Long term trends at a comprehensive cancer center during the COVID-19 pandemic.

BACKGROUND: As the ongoing public health crisis from Coronavirus Disease 2019 (COVID-19) pandemic puts strains on current models of cancer care, many health care centers had to adapt to minimize the risk of exposure and infection. The effects of the COVID-19 pandemic in a comprehensive cancer center were determined. AIMS: To measure the impact of the COVID-19 pandemic on care delivery at a comprehensive cancer center. METHODS: The number of on-site and telehealth visits (TH) were obtained from scheduling software. Multiple factors including total visits, telehealth visits, screenings for cancer diagnosis, and cancer treatments were tracked from 2 years before the pandemic onset through 2022. The length of stay (LOS) and Case Mix Index (CMI) were calculated using hospital database. RESULTS: In the third quarter of FY 2020, telehealth visits (TH) represented a fifth of total patient encounters. Cancer treatments, such as chemotherapy, radiation therapy, and surgery, decreased during the pandemic with number of surgeries being most affected (23% decrease in 2020 compared to the previous fiscal year). The average length of stay (LOS) was also longer with less discharges per given time during the pandemic. The increased LOS was related to increased severity of patient illnesses since CMI was higher. Screening mammograms decreased to a nadir of 58% in 2021 as compared to those screened in pre-pandemic fiscal years. CONCLUSION: The COVID-19 pandemic impacted many aspects of care, such as treatment and screenings. Many of these factors had to be postponed due to the fear of acquiring COVID-19 and access to care. The findings presented implicate that the delays and changes in cancer care during the pandemic resulted in less screening and treatment of more advanced disease.

Telemedicine trends at a comprehensive cancer center during the first wave of the COVID-19 pandemic.

INTRODUCTION: This article reports on the effects of an early outbreak during the COVID-19 pandemic on visit volume and telehealth use by various specialists at a comprehensive cancer center. MATERIALS AND METHODS: The number of on-site and telehealth visits (THV) for medical and surgical specialties were obtained from scheduling software. RESULTS: Total visits were most drastically limited in April 2020 to a low point of 3139; THV made up 28% of all visits. For head and neck surgery, THV made up 54% and 30% of visits in April and May, respectively. Other specialties, such as psychiatry and palliative care, had higher levels of THV. For most specialties, the rebound in June through September did not make up for visits lost during the outbreak, and fiscal year  (FY) 2020 had a 9% loss from FY 2019 with 5786 fewer total annual visits across all specialties. CONCLUSIONS: While telemedicine was a helpful part of this cancer center's response to the initial COVID-19 surge, it was not able to replace the in-person services offered at the same center. The main strategy of physicians at this cancer center was to defer care, with telemedicine being an auxiliary response.

Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma.

A paucity of advances in the development of novel therapeutic agents for squamous cell carcinomas of the head and neck, oral cavity (OSCC) and oropharynx, has stagnated disease free survival rates over the past two decades. Although immunotherapies targeted against checkpoint inhibitors such as PD-1 or CTLA-4 are just now entering the clinic for late stage disease with regularity the median improvement in overall survival is only about three months. There is an urgent unmet clinical need to identify new therapies that can be used alone or in combination with current approaches to increase survival by more than a few months. Activation of the apoptotic arm of the unfolded response (UPR) with small molecules and natural products has recently been demonstrated to be a productive approach in pre-clinical models of OSCC and several other cancers. The aim of current study was to perform a high throughput screen (HTS) with a diverse chemical library to identify compounds that could induce CHOP, a component of the apoptotic arm of the UPR. Disulfiram (DSF, also known as Antabuse) the well-known aversion therapy used to treat chronic alcoholism emerged as a hit that could generate reactive oxygen species, activate the UPR and apoptosis and reduce proliferation in OSCC cell cultures and xenografts. A panel of murine embryonic fibroblasts null for key UPR intermediates (e.g., Chop and Atf4) was resistant to DSF suggesting that an intact UPR is a key element of the mechanism regulating the antiproliferative effects of DSF.

Targeting the unfolded protein response in head and neck and oral cavity cancers.

Many FDA-approved anti-cancer therapies, targeted toward a wide array of molecular targets and signaling networks, have been demonstrated to activate the unfolded protein response (UPR). Despite a critical role for UPR signaling in the apoptotic execution of cancer cells by many of these compounds, the authors are currently unaware of any instance whereby a cancer drug was developed with the UPR as the intended target. With the essential role of the UPR as a driving force in the genesis and maintenance of the malignant phenotype, a great number of pre-clinical studies have surged into the medical literature describing the ability of dozens of compounds to induce UPR signaling in a myriad of cancer models. The focus of the current work is to review the literature and explore the role of the UPR as a mediator of chemotherapy-induced cell death in squamous cell carcinomas of the head and neck (HNSCC) and oral cavity (OCSCC), with an emphasis on preclinical studies.

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

Recent trends in oropharyngeal cancer funding and public interest.

OBJECTIVES/HYPOTHESIS: The incidence of oropharyngeal cancer (OPC) has increased in the United States. This has been driven by an increase in human papillomavirus (HPV)-positive OPC. Our objective is to determine trends in National Institutes (NIH)-supported research funding and public interest in OPC. METHODS: The NIH Research Portfolio Online Reporting Tools database was evaluated for projects related to OPC between 2004 and 2015. Projects were evaluated for total funding, relation to HPV, principal investigator departmental affiliation and degree, and NIH agency or center responsible for grant. The Google Trends database was evaluated for relative Internet search popularity of oropharyngeal cancer and related search terms between 2004 and 2015. RESULTS: In terms of NIH funding, 100 OPC-related projects representing 242 grant years and $108.5 million were funded between 2004 and 2015. Total NIH funding for OPC projects increased from $167,406 in 2004 to $16.2 million in 2015. Funding for HPV-related OPC increased from less than $2 million yearly between 2004 and 2010 up to $12.7 million in 2015. Principal investigators related to radiation oncology ($41.8 million) and with doctor of medicine degrees ($52.8 million) received the largest share of total funding. Relative Internet search popularity for oropharyngeal cancer has increased from 2004 to 2015 compared to control cancer search terms. CONCLUSION: Increased public interest and NIH funding has paralleled the rising incidence of OPC. NIH funding has been driven by projects related to the role of HPV in OPC. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:1345-1350, 2017.

Tumor Differentiation as a Prognostic Factor for Major Salivary Gland Malignancies.

Objective The effect of tumor differentiation on prognosis of major salivary gland malignancies is controversial. The aim of this study was to determine the effect of tumor differentiation on prognosis by stage in patients with major salivary gland malignancies and to analyze which patient factors are associated with tumor differentiation. Study Design and Setting Cross-sectional analysis of Surveillance, Epidemiology, and End Results (SEER) database. Subjects and Methods In total, 9810 patients who had a major salivary gland malignancy from 2004 to 2012 were identified using the SEER database. Patients with no staging information or no information on histologic differentiation were excluded. A total of 5366 patients were included in the study. For analysis, patients were categorized by American Joint Committee on Cancer (AJCC) stage and subdivided by tumor differentiation. Multivariate analysis was used to analyze the impact of tumor differentiation on survival, tumor location (parotid, submandibular, sublingual), and sex within each AJCC stage of disease. Results Data analysis demonstrated a significant difference in histologic differentiation by stage, with P < .0001. Within stages II, III, and IV, tumor differentiation was significantly associated with a decrease in survival. There was no significant difference in tumor differentiation between the parotid and submandibular gland. Conclusion For patients with stage II, III, and IV disease, tumor differentiation was an independent predictor of survival. This information can be useful when discussing prognosis and can potentially influence management of disease.

Head and Neck Cancer.

Despite a considerable expansion in our therapeutic repertoire for management of other malignancies, mortality from head and neck cancer (HNC) has not significantly improved in recent decades. Upon normalizing National Institutes of Health-awarded R01 and R01-equivalent grants by incidence, thyroid cancer ($214) and HNC ($1329) received the fewest funding dollars. Upon adjusting funding totals by mortality, HNC was 7th out of 9 cancers evaluated ($6138). These findings highlight HNC as an underfunded disease versus other cancers. As data detailing grant applications (including unsuccessful grants) are not publicly available, it is not clear if these disparities stem from fewer applications or fewer opportunities. Our hope is that this commentary will spur further investigation into strategies to increase HNC inquiry and funding for trainees as well as early-stage and established investigators.

Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis.

Oral squamous cell carcinoma (OSCC) is the most common cancer affecting the oral cavity, and US clinics will register about 30,000 new patients in 2015. Current treatment modalities include chemotherapy, surgery, and radiotherapy, which often result in astonishing disfigurement. Cancers of the head and neck display enhanced levels of glucose-regulated proteins and translation initiation factors associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Previous work demonstrated that chemically enforced UPR could overwhelm these adaptive features and selectively kill malignant cells. The threonyl-tRNA synthetase (ThRS) inhibitor borrelidin and two congeners were discovered in a cell-based chemical genomic screen. Borrelidin increased XBP1 splicing and led to accumulation of phosphorylated eIF2α and UPR-associated genes, prior to death in panel of OSCC cells. Murine embryonic fibroblasts (MEFs) null for GCN2 and PERK were less able to accumulate UPR markers and were resistant to borrelidin. This study demonstrates that UPR induction is a feature of ThRS inhibition and adds to a growing body of literature suggesting ThRS inhibitors might selectively target cancer cells.

Transoral robotic surgery for treatment of obstructive sleep apnea: factors predicting surgical response.

OBJECTIVES/HYPOTHESIS: We reviewed our experience with the use of transoral robotic surgery (TORS) for base of tongue (BOT) reduction either alone or as part of multilevel strategy in the treatment of obstructive sleep apnea/hypopnea syndrome (OSAHS) in order to identify clinical characteristics that may be associated with surgical response. STUDY DESIGN: Case series. METHODS: Between June 2010 and May 2014, BOT reduction via TORS ± partial epiglottectomy ± uvulopalatopharyngoplasty were performed on 72 patients with OSAHS. Thirty-nine patients (15 females and 24 males) with complete preoperative and postoperative clinical information including polysomnograms were included in this study. RESULTS: Mean apnea-hypopnea index (AHI) was 43.9 ± 32.3 preoperatively and 21.9 ± 23.5 postoperatively and reflected a statistically significant (P < 0.001) AHI reduction of 50.9% ± 38.1%. Statistical significant reduction in daytime somnolence, as measured by Epworth Sleepiness Scale (15.6 ± 5.4 preoperatively vs. 5.7 ± 4.3 postoperatively; P < 0.001), was also achieved. No statistical significant difference was found between preoperative and postoperative body mass index (BMI) (32.9 ± 7.0 vs. 32.4 ± 7.3; P = 0.270). Surgical response, as defined by > 50% reduction in AHI and final AHI < 15 with resolution of daytime somnolence, was achieved in 21 patients (53.8%). Clinical characteristics found to be significantly different between the responders and nonresponders were BMI, AHI, and lateral velopharyngeal collapse. Patients with BMI < 30, AHI < 60, or absence of lateral velopharyngeal collapse have excellent surgical response rate of 88.2%, 67.9%, or 66.7%, respectively. CONCLUSIONS: We identified three clinical characteristics associated with increased surgical response rate. This finding may be useful for patient selection and counseling prior to surgery.

Risk stratification based on thyroid cytology: can we rely on national data?

PURPOSE: Determine correlation of malignancy rates between fine needle aspiration (FNA) biopsy and surgical specimen in an urban academic environment. METHODS: Retrospective review at an academic medical center of fine needle aspiration biopsies and surgical specimens in a head and neck otolaryngology practice between 2000 and 2012. RESULTS: Of the 74 biopsies diagnosed as follicular lesion, 34 (45.9%) were malignant. Of the 45 biopsies diagnosed as follicular neoplasm, 22 (48.9%) were malignant. These results are significantly higher than the average risk of malignancy cited by the American Thyroid Association of 5%-10% and 20%-30% for follicular lesions and neoplasms respectively. CONCLUSIONS: The rate of malignancy based on a FNA diagnosis of indeterminate cytology (follicular lesion or follicular neoplasm) can vary greatly among different institutions. Thyroid surgeons should be aware of their local pathology practices to better guide therapy and counsel patients.

Serum prognostic biomarkers in head and neck cancer patients.

OBJECTIVES/HYPOTHESIS: A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Prospective cohort study. METHODS: A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient's serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. RESULTS: Poor overall survival was associated with African Americans (hazard ratio [HR] for death = 2.61; 95% confidence interval [CI]: 1.58-4.33; P = .000), advanced stage (HR = 2.79; 95% CI: 1.40-5.57; P = .004), and recurrent disease (HR = 6.66; 95% CI: 2.54-17.44; P = .000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. CONCLUSIONS: The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted.

Transoral robotic surgery for treatment of obstructive sleep apnea-hypopnea syndrome.

OBJECTIVES/HYPOTHESIS: To evaluate the efficacy of base of tongue (BOT) resection via transoral robotic surgery (TORS) in the treatment of obstructive sleep apnea/hypopnea syndrome (OSAHS). STUDY DESIGN: Case series METHODS: Between June 2010 and May 2012, BOT resection via TORS was performed on 27 patients with OSAHS. Patients were excluded from this analysis if other concomitant upper airway procedures such as uvulopalatopharyngoplasty were performed, or if postoperative polysomnograms were not available. RESULTS: Twelve patients who underwent BOT resection alone were included in this study. The median age for these 12 patients was 48.5 (range, 19-64) and included nine females and three males. The mean apnea-hypopnea index (AHI) was 43.9 ± 41.1 preoperatively and 17.6 ± 16.2 postoperatively. This difference in AHI was statistically significant (P = 0.007) and reflected an average AHI reduction of 56.2 ± 28.3%. Statistical significant reductions in daytime somnolence level, as measured by Epworth Sleepiness Scale (13.7 ± 5.2 preoperatively vs. 6.4 ± 4.5 postoperatively, P <0.001), and snoring intensity, as reported by a bed partner using a Visual Analogue Scale (8.6 ± 1.2 preoperatively vs. 4.2 ± 1.9 postoperatively, P <0.001), were achieved. There was no statistical significant difference between the preoperative and postoperative body mass index (34.5 ± 7.3 vs. 33.5 ± 6.7, P = 0.296) or minimum oxygen saturation (83.3 ± 5.5% vs. 84.0 ± 6.4%, P = 0.680). CONCLUSIONS: This is the first study looking at the use of TORS to address obstruction at the level of BOT only, not confounded by surgical alterations at other levels of upper airway. This preliminary result on the use of BOT resection via TORS for the treatment of patients with OSAHS is encouraging and warrants further investigations.

Single-incision transaxillary robotic thyroidectomy: challenges and limitations in a North American population.

OBJECTIVE: We reviewed our initial experience with robotic thy-roidectomy to identify challenges and limitations of this new surgical approach when applied to a North American population. STUDY DESIGN: Case series. SETTING: Academic institution. SUBJECTS/METHODS: Retrospective review of 18 consecutive robotic thyroid lobectomies performed from February 2010 to April 2012 involving 16 female patients. Two patients underwent robot-assisted completion thyroidectomy a few months following the initial thyroid surgery, one for cancer and the other for goiter. RESULTS: Median age was 47.5 years (range, 18-62 years), and median body mass index was 28.7 (range, 19.4-44.5). Median thyroid nodule size was 2.9 cm (range, 1.1-4.7 cm). All but 1 case (6%) was performed successfully via single axillary incision. There was no conversion to an open approach. Median operative time was 170 minutes (range, 95-220 minutes), and median blood loss was 12.5 mL (range, 5-75 mL). Complications occurred in 4 cases (22%) to include temporary vocal cord pareses (n = 3) and a postoperative hematoma that required exploration. Median hospital stay was 2 days (range, 1-3 days). CONCLUSION: Single-incision transaxillary robotic thyroidectomy can be technically challenging in North American patients with a larger body frame due to difficulty in optimal placement of all 4 robotic instruments via a single axillary incision. All 3 cases of temporary vocal cord paresis occurred early in our experience and may have been due to our relative inexperience with this new approach and associated instrumentation. Other limitations include less than optimal visualization of the recurrent laryngeal nerve in the contralateral lobe as well as poor access to the substernal region. LEVEL OF EVIDENCE: 4.

Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.

BACKGROUND: The appropriate management of the neck in patients with regionally advanced head and neck cancer remains controversial. The purpose of this study was to retrospectively analyze our institutional experience with up-front neck dissection followed by definitive chemoradiotherapy. METHODS: Fifty-five patients with radiographic evidence of large or necrotic lymph nodes underwent up-front neck dissection followed by definitive chemoradiation. RESULTS: The 5-year overall survival (OS) and progression-free survival (PFS) rates were estimated at 71.3% and 64.7%, respectively. There were 2 failures in the dissected neck, for a control rate of 96.7%. There were 7 locoregional failures and 12 distant failures, for locoregional and distant control rates of 87.3% and 78.2%, respectively. CONCLUSION: Up-front neck dissection followed by chemoradiotherapy resulted in excellent locoregional control, OS, and PFS. Utilization of this strategy should be considered in carefully selected patients with regionally advanced head and neck cancer. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.

Site involvement as a predictor of airway intervention in angioedema.

OBJECTIVES/HYPOTHESIS: To look for a relationship between which sites are involved in angioedema and the need for airway intervention (intubation, tracheotomy). STUDY DESIGN: Retrospective chart review. METHODS: Charts of 140 patients who were admitted to two hospitals at an academic medical center between July 1, 2006 and June 30, 2008 with the diagnosis of angioedema were reviewed. Charts were reviewed for pertinent data, including demographics, sites of involvement along the upper airway, medical therapy, and airway intervention. Subsites included lips, anterior tongue, floor of mouth, soft palate, base of tongue (BOT), and larynx. RESULTS: The BOT was involved in 19 patients and the larynx was involved in 29 patients. Airway intervention was required in 21 patients (16%). Patients with laryngeal and/or BOT involvement required intervention in 38% of cases (vs. 7% in patients without involvement). Patients with more than three sites involved had a 39% rate of intervention, compared with only 12% in patients with less than three sites involved. Among those patients with laryngeal/BOT involvement, 56% with more than three sites involved required intervention, as compared to 30% of patients with less than three sites involved. CONCLUSIONS: Site of involvement was found to correlate with airway intervention. Involvement of anterior tongue, BOT, and larynx significantly increased the likelihood of intubation or tracheostomy, as did involvement of multiple sites. Thorough evaluation, including fiberoptic laryngoscopy, can aid in determining which patients require airway intervention.

XRP6258-induced gene expression patterns in head and neck cancer carcinoma.

OBJECTIVES/HYPOTHESIS: XRP6258 is a novel taxoid, which has antitumor activity in preclinical mouse orthotopic and human xenograft cancer models. However, limited XRP6258 studies have been performed in head and neck squamous cell carcinoma cells (HNSCC). The objective of this study is to identify the antitumor activity of XRP6258 in HNSCC cell line models. METHODS: HNSCC cells (HN30 and HN12) were exposed to either XRP6258 or docetaxel. XRP6258-induced growth suppression, cell cycle arrest and apoptosis were measured. Further, XRP6258-induced expression patterns of selected genes were compared to docetaxel-induced expression patterns using Western blot analysis. RESULTS: XRP6258 suppressed proliferation and induced G(2)M arrest and apoptosis in both of the cell lines tested. XRP6258 and docetaxel produced similar alteration in the expression of cell cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and EGFR were decreased in both XRP6258 and docetaxel-treated HNSCC cells. Finally, XRP6258 induced a greater level of bcl2 phosphorylation than docetaxel in HN12 cell line. CONCLUSIONS: XRP6258 appeared to have a similar mechanism of action as docetaxel in the two HNSCC cell lines studied. XRP6258 induced cell cycle arrest, growth suppression, and apoptosis by altering gene expression patterns similar to that induced by docetaxel. These preclinical experiments suggest that XRP6258 may be useful in treating HNSCC, and the aforementioned genes can potentially be used as surrogate endpoint biomarkers.

Intratumoral delivery of docetaxel enhances antitumor activity of Ad-p53 in murine head and neck cancer xenograft model.

PURPOSE: The aim of this study is to determine the ability of intratumorally delivered docetaxel to enhance the antitumor activity of adenovirus-mediated delivery of p53 (Ad-p53) in murine head and neck cancer xenograft model. MATERIALS AND METHODS: A xenograft head and neck squamous cell carcinoma mouse model was used. Mice were randomized into 4 groups of 6 mice receiving 6 weeks of biweekly intratumoral injection of (a) diluent, (b) Ad-p53 (1 x 10(10) viral particles per injection), (c) docetaxel (1 mg/kg per injection), and (d) combination of Ad-p53 (1 x 10(10) viral particles per injection) and docetaxel (1 mg/kg per injection). Tumor size, weight, toxicity, and overall and disease-free survival rates were determined. RESULTS: Intratumoral treatments with either docetaxel alone or Ad-p53 alone resulted in statistically significant antitumor activity and improved survival compared with control group. Furthermore, combined delivery of Ad-p53 and docetaxel resulted in a statistically significant reduction in tumor weight when compared to treatment with either Ad-p53 or docetaxel alone. CONCLUSION: Intratumoral delivery of docetaxel enhanced the antitumor effect of Ad-p53 in murine head and neck cancer xenograft model. The result of this preclinical in vivo study is promising and supports further clinical testing to evaluate efficacy of combined intratumoral docetaxel and Ad-p53 in treatment of head and neck cancer.

A phase 2 trial of surgery with perioperative INGN 201 (Ad5CMV-p53) gene therapy followed by chemoradiotherapy for advanced, resectable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx: report of the Southwest Oncology Group.

OBJECTIVE: To assess the feasibility of treating patients with high-risk stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx with perioperative adenovirus-p53 (INGN 201) gene therapy along with surgery and chemoradiotherapy. DESIGN AND SETTING: A phase 2 study in a multi-institutional setting within the Southwest Oncology Group. PATIENTS: Thirteen individuals who met the following entry criteria: newly diagnosed, previously untreated squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; selected stage III or IV disease without distant metastases; and surgically resectable disease. INTERVENTIONS: Surgery, perioperative INGN 201 gene therapy, and postoperative chemoradiotherapy. MAIN OUTCOME MEASURES: Overall patient status, tumor status, adverse effects, accrual rate, and percentage of patients successfully receiving the required doses of INGN 201. RESULTS: All 13 patients received surgery and perioperative INGN 201 injections in the primary tumor bed and the ipsilateral neck. In addition, 3 patients received injections in the contralateral neck. Three patients did not receive chemoradiotherapy. One patient had a grade 2 fistula of the oral cavity. Of the 10 patients with evaluable data, 2 experienced grade 4 adverse events, 1 owing to hypokalemia, hyponatremia, vomiting, leukopenia, and neutropenia and 1 owing to increased aspartate aminotransferase and alanine aminotransferase levels. Seven other patients experienced grade 3 adverse events. The estimate of 1-year progression-free survival is 92%. CONCLUSIONS: This trial demonstrated the feasibility of handling and delivering a very complex gene vector safely in multiple cooperative group institutions without significant incident. Intraoperative INGN 201 gene therapy is technically feasible, but it has many logistical problems when performed in a multi-institutional setting. Regulatory requirements might have hindered accrual in this multi-institutional setting. Disease control seems to be promising; however, no definitive conclusion can be made with this small sample size. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00017173.