Phase 1 doseâ finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153201/1/cncr32539.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153201/2/cncr32539_am.pd

Metformin Increases Natural Killer Cell Functions in Head and Neck Squamous Cell Carcinoma Through CXCL1 Inhibition

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692). METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses. RESULTS: Increased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1. CONCLUSIONS: Our data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC

Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer

Introduction: Surgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection. Methods and materials: Findings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts-surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)-were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated. Results: Forty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years. Conclusions: Among patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts. Clinical trial registration: ClinicalTrials.gov, identifiers NCT02794675 and NCT02467738

Therapeutic Advancements in Metal and Metal Oxide Nanoparticle-Based Radiosensitization for Head and Neck Cancer Therapy

Although radiation therapy (RT) is one of the mainstays of head and neck cancer (HNC) treatment, innovative approaches are needed to further improve treatment outcomes. A significant challenge has been to design delivery strategies that focus high doses of radiation on the tumor tissue while minimizing damage to surrounding structures. In the last decade, there has been increasing interest in harnessing high atomic number materials (Z-elements) as nanoparticle radiosensitizers that can also be specifically directed to the tumor bed. Metallic nanoparticles typically display chemical inertness in cellular and subcellular systems but serve as significant radioenhancers for synergistic tumor cell killing in the presence of ionizing radiation. In this review, we discuss the current research and therapeutic efficacy of metal nanoparticle (MNP)-based radiosensitizers, specifically in the treatment of HNC with an emphasis on gold- (AuNPs), gadolinium- (AGdIX), and silver- (Ag) based nanoparticles together with the metallic oxide-based hafnium (Hf), zinc (ZnO) and iron (SPION) nanoparticles. Both in vitro and in vivo systems for different ionizing radiations including photons and protons were reviewed. Finally, the current status of preclinical and clinical studies using MNP-enhanced radiation therapy is discussed

Increased Pain Reporting by Head and Neck Cancer Patients at Radiation Oncology Consultation: A Quality‐of‐Life Analysis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166159/1/lary28784.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166159/2/lary28784_am.pd

Treatment of early stage vaginal cancer with EBRT and MRI-based intracavitary brachytherapy: A retrospective case review

This case series describes the use of pelvic radiotherapy (RT) and MRI-based intracavitary brachytherapy (ICBT) for patients with small volume, early-stage, primary vaginal cancer. A customized pelvic MRI protocol with a vaginal cylinder in place (MRVC) was used to measure disease extent and tumor thickness (defined as distance from lateral/apical margin of tumor to cylinder surface) at time of diagnosis. Non-bulky tumors with initial (pre-RT) thickness ≤ 2 cm from the cylinder surface received pelvic RT followed by ICBT. Ten patients with FIGO stage I–II primary vaginal cancer treated with pelvic RT +/− cisplatin and ICBT at our institution between 1998 and 2008 were included. Initial tumor thickness measured on MRVC ranged from 0 to 2 cm. Initial tumor volume ranged from 0 to 9.8 cm3. Mean pelvic RT dose was 45 Gy. At the time of ICBT, 60% of patients had a complete response (cR) and 40% had a partial response (pR). No patients with a cR had a recurrence whereas one patient with a pR had a local recurrence following ICBT. For the entire cohort, the median follow-up time was 59.9 months (range: 15–153). The estimated 5-year overall survival, disease-specific survival, and local failure-free survival were 67%, 80%, and 90%, respectively. Among survivors, there were no late grade 3–4 toxicities. In this series of patients with small primary early-stage vaginal tumors, long term clinical outcomes were acceptable following RT and MRI-based ICBT, especially among those with a cR at time of brachytherapy

Adjuvant radiation and cetuximab improves local control in head and neck cutaneous squamous cell carcinoma: Phase II study

BackgroundCutaneous squamous cell carcinoma of the head/neck (CSCCHN) is common due to chronic sun exposure. As CSCCHN highly expresses EGFR, we prospectively studied postoperative concurrent cetuximab with radiotherapy for locally advanced CSCCHN (LA- CSCCHN).Materials and methodsSingle- institutional phase II trial of LA- CSCCHN (NCT XXXX). Adjuvant radiation was given with concurrent cetuximab. Primary endpoint of 2- year LRC and secondary objectives of 2- year disease- free survival (DFS) and 2- year OS were assessed by Kaplan- Meier analysis.ResultsTwenty- four patients ages 47- 88 (median 71- years) were treated from 2014 to 2017. Fourteen patients had T3/4 disease, 5 had N1 disease, and 7 were N2/3. At median follow- up of 42- months, median OS and DFS was not reached and 64- months. Two- year OS was 75%, 2- year DFS was 70.8%. LRC was 91.1% at 2- years. All grade 3 adverse events were related to skin toxicity (12.5% radiation- related dermatitis, 16.7% cetuximab- related rash).ConclusionsLRC compares favorably to historical data examining postoperative radiation alone but requires further investigation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170792/1/hed26835_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170792/2/hed26835.pd

Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial.

PURPOSE: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response. PATIENTS AND METHODS: A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months. RESULTS: As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5-16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7-14.1) and 9.6 months (95% CI: 4.8-16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders. CONCLUSIONS: The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation