Radiotherapy for Head and Neck Cancer

Treatment for patients with head and neck cancer requires a multidisciplinary approach. Radiotherapy is employed as a primary treatment or as an adjuvant to surgery. Each specific subsite dictates the appropriate radiotherapy techniques, fields, dose, and fractionation scheme. Quality of life is also an important issue in the management of head and neck cancer. The radiation-related complications have a tremendous impact on the quality of life. Modern radiotherapy techniques, such as intensity-modulated radiotherapy and image-guided radiotherapy, can offer precise radiation delivery and reduce the dose to the surrounding normal tissues without compromise of target coverage. In the future, efforts should be made in the exploration of novel strategies to improve treatment outcome in patients with head and neck cancer

Calibration of the EBT3 Gafchromic Film Using HNN Deep Learning

To achieve a dose distribution conformal to the target volume while sparing normal tissues, intensity modulation with steep dose gradient is used for treatment planning. To successfully deliver such treatment, high spatial and dosimetric accuracy are crucial and need to be verified. With high 2D dosimetry resolution and a self-development property, the Ashland Inc. product EBT3 Gafchromic film is a widely used quality assurance tool designed especially for this. However, the film should be recalibrated each quarter due to the “aging effect,” and calibration uncertainties always exist between individual films even in the same lot. Recently, artificial neural networks (ANN) are applied to many fields. If a physicist can collect the calibration data, it could be accumulated to be a substantial ANN data input used for film calibration. We therefore use the Keras functional Application Program Interface to build a hierarchical neural network (HNN), with the inputs of net optical densities, pixel values, and inverse transmittances to reveal the delivered dose and train the neural network with deep learning. For comparison, the film dose calculated using red-channel net optical density with power function fitting was performed and taken as a conventional method. The results show that the percentage error of the film dose using the HNN method is less than 4% for the aging effect verification test and less than 4.5% for the intralot variation test; in contrast, the conventional method could yield errors higher than 10% and 7%, respectively. This HNN method to calibrate the EBT film could be further improved by adding training data or adjusting the HNN structure. The model could help physicists spend less calibration time and reduce film usage

Targeting PI3K/AKT/mTOR Signaling Pathway as a Radiosensitization in Head and Neck Squamous Cell Carcinomas

Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells’ radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway

Use Dose Bricks Concept to Implement Nasopharyngeal Carcinoma Treatment Planning

Purpose. A “dose bricks” concept has been used to implement nasopharyngeal carcinoma treatment plan; this method specializes particularly in the case with bell shape nasopharyngeal carcinoma case. Materials and Methods. Five noncoplanar fields were used to accomplish the dose bricks technique treatment plan. These five fields include (a) right superior anterior oblique (RSAO), (b) left superior anterior oblique (LSAO), (c) right anterior oblique (RAO), (d) left anterior oblique (LAO), and (e) superior inferior vertex (SIV). Nondivergence collimator central axis planes were used to create different abutting field edge while normal organs were blocked by multileaf collimators in this technique. Results. The resulting 92% isodose curves encompassed the CTV, while maximum dose was about 115%. Approximately 50% volume of parotid glands obtained 10–15% of total dose and 50% volume of brain obtained less than 20% of total dose. Spinal cord receives only 5% from the scatter dose. Conclusions. Compared with IMRT, the expenditure of planning time and costing, “dose bricks” may after all be accepted as an optional implementation in nasopharyngeal carcinoma conformal treatment plan; furthermore, this method also fits the need of other nonhead and neck lesions if organ sparing and noncoplanar technique can be executed

PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy.

Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC

Treatment Sequences in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Cetuximab Followed by Immunotherapy or Vice Versa

Background: The prognosis was poor when patients had recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Herein, we conducted an observational study of cetuximab followed by immunotherapy (Cet-IO) versus immunotherapy followed by cetuximab (IO-Cet) in patients with R/M HNSCC. Methods: Patients who were diagnosed with R/M HNSCC and treated with a sequential cetuximab-containing regimen and immunotherapy-containing regimen were enrolled in our study. Kaplan-Meier curves were estimated for progression-free survival (PFS) and overall survival (OS). Results: A total of 75 patients were enrolled in our study for oncologic outcomes evaluation, with 40 patients in Cet-IO and 35 patients in IO-Cet. The median PFS1 was 5.1 months in Cet-IO and 4.5 months in IO-Cet (p = 0.777) and the median PFS2 was 16.5 months in Cet-IO and 11.4 months in IO-Cet (p = 0.566). The median OS was 23.7 months versus 22.8 months in Cet-IO and IO-Cet, respectively (p = 0.484). The overall response rate (ORR) were 73% in Cet-IO versus 37% in IO-Cet (p = 0.002). Multivariate analysis demonstrated that the treatment sequences, Cet-IO or IO-Cet, were insignificantly different with survival. Conclusion: Both Cet-IO and IO-Cet are effective in R/M HNSCC patients with insignificant survival differences. The higher ORR of Cet-IO might render it to be considered in patients with large tumor burdens and urgent needs for treatment responses. Further prospective studies are merited to validate our conclusions

Impact of Parenteral Glutamine Supplement on Oncologic Outcomes in Patients with Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy

Background: Oral mucositis (OM) is a common toxic side effect in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) that has a negative impact on treatment outcomes and patients’ survival. Our study aimed to evaluate the impact of parenteral glutamine supplement (dipeptiven) on oncologic outcomes in patients with NPC treated with CCRT. Methods: Patients who were diagnosed with pathologically proved NPC and treated with CCRT were enrolled into our study. Patients were classified as dipeptiven (+) and dipeptiven (–). Oncologic outcomes were measured, and multivariate regression analysis was performed. Grade 3–4 treatment related toxicities were also documented. Results: A total of 144 patients with NPC were recruited in this study to evaluate oncologic outcomes, with 41 dipeptiven (+) and 103 dipeptiven (–). CCRT interruption rate and severe adverse effect (SAE) rate were significant lower in the dipeptiven (+) group than in the dipeptiven (–) group. The median overall survival (OS) was not mature yet in the dipeptiven (+) group and 30 months in the dipeptiven (–) group (p < 0.01). Multivariate analysis demonstrated that dipeptiven supplementation and CCRT interruption were independent predictors associated with better survival. The OS was longest in patients with a dipeptiven supplement and patients who had CCRT interruption had significantly worst OS. As for safety profiles, grade 3 to 4 adverse effects were fewer in dipeptiven (+) than in dipeptiven (–). Conclusion: Dipeptiven supplementation is crucial in NPC patients treated with CCRT, which can ameliorate treatment-related toxicity and augment treatment efficacy. Further prospective clinical trials are warranted to validate our results

Tegafur-Uracil versus 5-Fluorouracil in Combination with Cisplatin and Cetuximab in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Propensity Score Matching Analysis

There are increasing incidences of elderly patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, the treatment is not yet established. We conducted a propensity score matching analysis to evaluate the efficacy and safety of tegafur–uracil versus 5-fluorouracil in combination with cisplatin plus cetuximab in elderly patients with R/M HNSCC. Elderly patients with R/M HNSCC treated with cetuximab-containing chemotherapy were recruited into this study. In order to reduce the selection bias, propensity score matching was performed. Kaplan–Meier curves were plotted for progression-free survival (PFS) and overall survival (OS). Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria V3.0. After propensity sore matching, 54 patients with tegafur–uracil, cisplatin plus cetuximab (UPEx), and 54 patients with 5-fluorouracil, cisplatin plus cetuximab (EXTREME) were identified. The median PFS was 5.4 months in UPEx and 5.8 months in EXTREME (p = 0.451). The median OS was 10.8 months in UPEx and 10.2 months in EXTREME (p = 0.807). The overall response rate (ORR) and disease control rate (DCR) were insignificant in both arms, accounting for 61% versus 59% (p = 0.680) and 72% versus 70% (p = 0.732) in the UPEx arm and the EXTREME arm, respectively. A multivariate analysis showed that age and ECOG PS were, independently, predictors. Grade 3/4 adverse events were much fewer in UPEx than in EXTREME (p &lt; 0.001). Both cetuximab-containing chemotherapies are effective in elderly patients with R/M HNSCC. Safety profiles are improved when tegafur–uracil is substituted for 5-fluorouracil. Further prospective studies are warranted to validate our conclusions

Platinum Plus Tegafur&ndash;Uracil versus Platinum Alone during Concurrent Chemoradiotherapy in Patients with Nonmetastatic Nasopharyngeal Carcinoma: A Propensity-Score-Matching Analysis

Concurrent chemoradiotherapy (CCRT) with a cisplatin-based regimen is the standard treatment for patients with nasopharyngeal carcinoma (NPC). Our study was a propensity-score-matching analysis and it aimed to investigate the oncologic outcomes of platinum plus tegafur&ndash;uracil versus platinum alone during CCRT in patient with nonmetastatic NPC. Patients with pathologic confirmed NPC in 2018&ndash;2022 were reviewed. Patients treated with platinum plus tegafur&ndash;uracil (CCRT-UP) or platinum alone (CCRT-P) during CCRT were recruited into this study. A propensity-score-matching analysis was conducted to diminish the selection bias. The recurrence-free survival (RFS) and overall survival (OS) were presented with Kaplan&ndash;Meier curves. The treatment-related adverse effects (AEs) were recorded according to the National Cancer Institute&rsquo;s Common Terminology Criteria V3.0. A total of 44 patients with CCRT-UP and 44 patients with CCRT-P were identified after propensity score matching. The median RFS was not reached (NR) in the CCRT-UP group, and it was 12.5 months in the CCRT-P group (p &lt; 0.001). The median OS was NR in the CCRT-UP group, and it was 15.9 months in the CCRT-P group (p &lt; 0.001). The overall response rate and disease-control rate were insignificant between the CCRT-UP and CCRT-P groups. A subgroup analysis showed that the median OS was significantly longer in the CCRT-UP group than in the CCRT-P group, regardless of the clinical stage. A multivariate analysis exhibited that CCRT-UP was independently correlated with survival. The grade 3&ndash;4 AEs were insignificant between the CCRT-UP and CCRT-P arms. CCRT-UP had better RFS and OS in nonmetastatic NPC patients with similar toxic profiles. Further larger-scaled prospective randomized control trials are warranted to validate our conclusions