Advanced Oropharyngeal Cancer Research Articles

Cost-effectiveness of weekly adaptive radiotherapy versus standard IMRT in head and neck cancer alongside the ARTIX trial

Background and purposeWe performed a cost-effectiveness analysis (CEA) comparing an adaptive radiotherapy (ART) strategy, based on weekly replanning, aiming to correct the parotid gland overdose during treatment and expecting therefore to decrease xerostomia, when compared to a standard IMRT. Materials and methodsWe conducted the ARTIX trial, a randomized, parallel-group, multicentric study comparing a systematic weekly replanning ART to a standard IMRT. The primary endpoint was the frequency of xerostomia at 12 months, measured by stimulating salivary flow with paraffin. The CEA was designed alongside the ARTIX trial which was linked to the French national health data system (SNDS). For each patient, healthcare consumptions and costs were provided by the SNDS. The reference case analysis was based on the primary endpoint of the trial. Sensitivity and scenario analyses were performed. ResultsOf the 129 patients randomly assigned between 2013 and 2018, only 2 records were not linked to the SNDS, which provides a linkage proportion of 98.4%. All of the other 127 records were linked with good to very good robustness. On the intent-to-treat population at 12 months, mean total costs per patient were €41,564 (SD 23,624) and €33,063 (SD 16,886) for ART and standard IMRT arms, respectively (p = 0.033). Incremental cost effectiveness ratio (ICER) was €162,444 per xerostomia avoided. At 24 months, ICER was €194,521 per xerostomia avoided. For both progression-free and overall survival, ART was dominated by standard IMRT. ConclusionThe ART strategy was deemed to be not cost-effective compared with standard IMRT for patients with locally advanced oropharyngeal cancer.

Eliminating Medicaid dental benefits and early-stage oral cancer diagnoses.

Despite the importance of regular dental visits for detecting oral cancer, millions of low-income adults lack access to dental services. In July 2009, California eliminated adult Medicaid dental benefits. We tested if this impacted oral cancer detection for Medicaid enrollees. We analyzed Surveillance, Epidemiology, and End Results-Medicaid data, which contains verified Medicaid enrollment status, to estimate a difference-in-differences model. Our design compares the change in early-stage (Stages 0-II) diagnoses before and after dropping dental benefits in California with the change in early-stage diagnoses among eight states that did not change Medicaid dental benefits. Patients were grouped by oropharyngeal cancer (OPC) and non-OPC (oral cavity cancer), type, and the length of Medicaid enrollment. We also assessed if the effect of dropping dental benefits varied by the number of dentists per capita. Dropping Medicaid dental benefits was associated with a 6.5%-point decline in early-stage diagnoses of non-OPC (95% CI = -14.5, -3.2, p = 0.008). This represented a 20% relative reduction from baseline rates. The effect was highest among beneficiaries with 3 months of continuous Medicaid enrollment prior to diagnosis who resided in counties with more dentists per capita. Specifically, dropping dental coverage was associated with a 1.25%-point decline in the probability of early-stage non-OPC diagnoses for every additional dentist per 5000 population (p = 0.006). Eliminating Medicaid dental benefits negatively impacted early detection of cancers of the oral cavity. Continued volatility of Medicaid dental coverage and provider shortages may be further delaying oral cancer diagnoses. Alternative approaches are needed to prevent advanced stage OPC.

Volumetric and geometric changes in the parotid glands and target volume during image-guided radiotherapy for locally advanced oropharyngeal cancers.

This study aimed to evaluate the volumetric and geometric changes in the parotid glands and target volume during image-guided radiotherapy (IGRT) for locally advanced oropharyngeal cancers. Twenty patients receiving radiotherapy using IGRT at a dose of 70 Gy/35 fractions/7 weeks for locally advanced oropharyngeal cancers were accrued. Radiotherapy planning computed tomography (CT) scans were performed at pre-radiotherapy (RT), 20, 40, and 60 Gy for each patient. Volume changes in target and parotids along with shifts of parotids were assessed with respect to pre-RT scan after co-registration. In study scans, GTVp and GTVn were recontoured as per particular CT. CTV and PTV were copied from planning CT to study CT. CTV was edited from anatomical barriers, and PTV was edited only from the skin in the study CT. The parotids were recontoured on each study scan. The center of mass (COM) of C2 vertebral body was considered as the reference to evaluate its shifts. There was a statistically significant percentage regression of ipsilateral and contralateral parotid mean volumes at the rate of 0.85%/0.207 cc and 0.98%/0.26 cc per day, respectively. We observed the mean medial shift of center of mass of ipsilateral parotid of 2.23 mm (p = 0.011) and contralateral parotid of 2.67 mm (p = 0.069) at the end of 60 Gy. GTVp (mean) reduced from 41.87 cc at 0 Gy to 31.13 cc (25.65%) at 60 Gy (p = 0.003), while GTVn (mean) reduced from 19.98 cc at 0 Gy to 10.79 cc (45.99%) at 60 Gy (p = 0.003). There was a statistically significant reduction in CTV and PTV volumes at 60 Gy. Statistically significant volumetric and geometric changes occurred during intensity-modulated radiation (IMRT), which were most prominent after 40 Gy and were maximum at 60 Gy. There was a medial shift of parotid glands toward the high-dose region. This study can be useful to devise an adaptive radiotherapy strategy.

Radiomics analysis for the prediction of locoregional recurrence of locally advanced oropharyngeal cancer and hypopharyngeal cancer.

By radiomic analysis of the postcontrast CT images, this study aimed to predict locoregional recurrence (LR) of locally advanced oropharyngeal cancer (OPC) and hypopharyngeal cancer (HPC). A total of 192 patients with stage III-IV OPC or HPC from two independent cohort were randomly split into a training cohort with 153 cases and a testing cohort with 39 cases. Only primary tumor mass was manually segmented. Radiomic features were extracted using PyRadiomics, and then the support vector machine was used to build the radiomic model with fivefold cross-validation process in the training data set. For each case, a radiomics score was generated to indicate the probability of LR. There were 94 patients with LR assigned in the progression group and 98 patients without LR assigned in the stable group. There was no significant difference of TNM staging, treatment strategies and common risk factors between these two groups. For the training data set, the radiomics model to predict LR showed 83.7% accuracy and 0.832 (95% CI 0.72, 0.87) area under the ROC curve (AUC). For the test data set, the accuracy and AUC slightly declined to 79.5% and 0.770 (95% CI 0.64, 0.80), respectively. The sensitivity/specificity of training and test data set for LR prediction were 77.6%/89.6%, and 66.7%/90.5%, respectively. The image-based radiomic approach could provide a reliable LR prediction model in locally advanced OPC and HPC. Early identification of those prone to post-treatment recurrence would be helpful for appropriate adjustments to treatment strategies and post-treatment surveillance.

Neo-adjuvant chemotherapy and transoral robotic surgery in locoregionally advanced oropharyngeal cancer

PurposeTo analyze the oncological outcomes and patterns of recurrence of patients with locoregionally advanced oropharyngeal squamous cell carcinoma (OPSCC) who underwent neo-adjuvant chemotherapy (NCT) with subsequent transoral robotic surgery (TORS). MethodsA single-center retrospective cohort study was performed, including 198 patients (mean age: 58.6, SD: 9.2). The primary outcome was disease-free survival (DFS). ResultsThe median follow-up time was 26.5 months (IQR: 16.0–52.0). Estimated DFS rates (95 % CI) at 1 and 3 years were 86.6 % (81.9–91.7), and 81.4 % (75.7–87.6), respectively. Estimated DSS rates (95 % CI) at 1 and 3 years were 96.7 % (94.1–99.3), and 92.6 % (88.4–97.0), respectively. Estimated OS rates (95 % CI) at 1 and 3 years were 96.2 % (93.4–99.0), and 88.7 % (83.4–94.2), respectively. A total of 31 (15.6 %) patients showed a disease relapse after a median time of 8 months (IQR: 4.0–12.0), but only 12 (6 %) patients died of the disease during the study period. ConclusionsThis study demonstrates that NCT and TORS can obtain excellent tumor control and survival in locoregionally advanced OPSCC. NCT might reduce the need for adjuvant treatments, and randomized clinical trials should be conducted to better define this aspect.

Comparison of Dynamic Trajectory Radiotherapy and Volumetric Modulated Arc Therapy for Loco-Regionally Advanced Oropharyngeal Cancer

Dynamic trajectory radiotherapy (DTRT) extends volumetric modulated arc therapy (VMAT) with dynamic table and collimator rotation. We investigate the potential benefit of DTRT over VMAT with respect to organ-at-risk (OAR) sparing for patients with loco-regionally advanced oropharyngeal cancer (OPC). We created DTRT and VMAT plans for 46 cases with prescribed doses of 50-70 Gy (2 Gy fractions, sequential boost) using 6 MV flattened beam on c-arm Linacs. For DTRT: case-specific collision avoidance maps were created and gantry-table paths were determined based on contoured structures to minimize fractional target/OAR overlap in beam's eye view. Gantry-collimator paths minimized field width in the leaf-travel direction. DTRT paths were imported in a research version of a commercial treatment planning system for intensity modulation optimization using the same optimizer and dose calculation algorithms as for VMAT. Plans at each dose level were normalized with 100% of the prescribed dose to 95% of the planning target volume (PTV). PTV coverage and OAR sparing for DTRT and VMAT were compared using Wilcoxon matched-pair signed rank test (5% significance level). The correlation between the fractional OAR/PTV50Gy volume overlap and difference in OAR Dmean between the two techniques was evaluated using Spearman's correlation coefficient. Plans at each dose level were all acceptable and had D0.03cc<110% prescription dose (difference between DTRT and VMAT were not statistically significant). In the combined plans, PTV50Gy D95% and D98% and PTV70Gy D95% were significantly higher with DTRT compared to VMAT. Differences in PTV66Gy coverage and PTV70Gy D5% were not statistically significant. Mean Dmean to the contralateral (CL) parotid gland was 13.99 / 15.28 Gy for DTRT / VMAT respectively, it was 25.75 / 28.05 Gy for the CL submandibular gland, 44.88 / 45.82 Gy for the pharynx and 30.90 / 33.93 Gy for the oral cavity (all with p<.001). Mean Dmean to the ipsilateral (IL) parotid gland was 29.00 / 29.28 Gy for DTRT / VMAT respectively (p = .77) and 57.71 / 57.91 Gy for the IL submandibular gland (p = .99). Significantly higher doses were observed with DTRT than with VMAT for the optical and auditory OARs and for the brain, but well below the clinical goals. The difference in Dmean (VMAT-DTRT) was negatively correlated to the fractional OAR/PTV50Gy overlap for the CL parotid and submandibular gland and the IL submandibular gland (r = -0.55 to -0.51, p<.001) but not for IL parotid gland (r = -0.17, p = .26), oral cavity (r = -0.13, p = .41) or pharynx (r = -011, p = .47). For at least the same target coverage, DTRT statistically significantly improves sparing for OARs related to salivary and swallowing functions compared to state-of-the-art VMAT. The advantage of DTRT decreases with increasing fractional OAR/PTV50Gy volume overlap for some salivary glands but not for pharynx or oral cavity. DTRT is promising to reduce treatment-related toxicity for patients with OPC.

Abstract 1005: LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

Abstract Background: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients, and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. Results: In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival - OS: 28.1% for LINE-1 methylation&amp;lt;35% versus 69.1% for ≥55%; p&amp;lt;0.0001). When LINE-1 methylation was dichotomized as &amp;lt;55% vs. ≥55%, interaction with HPV16 emerged: compared with hypermethylated HPV-16 positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR: 4.83, 95% CI: 2.24-10.38) and progression (HR: 4.54, 95% CI: 2.18-9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53≥50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53≥50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine-phosphate-guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. Conclusions: Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations, and lead to altered gene expression in OPSCC. Citation Format: Mariateresa Casarotto, Valentina Lupato, Giorgio Giurato, Roberto Guerrieri, Sandro Sulfaro, Annamaria Salvati, Elisa D'Angelo, Carlo Furlan, Anna Menegaldo, Lorena Baboci, Barbara Montico, Irene Turturici, Riccardo Dolcetti, Salvatore Romeo, Vittorio Baggio, Stefania Corrado, Gianluca Businello, Maria Guido, Alessandro Weisz, Vittorio Giacomarra, Giovanni Franchin, Agostino Steffan, Luca Sigalotti, Emanuela Vaccher, Paolo Boscolo-Rizzo, Jerry Polesel, Giuseppe Fanetti, Elisabetta Fratta. LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1005.

HPV and RAD51 as Prognostic Factors for Survival in Inoperable Oral and Oropharyngeal Cancer in Patients Unfit for Chemotherapy Treated with Hyperfractionated Radiotherapy.

The incidence of advanced oral cavity and oropharyngeal cancers is generally high. Treatment outcomes for patients, especially those unfit for comprehensive cancer treatment, are unsatisfactory. Therefore, the search for factors to predict response to treatment and increase overall survival is underway. This study aimed to analyze the presence of 32 HPV genotypes in tumor samples of 34 patients and the effect of HPV status and RAD51 on overall survival. Tumor samples of 34 patients with locally advanced oropharyngeal or oral cavity cancer treated with accelerated radiotherapy in monotherapy were analyzed using reverse hybridization and immunohistochemistry for the presence of HPV and RAD51. Its effect on overall survival was examined. Only two types of HPV were identified-HPV 16 (dominant) and HPV 66 (two samples). The HPV positivity was associated with a borderline insignificant improvement in 2-year (p = 0.083), 5-year (p = 0.159), and overall survival (p = 0.083). Similarly, the RAD51 overexpression was associated with borderline insignificant improvement in 2-year (p = 0.083) and 5-year (p = 0.159) survival. We found no statistically significant differences but detected trends toward improvement in the survival of HPV-positive and RAD51 overexpressing patients unfit for surgical treatment or chemotherapy treated with hyperfractionated radiotherapy. The trends, however, indicate that in a larger group of patients, the effects of these two parameters would likely be statistically significant.

Surgical Treatment for Advanced Oropharyngeal Cancer: A Narrative Review

Background and Objectives: to describe current scientific knowledge regarding the treatment options in advanced oropharyngeal cancer. The standard care for advanced oropharyngeal cancer (OPSCC) has been chemoradiotherapy, although surgical approaches followed by adjuvant treatment have been proposed. The best therapy for each patient should be decided by an interdisciplinary tumour-board. Different strategies should be considered for the specific patient's treatment: surgery, chemotherapy and radiation therapy or combinations of them. The treatment choice is influenced by tumour variability and prognostic factors, but it also depends on cancer extension, extranodal extension, nervous invasion, human papilloma virus (HPV) presence, making the decisional algorithm not always clear. HPV-related OPSCC is strongly associated with a favourable overall survival (OS) and disease-free survival rate (DSS); by contrast, HPV-negative OPSCC often flags a worse prognosis. Consequently, the American Joint Committee on Cancer (AJCC) differentiates OPSCC treatment and prognosis based on HPV status. Methods: we carried out a review of current scientific literature to analyze the different indications and limitations of surgical treatment options in OPSCC stage III and IV. Conclusion: robotic surgery or open approaches with reconstructive flaps can be considered in advanced stages, resulting in the de-intensification of subsequent systemic therapy and fewer related side effects. Furthermore, in the event of the primary failure of systemic therapy or disease recurrence, the surgical approach constitutes an additional therapeutic option which lengthens patient survival functions.

Correlation of oral mucosa dose and volume parameters with Grade 3 mucositis, in patients treated with volumetric modulated arc radiotherapy for oropharyngeal cancer?

Oral mucositis is the dose-limiting toxicity of chemoradiation in oropharyngeal cancer patients, which can be minimized by giving constraints to oral mucosa. However, the constraints defined in literature are extrapolated from chemoradiation in head and neck cancers as a whole. This study aims to determine oral mucosa dose-volume parameters that can predict grade≥3 acute oral mucositis in oropharyngeal cancer patients treated with volumetric modulated arc radiotherapy. This prospective study was done in 52 patients of locally advanced oropharyngeal cancer treated with Volumetric modulated arc radiotherapy. Dose-volume histogram data were extracted and then acute oral mucosa toxicity was analysed. Receiver operating characteristic analysis and logistic regression were carried out to determine predictive factors for grade≥3 mucositis. Grade≥3 acute oral mucositis occurred in 57.6% (30/52) patients in the study. V30Gy>53.35% (P=0.005) was an independent dosimetric factor related to grade≥3 acute toxicity. In the receiver operating characteristic curve, the area under V30Gy was 0.770 (P=0.001); the cut-off value of V30 was 46.23% (sensitivity, 0.80; specificity, 0.91). Dose-volume histogram analysis predicts V30>53.35% as independent factors for grade≥3 acute oral mucositis in patients with oropharyngeal cancers treated with Volumetric modulated arc radiotherapy. Studies in future with more patient number can further validate the above results.

Patient-reported outcomes in terms of swallowing and quality of life after prophylactic versus reactive percutaneous endoscopic gastrostomy tube placement in advanced oropharyngeal cancer patients treated with definitive chemo-radiotherapy: Swall PEG study

BackgroundPercutaneous endoscopic gastrostomy (PEG) is often used to provide nutritional support in locally advanced head and neck cancer patients undergoing multimodality treatment. However, there is little published data on the impact of prophylactic versus reactive PEG. PEG placement may affect swallowing-related physiology, function, and quality of life. The Swall PEG study is a randomized controlled phase III trial testing the impact of prophylactic versus reactive PEG on patient-reported outcomes in terms of swallowing and quality of life in oropharyngeal cancer patients.MethodsPatients with locally advanced oropharyngeal cancer receiving chemo-radiotherapy will be randomized to either the prophylactic or reactive PEG tube group. Randomization will be stratified by human papillomavirus (HPV) status and unilateral versus bilateral positive neck lymph nodes. The primary objective of the study is the patient’s reported outcome in terms of swallowing (MD Anderson Dysphagia Inventory (MDADI)) at 6 months. Secondary objectives include health-related quality of life, dosimetric parameters associated with patient-reported outcomes, chemo-radiation toxicities, PEG tube placement complications, the impact of nutritional status on survival and toxicity outcomes, loco-regional control, overall survival, the impact of HPV and tobacco smoking on survival outcomes and toxicities, and the cost-effectiveness of each treatment strategy.DiscussionFindings from this study will enhance clinical evidence regarding nutritional management in oropharyngeal cancer patients treated by concurrent chemo-radiation.Trial registrationClinicalTrials.gov NCT04019548, study protocol version 2.0_08/08/2019. Registered on 15 July 2019

The Interplay between Age and Viral Status in EBV-Related Nasopharyngeal and HPV-Related Oropharyngeal Carcinoma Patients.

The aim of this work was to analyze the interplay between age and viral status on the outcomes in loco-regionally advanced oropharyngeal and nasopharyngeal cancer patients treated with radiotherapy and different chemotherapy combinations. A retrospective (2006-2017) analysis was performed on non-metastatic loco-regionally advanced oropharyngeal (both HPV+ and HPV-) and EBV+ nasopharyngeal cancer patients (young: &lt;65 years vs. elderly: ≥65 years) treated with radiotherapy with or without chemotherapy. The impact of age and viral status on overall (OS) and disease-free survival (DFS) were studied with multivariable models, which were adjusted for smoking, stage, comorbidities, chemotherapy dose intensity and treatment strategy. We analyzed 324 patients (146 HPV+ oropharynx, 63 HPV-, 115 nasopharynx). Elderly patients had more comorbidities, and received less intensive treatments when compared to younger subjects. Although OS and DFS were shorter in older patients, after adjustment for stage, smoking, comorbidities, treatment strategy and dose intensity, no significant differences in terms of survival were observed according to age (65 vs. 50 years of age: HR 1.89, 95% CI 0.45-7.84 for HPV+ OPC; HR 0.91, 95% CI 0.29-2.89 for HPV- OPC; HR 1.99, 95% CI 0.9-4.39 for NPC; p = 0.395). Several potential age-related (comorbidities, treatment intensity) and disease-related (stage) confounding factors play a prognostic role with differential impacts on both virus and non-virus-related tumors. In HPV+ oropharyngeal cancer and in EBV+ nasopharyngeal cancer patients, age should be considered as the expression of an array of host- and tumor-related features rather than an independent prognostic factor.

LINE-1 hypomethylation is associated with poor outcomes in locoregionally advanced oropharyngeal cancer

Background and purposeCurrently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation.ResultsIn this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue samples retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival—OS: 28.1% for LINE-1 methylation < 35% vs. 69.1% for ≥ 55%; p < 0.0001). When LINE-1 methylation was dichotomized as < 55% versus ≥ 55%, interaction with HPV16 emerged: compared with hypermethylated HPV16-positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR 4.83, 95% CI 2.24–10.38) and progression (HR 4.54, 95% CI 2.18–9.48). Tumor protein p53 (TP53) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53 ≥ 50%, LINE-1 methylation levels declined and remained stable at approximately 43%; any HPV16-positive patient reported p53 ≥ 50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine–phosphate–guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences.ConclusionsEvaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations and lead to altered gene expression in OPSCC.

Treatment Deintensification for Human Papillomavirus-Associated Oropharyngeal Cancer: Focused Review of Published Data

Human papillomavirus (HPV) is a causative agent for a subset of oropharyngeal cancer (OPC). The current standard of care (SOC) for locally advanced OPC is 70 Gy definitive radiotherapy (RT) concurrent with cisplatin, which entails significant proportions of acute and late grade 3 or higher toxicities. Accordingly, discovery of favorable prognosis of HPV-related OPC has led to enthusiasm to attenuate subspecialties therapy in multidisciplinary treatment. Diverse deintensification strategies were investigated in multiple phase 2 trials with an assumption that attenuated treatments result in comparable oncologic outcome and less toxicities compared with SOC. Several trials on chemotherapy deintensification revealed that concomitant administration of cisplatin is not to be omitted or substituted for cetuximab without compromising progression-free survival or local control. A transoral robotic surgery (TORS) is investigated as alternative local treatment, but TORS plus SOC or mild deintensified adjuvant RT showed similar toxicities and inferior oncologic outcomes compared with SOC definitive RT or moderately deintensified RT. However, it has been reported that TORS plus deintensified 30-36 Gy adjuvant RT results in excellent outcome and less late toxicity compared with SOC adjuvant RT. Several phase 2 trials reported apparently equivalent progression-free survival and local control and similar adverse effects with moderately deintensified 60 Gy RT compared with SOC 70 Gy RT. Further dose reduction below 60 Gy has been investigated using biology-directed approaches, which use response to induction chemotherapy or metabolic images to triage HPV-positive OPC for deintensified RT. In summary, these trials provide valuable insights for future directions. Available evidence consistently showed that moderately deintensified RT is effective and safe for HPV-positive OPC in both definitive and adjuvant settings. Concurrent cisplatin remains an essential component without which progression-free survival is significantly compromised for advanced HPV-positive OPC. A simple incorporation of TORS to SOC may be detrimental for oncologic outcome without anticipated toxicity reduction. Given the lack of level 1 evidence, it is prudent to curb an unjustified deviation from the current SOC and limit any deintensified strategies to clinical trials and adhere to the current SOC.

Dynamic nomogram for long-term survival in patients with locally advanced oropharyngeal cancer after (chemo)radiotherapy.

This study aimed to establish a nomogram for predicting overall survival (OS) in oropharyngeal cancer patients treated with curative (chemo)radiotherapy. The dynamic nomogram was constructed on 273 patients with oropharyngeal squamous cell carcinoma treated in a Tertiary Head and Neck Cancer Unit. The clinical features that were previously reported to be associated with OS were analyzed. The performance of the nomogram was assessed using concordance index (C-index) and calibration curves. The nomogram incorporated three explanatory variables derived from a decision tree approach including HPV status, N classification according to 8th edition TNM and early response to (chemo)radiotherapy. The nomogram was capable to predict OS with a validation C-index of 0.768. The proposed stratification in risk groups allowed significant distinction between Kaplan-Meier curves for OS outcome (p < 0.0001). The nomogram provided an accurate evaluation of OS for oropharyngeal cancer patients treated with curative (chemo)radiotherapy.

Hippocampus sparing volumetric modulated arc therapy in patients with loco-regionally advanced oropharyngeal cancer.

This study aimed to assess the incidental radiation exposure of the hippocampus (HC) in locoregionally-advanced oropharyngeal cancer patients undergoing volumetric modulated arc therapy and the feasibility of HC-sparing plan optimization. The initial plans were generated without dose-volume constraints to the HC and were compared with the HC-sparing plans. The incidental Dmean_median doses to the bilateral, ipsilateral and contralateral HC were 2.9, 3.1, and 2.5 Gy in the initial plans and 1.4, 1.6, and 1.3 Gy with HC-sparing. It was feasible to reduce the HC dose with HC-sparing plan optimization without compromising target coverage and/or dose constraints to other OARs.

Survival rate and quality of life of human papillomaviruse-negative patients with advanced oropharyngeal cancer receiving different treatments

To analyze the survival rates and quality of life of human papillomaviruse (HPV)-negative patients with advanced oropharyngeal cancer after different combined treatments with chemotherapy, surgery and radiotherapy. We retrospectively analyzed the data of patients with oropharyngeal cancer hospitalized in our hospital from January, 2015 to December, 2020, and after case analysis of the clinical, imaging and pathological data, 405 patients were included in this study and grouped according to the treatments they received. Kaplan-Meier and Log-rank analysis were used to calculate the overall survival rate and the survival rate of patients with different treatments. The self-rated quality of life of the tumor-free survivors was assessed using UW-QOL (4) questionnaire and compared among the patients with different treatments. Among the 405 patients included in this study, 146 received treatments with chemotherapy+surgery+radiotherapy (CSRT), 138 received surgery+radiotherapy (SRT) and 121 were treated with radiotherapy+chemotherapy (RCT). The overall survival rates of the 3 groups at 1, 3 and 5 years were 85.1%, 67.1% and 56.9%, respectively, and the survival rates of patients receiving CSRT, SRT and RCT did not differ significantly (P > 0.05). A total of 280 UW-QOL (4) questionnaires were distributed and 202 (72.14%) were retrieved. The average total scores decreased in the order of CSRT > SRT > RCT; the scores were significantly higher in CSRT group than in SRT and RCT (P < 0.05), but did not differ significantly between SRT and RCT groups (P > 0.05). CSRT, SRT and RCT are all treatment options for locally advanced oropharyngeal cancer, but CSRT may achieve better quality of life of the patients than SRT and RCT.

The Prognostic Role of Baseline Eosinophils in HPV-Related Cancers: a Multi-institutional Analysis of Anal SCC and OPC Patients Treated with Radical CT-RT

Background and AimAnal squamous cell carcinoma (SCC) and oropharyngeal cancer (OPC) are rare tumors associated with HPV infection. Bioumoral predictors of response to chemoradiation (CT-RT) are lacking in these settings. With the aim to find new biomarkers, we investigated the role of eosinophils in both HPV-positive anal SCC and HPV-related oropharyngeal cancer (OPC).MethodsWe retrieved clinical and laboratory data of patients with HPV-positive anal SCC treated with CT-RT in 5 institutions, and patients with locally advanced OPC SCC treated with CT-RT in 2 institutions. We examined the association between baseline eosinophil count (the best cutoff has been evaluated by ROC curve analysis: 100 × 10^9/L) and disease-free survival (DFS). Unadjusted and adjusted hazard ratios by baseline characteristics were calculated using the Cox proportional hazards model.ResultsThree hundred four patients with HPV-positive anal SCCs and 168 patients with OPCs (122 HPV-positive, 46 HPV-negative diseases) were analyzed. In anal SCC, low eosinophil count (< 100 × 10^9/L) correlates to a better DFS (HR = 0.59; p = 0.0392); likewise, in HPV-positive OPC, low eosinophil count correlates to a better DFS (HR = 0.50; p = 0.0428). In HPV-negative OPC, low eosinophil count confers worse DFS compared to high eosinophil count (HR = 3.53; p = 0.0098). After adjustment for age and sex, eosinophils were confirmed to be independent prognostic factors for DFS (HR = 4.55; p = 0.0139).ConclusionEosinophil count could be used as a prognostic factor in anal HPV-positive SCC. The worse prognosis showed in HPV-positive patients with high eosinophil count is likely to derive from an unfavorable interaction between the HPV-induced immunomodulation and eosinophils, which may hamper the curative effect of RT.

A predictive model for advanced oropharyngeal cancer patients treated with chemoradiation

BackgroundTo analyze clinical characteristics in the prediction of death within 1 year in advanced oropharyngeal cancer patients treated with chemoradiation.MethodsOne hundred forty-seven advanced oropharyngeal cancer patients who underwent curative-intent chemoradiation treatment were retrospectively enrolled. The pre-treatment clinical parameters including inflammatory markers were reviewed.ResultsThe 1-year death rate for all patients was 29% [95% confidence interval (CI): 23–37%]. In multivariate logistic regression analysis, hemoglobulin (Hb) < 13.5 g/dl was an independent indicator of death within 1-year [Odds ratio (OR) 5.85, 95% CI 2.17–15.75, p < 0.001]. Systemic immune inflammation (SII) ≥ 1820 was also a significant factor for prediction of death within 1 year (OR 4.78, 95% CI 1.44–15.85, p = 0.011). We further used gander, age, Hb and SII to develop a nomogram to predict death within 1 year. The c-index of the model was 0.75 (95%CI 0.66–0.83). For patients with low nomogram score (< 14) versus high nomogram score (≥ 14), the 1-year and 2-year OS rates were 91 and 71% versus 53 and 29%, respectively. (p < 0.001). A difference in the disease persistence or recurrence rate between patients with high and low nomogram score was significant (73 and 28%, respectively; p < 0.001).ConclusionsThe pre-treatment Hb < 13.5 g/dl and SII ≥ 1820 are associated with higher risks of death within 1-year in patients with advanced oropharyngeal cancers. Nomogram can aid in patient counseling and treatment modality adjustment. The development of a more effective treatment protocol for patients with high nomogram score will be essential.

Recurrence pattern after chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma with respect to induction chemotherapy and escalated radiation dose-results from a prospective randomized phase II study.

6074 Background: Patients with HPV associated squamous cell carcinoma of the oropharynx have a favorable outcome with respect to tumor control and overall survival (OS) after treatment with chemoradiotherapy (CRT). The leading cause of death in these patients is reported to be peripheral metastases. Because of the favorable outcome for these patients, the medical community tries to find methods to ameliorate treatment intensity, mainly in order to reduce long term morbidity. However, between 10 and 15 % of patients relapse locally in the primary tumor as first site of disease failure. Methods: In this multicentre, randomized, controlled, phase II trial 152 patients with locoregionally advanced oropharyngeal cancer were randomized in a 1:1 ratio to either radiotherapy with cetuximab (arm B) versus the same regimen preceded by 2 cycles of induction chemotherapy (IC) with taxotere/cisplatin/5-FU (arm A). To decrease risk of local failure, an escalated radiation (RT) dose of 74.8 Gy was delivered to T3/T4 tumors and to T2 tumors &gt; 3 cm in the base of tongue. Eligibility criteria included patients 18-75 years, ECOG performance status 0-1 and adequate organ functions. Primary endpoint of the study was to compare PFS between the treatment arms, secondary objectives were recurrence pattern, locoregional control, OS and toxicity. Results: PFS at 2 years was 84.2% (95%CI 76.4-92.8) in arm A and 78.4 (95%CI 69.5-88.3) in arm B (p = 0.20). At the time of analysis there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A there were 3 local, 2 regional and 4 distant relapses as first site of recurrence, and in arm B 4, 4 and 9 relapses in corresponding sites. Local relapse rate as first site of failure was low, i.e. in 4.7%. Local failures constituted 7 relapses out of all 26 (27%), and in 4 of these local failures (57%), the escalated dose was given. In arm B, patients who had no IC, there were more than twice as many patients who had distant metastases as first site of relapse compared to arm A (n.s.). No patient who had a response to IC in the primary tumor or in regional lymph nodes, respectively, measured with CT or MRI, of either CR+CR or CR+PR, had any recurrence, local, regional or distant. So, IC could identify 22 out of 73 evaluable patients (30%) in arm A, who never had any recurrence during follow up. Conclusions: A high incidence of distant metastases as first site of failure is recognized while local failure rate is low. However, despite a high RT dose of 74.8 Gy, delivered to the primary tumor, relapses can appear in this site. Radiological response of tumor to IC could identify patients with no tumor relapse, at least within the first years of follow up, possible candidates for de-escalation treatment protocols. Clinical trial information: 2009-013438-26.