODS: A case series of 328 patients underwent oral tongue reconstruction between March 2011 and March 2022. Functional evaluation was performed in all patients 3 months after reconstruction (where the patients required no adjuvant radiotherapy) or after radiotherapy. RESULTS: Total flap necrosis was seen in 5 patients with free flap reconstruction (2 radial forearm flaps, 1 lateral arm flap, and 2 anterolateral thigh flaps), 5 patients with infrahyoid myocutaneous flap, and 1 patient reconstructed with a supraclavicular flap. Our success rate is 96.6%; partial flap necrosis was observed in 11 patients with infrahyoid myocutaneous flap and 2 patients with a supraclavicular flap. Most patients with subtotal glossectomy or smaller defects (type II-IVA defects) could communicate on the phone and had the near-normal capacity for an oral diet. The remaining patients (type IVB-V defects) had significantly lower speech scores. The majority of patients could eat liquid and semiliquid foods. CONCLUSION: Tongue cancer surgery and subsequent reconstruction posed exciting challenges for the surgeon to optimize tongue function and quality of life for patients. Attention to the principles of tongue reconstruction and choosing appropriate flap for each defect achieve better functional results.

Brachytherapy and osteoradionecrosis in patients with base of tongue cancer.

BACKGROUND: Base of tongue cancer incidence and patient survival is increasing why treatment sequelae becomes exceedingly important. Osteoradionecrosis (ORN) is a late adverse effect of radiotherapy and brachytherapy (BT) could be a risk factor. Brachytherapy is used in three out of six health care regions in Sweden. AIMS: Investigate if patients treated in regions using BT show an increased risk for ORN and whether brachytherapy has any impact on overall survival. MATERIAL AND METHODS: We used data from the Swedish Head and Neck Cancer Register between 2008-2014. Due to the nonrandomized nature of the study and possible selection bias we compared the risk for ORN in brachy vs non-brachy regions. RESULTS: Fifty out of 505 patients (9.9%) developed ORN; eight of these were treated in nonbrachy regions (16%), while 42 (84%) were treated in brachy regions. Neither age, sex, TNM-classification/stage, p16, smoking, neck dissection, or chemotherapy differed between ORN and no-ORN patients. The risk for ORN was significantly higher for patients treated in brachy regions compared to non-brachy regions (HR = 2,63, p = .012), whereas overall survival did not differ (HR = 0.95, p = .782). CONCLUSIONS AND SIGNIFICANCE: Brachytherapy ought to be used cautiously for selected patients or within prospective randomized studies.

WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status.

OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro. MATERIALS AND METHODS: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK-1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio-sensitizing effects of MK-1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined. RESULTS: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK-1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation-induced G2 arrest. CONCLUSION: These results demonstrate the efficacy of MK-1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status.

The combination of volumetric arc radiation therapy and boost high-dose rate interstitial brachytherapy for T3N2c tongue cancer: a technical report.

Currently, tongue cancers are primarily managed by surgery, and interstitial brachytherapy is only recommended for a selected group of early state T1-2N0 patients who refuse surgery or are medically inoperable. In this report, a case with T3N2cM0 tongue cancer who has been effectively treated by the combination of concurrent chemoradiotherapy involving volumetric arc therapy and boost high-dose rate interstitial brachytherapy is presented. Of course, surgery remains the main treatment strategy for tongue cancer patients; however, the authors believe that if volumetric arc therapy is carefully planned to reduce the mandible dose as much as possible and high-dose rate interstitial brachytherapy with a mouthpiece that protects the mandible is combined, it is possible to treat T3N2 disease, and this can be considered for patients who want to preserve organ function.

Radiation modulates expression and related activities of c-Met protein in oral tongue squamous cell carcinoma cell lines.

OBJECTIVES: c-Met, a receptor tyrosine kinase, is involved in the growth, invasion and metastasis of a variety of cancers. In a set of cell lines from several solid tumors, a five-fold increase in c-Met expression after irradiation has been reported. This study aimed to assess if c-Met is likewise abundantly expressed in oral tongue squamous cell carcinoma (OTSCC) upon exposure to irradiation, followed by a Met-induced biological response. MATERIALS AND METHODS: Six OTSCC cell lines were exposed to gamma radiation doses of 2, 4, and 6 Gray. The changes in c-Met protein levels were assessed by western blot and flow cytometry. c-Met gene expression, cell migration, proliferation and cell cycle assays were performed as phenotypic readouts. RESULTS: Irradiation resulted in upregulation of c.Met in all cell lines with different time kinetics. On average the cells displayed minimal c-Met expression on their surface ranging from 5 to 30% of total protein. Abrupt downregulation of c-Met surface expression occurred one hour after radiation but recovered 48 h post-radiation. Intracellularly, the highest level of expression was found on day 5 after radiation exposure. Irradiation induced aggressive invasive potential of the cells as determined in cell migration assays, particularly in cell lines with the highest c-Met expression. CONCLUSIONS: These results provide novel insights into both intracellular and extracellular dynamics of c-Met expression profiles upon irradiation of OTSCC cells in vitro. It might also suggest that radiation enhances cell migration, indicative of invasiveness, through c-Met up-regulation, at least for certain types of OTSCC cells.

TRPC1 correlates with poor tumor features, radiotherapy efficacy and survival in tongue squamous cell carcinoma.

Aim: The present study aimed to explore the clinical association of TRPC1 with tongue squamous cell carcinoma (TSCC) tumor features and prognosis. Methods: A total of 246 TSCC patients who underwent surgical resection were retrospectively analyzed, and their tissue specimens were acquired for TRPC1 protein and mRNA detection. Results: TRPC1 protein immunohistochemistry score and mRNA expression were of good value in differentiating TSCC tissue from tumor-adjacent tissue and were positively correlated with pathological grade and tumor node metastasis stage. A high TRPC1 protein score was negatively correlated with overall survival, and this correlation was dramatically obvious in patients who received adjuvant radiotherapy. Conclusion: TRPC1 correlates with poor tumor features and unfavorable survival in TSCC patients.

Results of sole postoperative interstitial, high-dose-rate brachytherapy of T1-2 tongue tumours.

PURPOSE: To describe the results of treating tongue cancer patients with single postoperative interstitial, high-dose-rate (HDR) brachytherapy (BT) after resection. METHODS: Between January 1998 and April 2019, 45 patients with squamous cell histology, stage T1-2N0-1M0 tongue tumours were treated by surgery followed by a single HDR BT in case of negative prognostic factors (close or positive surgical margin, lymphovascular and/or perineural invasion). The average dose was 29 Gy (range: 10-45 Gy) and rigid metal needles were used in 11 (24%) and flexible plastic catheters in 34 cases (76%). Survival parameters, toxicities and the prognostic factors influencing survival were analysed. RESULTS: During a mean follow-up of 103 months (range: 16-260 months) for surviving patients, the 10-year local and regional control (LC, RC), overall survival (OS), and disease-specific survival (DSS) probabilities were 85, 73, 34 and 63%, respectively. The incidence of local grade 1, 2 and 3 mucositis was 23, 73 and 4%, respectively. As a serious (grade 4), late side effect, soft tissue necrosis developed in 3 cases (7%). In a univariate analysis, there was a significant correlation between lymphovascular invasion and RC (p = 0.0118) as well as cervical recurrence and DSS (p < 0.0001). CONCLUSION: Sole postoperative HDR brachytherapy can be an effective method in case of negative prognostic factors in the treatment of early, resectable tongue tumours. Comparing the results of patients treated with postoperative BT to those who were managed with surgery or BT alone known from the literature, a slightly more favourable LC can be achieved with the combination therapy, demonstrating the potential compensating effect of BT on adverse prognostic factors, while the developing severe, grade 4 toxicity rate remains low.

Efficacy and Safety of Induction Chemotherapy and/or External Beam Radiotherapy Followed by Brachytherapy in Patients With Tongue Cancer.

BACKGROUND/AIM: To evaluate the outcomes of induction chemotherapy and/or external beam radiotherapy (EBRT) followed by brachytherapy (BT) in patients with tongue cancer who had a waiting period for BT or a large tumor that was not suitable for BT. PATIENTS AND METHODS: As an induction therapy, chemotherapy with tegafur/gimeracil/oteracil (S-1), EBRT or both S-1 chemotherapy and EBRT was prescribed. BT was performed using Au-198 grains or Ir-192 pins. Local control (LC), lymph node metastasis-free survival (LNMFS), overall survival (OS), and complication rates were calculated. RESULTS: Forty-nine patients were enrolled in this study. The 3-year LC, LNMFS, and OS rates for cT1-2 patients were 84%, 45%, and 69%, respectively. The 3-year LC, LNMFS, and OS rates for cT3 patients were 77%, 58%, and 79%, respectively. The incidence of Grade 3 or 4 complications was 6%. CONCLUSION: Induction therapy contributed to the efficacy of the subsequent BT in LC rate.

Population-based comparative survival analysis of surgery with or without adjuvant radiotherapy and non-operative primary radiotherapy in patients with early-stage oral tongue squamous cell carcinoma.

PURPOSE: Although recent clinical guidelines do allow primary radiotherapy for selected patients with early-stage oral tongue cancer, there has been little knowledge on the treatment outcomes of non-operative radiotherapy using modern treatment techniques. This study evaluated recent prognostic differences between primary radiotherapy and surgical resection in T1‒2N0 oral tongue squamous cell carcinoma. METHODS: Patients diagnosed with T1‒2N0 oral tongue squamous cell carcinoma were identified from the Surveillance, Epidemiology, and End Results database. After propensity score matching, the disease-specific survival of primary radiotherapy and surgery was compared. RESULTS: From a total of 8,458 patients initially identified, we defined matched cohorts: cohort A, comparing surgery alone vs. primary radiotherapy (n = 230 vs. 230), and cohort B, comparing surgery plus adjuvant radiotherapy vs. primary radiotherapy (n = 230 vs. 230). The 7-year disease-specific survival rates were 77% vs. 35% (cohort A) and 65% vs. 35% (cohort B) (P < 0.001 for all comparisons). Primary radiotherapy was independently associated with worse disease-specific survival in both cohorts A (hazard ratio 4.06; 95% confidence interval 2.53‒6.52) and B (hazard ratio 2.81; 95% confidence interval 1.96‒4.04). Time-course hazard rate function plots showed a distinct short-term risk increment in disease-specific mortality in the primary radiotherapy group. CONCLUSION: In the contemporary treatment era, the use of radiotherapy as a definitive treatment resulted in an inferior prognosis in patients with T1‒2N0 oral tongue squamous cell carcinoma. The present population-based data suggest that primary radiotherapy cannot be used as an alternative to surgical management and it needs to be avoided as much as possible in early-stage tumors.

Impact of Tenascin-C on Radiotherapy in a Novel Syngeneic Oral Squamous Cell Carcinoma Model With Spontaneous Dissemination to the Lymph Nodes.

Radiotherapy, the most frequent treatment of oral squamous cell carcinomas (OSCC) besides surgery is employed to kill tumor cells but, radiotherapy may also promote tumor relapse where the immune-suppressive tumor microenvironment (TME) could be instrumental. We established a novel syngeneic grafting model from a carcinogen-induced tongue tumor, OSCC13, to address the impact of radiotherapy on OSCC. This model revealed similarities with human OSCC, recapitulating carcinogen-induced mutations found in smoking associated human tongue tumors, abundant tumor infiltrating leukocytes (TIL) and, spontaneous tumor cell dissemination to the local lymph nodes. Cultured OSCC13 cells and OSCC13-derived tongue tumors were sensitive to irradiation. At the chosen dose of 2 Gy mimicking treatment of human OSCC patients not all tumor cells were killed allowing to investigate effects on the TME. By investigating expression of the extracellular matrix molecule tenascin-C (TNC), an indicator of an immune suppressive TME, we observed high local TNC expression and TIL infiltration in the irradiated tumors. In a TNC knockout host the TME appeared less immune suppressive with a tendency towards more tumor regression than in WT conditions. Altogether, our novel syngeneic tongue OSCC grafting model, sharing important features with the human OSCC disease could be relevant for future anti-cancer targeting of OSCC by radiotherapy and other therapeutic approaches.

Treatment outcomes of real-time intraoral sonography-guided implantation technique of 198Au grain brachytherapy for T1 and T2 tongue cancer.

It is often challenging to determine the accurate size and shape of oral lesions through computed tomography (CT) or magnetic resonance imaging (MRI) when they are very small or obscured by metallic artifacts, such as dental prostheses. Intraoral ultrasonography (IUS) has been shown to be beneficial in obtaining precise information about total tumor extension, as well as the exact location and guiding the insertion of catheters during interstitial brachytherapy. We evaluated the role of IUS in assessing the clinical outcomes of interstitial brachytherapy with 198Au grains in tongue cancer through a retrospective medical chart review. The data from 45 patients with T1 (n = 21) and T2 (n = 24) tongue cancer, who were mainly treated with 198Au grain implants between January 2005 and April 2019, were included in this study. 198Au grain implantations were carried out, and positioning of the implants was confirmed by IUS, to ensure that 198Au grains were appropriately placed for the deep border of the tongue lesion. The five-year local control rates of T1 and T2 tongue cancers were 95.2% and 95.5%, respectively. We propose that the use of IUS to identify the extent of lesions and the position of implanted grains is effective when performing brachytherapy with 198Au grains.

Noncoplanar Versus Coplanar Intensity-Modulated Radiation Therapy (IMRT) for Protection of the Lip and Buccal Mucosa.

OBJECTIVE: In this study, by comparing coplanar and noncoplanar intensity-modulated radiation therapy (IMRT) treatment planning in treating tongue cancer, the significance of noncoplanar fields in the protection of the lip and buccal mucosa was determined, and a reasonable solution was selected. METHODS: Forty-eight tongue cancer patients treated from June 2019 to February 2021 were selected and randomly divided into a coplanar field group and a noncoplanar field group. The mucosal dose limit changed from 15 Gy to 45 Gy for comparison of the two treatment plans. The evaluation indicators (conformal index (CI); homogeneity index (HI); D5, D50, and D98 of the target volume; and the dose of normal tissues) were calculated under different mucosal dose limits. The clinical observation of the lip and buccal mucosa of 48 cases was monitored and graded carefully according to NCI-CTCAE V4.0. Statistical analyses were performed. RESULTS: The differences in CI, HI, D98, D50 and D5 between the two groups in the target volume tended to decrease when the mucosal dose limit was less than 30 Gy, with a significant difference (P < 0.05). When the limit exceeded 30 Gy, significant differences in other indicators except CI (P < 0.05) were still noted. In normal tissue, differences in doses between the two groups existed when the mucosal limit was less than 20 Gy, with a significant difference (P < 0.05). When the limit exceeded 20 Gy, no significant difference was noted. Patients in the noncoplanar group showed significantly better results than those in the other group in terms of the radiation-related toxicity of the lip and cheek membrane(P < 0.001). CONCLUSIONS: Compared with coplanar field radiotherapy, noncoplanar field radiotherapy can effectively reduce the exposure dose to the lip and buccal mucosa. The application of noncoplanar treatment plans exhibits good clinical significance and deserves to be promoted.

Locally advanced tongue squamous cell carcinoma in epidermolysis simplex bullosa patient: a therapeutic conundrum.

Epidermolysis bullosa simplex (EBS) is a debilitating condition affecting the skin and mucous membranes that is characterised by frequent ulceration and blistering on trivial trauma. In EBS, oral cavity mucosal injuries lead to a high propensity for developing squamous cell carcinomas. Locally advanced tongue carcinoma arising in this background presents a challenging therapeutic conundrum. To our knowledge, this is the first case of aggressive locally advanced tongue carcinoma that has developed sporadically in a patient with EBS and no family history. Routine screening of oral mucosal lesions will lead to early detection and timely management of this debilitating condition.

Carbon Ion Irradiation Enhances the Anti-tumor Efficiency in Tongue Squamous Cell Carcinoma via Modulating the FAK Signaling.

Oral cancer is a very aggressive disease with high rates of recurrence and metastasis. This study aimed at addressing how efficiently tongue cancer is suppressed after carbon ion irradiation. Here, the close relationship between upregulated expression of focal adhesion kinase (FAK) and high metastatic status in tongue squamous cell carcinoma patients was validated using bioinformatics and immunohistochemical analyses. Our data indicated that FAK suppression significantly enhanced the killing effect induced by irradiation in the tongue cancer cell line CAL27, as evidenced by increased apoptotic induction and reduced colony formation. More importantly, in FAK-deficient cells, carbon ion irradiation was shown to remarkably inhibit migration and invasion by delaying wound healing and slowing down motility. Further studies revealed that irradiation exposure caused disorganization of the actin cytoskeleton and reduced cell adhesive energy in FAK-deficient cells. Moreover, carbon ion treatment, in combination with FAK silencing, markedly blocked the phosphorylation levels of FAK, and paxillin, which partly contributed to the reduced motility of tongue squamous cell carcinoma CAL27 cells. Collectively, these results suggest that the prominent obstructing role of carbon ion irradiation in the growth inhibition and metastatic behavior of tumors, including attenuation of cell adhesiveness, motility, and invasiveness, could be distinctly modulated by FAK-mediated downstream pathways.