Phase III Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma of the Head and Neck

Purpose To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with gefitinib 250 or 500 mg/day or standard methotrexate. Patients and Methods Four hundred eighty-six patients with recurrent SCCHN were randomly assigned to oral gefitinib 250 mg/day, gefitinib 500 mg/day, or methotrexate 40 mg/m2 intravenously weekly. Primary end point was overall survival, secondary end points were objective response rate (ORR), safety, symptom improvement, and quality of life (QOL). Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers. Results Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate (hazard ratio [HR], 1.22; 95% CI, 0.95 to 1.57; P = .12; and HR, 1.12; 95% CI, 0.87 to 1.43; P = .39, respectively). In the gefitinib 250 mg/day, 500 mg/day, and methotrexate groups, respectively, median overall survival was 5.6, 6.0, and 6.7 months; ORRs (Response Evaluation Criteria in Solid Tumors) were 2.7%, 7.6% and 3.9%, with no statistically significant difference between either gefitinib arm and methotrexate. No unexpected adverse events were observed, except for tumor hemorrhage-type events with gefitinib (8.9%, gefitinib 250 mg/day; 11.4%, gefitinib 500 mg/day; 1.9%, methotrexate). QOL improvement rates (Functional Assessment of Cancer Therapy-Head & Neck total score) were 13.4%, 18.0%, and 6.0% for gefitinib 250 mg/day, 500 mg/day, and methotrexate, respectively. Conclusion In patients with recurrent or metastatic SCCHN, while responses with gefitinib were seen, neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate. With the exception of tumor hemorrhage–type events with gefitinib, the adverse event profiles were generally consistent with those previously observed.

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Phase III Randomized Trial of Cisplatin Plus Placebo Compared With Cisplatin Plus Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An Eastern Cooperative Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.4646 ◽

2005 ◽

Vol 23 (34) ◽

pp. 8646-8654 ◽

Cited By ~ 656

Author(s):

Barbara Burtness ◽

Meredith A. Goldwasser ◽

William Flood ◽

Bassam Mattar ◽

Arlene A. Forastiere

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Response Rate ◽

Hazard Ratio ◽

Phase Iii ◽

End Points ◽

Metastatic Squamous Cell Carcinoma

Purpose Therapy of recurrent/metastatic squamous cell carcinoma of the head and neck results in median progression-free survival (PFS) of 2 months. These cancers are rich in epidermal growth factor receptor (EGFR). We wished to determine whether the addition of cetuximab, which inhibits activation of EGFR, would improve PFS. Patients and Methods Patients with recurrent/metastatic squamous cell carcinoma of the head and neck were randomly assigned to receive cisplatin every 4 weeks, with weekly cetuximab (arm A) or placebo (arm B). Tumor tissue was assayed for EGFR expression by immunohistochemistry. The primary end point was PFS. Secondary end points of interest were response rate, toxicity, overall survival, and correlation of EGFR with clinical end points. Results There were 117 analyzable patients enrolled. Median PFS was 2.7 months for arm B and 4.2 months for arm A. The hazard ratio for progression of arm A to arm B was 0.78 (95% CI, 0.54 to 1.12). Median overall survival was 8.0 months for arm B and 9.2 months for arm A (P = .21). The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26% for arm A and 10% for arm B (P = .03). Enhancement of response was greater for patients with EGFR staining present in less than 80% of cells. Conclusion Addition of cetuximab to cisplatin significantly improves response rate. There was a survival advantage for the development of rash. Progression-free and overall survival were not significantly improved by the addition of cetuximab in this study.

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Expression of the Extracellular Sulfatase SULF2 Affects Survival of Head and Neck Squamous Cell Carcinoma Patients

Frontiers in Oncology ◽

10.3389/fonc.2020.582827 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Yang ◽

Jaeil Ahn ◽

Rekha Raghunathan ◽

Bhaskar V. Kallakury ◽

Bruce Davidson ◽

...

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Hpv Infection ◽

Neck Squamous Cell Carcinoma ◽

Therapeutic Interventions ◽

Tumor Tissues ◽

Significant Difference

Sulfation of heparan sulfate proteoglycans (HSPG) regulates signaling of growth factor receptors via specific interactions with the sulfate groups. 6-O-Sulfation of HSPG is an impactful modification regulated by the activities of dedicated extracellular endosulfatases. Specifically, extracellular sulfatase Sulf-2 (SULF2) removes 6-O-sulfate from HS chains, modulates affinity of carrier HSPG to their ligands, and thereby influences activity of the downstream signaling pathway. In this study, we explored the effect of SULF2 expression on HSPG sulfation and its relationship to clinical outcomes of patients with head and neck squamous cell carcinoma (HNSCC). We found a significant overexpression of SULF2 in HNSCC tumor tissues which differs by tumor location and etiology. Expression of SULF2 mRNA in tumors associated with human papillomavirus (HPV) infection was two-fold lower than in tumors associated with a history of tobacco and alcohol consumption. High SULF2 mRNA expression is significantly correlated with poor progression-free interval and overall survival of patients (n = 499). Among all HS-related enzymes, SULF2 expression had the highest hazard ratio in overall survival after adjusting for clinical characteristics. SULF2 protein expression (n = 124), determined by immunohistochemical analysis, showed a similar trend. The content of 6-O-sulfated HSPG, measured by staining with the HS3A8 antibody, was higher in adjacent mucosa compared to tumor tissue but revealed no difference based on SULF2 staining. LC-MS/MS analysis showed low abundance of N-sulfation and O-sulfation in HS but no significant difference between SULF2-positive and SULF2-negative tumors. Levels of enzymes modifying 6-O-sulfation, measured by RT-qPCR in HNSCC tumor tissues, suggest that HSPG sulfation is carried out by the co-regulated activities of multiple genes. Imbalance of the HS modifying enzymes in HNSCC tumors modifies the overall sulfation pattern, but the alteration of 6-O-sulfate is likely non-uniform and occurs in specific domains of the HS chains. These findings demonstrate that SULF2 expression correlates with survival of HNSCC patients and could potentially serve as a prognostic factor or target of therapeutic interventions.

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Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.77.0941 ◽

2018 ◽

Vol 36 (13) ◽

pp. 1275-1283 ◽

Cited By ~ 49

Author(s):

Sandro Virgilio Porceddu ◽

Mathias Bressel ◽

Michael Geoffrey Poulsen ◽

Adam Stoneley ◽

Michael John Veness ◽

...

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Postoperative Radiotherapy ◽

Cutaneous Squamous Cell Carcinoma ◽

Phase Iii ◽

Disease Free

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

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Evaluation of the Relationship between Age and Outcome after Microvascular Reconstruction among Patients with Recurrent Head and Neck Squamous Cell Carcinoma

Journal of Reconstructive Microsurgery ◽

10.1055/s-0037-1598621 ◽

2017 ◽

Vol 33 (05) ◽

pp. 336-342 ◽

Cited By ~ 1

Author(s):

Viraj Patel ◽

Carrie Stern ◽

Amar Miglani ◽

Katie Weichman ◽

Juan Lin ◽

...

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Microvascular Reconstruction ◽

Complication Rates ◽

Term Survival ◽

Significant Difference

Background In patients with head and neck squamous cell carcinoma (HNSCC), disease recurrence remains a significant obstacle to long-term survival. If possible, surgical salvage with reconstruction remains the best treatment option for patients with recurrence. Currently, there is no literature discussing whether age should preclude microvascular reconstruction in these patients. We hypothesize that older age alone does not affect outcomes. Methods A retrospective chart review of patients with HNSCC at our institution between 2008 and 2015 was performed. Patients were included if they underwent simultaneous resection and flap reconstruction for recurrent HNSCC. Data collected included age, sex, primary site, type of reconstruction, previous treatments, postoperative complications (systemic and reconstructive), and overall survival. Results A total of 65 patients met inclusion criteria for the review: 42 (64.6%) patients ≤70 years and 23 (35.4%) patients > 70 years. Overall survival was not significantly different between the younger and older groups (p = 0.199). Five-year survival was 60.1% in the younger group and 46.8% in the older group. No significant difference was found in reconstructive complication rates (p = 0.179) or systemic complication rates (p = 0.241) between the two groups. Multivariate logistic regression analysis further showed no significant association between patients' age (≤70 years or > 70 years) and reconstructive complications (p = 0.396) or systemic complications (p = 0.119). Conclusion Age is not significantly associated with complications among patients undergoing resection and reconstruction for recurrent HNSCC. Microvascular reconstruction remains a feasible option in older patients with recurrent HNSCC. Advanced age alone should not preclude the surgical management of recurrent HNSCC.

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Effectiveness of PD-L1 inhibitors in metastatic or recurrent squamous cell carcinoma of head and neck: An observational, indirect comparison.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18503 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18503-e18503

Author(s):

Michel Bila ◽

Paul M. Clement ◽

Jeroen Van Dessel

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cox Regression ◽

Indirect Comparison ◽

Beneficial Effects ◽

Significant Difference ◽

The Mean

e18503 Background: The prognosis for recurrent or metastatic Squamous Cell Carcinoma of Head and Neck (HNSCC) remains dismal and its treatment poses a challenge for oncologists. Agents against programmed cell death ligand 1 (PD-L1) have shown beneficial effects on overall survival (OS) for HNSCC. The aim of the present study was to compare differential effects of PD-L1 inhibitors on recurrent and metastatic HNSCC. Methods: In an indirect comparison of patients with recurrent HNSCC were matched to patients with metastatic HNSCC. All patients were treated with PD-L1 inhibitors at the general medical oncology department of UZ Leuven. Kaplan-Meier methods and Cox regression models were used to calculate the overall survival. Results: From December 2013 to July 2019, 68 patients with metastatic and 59 with recurrent HNSCC were enrolled and evaluable. A significant difference in OS was found between recurrent and metastatic groups (p < 0.02). The mean OS was 7.6 months (95% CI: 2.4-11.3 months) for the recurrent group, while in the metastatic group the mean OS was 13.7 months (95% CI: 5.7-16 months). Conclusions: As a second-line therapy, PD-L1 inhibitors were associated with longer overall survival in metastatic compared to recurrent HNSCC.

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Bioinformatics analysis of DNMT1 expression and its role in head and neck squamous cell carcinoma prognosis

Scientific Reports ◽

10.1038/s41598-021-81971-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jili Cui ◽

Lian Zheng ◽

Yuanyuan Zhang ◽

Miaomiao Xue

Keyword(s):

Gene Expression ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Immune Cell ◽

Neck Squamous Cell Carcinoma ◽

Hub Genes ◽

Significant Difference ◽

Dnmt1 Expression

AbstractHead and neck squamous cell carcinoma (HNSCC) is the sixth most common type of malignancy in the world. DNA cytosine-5-methyltransferase 1 (DNMT1) play key roles in carcinogenesis and regulation of the immune micro-environment, but the gene expression and the role of DNMT1 in HNSCC is unknown. In this study, we utilized online tools and databases for pan-cancer and HNSCC analysis of DNMT1 expression and its association with clinical cancer characteristics. We also identified genes that positively and negatively correlated with DNMT1 expression and identified eight hub genes based on protein–protein interaction (PPI) network analysis. Enrichment analyses were performed to explore the biological functions related with of DNMT1. The Tumor Immune Estimation Resource (TIMER) database was performed to explore the relationship between DNMT1 expression and immune-cell infiltration. We demonstrated that DNMT1 gene expression was upregulated in HNSCC and associated with poor prognosis. Based on analysis of the eight hub genes, we determined that DNMT1 may be involved in cell cycle, proliferation and metabolic related pathways. We also found that significant difference of B cells infiltration based on TP 53 mutation. These findings suggest that DNMT1 related epigenetic alterations have close relationship with HNSCC progression, and DNMT1 could be a novel diagnostic biomarker and a promising therapeutic target for HNSCC.

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659 AN SINGLE-ARM OPEN-LABEL PHASE II STUDY OF CAMRELIZUMAB PLUS APATINIB AS SECOND-LINE TREATMENT FOR ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Diseases of the Esophagus ◽

10.1093/dote/doab052.659 ◽

2021 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Feng Wang ◽

Qingxia Fan ◽

Junsheng Wang ◽

Tao Wu ◽

Yonggui Hong ◽

...

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Squamous Cell ◽

Objective Response ◽

Phase Iii ◽

Line Treatment ◽

Second Line

Abstract Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

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