Recurrent Squamous Cell Cancer Research Articles

Oncologic Outcomes of Salvage Abdominoperineal Resection for Anal Squamous Cell Carcinoma Initially Managed with Chemoradiation.

Background: Abdominoperineal resection (APR) has been advocated for persistent or recurrent disease after failure of chemoradiation (CRT) for anal squamous cell cancer (SCC). Treatment with salvage APR can potentially achieve a cure. This study aimed to analyze oncological outcomes for salvage APR in a recent time period at a comprehensive cancer center. Methods: A retrospective review of all patients who underwent APR for biopsy-proven persistent or recurrent anal SCC between 1 January 2007 and 31 December 2020 was performed. Patients with stage IV disease at the time of initial diagnosis and patients with missing data were excluded. Univariate analysis was used with a chi-square test for categorical variables, and non-parametric tests were used for continuous variables. Kaplan-Meier survival analysis was performed to evaluate disease-specific (DSS), post-APR local recurrence-free (RFS), and disease-free survival (DFS). Results: A total of 96 patients were included in the analysis: 39 (41%) with persistent disease and 57 (59%) with recurrent SCC after chemoradiation had been completed. The median follow-up was 22 months (IQR 11-47). Forty-nine patients (51%) underwent extended APR and/or pelvic exenteration. Eight (8%) patients developed local recurrence, 30 (31%) developed local and distant recurrences, and 16 (17%) developed distant recurrences alone. The 3-year DSS, post-APR local recurrence-free survival, and disease-free survival were 53.8% (95% CI 43.5-66.5%), 54.5% (95% CI 44.4-66.8%), and 26.8% (95% CI 18.6-38.7%), respectively. In multivariate logistic regression analysis, positive microscopic margin (OR 10.0, 95% CI 2.16-46.12, p = 0.003), positive nodes in the surgical specimen (OR 9.19, 95% CI 1.99-42.52, p = 0.005), and lymphovascular invasion (OR 2.61 95% CI 1.05-6.51, p = 0.04) were associated with recurrence of disease. Gender, indication for APR (recurrent vs. persistent disease), HIV status, extent of surgery, or type of reconstruction did not influence survival outcomes. Twenty patients had targeted tumor-sequencing data available. Nine patients had PIK3CA mutations, seven of whom experienced a recurrence. Conclusions: Salvage APR for anal SCC after failed CRT was associated with poor disease-specific survival and low recurrence-free survival. Anal SCC patients undergoing salvage APR should be counseled that microscopic positive margins, positive lymph nodes, or the presence of lymphovascular invasion in the APR specimen are prognosticators for disease relapse. Our results accentuate the necessity for additional treatment strategies for the ongoing treatment challenge of persistent or recurrent anal SCC after failed CRT.

Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. This study is registered on ClinicalTrials.gov: NCT04375384.

B-cell infiltration is associated with survival outcomes following programmed cell death protein 1 inhibition in head and neck squamous cell carcinoma

Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P= 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P= 0.013 and P= 0.0028, respectively). Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.

Patterns of failure for recurrent head and neck squamous cell carcinoma treated with salvage surgery and postoperative IMRT reirradiation

Purpose/ObjectivesThe purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT for recurrent head and neck squamous cell cancer (HNSCC). Materials/MethodsPatterns of LRR for 61 patients treated consecutively between 2003 and 2014 who received post-operative IMRT reirradiation to ≥ 60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR. ResultsA total of 55 patients were eligible for analysis and 23 (42 %) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the most significant predictor of LRR after post-operative reirradiation with salvage rate of 67 % for lymphatic vs. 33 % for mucosal sites (p = 0.037). Physician classification of LRR yielded 14 (61 %) in-field failures, 3 (13 %) marginal failures, and 6 (26 %) out-of-field failures, while DIR yielded 10 (44 %) in-field failures, 4 (17 %) marginal failures, and 9 (39 %) out-of-field failures. Most failures (57 %) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56 % of failures occurred within 1 cm of the surgical flap. ConclusionOur study highlights the role of DIR in enhancing the accuracy and consistency of POF analysis. Compared to traditional visual inspection, DIR reduces interobserver variability and provides more nuanced insights into dose-specific and spatial parameters of locoregional recurrences. Additionally, the study identifies the location of the initial recurrence as a key predictor of subsequent locoregional recurrence after salvage surgery and re-IMRT.

A phase 1 study of concurrent cabozantinib and cetuximab in recurrent or metastatic head and neck squamous cell cancer.

6025 Background: Epidermal growth factor receptor (EGFR) targeting with cetuximab (CTX) is a standard therapy for head and neck squamous cell carcinoma (HNSCC). Resistance to CTX can be mediated by activation of the receptor tyrosine kinase AXL. Cabozantinib (cabo) is a tyrosine kinase inhibitor (TKI) of AXL/c-MET/VEGFR which demonstrated antitumor activity in HNSCC preclinical models. We conducted a phase I trial to assess the safety and efficacy of the cabo-CTX combination in recurrent or metastatic (R/M) HNSCC. Methods: Eligibility criteria included RECIST v1.1 measurable disease and incurable R/M HNSCC. Prior treatment with CTX was allowed. Patients received an initial CTX loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. CTX maintenance dose was later amended to 500 mg/m2 biweekly. Cabo was given concurrently on days 1-28 of each 28-day cycle. Primary endpoint was maximally tolerated dose (MTD) of cabo, as identified using a 3+3 dose-escalation design. Tumor responses were assessed every 2 cycles. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Of 22 patients enrolled between 2018 and 2022, 2 did not start therapy. Among treated patients, median age was 59 (range 33-71) and 90% (n = 18) of patients were male. Primary tumor sites included the oropharynx (n = 13), oral cavity (n = 3), larynx (n = 2), hypopharynx (n = 1) and unknown primary (n = 1). p16 antigenic testing for HPV status was positive in 11 oropharyngeal cancers (85%). Most patients were previously treated with immune checkpoint inhibitors (n = 19), chemotherapy (n = 19), CTX (n = 16), or other TKI (n = 2). 12 patients received biweekly CTX dosing at 500 mg/m2. Initial cabo dose was 40 mg for the first 11 patients, and 60 mg afterwards (MTD). No dose-limiting toxicity (DLT) was recorded. Common adverse events (AEs) included fatigue (80%), acneiform rash (75%), increased aspartate aminotransferase (AST) (70%), anemia (70%) and hypothyroidism (70%). Grade ≥3 AEs occurred in 65% (n = 13), including increased AST (45%), increased alkaline phosphatase (15%), increased bilirubin (10%) and erythrodysesthesia (10%). AEs led to dose reductions in 20% (n = 4) and treatment discontinuation in 15% (n = 3). In the preliminary efficacy analysis, 4 patients had partial responses (PRs) with an ORR of 20%, including 2 PRs in patients with prior CTX resistance. Disease control rate (DCR) was 75% in the overall population and 75% in those with previous CTX treatment. Median PFS was 3.4 mo and median OS was 8.1 mo. PFS differed according to HPV status, with median PFS 7.1 mo versus 3.1 mo in HPV-positive and -negative patients respectively (p = 0.03). Conclusions: The cabo and CTX combination showed an acceptable toxicity profile with liver toxicity as a common AE. The regimen showed preliminary efficacy data in patients with R/M HNSCC, including those with prior CTX resistance. Clinical trial information: NCT03667482 .

Abstract CT047: A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck

Abstract Background: Single agent pembrolizumab in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an ORR of 19% and mOS of 13.6 months. There are many factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment (TME). Low Tregs in the TME have been correlated with clinical efficacy with PD-1 blockade in various solid tumors. Tregs play an active role in HNSCC. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. In the Ice-CAP phase I solid tumor trial, combination PD-L1 antibody and Ipatasertib demonstrated reduction of Tregs and increased CD8+ effector T cells in paired biopsy specimens. This trial is designed to compare the efficacy of combination ipatasertib plus pembrolizumab compared to pembrolizumab monotherapy in R/M HNSCC. Methods: In this prospective, two-arm, phase II, multicenter trial, patients with R/M HNSCC will be treated with pembrolizumab 200mg on day 1 with or without ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ≥ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with Ipatasertib plus pembrolizumab compared to pembrolizumab using the Cox Model where randomized treatment assignment is the only variable in the model. A total of 48 patients will be enrolled, with 24 patients in each cohort. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Accrual is ongoing (NCT05172258). Citation Format: Jacob S. Thomas, Robert Hsu, Victoria Villaflor, Jonathan Riess, Jorge Nieva, Mark Krailo, Silvio Gutkind, Dimitri Colevas. A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT047.

Anti-PD‑1-induced type 1 diabetes mellitus in patient with recurrent oropharyngeal squamous cell cancer

Immune checkpoint inhibitors targeting a programmed cell death ligand (PD-L1) have been a major breakthrough in the treatment of many cancers . Nivolumab is an antibody that selectively blocks the PD‑1 receptor on the surface of cytotoxic T- cells to prevent downregulation of the immune response . Immune checkpoint inhibitors can cause immune-related adverse events , including endocrine ones . Type 1 diabetes mellitus is one of the severe rare and potentially lethal immune-related adverse events diagnosed in less than 1% of patients receiving immune checkpoint inhibitors . The total incidence of type 1 diabetes mellitus associated with the PD‑1 inhibitor is relatively low ; however , it develops rapidly and is potentially life-threatening without timely diagnosis and treatment . Since PD‑1 inhibitors are widely used in cancer treatment , complications such as type 1 diabetes mellitus should attract medical attention . During treatment , specialists should help patients better recognize the symptoms of hyperglycemia or diabetic ketoacidosis , which requires careful observation , regular monitoring of blood glucose levels , rapid detection and correct diagnosis and treatment of diabetes mellitus .

228MO Impact of EXTREME regimen and cetuximab, cisplatin, and paclitaxel-based regimen on clinical and humanistic outcomes in patients suffering from recurrent or metastatic head and neck squamous cell cancer

This study aimed to assess the impact of the EXTREME regimen and cetuximab, cisplatin, and paclitaxel-based regimen on clinical and humanistic outcomes in patients suffering from recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC).

Association between Submucosal Fibrosis and Endoscopic Submucosal Dissection of Recurrent Esophageal Squamous Cell Cancers after Chemoradiotherapy.

Simple SummaryThe efficacy and safety of endoscopic submucosal dissection for early esophageal cancer after chemoradiotherapy have not been established. In this study, we focused on the fibrosis of the submucosa. As a result, we found that endoscopic submucosal dissection for early esophageal cancer can be performed reliably without adverse events, but the procedure takes longer for lesions with strong fibrosis of the submucosa.Endoscopic resection is a treatment of choice for a metachronous early-stage esophageal squamous cell carcinoma (ESCC) appearing after a radical cure of esophageal cancer by chemoradiotherapy (CRT). However, non-curative resection, and procedural complications including perforation due to radiation-induced submucosal fibrosis, are a concern. This study aimed to evaluate the association between submucosal fibrosis and the usefulness and safety of endoscopic submucosal dissection (ESD) in ESCC after CRT. This study retrospectively analyzed 13 lesions in 11 patients in our institute. Submucosal fibrosis under the lesion (F score) was classified into three levels (F0: none or mild, F1: moderate, and F2: severe) based on endoscopic and histopathologic findings. All lesions were F1 or greater (F1: 8 lesions and F2: 5 lesions). En bloc and R0 resection rates were both 100%. The procedural speed was slower in F2 than in F1 (F1 vs. F2; 15.1 mm2/min vs. 7.1 mm2/min, p = 0.019), without procedure-related adverse events. At a median follow-up of 42 months (range: 14–117 months) after ESD, 7 of 11 (63.6%) patients were alive without recurrence, and without ESCC-related death. ESCC after CRT reliably and safely resected en bloc by ESD but was more difficult in lesions with strong submucosal fibrosis.

Gut microbiome/metabolome predicts response to immune checkpoint blockers (ICB) in patients with recurrent metastatic head and neck squamous cell cancer (RM HNSCC).

6055 Background: Gut microbiome has emerged as an important predictor of response to ICB therapy in various cancers, most notably in melanoma. Due to functional redundancy of microbiota, there has been lack of consistency in gut microbial signature associated with ICB response. Microbial metabolites in addition to taxonomy may play a superior role in predicting response to ICB. Gut microbiome/metabolome signatures of ICB response is unknown in RM HNSCC patients. Methods: Two cohorts of patients were included (stool and plasma samples were collected)- cohort 1, newly diagnosed RM HNSCC patients starting first line ICB, for whom samples were collected before ICB initiation (baseline) and post-treatment at 3, 6, and 12 months. Cohort 2 with durable response (disease control lasting ≥ 6 months), with single sample collected at study entry. 16s rRNA sequencing was performed on stool samples while plasma metabolites were quantitated using Q Exactive plus Orbitrap mass spectrometer. Response was defined as partial response (PR) or complete response (CR) as per RECIST 1.1 Results: The 16-S sequence was carried on 31 samples (cohort 1- 16 baseline, 7 post treatment; cohort 2- 8 durable responders). Targeted metabolomics was completed on 92 plasma samples [cohort 1-27 baseline and 50 post-treatment, cohort 2- 15]. Responders had a significantly higher Shannon’s diversity index, lower Fermicutes to Bacteroidetes ratio, and were enriched with genus Bacteroides and Lachnospiracea incerate sedis at baseline and post treatment, compared to non-responders (p < 0.05). At species level, baseline and post treatment microbiome of responders was enriched with Eubacterium oxidoreducens and Bacteroides uniformis. Ruminococcus was preferentially enriched in durable responders. Targeted analysis of plasma metabolites (associated with gut microbial metabolism) showed that responders had a significantly lower baseline adenosine, Inosine and xanthine level as compared to non responders. Further, Inosine levels decreased with response, while levels increased in non-responders (p < 0.05), suggestive of consumption by re-activated T cells Further, ICB responders had significantly lower Kynurenine to tryptophan ratio compared to non responders Conclusions: This is the first study evaluating association of gut microbiome and metabolome on response to first line ICB, in RM HNSCC patients. We found higher diversity and specific gut microbial signatures associated with ICB response. Interestingly, we found that inosine and kynurenine/tryptophan pathways, both which play a crucial role in host as well as gut microbial metabolism were differentially expressed in ICB responders. Our results if validated in larger cohort, lays groundwork for gut microbiome and importantly microbial metabolite modulation to improve response to ICB in RM HNSCC.

A randomized phase II study comparing the efficacy and safety of the glyco-optimized anti-EGFR antibody tomuzotuximab against cetuximab in patients with recurrent and/or metastatic squamous cell cancer of the head and neck – the RESGEX study

BackgroundThe aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment.Patients and methodsIn this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival.ResultsMedian progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02).ConclusionsThe glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors.

890P Concordance analysis of PD-L1 CPS in different sample types of head and neck squamous cell cancer

For patients with recurrent or metastasized squamous cell cancer of the head and neck (R/M SCCHN), the PD-L1 Combined Positive Score (CPS) is currently the only predictive biomarker for treatment with anti-PD-1 inhibitors. However, ambiguous results have been delivered regarding the overall response rate (ORR) of these immunotherapeutic agents. This issue may be attributed to the intratumoral, intertumoral and temporal heterogeneity of PD-L1 expression.

Near infrared photoimmunotherapy for cancers: A translational perspective.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly-developed, highly-selective cancer treatment, which utilizes a monoclonal antibody conjugated to a photoabsorbing dye, IRDye700DX (IR700). The antibody conjugate is injected into the patient and accumulates in the tumour. Within 24 h of injection the tumour is exposed to NIR light which activates the conjugate and causes rapid, selective cancer cell death. A global phase III clinical trial of NIR-PIT in recurrent head and neck squamous cell cancer (HNSCC) patients is currently underway. Conditional clinical approval for NIR-PIT in recurrent HNSCC has been granted in Japan as of September 2020. Not only does NIR-PIT induce highly selective and immediate cancer cell killing, but it also stimulates highly active anti-tumour immunity. While monotherapy with NIR-PIT has proven effective it is likely that combinations with immune-checkpoint inhibitors or additional NIR-PIT targeting immune suppressive cells in the tumour microenvironment will further improve results. In this review, we discuss the translational aspects of NIR-PIT especially in HNSCC, and potential future applications.

A Prospective Real-World Multi-Center Study to Evaluate Progression-Free and Overall Survival of Radiotherapy with Cetuximab and Platinum-Based Chemotherapy with Cetuximab in Locally Recurrent Head and Neck Cancer.

Simple SummaryDespite recent developments in immune checkpoint inhibitors, the treatment of locoregionally recurrent head and neck squamous cell cancer (HNSCC) remains challenging. Prospective data comparing re-irradiation with systemic treatment are not available. The SOCCER trial represents a prospective non-interventional multicenter trial that enrolled patients with locoregionally recurrent HNSCC treated with cetuximab in combination with re-radiotherapy or chemotherapy. A total of 192 patients were analyzed. Radiotherapy combined with cetuximab had superior progression-free and overall survival compared to chemotherapy with cetuximab. This highlights the high efficacy of local re-radiotherapy in combination with cetuximab in patients with locoregionally recurrent HNSCC.Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27–0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33–0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.

Treatment patterns for patients with metastatic or recurrent head and neck cancer in a large integrated health-care system.

e18015 Background: Since publication of the landmark KEYNOTE-048 Trial, pembrolizumab alone or with platinum-based chemotherapy and 5-fluorouracil (5FU) was established as a standard of care for the frontline treatment of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC), replacing the EXTREME regimen of Cetuximab with platinum and 5FU. In clinical practice, some clinicians modify the KEYNOTE-048 regimen by substituting a taxane for 5FU (i.e., Paclitaxel + Carboplatin + Pembrolizumab, PCT). Within the Kaiser Permanente Northern California (KPNCAL) network, we identified a cohort of 123 patients who received palliative first-line therapy for metastatic HNSCC to identify practice patterns in a real-world setting within a large health care delivery system. Methods: This is a data-only cohort study of all adult KPNCAL members diagnosed with metastatic HNSCC treated with palliative combination chemotherapy and/or immunotherapy between January 1, 2018 and July 31, 2020. Results: Among a cohort of 123 patients, 28 patients received the EXTREME regimen (platinum + 5FU + cetuximab), 10 received modified EXTREME (platinum + taxane + cetuximab), 14 received platinum + 5FU + pembrolizumab, 9 received platinum + taxane + pembrolizumab and 62 received single agent immunotherapy. From 2018 through mid-2020, there was an apparent shift away from cetuximab based regimens and a concurrent rise in immunotherapy-based regimens. By mid-2020, the majority of patients received an immunotherapy-based regimen (28 patients), while only 5 patients received a cetuximab based regimen (Table). Conclusions: Data from our cohort reported clinical practice patterns within a large multispecialty integrated health-care system in Northern California. Our findings highlight the marked variability in practice patterns within a single health care system for first-line metastatic therapy. While we identified trends away from cetuximab based therapy and toward immunotherapy-based therapy in clinical practice there remained wide practice variations among clinical oncologist treating patients with newly diagnosed metastatic HNSCC. This further emphasizes the need for prospective clinical trials to identify the optimal regimen or to confirm clinical equipoise between regimens among patients with metastatic or recurrent head and neck cancer. [Table: see text]

Immunotherapy-Related Autoimmune Diabetes Mellitus and Exogenous Insulin Antibody Syndrome in a Patient With Metastatic Oral Squamous Cell Carcinoma

Introduction: Exogenous insulin antibody syndrome (EIAS) is a rare condition characterized by wide glycemic excursions and recurrent hypoglycemia in the presence of high insulin antibody titers. It has been described in diabetic patients treated with exogenous insulin. Programmed death ligand 1 (PD-L1) inhibitors are known to cause autoimmune diabetes mellitus, but PD-L1-related EIAS has not yet been reported to our best knowledge. Case Description: A 63 years old Caucasian man with history of recurrent oral squamous cell cancer presented to emergency room with polyuria, polydipsia, nausea, and vomiting 3 months after initiation of immunotherapy (Durvalumab and cetuximab). He had no prior history of diabetes mellitus or hypoglycemia. He was admitted to hospital for management of diabetic ketoacidosis (Anion gap of 24 mEq/L, venous blood glucose of 805 mg/dL, Venous PH of 7.12, large urine ketone, A1C of 8.9%). After a brief hospital stay, the patient was discharged home on insulin glargine and metformin. His immunotherapy was resumed after hospital discharge. When the patient was seen by Endocrinologist in the clinic, metformin was discontinued and prandial insulin lispro was added. This basal-bolus insulin regimen improved his glycemic control initially. However, without significant changes in his lifestyle or medical condition, he developed worsening postprandial hyperglycemia and recurrent fasting hypoglycemia. Up-titration of his mealtime insulin did not lower postprandial hyperglycemia but possibly worsened fasting hypoglycemia. EIAS was suspected after reviewing his continuous glucose monitoring data. Further work up at this point revealed mildly elevated glutamic acid decarboxylase antibodies (5.9 units/mL, normal range 0.5 - 5.0) and markedly elevated insulin antibody level (77.0 µU/mL, normal range <5). His blood C-peptide was undetectable when his venous blood glucose was 252 mg/dl. In addition, his total insulin level (198 uU/mL) was much higher than his free insulin level (38 uU/mL) following an insulin lispro injection. The patient was diagnosed with EIAS. Switching insulin lispro to insulin aspart while he was on a different immunotherapy medication (Pembrolizumab) immediately reduced his average blood glucose and reduced his total daily insulin dosage by more than 50%. This improvement in glycemic control with insulin aspart only lasted for about 1 week. Unfortunately, the patient’s squamous cancer progressed on immunotherapy. He was referred to hospice care and passed away. Conclusion: Evaluation for EIAS would be reasonable in insulin-treated diabetic patients who develop wide glucose excursions and unexplained fasting hypoglycemia while on immunotherapy.

Paclitaxel-loaded polymeric nanoparticles based on α-tocopheryl succinate for the treatment of head and neck squamous cell carcinoma: in vivo murine model

: The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC) is generally poor. New treatments are required to supplement the current standard of care. Paclitaxel (PTX), an effective chemotherapeutic for HNSCC, has serious side effects. A polymeric nanocarrier system was developed for the delivery of PTX to improve HNSCC treatment. This study aimed to evaluate the antitumor efficacy of PTX-loaded polymeric nanoparticles based on α-TOS (PTX-NPs) administered by direct intratumoral injection into a Hypopharynx carcinoma squamous cells (FaDu) tumor xenograft mouse model. The nanocarrier system based on block copolymers of polyethylene glycol (PEG) and a methacrylic derivative of α-TOS was synthesized and PTX was loaded into the delivery system. Tumor volume was measured to evaluate the antitumor effect of the PTX-NPs. The relative mechanisms of apoptosis, cell proliferation, growth, angiogenesis, and oxidative and nitrosative stress were detected by Western blotting, fluorescent probes, and immunohistochemical analysis. The antitumor activity results showed that compared to free PTX, PTX-NPs exhibited much higher antitumor efficacy and apoptosis-inducing in a FaDu mouse xenograft model and demonstrated an improved safety profile. Ki-67, EGFR, and angiogenesis markers (Factor VIII, CD31, and CD34) expression were significantly lower in the PTX-NPs group compared with other groups (p < .05). Also, PTX-NPs induced oxidative and nitrosative stress in tumor tissue. Direct administration of PTX-loaded polymeric nanoparticles based on α-Tocopheryl Succinate at the tumor sites, proved to be promising for HNSCC therapy.

Addressing the contralateral neck for ipsilateral disease recurrence in oral cavity cancers

BackgroundEvidence for performing contralateral neck dissection (CND) of recurrent oral cavity squamous cell cancers (OCSCC) is lacking. Material and methodsThis is a retrospective study of 78 consecutive OCSCC having ipsilateral recurrence recorded over five years. We screened 1658 OCSCC patients and selected those patients who underwent CND as part of treatment for ipsilateral recurrence. ResultsThe median disease-free interval was 32 months. Incidence of contralateral nodal metastasis (CNM) in recurrent OCSCC was 23.1% and of which 14% were occult. The factor significantly influencing CNM was the depth of invasion (DOI) > 10 mm (p < 0.01). In our study, imaging had suboptimal PPV (33%) while it had high NPV (88%) in diagnosing nodal metastasis in recurrent OCSCC. ConclusionDOI is the most important factor predicting CNM in case of ipsilateral primary recurrence. PET-CECT has a high NPV and contralateral neck should be addressed in case of tumours with higher DOI.

Unanswered Questions on the Optimal Extent of Tongue Cancer Resections.

Owing to the site- and stage-dependent molecular changes beyond the excised surgical margins of mucosal head and neck squamous cell cancers [HNSCC], an absolute cutoff for safe margins is difficult to define. Entrapment of the primary tumor in a specified compartment by a barrier clearance concept can circumvent this to a considerable extent, but it is not possible in all sites. A case of recurrent squamous cell cancer (SCC) of the tongue which had undergone wide excision of the lesion twice and later required a total laryngectomy because of crossover of the recurrent disease to the preepiglottic space and thereby to the glottis-supraglottic region is presented as an example to illustrate this predicament.

Radiomic response evaluation of recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC) patients receiving pembrolizumab on KEYNOTE-012 study.

6545 Background: Immunotherapy has become a standard of care in the treatment of R/M HNSCC, however only a subset of patients respond, highlighting the need for predictive and prognostic biomarkers. Radiomics is a non-invasive method to quantitatively analyze tumors through conventional imaging. Methods: The pre-treatment and first-on-treatment (after 8 weeks) computed tomography (CT) scans from 132 R/M HNSCC patients treated with single-agent Pembrolizumab (10mg/kg Q2W or 200mg Q3W IV) on the KEYNOTE-012 study were analyzed. Identified target lesions, per RECIST 1.1, were manually contoured, and radiomic features from the tumor and peritumoral region (3 mm expansion of the tumor) were extracted using PyRadiomics. All combinations of image filters and feature classes, not including shape descriptors of peritumoral region, were extracted. Feature space dimensionality was reduced by clustering features (hierarchical clustering using Pearson-based distance and complete linkage) and selecting the medoid of each cluster. Correlation with lesion-level response (LLR) at first-on-treatment CT and overall response (OR) was evaluated using concordance index (CI) with Benjamini-Hochberg multiple testing correction. Results: A total of 406 lesions were included (45 head &amp; neck (HN), 207 lung, 57 liver, 86 lymph nodes (LN), 11 other). 3562 features were extracted from pre-treatment scans (2246 tumor, 1316 peritumor). Considering all lesion sites collectively, 27 of 110 feature clusters were significantly correlated with LLR (false discovery rate (FDR) &lt; 0.05) but not with best overall RECIST response per patient on study. However, when grouped by organ, a number of feature cluster medoids were significantly associated (FDR &lt; 0.05) with LLR (HN: 1, lung: 28, liver: 8, LN: 1) and OR (liver: 18). Feature clusters predictive of LLR and OR included descriptors of both tumor-specific and tumor/peritumoral gray-level intensity and texture (e.g. 74% tumor and 26% peritumoral features in clusters significantly associated with OR in liver). Conclusions: Tumor and peritumoral radiomic features at baseline correlate with LLR and OR to immunotherapy in R/M HNSCC. Despite significant heterogeneity in lesion site, both global and site-specific significant feature clusters could be identified.