Athanassios Argiris

Head and neck cancer

Most head and neck cancers are squamous cell carcinomas that develop in the upper aerodigestive epithelium after exposure to carcinogens such as tobacco and alcohol. Human papillomavirus has also been strongly implicated as a causative agent in a subset of these cancers. The complex anatomy and vital physiological role of the tumour-involved structures dictate that the goals of treatment are not only to improve survival outcomes but also to preserve organ function. Major improvements have been accomplished in surgical techniques and radiotherapy delivery. Moreover, systemic therapy including chemotherapy and molecularly targeted agents--namely, the epidermal growth factor receptor inhibitors--has been successfully integrated into potentially curative treatment of locally advanced squamous-cell carcinoma of the head and neck. In deciding which treatment strategy would be suitable for an individual patient, important considerations include expected functional outcomes, ability to tolerate treatment, and comorbid illnesses. The collaboration of many specialties is the key for optimum assessment and decision making. We review the epidemiology, molecular pathogenesis, diagnosis and staging, and the latest multimodal management of squamous cell carcinoma of the head and neck.

Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies

Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non–dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non–small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. Conclusions: Both schedules of vorinostat (400 mg oral qd × 14 days or 300 mg bd × 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL × min) and paclitaxel (200 mg/m2). Encouraging anticancer activity was noted in patients with previously untreated non–small cell lung cancer.

Stereotactic Body Radiotherapy for Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of a Phase I Dose-Escalation Trial

PURPOSE To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) in previously irradiated patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS In this Phase I dose-escalation clinical trial, 25 patients were treated in five dose tiers up to 44 Gy, administered in 5 fractions over a 2-week course. Response was assessed according to the Response Evaluation Criteria in Solid Tumors and [(18)F]-fluorodeoxyglucose standardized uptake value change on positron emission tomography-computed tomography (PET-CT). RESULTS No Grade 3/4 or dose-limiting toxicities occurred. Four patients had Grade 1/2 acute toxicities. Four objective responses were observed, for a response rate of 17% (95% confidence interval 2%-33%). The maximum duration of response was 4 months. Twelve patients had stable disease. Median time to disease progression was 4 months, and median overall survival was 6 months. Self-reported quality of life was not significantly affected by treatment. Fluorodeoxyglucose PET was a more sensitive early-measure response to treatment than CT volume changes. CONCLUSION Reirradiation up to 44 Gy using SBRT is well tolerated in the acute setting and warrants further evaluation in combination with conventional and targeted therapies.

The Impact of Health Insurance Status on the Survival of Patients With Head and Neck Cancer

In 2006, it was estimated that 47 million people in the United States are without insurance. Studies have shown that patients who are uninsured or are insured by Medicaid are more likely to present with more advanced cancer. The objective of this study was to examine whether cancer recurrence and mortality of patients diagnosed with squamous cell carcinoma of the head and neck are associated with insurance status, after adjusting for known cancer risk factors. The main outcome measures were overall survival and relapse‐free survival.

Induction Docetaxel, Cisplatin, and Cetuximab Followed by Concurrent Radiotherapy, Cisplatin, and Cetuximab and Maintenance Cetuximab in Patients With Locally Advanced Head and Neck Cancer

PURPOSE We incorporated cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), into the induction therapy and subsequent chemoradiotherapy of head and neck cancer (HNC). PATIENTS AND METHODS Patients with locally advanced HNC, including squamous and undifferentiated histologies, were treated with docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and cetuximab 250 mg/m2 days 1, 8, and 15 (after an initial loading dose of 400 mg/m2), termed TPE, repeated every 21 days for three cycles, followed by radiotherapy with concurrent cisplatin 30 mg/m2 and cetuximab weekly (XPE), and maintenance cetuximab for 6 months. Quality of life (QOL) was assessed using Functional Assessment of Cancer Therapy-Head and Neck. In situ hybridization (ISH) for human papillomavirus (HPV), immunohistochemistry for p16, and fluorescence ISH for EGFR gene copy number were performed on tissue microarrays. RESULTS Of 39 enrolled patients, 36 had stage IV disease and 23 an oropharyngeal primary. Acute toxicities during TPE included neutropenic fever (10%) and during XPE, grade 3 or 4 oral mucositis (54%) and hypomagnesemia (39%). With a median follow-up of 36 months, 3-year progression-free survival and overall survival were 70% and 74%, respectively. Eight patients progressed in locoregional sites, three in distant, and one in both. HPV positivity was not associated with treatment efficacy. No progression-free patient remained G-tube dependent. The H&N subscale QOL scores showed a significant decrement at 3 months after XPE, which normalized at 1 year. CONCLUSION This cetuximab-containing regimen resulted in excellent long-term survival and safety, and warrants further evaluation in both HPV-positive and -negative HNC.

Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial

PURPOSE We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing. RESULTS Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response. CONCLUSION The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.

Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples

Myeloid-derived suppressor cells (MDSC) present in the human peripheral blood, represent a heterogeneous population of cells with monocytic and granulocytic features. To provide guidelines for reliable assessments of the frequency and function of MDSC, we compared fresh vs. cryopreserved peripheral blood mononuclear cell (PBMC) samples obtained from normal controls and patients with cancer. PBMC were obtained from 4 healthy donors and 21 patients with cancer. They were stained with labeled antibodies, and the frequency of DR⁻/LIN⁻/CD11b+, DR⁻/LIN⁻/CD15+, DR⁻/LIN⁻/CD33+ and DR(-/low)/CD14+ cells was determined by flow cytometry before and after cryopreservation. CFSE-based suppressor assays were used to test inhibitory functions of MDSC. Arginase I expression and reactive oxygen species (ROS) upregulation in MDSC subsets were evaluated by flow cytometry. The DR(-/low)/CD14+ and DR⁻/LIN⁻/CD11b+ subsets of MDSC were found to be more resistant to the cryopreservation/thawing procedure compared to the DR⁻/LIN⁻/CD15+ and DR⁻/LIN⁻/CD33+ subsets. The frequency of the latter two MDSC subsets was significantly reduced after cryopreservation. All but DR⁻/LIN⁻/CD15+ cells inhibited proliferation of autologous CSFE-labeled CD4+ cells but lost suppressor activity after cryopreservation. Only DR⁻/LIN-/CD15+ cells were positive for Arginase I, but lost its expression after cryopreservation. Only fresh DR⁻/LIN⁻/CD11b+ and DR⁻/LIN⁻/CD15+ cells produced ROS after in vitro stimulation. Studies of human MDSC should be performed in fresh blood samples. If samples have to be cryopreserved, monitoring of CD11b+ and CD14+ MDSC subsets provides the most reliable results. Arginase I expression or stimulated ROS production assessed by flow cytometry are useful markers for MDSC subsets only in fresh samples.

Deferring Planned Neck Dissection Following Chemoradiation for Stage IV Head and Neck Cancer: The Utility of PET-CT†

Objective: To determine whether combined positron emission tomography and computed tomography (PET‐CT) may be of value in deferring planned neck dissections for patients with advanced head and neck squamous cell carcinoma (HNSCC).

Phase II Study of Everolimus (RAD001) in Previously Treated Small Cell Lung Cancer

Purpose: Mammalian target of rapamycin (mTOR) is a promising target in small cell lung cancer (SCLC). We designed a phase II study of everolimus, an mTOR inhibitor, in previously treated, relapsed SCLC. Experimental Design: Patients were treated with everolimus 10 mg orally daily until disease progression. The primary endpoint was disease control rate (DCR) at 6 weeks. PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue. Results: A total of 40 patients were treated: 23 had 1 prior regimen/sensitive relapse, 4 had 1 prior regimen/refractory, and 13 had 2 prior regimens. Twenty-eight patients received 2 or more cycles of everolimus, 7 received 1 cycle, and 5 did not complete the first cycle. Best response in 35 evaluable patients: 1 (3%) partial response (in sensitive relapse), 8 (23%) stable disease, and 26 (74%) progression; DCR at 6 weeks was 26% (95% CI = 11–40). Median survival was 6.7 months and median time to progression was 1.3 months. Grade 3 toxicities included thrombocytopenia (n = 2), neutropenia (n = 2), infection (n = 2), pneumonitis (n = 1), fatigue (n = 1), elevated transaminases (n = 1), diarrhea (n = 2), and acute renal failure (n = 1). High phosphorylated AKT expression was modestly associated with overall survival (HR = 2.07; 95% CI = 0.97–4.43). Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression (P = 0.0093). Conclusions: Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC. Further evaluation in combination regimens for patients with sensitive relapse may be considered. Clin Cancer Res; 16(23); 5900–7. ©2010 AACR.

CTLA-4+ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis

The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype, and activation status of Treg and natural killer (NK) cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated patients with HNSCC enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4(+)FOXP3(+) intratumoral Treg expressing CTLA-4, CD39, and TGFβ. These Treg suppressed cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4(+)FOXP3(+) Treg in vitro, in part, by inducing dendritic cell maturation, in combination with TGFβ and T-cell receptor triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4(+) Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote antitumor immunity.