Lisa Clemons

Safety and Tumor-specificity of Cetuximab-IRDye800 for Surgical Navigation in Head and Neck Cancer

Purpose: Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer. Experimental Design: A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology. Results: There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels. Conclusions: We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology. Clin Cancer Res; 21(16); 3658–66. ©2015 AACR.

Robot-Assisted Surgery for Upper Aerodigestive Tract Neoplasms

OBJECTIVES To assess the feasibility and safety of performing robot-assisted resections of head and neck tumors, and to predict which variables lead to successful robot-assisted resection and better functional outcome. DESIGN Prospective nonrandomized clinical trial. SETTING Academic tertiary referral center. PATIENTS Thirty-six patients with oral cavity, oropharyngeal, hypopharyngeal, or laryngeal tumors. INTERVENTION Robot-assisted resection of indicated tumors. MAIN OUTCOME MEASURES Ability to perform robot-assisted resection, final pathologic margin status, ability to extubate postoperatively, need for tracheotomy tube, and need for gastrostomy tube. Any clinically significant complications were recorded. RESULTS Thirty-six patients participated in the study. Eight patients had previously been treated for head and neck cancer. Twenty-nine patients (81%) underwent successful robotic resection. Negative margins were obtained in all 29 patients. Twenty-one of 29 patients were safely extubated prior to leaving the operating room. One patient required short-term tracheotomy tube placement. A total of 9 patients were gastrostomy tube dependent (2 preoperatively, 7 postoperatively). Factors associated with successful robotic resection were lower T classification (P = .01) and edentulism (P = .07). Factors associated with gastrostomy tube dependence were advanced age (P = .02), tumor location in the larynx (P < .001), higher T classification (P = .02), and lower preoperative M. D. Anderson Dysphagia Inventory score (P = .04). CONCLUSIONS Robot-assisted surgery is feasible and safe for the resection of select head and neck tumors. This clinical series demonstrates that robotic surgery can be utilized successfully in patients with T1 to T4 lesions located in the oral cavity, oropharynx, hypopharynx, and larynx with good preservation of swallow function.

Robotic-Assisted Surgery for Primary or Recurrent Oropharyngeal Carcinoma

OBJECTIVE To determine the feasibility of robotic-assisted salvage surgery for oropharyngeal cancer. DESIGN Retrospective case-controlled study. SETTING Academic, tertiary referral center. PATIENTS Patients who underwent surgical resection for T1 and T2 oropharyngeal cancer between 2001 and 2008 were classified into the following 3 groups based on type of resection: (1) robotic-assisted surgery for primary neoplasms (robotic primary) (n = 15), (2) robotic-assisted salvage surgery for recurrent disease (robotic salvage) (n = 7), and (3) open salvage resection for recurrent disease (n = 14). MAIN OUTCOME MEASURES Data regarding tumor subsite, stage, and prior treatment were evaluated as well as margin status, nodal disease, length of hospital stay, diet, and tracheotomy tube dependence. RESULTS The median length of stay in the open salvage group was longer (8.2 days) than robotic salvage (5.0 days) (P = .14) and robotic primary (1.5 days) resection groups (P < .001). There was no difference in postoperative diet between robotic primary and robotic salvage surgery groups. However, a greater proportion of patients who underwent open salvage procedures were gastrostomy tube dependent 6 months following treatment (43%) compared with robotic salvage resection (0%) (P = .06). A greater proportion of patients who underwent open salvage procedures also remained tracheotomy tube dependent after 6 months (7%) compared with robotic salvage or robotic primary patients (0%) (P = .48). No complications were reported in the robotic salvage group. Two patients who underwent open salvage resection developed postoperative hematomas and 2 developed wound infections. CONCLUSION When feasible, robotic-assisted surgery is an acceptable procedure for resection of both primary and recurrent oropharyngeal tumors. Trial Registration clinicaltrials.gov Identifier: NCT00473564.

Management of the N0 neck in recurrent laryngeal squamous cell carcinoma

To evaluate the utility of neck dissections in patients undergoing salvage laryngectomy with a clinically negative neck.

Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma.

PURPOSE To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma. METHODS AND MATERIALS This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method. RESULTS The majority of patients were male (87%) and presented with T4 disease (93%). The most common toxicity attributed to erlotinib was a grade 2-3 dermatologic reaction occurring in 100% of the patients, followed by mucositis (87%). Diarrhea occurred in 20% of the patients. The 2-year recurrence rate was 26.7%, and mean time to cancer recurrence was 10.5 months. Two-year overall survival was 65%, and disease-free survival was 60%. CONCLUSIONS Erlotinib and radiation therapy had an acceptable toxicity profile in patients with advanced cutaneous squamous cell carcinoma. The disease-free survival in this cohort was comparable to that in historical controls.

Assessment of tissue autofluorescence and reflectance for oral cavity cancer screening.

Objective. Although approved by the US Food and Drug Administration for clinical use, the utility of handheld tissue reflectance and autofluorescence devices for screening head and neck cancer patients is poorly defined. There is limited published evidence regarding the efficacy of these devices. The authors investigated the sensitivity and specificity of these modalities compared with standard examination. Study Design. Prospective, cross-sectional analysis. Setting. Tertiary care medical center. Subjects and Methods. Patients who were treated previously for head and neck cancer (n = 88) between 2009 and 2010 were included. Patients were screened using white light visualization (standard of care) and compared with tissue reflectance and autofluorescence visualization. Screening results were compared with biopsy or long-term follow-up. Results. Autofluorescence visualization had a specificity of 81% and a sensitivity of 50% for detecting oral cavity cancer, whereas white light visualization had a specificity of 98% and a sensitivity of 50%. Tissue reflectance visualization had low sensitivity (0%) and good specificity (86%). The power of this study was insufficient to compare the positive and negative predictive values of standard white light examination (50% and 98%, respectively) to tissue autofluorescence (11% and 97%) or reflectance (0% and 95%). In addition, stratification by previous radiation therapy found no statistically significant difference in screening results. Conclusion. Standard clinical lighting has a higher specificity than tissue reflectance and autofluorescence visualization for detection of disease in patients with a history of head and neck cancer. This study does not support the added costs associated with these devices.

Anti-EMMPRIN antibody treatment of head and neck squamous cell carcinoma in an ex-vivo model

Targeting the molecular pathways associated with carcinogenesis remains the greatest opportunity to reduce treatment-related morbidity and mortality. Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a cell surface molecule known to promote tumor growth and angiogenesis in preclinical studies of head and neck carcinoma making it an excellent therapeutic target. To evaluate the feasibility of anti-EMMPRIN therapy, an ex-vivo human head and neck cancer model was established using specimens obtained at the time of surgery (n=22). Tumor slices were exposed to varying concentrations of anti-EMMPRIN monoclonal antibody and cetuximab for comparison purposes. Cetuximab is the only monoclonal antibody currently approved for the treatment of head and neck carcinoma. After treatment, tumor slices were assessed by immunohistochemistry and western blot analysis for apoptosis (TUNEL) and EMMPRIN expression. Of the tumor specimens 33% showed a significant reduction in mean ATP levels after treatment with cetuximab compared with untreated controls, whereas 58% of the patients responded to anti-EMMPRIN therapy (P<0.05). Samples, which showed reactivity to anti-EMMPRIN, also had greater EMMPRIN expression based on immunohistochemistry staining (49%) when compared with nonresponders (25%, P=0.06). In addition, TUNEL analysis showed a larger number of cells undergoing apoptosis in antibody-treated tumor slices (77%) compared with controls (30%, P<0.001) with activation of apoptotic proteins, caspase 3 and caspase 8. This study shows the potential of anti-EMMPRIN to inhibit proliferation and promote apoptosis and suggests its future role in the targeted treatment of head and neck carcinoma.

Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors

BACKGROUND The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation. PATIENTS AND METHODS A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to evaluate safety and efficacy of an intratumoral injection of adenoviral vector expressing E. coli PNP in combination with intravenous fludarabine for the treatment of solid tumors. The study was designed with escalating doses of fludarabine in the first three cohorts (15, 45, and 75 mg/m(2)) and escalating virus in the fourth (10(11)-10(12) viral particles, VP). RESULTS All 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients in cohorts 3 and 4 achieving significant tumor regression compared with 0 responsive subjects in cohorts 1 and 2. The overall adverse event rate was not dose-dependent. Most common adverse events included pain at the viral injection site (92%), drainage/itching/burning (50%), fatigue (50%), and fever/chills/influenza-like symptoms (42%). Analysis of serum confirmed the lack of systemic exposure to fluoroadenine. Antibody response to adenovirus was detected in two patients, suggesting that neutralizing immune response is not a barrier to efficacy. CONCLUSIONS This first-in-human clinical trial found that localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective. The pronounced effect on tumor volume after a single treatment cycle suggests that phase II studies are warranted. CLINICALTRIALSGOV IDENTIFIER NCT01310179.

Outcomes after surgical salvage for recurrent oropharyngeal squamous cell carcinoma.

OBJECTIVE Compare human papillomavirus (HPV) status and outcomes in patients undergoing salvage surgical resection for a recurrent oropharyngeal squamous cell carcinoma (OPSCC). METHODS Case series with chart review (2005-2013). RESULTS Sixty-nine patients were identified who underwent salvage surgical resection for a recurrent OPSCC after primary radiation therapy. There was no difference in the incidence of HPV negative (52%; n=36) and HPV positive (48%; n=33) tumors. The mean time from completion of radiation therapy to salvage surgery was 2.4years. At the time of salvage operation, there was no correlation with HPV status, as assessed by p16 immunohistochemistry, and lymph node metastases (p=0.21), T classification (p=0.22), tracheostomy dependence (p=0.59), gastrostomy tube dependence (p=0.82), or duration from radiation therapy (p=0.63). The majority of patients were either current or former tobacco users (75%) and of the HPV positive patients, 66% were tobacco users. Development of a new recurrence after salvage surgical resection occurred in 33% of patients (n=26), with a higher incidence in patients with HPV negative disease (52%, n=17/33; p=0.05). The overall 2- and 5-year survival rates were 0.47 and 0.23. There was no difference in overall survival rates when stratified by HPV status or tobacco use. Decreased overall 5-year survival rates did correlate with cervical lymph node metastases (p=0.01), advanced tumor stage (p=0.04) and dependence on gastrostomy tube postoperatively (p=0.04). CONCLUSIONS This study found cervical lymph node metastases, clinical stage, and dependence on gastrostomy tube for nutrition to have the greatest impact on overall survival for patients with recurrent OPSCC.

Porcine small intestine submucosal grafts improve remucosalization and progenitor cell recruitment to sites of upper airway tissue remodeling: Upper airway wound healing through donor site grafting

To better understand upper airway tissue regeneration, the exposed cartilage and bone at donor sites of tissue flaps may serve as in vivo “Petri dishes” for active wound healing. The pedicled nasoseptal flap (NSF) for skull‐base reconstruction creates an exposed donor site within the nasal airway. The objective of this study is to evaluate whether grafting the donor site with a sinonasal repair cover graft is effective in promoting wound healing.