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To evaluate the efficacy and safety of cetuximab instead of cisplatin in combination with downstaging radiotherapy for papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV OPSCC). Meta-analysis and systematic evaluation. The PubMed, Embase, Web of Science, and Cochrane library databases were searched up to June 8, 2023, as well as Clinicaltrials.gov Clinical Trials Registry, China Knowledge Network, Wanfang Data Knowledge Service Platform, and Wiprojournal.com. Randomized controlled trials reporting results of standard regimens of cetuximab + radiotherapy vs cisplatin + radiotherapy in treating HPV OPSCC were included. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), local regional failure rate (LRF), distant metastasis rate (DM), and adverse events (AE). Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data. A total of 874 relevant papers were obtained from the initial search, and five papers that met the inclusion criteria were included; a total of 1,617 patients with HPV OPSCC were enrolled in these studies. Meta-analysis showed that OS and PFS were significantly shorter in the cetuximab + radiotherapy group of patients with HPV OPSCC compared with those in the conventional cisplatin + radiotherapy group (HR = 2.10, 95% CI [1.39-3.15], = 0.0004; HR = 1.79, 95% CI [1.40-2.29], < 0.0001); LRF and DM were significantly increased (HR = 2.22, 95% CI [1.58-3.11], < 0.0001; HR = 1.66, 95% CI [1.07-2.58], = 0.02), but there was no significant difference in overall grade 3 to 4, acute and late AE overall (OR = 0.86, 95% CI [0.65-1.13], = 0.28). Cisplatin + radiotherapy remains the standard treatment for HPV OPSCC. According to the 7th edition AJCC/UICC criteria, low-risk HPV OPSCC patients with a smoking history of ≤ 10 packs/year and non-pharyngeal tumors not involved in lymphatic metastasis had similar survival outcomes with cetuximab/cisplatin + radiotherapy. However, further clinical trials are necessary to determine whether cetuximab + radiotherapy can replace cisplatin + radiotherapy for degraded treatment in individuals who meet the aforementioned characteristics, particularly those with platinum drug allergies. CRD42023445619.

Use of proton beam therapy has expanded, with the number of proton centres rapidly increasing not only in the USA but also worldwide. The physical characteristics of the proton beam offer important advantages versus widely used photon techniques in terms of radiation precision. In head and neck cancer in particular, proton beam therapy is uniquely suited for the complex anatomy of tumours and sensitive surrounding organs. De-intensification and personalisation of treatment to limit toxicity are of renewed importance in the context of human papilloma virus-associated disease, in which young patients will be cured but bear the consequences of adverse effects for decades. Comparisons of radiation dose distributions between photon and proton techniques suggest considerable benefit in terms of toxicity sparing, but this has only recently been confirmed by substantial clinical data. In this Review, we attempt to define the role of this method in the contemporary multidisciplinary management of various types of head and neck cancer.

Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195. Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. University of California.

Objectives: We sought to describe the findings of modified barium swallow study after chemoradiation in patients with head and neck cancer and to correlate these findings with clinical variables, including gastrostomy tube dependence and clinical pneumonia. Methods: We retrospectively reviewed 49 patients at a tertiary care center who underwent modified barium swallow study for dysphagia after chemoradiation. Results: Patients with nonlaryngeal lesions had increased cricopharyngeal impairment (27.8% versus 0.0%; p = .04). Patients who underwent concomitant chemotherapy had increased epiglottic changes relative to those who had radiotherapy alone (66.7% versus 30.8%; p = .05). Clinical pneumonia developed in 31.9% of the patients, and 79.6% required gastrostomy tube placement for a mean duration of 18.1 months. Conclusions: Chemoradiation effects deglutition at multiple levels. A large percentage of patients will develop pneumonia and feeding tube dependence. This study is among the largest to correlate the results of modified barium swallow studies to clinical variables in this patient population. This study highlights the significant incidence of gastrostomy tube dependence and pneumonia in these patients.

In this study, we developed new gadolinium-graphene quantum dot nanoparticles (Gd-GQDs) as a theranostic platform for magnetic resonance imaging and improved the efficiency of radiotherapy in HPV-positive oropharyngeal cancer. Based on cell toxicity results, Gd-GQD NPs were nontoxic for both cancer and normal cell lines up to 25 µg/ml. These NPs enhance the cytotoxic effect of radiation only on cancer cells but not on normal cells. The flow cytometry analysis indicated that cell death mainly occurred in the late phase of apoptosis. The immunocytochemical analysis was used to evaluate apoptosis pathway proteins. The Bcl-2 and p53 protein levels did not differ statistically significantly between radiation alone group and those that received irradiation in combination with NPs. In contrast, the combination group exhibited a significant increase in Bax protein expression, suggesting that cells could undergo apoptosis independent of the p53 pathway. Magnetic resonance (MR) imaging showed that Gd-GQD NPs, when used at low concentrations, enhanced T1-weighted signal intensity resulting from T1 shortening effects. At higher concentrations, the T2 shortening effect became predominant and was able to decrease the signal intensity. Gd-GQD appears to offer a novel approach for enhancing the effectiveness of radiation treatment and facilitating MR imaging for monitoring HPV-positive tumors. Graphical abstract

Standard adjuvant chemoradiotherapy (60–66 Gy) following surgery for HPV-associated oropharyngeal squamous cell carcinoma has excellent oncological control but high treatment morbidity. We aimed to compare toxicity of a 30–36 Gy regimen of de-escalated adjuvant radiotherapy and standard of care treatment. We did this phase 3, open-label, randomised controlled trial in two academic sites in the USA. Eligible participants were adults aged 18 years or older, with American Joint Committee on Cancer 7th edition pathological stage III–IV HPV-associated oropharyngeal squamous cell carcinoma and had more than 70% p16-immunoreactivity on immunohistochemistry evaluation of the surgical specimen. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less and at least one intermediate pathological risk factor. Patients were stratified by the presence of extranodal extension and smoking status (<10 packs per year vs ≥10 packs per year) Eligible patients were randomly assigned (2:1) using a minimisation method with a random element to receive de-escalated adjuvant radiotherapy (30–36 Gy in 1·5–1·8 Gy fractions twice per day over 2 weeks plus intravenous docetaxel 15 mg/m2 on days 1 and 8 of treatment) or standard of care (60 Gy in 2 Gy fractions once daily over 6 weeks plus intravenous cisplatin 40 mg/m2 once a week). The primary endpoint was cumulative, chronic grade 3 or higher toxicity rate 3–24 months after radiotherapy. Primary analysis was done in patients who received treatment and had no missing data. This trial is registered with ClinicalTrials.gov, NCT02908477, and is complete. Between Oct 11, 2016, and Aug 20, 2020, 254 patients with newly diagnosed oropharyngeal squamous cell carcinoma were assessed for inclusion. Nine did not meet inclusion criteria and 17 declined to participate. 228 patients were enrolled, with 194 proceeding to protocol treatment and analysis (130 in the de-escalated adjuvant radiotherapy group and 64 in the standard of care group). Median patient age was 59·4 years (range 37·9–81·6). 173 (89%) of 194 patients were male and 21 (11%) were female. 183 (95%) of 194 patients were White, four (2%) were Hispanic, three (2%) were Asian, and one (1%) was Native American. Median follow-up was 37·3 months (IQR 27·6–49·2). Seven patients were excluded from analysis of the primary late toxicity endpoint (five patients in the de-escalated adjuvant radiotherapy group and two patients in the standard of care group). The cumulative chronic grade 3 or higher toxicity rate at 3–24 months was 3% (four of 125 patients) in the de-escalated adjuvant radiotherapy group and 11% (seven of 62 patients) in the standard of care group (p=0·042) with a cumulative chronic percutaneous endoscopic gastric (PEG) tube rate of 2% (two of 125 patients) in the de-escalated adjuvant radiotherapy group and 8% (five of 62 patients) in the standard of care group (p=0·039). The most common grade 3 or higher toxic effects in the de-escalated adjuvant radiotherapy group were dysphagia (two [2%] of 125 patients), oesophagitis (one patient [1%]) and hearing impairment (one patient [1%]). The most common grade 3 or higher toxic effects in the standard of care group were dysphagia (five [8%] of 61 patients), oesophagitis (one patient [2%]), fatigue (one patient [2%]), pain (one patient [2%]), and osteonecrosis of the jaw (one patient [2%]). De-escalated adjuvant radiotherapy was a more tolerable treatment in terms of chronic toxicities, demonstrating less cumulative grade 3 or higher toxicity compared with standard of care. Further clinical trials exploring indications for the DART regimen are warranted. The Department of Radiation Oncology, Mayo Clinic, Minnesota and Arizona, the Braillier Family Research Fund, and the Matteson Family Research Fund.

Objective: This study examines the prognostic significance of human papillomavirus (HPV) in patients with locally advanced oropharyngeal squamous cell carcinoma (SCC) treated primarily with surgery or definitive radiotherapy. Methods: One hundred and ninety-eight patients with Stage 3/4 SCC were followed up for recurrence in any form or death from any cause for between 1 and 235 months after diagnosis. HPV status was determined using HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox's regression with censoring at follow-up dates. Results: Forty-two per cent of cancers were HPV-positive (87% type 16). HPV predicted loco-regional control, event-free survival and overall survival in multivariable analysis. Within the surgery with adjuvant radiotherapy ( n =110), definitive radiotherapy-alone ( n =24) and definitive radiotherapy with chemotherapy ( n =47) groups, patients with HPV-positive cancers were one-third or less as likely to have loco-regional recurrence, an event or to die of any cause as those with HPV-negative cancers after adjusting for age, gender, tumour grade, AJCC stage and primary site. The 14 patients treated with surgery alone were considered too few for multivariable analysis. Conclusion: HPV status predicts better outcome in oropharyngeal cancer treated with surgery plus adjuvant radiotherapy as well as with definitive radiation therapy±chemotherapy.

Background/Objectives: Severe radiation-induced mucositis (RIM) is the most distressing acute side effect experienced by oropharyngeal squamous cell carcinoma (OPSCC) patients during chemo-radiotherapy (CRT), with a prevalence between 40 and 68%. RIM severity exhibits a multifactorial etiology that remains unclear. We aimed to analyze nutritional and morphofunctional predictive factors for severe RIM in OPSCC patients undergoing CRT. Methods: A prospective cohort study was conducted. Global Leadership Initiative on Malnutrition (GLIM) criteria, bioelectrical impedance vector analysis (BIVA), functional assessment and dosimetric analysis were performed prior to radiotherapy. Results: Eighty-two patients were analyzed. Severe RIM affected 46.3% of patients. Severe malnutrition according to GLIM (p = 0.011), prolonged Timed Up and Go (TUG) test (p = 0.025) and larger PTV54 volume (p = 0.049) were independent predictive factors for severe RIM, while higher fat-free mass (FFM) (p = 0.006) showed a protective effect. Conclusions: These findings highlight the importance of a comprehensive early nutritional assessment for accurately identifying patients at a higher risk of severe RIM.

Human papillomavirus (HPV)-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV+ OPSCC from its HPV-negative (HPV−) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV+ OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV+ OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.The incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in most developed countries. In this Review, the authors provide an overview of the epidemiology, molecular biology and treatment of HPV-positive OPSCC, including discussions of the role of treatment de-escalation and emerging novel therapies.