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Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab—an antibody against the epidermal growth factor receptor—can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity. RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1–T2, N2a–N3 M0 or T3–T4, N0–N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1–T2 vs T3–T4), N category (N0–N2a vs N2b–N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5–7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834. Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4–82·5) in the cetuximab group versus 84·6% (80·6–88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29–2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4–72·2 vs 78·4%, 73·8–83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35–3·10; 5-year proportions 17·3%, 95% CI 13·7–21·4 vs 9·9%, 6·9–13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0–81·5 vs 81·7%, 77·5–85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9–20·7 vs 20·4%, 16·4–24·8; p=0·1904) were similar between the cetuximab and cisplatin groups. For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma. National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.

BACKGROUND. Minimally invasive biomarkers predicting immunotherapy response in head and neck squamous cell carcinoma (HNSCC) remain an unmet clinical need. METHODS. Using patients from a prospective, multi-institutional phase II trial, we performed whole-genome sequencing of 185 longitudinal plasma cell-free DNA (cfDNA) samples from 68 patients with locally advanced, surgically resectable HNSCC who received neoadjuvant and adjuvant pembrolizumab. We developed the regional motif diversity score (rMDS), a fragmentomic metric that quantifies the entropy of cfDNA 5′-end motifs across genomic regions. RESULTS. Unsupervised analysis showed rMDS robustly distinguished responders from non-responders, outperforming established fragmentomic metrics and copy number alterations while remaining independent of technical confounders. Longitudinal rMDS changes localized to regions enriched for immune-, lectin-, and keratinization-related genes — hallmarks of squamous cell carcinoma — reflecting tumor–peripheral immunity interplay during treatment. The most dynamic regions clustered at telomere-proximal loci, suggesting a link between telomere biology and cfDNA fragmentation. An rMDS-based machine learning classifier achieved AUC 0.89–0.99 across validation settings, with the highest accuracy post-treatment, outperforming PD-L1 expression and tumor fraction in matched samples. Predicted responders showed improved disease-free survival (log-rank P = 0.035; HR 2.67, 95% CI 1.03–6.92). CONCLUSION. rMDS represents a biologically meaningful, clinically actionable biomarker for immunotherapy response in HNSCC, supporting integration into future risk assessment frameworks. TRIAL REGISTRATION. ClinicalTrials.gov NCT02641093. FUNDING. NHGRI R56HG012360 and startup funds from Cincinnati Children’s Hospital Medical Center, Northwestern University, and Robert H. Lurie Comprehensive Cancer Center (Y.L.); Science Olympiad Alumni Research Grant, Science Olympiad USA Foundation (R.B.); Merck Sharp & Dohme Corp. (T.W.D.).

Submental muscles (i.e., mylohyoid and geniohyoid) play a vital role during swallowing, protecting the airway from ingested material. To design therapies to reduce the functional deficits associated with radiation treatment relies in part on our understanding of the changes in the cytokine and growth factor response that can impact muscle function. The purpose of this study is to quantify changes in the inflammatory, pro-fibrotic, and pro-angiogenic factors following 48 Gy of fractionated radiation to the mylohyoid muscle. We hypothesized that (1) irradiation will provoke increases in TGF-1β and MMP-2 mRNA in the mylohyoid muscle; and (2) muscles surrounding the target location (i.e., geniohyoid and digastric muscles) will exhibit similar alterations in their gene expression profiles. Rats were exposed to 6 fractions of 8 Gy using a 6 MeV electron beam on a clinical linear accelerator. The highest dose curve was focused at the mylohyoid muscle. After 2- and 4-weeks post-radiation, the mylohyoid, geniohyoid, and digastric muscles were harvested. Expression of TNF-α, IFNγ, IL-1β, IL-6, TGF-1β, VEGF, MMP-2, and MMP-9 mRNA was analyzed via PCR and/or RT-PCR. TGF-1β, MMP-2, and IL-6 expression was upregulated in the irradiated mylohyoid compared to non-irradiated controls. No notable changes in TNF-α, IFNγ, and IL-1β mRNA expression were observed in irradiated muscles. Differing expression profiles were found in the surrounding muscles post-radiation. Results demonstrated that irradiation provokes molecular signals involved in the regulation of wound healing, which could lead to fibrosis or atrophy in the swallowing muscle after radiation.

The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51–62). Median follow-up was 4·2 years (3·1–5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Background Neoadjuvant chemoradiotherapy followed by resection is standard of care for patients with locally advanced esophageal cancer, however, a significant portion of these patients do not undergo surgical intervention. This study evaluates radiation dose and other factors associated with undergoing esophageal resection and their impact on outcomes including survival. Methods Patients diagnosed with esophageal cancer between 2010 and 15 were queried from the National Cancer Database and stratified into low-dose radiation (41.4 Gy) (LDR) or high-dose radiation (50.0 or 50.4 Gy) (HDR) groups. Multivariable Logistic and Cox Regression analyses were performed to investigate the effect of multiple variables on the likelihood of undergoing esophagectomy and overall survival, respectively. Propensity score matching was performed to reduce bias between groups. Results A total of 3633 patients met study criteria with 3005 (82.7%) undergoing esophagectomy. A greater proportion received HDR (3163 (87.1%)) than LDR (470 (12.9%)). The use of LDR increased from 4.7% ( n  = 22) in 2010 to 20.7% ( n  = 154) in 2015. Factors associated with undergoing esophagectomy included LDR, adenocarcinoma histology, and younger age. Radiation dosage did not impact overall survival, but undergoing esophagectomy was associated with improved survival. After propensity matching, a greater portion of the LDR group underwent esophagectomy (87.0 vs 81.1%, p  = 0.013). There was no difference in R0 3 resection (93.2 vs 92.4%, p  = 0.678) or complete pathologic response (19.3 vs 21.5%, p  = 0.442) between LDR and HDR groups. Conclusion The use of LDR is increasing but still underutilized. LDR is associated with increased rates of esophagectomy without negatively impacting overall survival, R0 resection, or complete pathologic response.

Introduction There are insufficient data on surface mold brachytherapy (SMB) in treating oral cancers. We reviewed our institutional experience to investigate the efficacy and toxicity of this treatment modality. Material and methods We retrospectively reviewed all the patients treated between 1989 and 2018 with high-dose-rate iridium-192 SMB for oral and oropharyngeal squamous cell carcinomas at our institution. Surface mold brachytherapy was delivered via an acrylic surface mold with 1–5 inserted catheters spaced 1 cm apart fabricated by our dental oncologist. The Kaplan-Meier product estimator was used to assess local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Cox proportional hazards regression analysis was used to assess the relationship of various variables and patient outcomes. Results Eighteen patients met the inclusion criteria and were evaluated. Indications for treatment were primary tumor (n = 13), local recurrence (2), locoregional recurrence (1), and oligometastatic disease (1). Ten patients received SMB alone and 8 received external beam radiotherapy with an SMB boost. The acute toxicity outcomes were as follows: no toxicity (n = 1), grade 1 (7), grade 2 (9), and grade 3 (1). Late effects were rare, only occurring in 3 patients. The one- and two-year LC were 81% and 68%, LRC 77% and 64%, DMFS 81% and 81%, and OS 77% and 46%. Conclusions Surface mold brachytherapy is a viable modality as either primary or boost treatment for superficial oral cancers. In our patients, this treatment method has a low toxicity profile and resulted in reasonable LC.

BackgroundPatients with newly diagnosed, resected, head and neck squamous cell carcinoma (HNSCC) with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year disease free survival (DFS) of 65% and 69%, respectively.1 PD-1/PD-L1 immune checkpoint blockade has improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiation upregulates PD-L1.2 Therefore, we hypothesized that pre and post-operative administration of the PD-1 inhibitor pembrolizumab would improve 1-year DFS for patients with resectable, loco-regionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093).MethodsEligible patients received pembrolizumab (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembrolizumab (q3 wks x 6 doses) was administered with weekly cisplatin (40mg/m2 X 6) and radiation (60-66Gy) for those with high-risk features and radiation alone for patients with intermediate-risk features. The primary endpoint was DFS, which was compared by log-rank test to historical controls (RTOG 9501). Evidence of pathological response to neoadjuvant pembrolizumab was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE) defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. Response was classified as none (NPR, <20%), partial (PPR, ≥20% and <90%) and major (MPR, ≥90%) pathological response. Gene expression analysis in paired tumor specimens was evaluated by Nanostring.ResultsSixty-six of 84 enrolled patients had received adjuvant pembrolizumab and therefore were evaluable for DFS at the time of interim analysis. Patient characteristics included: median age 59 (range of 27 – 76) years; 30% female; 85% oral cavity, 11% larynx, and 2% human papillomavirus negative oropharynx; 85% clinical T3/4 and 68% ≥2N; 41(51%) high-risk (positive margins, 49%; ECE, 80%). At a median follow-up of 16 months, 1-year DFS was 66% (95%CI 0.48-0.84) in the high-risk group (p=1) and 91% (95%CI 0.79-1) in the intermediate-risk group (versus 69% in RTOG 9501, p=0.05) (figure 1). Among 70 patients evaluable for pathological response, TE was scored as NPR in 40, PPR in 27, and MPR in 3 patients. Patients with pathological response that were also evaluable for DFS (PPR + MPR) had significantly improved 1-year DFS when compared with those with NPR (100% versus 57%, p=0.0033; HR = 0.18 [95%CI 0.05-0.64]) (figure 2). PPR/MPR was associated with robust macrophage infiltration via Nanostring.Abstract 809 Figure 1Disease Free Survival by Pathological RiskPatients were stratified by pathological risk and DFS was measuredAbstract 809 Figure 2Disease Free Survival by Pathological ResponsePaired patient tissue was assessed for treatment effect (TE) and patients with greater than or equal to 20% TE were considered to have developed pathological response. Patients were stratified into responders and non-responders and DFS was determined.ConclusionsNeoadjuvant and adjuvant pembrolizumab led to high DFS in intermediate-risk, but not high-risk, resected HNSCC patients. Pathological response to neoadjuvant pembrolizumab was associated with high 1-year DFS.AcknowledgementsWe’d like to acknowledge the UCCC clinical trials office for their hard work on this study as well as our patients. We’d also like to acknowledge Merck & Co, Inc as they partially funded the clinical trial.Trial RegistrationNCT02641093Ethics ApprovalThis study was approved by the University of Cincinnati IRB with approval number 2015-6798ReferencesCooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19):1937-1944. doi:10.1056/NEJMoa032646Oweida A, Lennon S, Calame D, et al. Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. Oncoimmunology2017;6(10):e1356153. Published 2017 Aug 3. doi:10.1080/2162402X.2017.1356153

Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III–IVB p16-negative HNSCC or unfavourable stage I–III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64–77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9–3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5–59·8) in the durvalumab group versus 63·7% (51·3–76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84–2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3–4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group). Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population. US National Cancer Institute and AstraZeneca.

BackgroundImmunosuppression (IS) currently is not considered in staging for Merkel cell carcinoma (MCC). An analysis of the National Cancer Database (NCDB) was performed to investigate immune status as an independent predictor of overall survival (OS) for patients with MCC and to describe the relationship between immune status and other prognostic factors.MethodsThe NCDB was queried for patients with a diagnosis of MCC from 2010 to 2016 who had known immune status. Multivariable Cox proportional hazards models were used to define factors associated with OS. Secondary models were constructed to assess the association between IS etiology and OS. Multivariable logistic regression models were used to characterize relationships between immune status and other factors.ResultsThe 3-year OS was lower for the patients with IS (44.6%) than for the immunocompetent (IC) patients (68.7%; p < 0.0001). Immunosuppression was associated with increased adjusted mortality hazard (hazard ratio [HR], 2.36, 95% confidence interval [CI], 2.03–2.75). The etiology of IS was associated with OS (p = 0.0015), and patients with solid-organ transplantation had the lowest 3-year OS (32.7%). Immunosuppression was associated with increased odds of greater nodal burden (odds ratio [OR], 1.70; 95% CI, 1.37–2.11) and lymphovascular invasion (OR, 1.58; 95% CI, 1.23–2.03).ConclusionsImmune status was independently prognostic for the OS of patients with localized MCC. The etiology of IS may be associated with differential survival outcomes. Multiple adverse prognostic factors were associated with increased likelihood of IS. Immune status, and potentially the etiology of IS, may be useful prognostic factors to consider for future MCC staging systems.