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Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0–2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2–3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002–4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0–12·8) in the pazopanib group versus 7·3 months (4·3–10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52–1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1–53·2) in the pazopanib group and 29·0% (13·2–44·8) in the placebo group. The incidence of grade 3–5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3–4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. National Cancer Institute and Novartis.

Human Papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy, with radiotherapy, alone or combined with immune checkpoint inhibitors, often failing to achieve durable disease control. Here, by conducting longitudinal multi-omic analyses of pre- and post-radiation biopsies from patients receiving a pre-operative hypofractionated radiation regimen, we uncover that radiation rapidly depletes a subpopulation of tumor-infiltrating lymphocytes (TIL), characterized by a proliferative, cytotoxic, and tissue-resident gene signature (T Prolif_Tox ). We provide multi-dimensional evidence for tumor antigen-specificity of T Prolif_Tox clonotypes and show that post-radiation tumors are instead repopulated by regulatory and non-specific clones. Finally, TIL depletion correlates with radiorecurrent disease after conventional radiation, emphasizing the potential impact of radiation-induced TIL loss regardless of fractionation. Thus, this study provides key insights into radiotherapy-induced alterations in the immune microenvironment that drive immunologic radioresistance and proposes restoring tumor antigen-specific T cell clonotypes as a strategy to improve radioimmunotherapy responses in HNSCC. Combining radiation therapy (RT) with immunotherapy has had limited therapeutic benefits in the treatment of head and neck cancer (HNSCC). Here, the authors present a multi-omics analysis of patient biopsies pre- and post- hypofractionated RT and uncover RT-mediated depletion of tumor-reactive CD8+ T cells as the underlying cause of immunologic radioresistance in HNSCC.

Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7·1 months (95% CI 5·7–9·0) and 4·1 months (2·8–4·4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0·704 vs 0·386, p=0·036 and 0·949 vs 0·332, p=0·036, respectively) and tumour shrinkage (p=0·007 and p=0·008, respectively) in a subset of 11 patients with available tissue. The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA (grant number N01-CM-17102) and the University of Chicago Cancer Research Center, Chicago, IL, USA (grant number P30 CA14599).

BackgroundRecurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a high recurrence rate after first-line immunotherapy or chemoimmunotherapy. The presence of a high density of tumor-infiltrating lymphocytes (TILs) in HNSCC tumors was shown to be associated with improved clinical outcomes. One-time autologous TIL cell therapy was evaluated in patients with recurrent and/or metastatic HNSCC.MethodsC-145-03 (NCT03083873) was a phase 2 study of TIL in patients with recurrent and/or metastatic HNSCC assigned to 1 of 4 treatment cohorts: cohort 1, non-cryopreserved TIL; cohort 2, cryopreserved lifileucel (22-day manufacturing); cohort 3, cryopreserved lifileucel (16-day manufacturing); cohort 4, cryopreserved LN-145-S1 programmed cell death protein-1 (PD-1) selected. Patients underwent tumor resection for TIL generation. After preparative non-myeloablative lymphodepletion, patients received a single infusion of TIL followed by interleukin-2 (IL-2) infusion(s). The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria for Solid Tumors (RECIST) V.1.1. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, and incidence of treatment-emergent adverse events.ResultsOverall, 53 patients received TIL: cohort 1 (n=8), cohort 2 (n=17), cohort 3 (n=16), cohort 4 (n=12). Median age was 57 years and most patients were males (87%; 46/53) with stage IV disease (98%; 52/53). Patients had a median of two prior lines of systemic therapy; 87% (46/53) of patients had prior anti-PD-1/programmed cell death ligand-1 therapy and 72% (38/53) had prior chemotherapy. The ORR was 11% (6/53) with six patients achieving partial response (cohort 1, n=3; cohort 2, n=1; cohort 4, n=2). At median follow-up of 17.9 months, the median DOR was 7.6 months. The DCR was 76% (40/53); 64% (34/53) of patients had stable disease. The safety profile was consistent with known toxicities associated with non-myeloablative lymphodepletion and IL-2 administration.ConclusionsThis study demonstrated the feasibility of consistently generating sufficient TIL from HNSCC tumors. Results from this study suggest TIL cell therapy may serve as a potential treatment option for patients with HNSCC and support further development, including TIL cell therapy combined with immune checkpoint inhibitors or other agents or with other TIL products.Trial registration numberNCT03083873.

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.

This study reports the first clinical evidence of significantly high secretion of matrine in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. This is of high clinical significance as matrine can be used as a monitoring tool during longitudinal clinical studies to overcome the key limitation of poor patient compliance often reported in cancer chemoprevention trials. Both matrine and dictamine were detected in the saliva and plasma samples but only matrine was quantifiable after the oral administration of ATB tablets (2400 mg) in 8 healthy volunteers. A significantly high saliva/plasma ratios for Cmax (6.5 ± 2.0) and AUC0–24 (4.8 ± 2.0) of matrine suggested an active secretion in saliva probably due to entero-salivary recycling as evident from the long half-lives (t1/2 plasma = 10.0 ± 2.8 h, t1/2 saliva = 13.4 ± 6.9 h). The correlation between saliva and plasma levels of matrine was established using a population compartmental pharmacokinetic co-model. Moreover, a species-relevant PBPK model was developed to adequately describe the pharmacokinetic profiles of matrine in mouse, rat, and human. In conclusion, matrine saliva concentrations can be used as an excellent marker compound for mechanistic studies of active secretion of drugs from plasma to saliva as well as monitor the patient’s compliance to the treatment regimen in upcoming clinical trials of ATB.

Goals of work We report the first analysis of demographic, socioeconomic, and toxicity data from the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN). Materials and methods Eligible patients include newly diagnosed Head and Neck Cancer (HNC) patients, scheduled to receive radiotherapy or drug therapy, ≥18 years of age, and able to provide informed consent. Assessments are completed at baseline, at the completion of therapy, and yearly thereafter. Patient data are entered in the registry electronically and transferred via Secure HTTP protocols. Results Reported use of supportive care differed by treatment setting. When compared to community sites, patients at academic centers received more supportive interventions: feeding tube (59% vs. 48%; p  = 0.001), tracheotomy tube (16% vs. 9%; p  = 0.002), opioid analgesics (89% vs. 59%; p  < 0.0001), anti-emetics (83% vs. 68%; p  < 0.0001), and amifostine (17% vs. 12%; p  = 0.02). Reported grades 3–4 mucositis/stomatitis was also higher in patients treated at academic centers (38% vs. 28%; p  = 0.001). Conclusion There was a marked decrease in the documented use of supportive care measures in the community setting. This may be due to (1) lower rates of toxicity requiring less supportive care, (2) less stringent documentation, or (3) less aggressive use of supportive care measures. The documented rate of mucositis was less than expected. This is likely due to inadequate assessment or documentation. Further exploration of these findings is warranted as they may indicate an under appreciation and undertreatment of clinically significant acute tumor and treatment-related toxicities.