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Objectives: To investigate the prognostic impact of primary tumor-specific growth rate (TSGR) on treatment outcomes after definitive radiation therapy (RT) for nonoropharyngeal squamous cell carcinoma (non-OPSCC)., Methods: The diagnostic tumor and nodal volumes of 39 non-OPSCC patients were contoured and compared to corresponding RT planning scan volumes to determine TSGR. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were evaluated according to the Kaplan-Meier method; and hazard ratios (HR) were estimated using Cox regression. Based on the 75th percentile TSGR of 2.18%, we stratified patients into a high TSGR group (≥ 2.18% per day) and low TSGR group (< 2.18% per day)., Results: The median follow-up was 22 months (range: 1-86 months) and median time between diagnostic and simulation computed tomography scans was 22 days (range: 7-170 days). Median RT dose was 70 Gy (range: 60-79.2 Gy). Based on the 75th percentile TSGR, OS at median follow-up was 50.0% for the high TSGR group compared to 92.5% for the low TSGR group (HR [95% confidence interval (CI)] = 2.12[1.16-11.42], P = 0.018). There was a trend toward worse DFS at median follow-up for the high versus low TSGR groups, at 55.6% and 82.3%, respectively (HR [95% CI] = 2.29[0.82-6.38], P = 0.103)., Conclusion: Our study contributes to growing literature on TSGR as a temporal biomarker in patients with non-OPSCC. Patients with high TSGR ≥2.18% per day have significantly worse OS compared to those with TSGR below this threshold. Efforts to address treatment initiation delays may benefit patients with particularly aggressive and rapidly growing tumors., Level of Evidence: 4 Laryngoscope, 130:2378-2384, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

We conducted a retrospective study to determine the incidence and treatment outcomes of neck metastases in patients with squamous cell carcinoma (SCC) of the hard palate and/or maxillary alveolus after surgical excision of the primary tumor. We also sought to identify any risk factors for recurrence. Our study population was made up of 20 patients-9 men and 11 women, aged 46 to 88 years (mean: 72.6)-who had undergone excision of an SCC of the hard palate and/or maxillary alveolus at a tertiary care cancer center over a 7-year period. Half of all patients were former tobacco users. Of the 20 tumors, 10 involved the maxillary alveolus, 4 involved the hard palate, and 6 involved both sites. Three patients were clinically categorized as T1, 9 as T2, 6 as T3, and 2 as T4; pathologically, 8 tumors were categorized as T4a. In addition to maxillectomy, a neck dissection was performed in 7 patients-4 therapeutically and 3 electively. Eight of 20 patients experienced a recurrence: 4 local, 6 regional, and 2 distant (several patients had a recurrence at more than one site). Univariate analysis identified perineural invasion (p = 0.04) as a statistically significant risk factor for recurrence. Of 14 patients with a clinicopathologically negative neck, 5 (36%) developed a cervical recurrence, and 4 of them died of their disease. An advanced stage (T4 vs.

Background: Dysphagia-related symptoms in patients with head and neck cancer are common before treatment. We hypothesized greater self-reported baseline dysphagia would predict gastrostomy placement during primary radiation., Methods: Swallowing-specific/general surveys (SwalQOL/EuroQOL) collected prospectively before definitive radiation were analyzed for associations with gastrostomy placement. Prophylactic gastrostomy was recommended at the discretion of a multidisciplinary team blinded to the surveys., Results: Of 84 patients in the cohort, 42 patients (50%) received feeding tubes. Eleven patients (13%) who underwent prophylactic feeding tube placement reported the greatest pretreatment dysphagia, whereas those who avoided gastrostomies reported the least. Prophylactic gastrostomy was more strongly associated with patient-reported measures than other clinical criteria. Controlling for stage IV, T3 to T4 classification, smoking, chemotherapy, and pretreatment weight loss, baseline dysphagia remained an independent predictor of feeding tube placement (odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.05-0.55; p = .01). Patients without gastrostomies during treatment avoided persistent gastrostomy dependence., Conclusion: Baseline dysphagia-related symptoms before radiation are independent predictors of gastrostomy placement. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1318-E1324, 2016., (© 2015 Wiley Periodicals, Inc.)

Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1.

Background: The purpose of this study was to report associations between p16 status, clinicopathologic characteristics, and outcomes for head and neck squamous cell carcinoma of unknown primary (CUP)., Methods: Specimens of squamous cell CUP were reanalyzed. Human papillomavirus (HPV) status was determined by p16 stain. A tissue microarray (TMA) was constructed to evaluate biomarkers potentially prognostic in head and neck squamous cell carcinoma (HNSCC)., Results: A majority of the population (n = 26; 74%) was p16 positive (+). Prognostic factors benefiting survival were p16+ status (p < .0001), absence of macroscopic extracapsular extension (ECE; p = .004), younger age (p = .01), and higher grade (p = 0.007). The prognostic implication of worse overall survival (OS) with macroscopic ECE (p = .009) remained significant when limited to patients who were p16+ (p = .002). Exploratory TMA between unknown primary and controls suggested a biomolecular difference between squamous cell CUP and known-primary cancer., Conclusion: The majority of patients with squamous cell CUP were p16+, indicative of HPV association. P16 staining and ECE seem to be the most prognostic features in squamous cell CUP., (© 2014 Wiley Periodicals, Inc.)

Background: Psychosocial functioning is associated with vascular endothelial growth factor (VEGF) in various patient populations. This study examined whether psychosocial functioning in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor VEGF expression, a protein that stimulates angiogenesis and is associated with poor prognosis., Methods: Forty-two newly diagnosed patients completed assessments of psychosocial functioning (ie, depressive symptoms, perceived stress, anxiety, social support) before surgery. Tumor samples were obtained for VEGF analysis and human papillomavirus (HPV)-typing., Results: Poorer psychosocial functioning was associated with greater VEGF expression controlling for disease stage (odds ratio [OR], 4.55; 95% confidence interval [CI], 1.72-12.0; p < .01). When examined by HPV status, the association between psychosocial functioning and VEGF remained significant among patients who were HPV negative (OR, 5.50; 95% CI, 1.68-17.3; p < .01), but not among patients who were HPV positive., Conclusion: These findings inform our understanding of the biobehavioral pathways that may contribute to poor outcomes in non-HPV-associated HNSCCs., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: Multimodality treatment of squamous cell carcinoma of the head and neck (SCCHN) often involves radiotherapy and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined excision repair cross-complementing group 1 (ERCC1) expression in human papillomavirus (HPV)-negative SCCHN treated with surgery [± adjuvant radiotherapy/chemoradiation (CRT)]., Experimental Design: We assessed ERCC1 protein expression in archival tumors using immunofluorescence staining and automatic quantitative analysis (AQUA) with three antibodies to ERCC1 (8F1, FL297, and HPA029773). Analysis with Classification and Regression Tree (CART) methods ascertained the cutoff points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T, and N stage. Kaplan-Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed., Results: ERCC1 low/high groups were defined on the basis of AQUA analysis with 8F1/2009, FL297, and HPA029773. Among patients treated with surgery plus adjuvant radiotherapy/CRT, longer median survival was observed in ERCC1-low versus ERCC1-high tumors (64 vs. 29 months; P = 0.02; HPA029773). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody., Conclusions: Using AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low-ERCC1 tumors from patients treated with surgery and adjuvant radiotherapy., (©2013 AACR.)

Purpose: This is a retrospective analysis of the impact of moderate dysplasia at the resection margin for early stage cancer of the oral tongue., Materials and Methods: Patients with T1-2N0 oral tongue cancer treated with surgery alone at Fox Chase Cancer Center (FCCC) from 1990 to 2010 were reviewed. Tumor and margin characteristics were abstracted from the pathology report. Overall survival (OS), disease-free survival (DFS) and local control (LC) were calculated using the Kaplan Meier method. Predictors of LC, OS and DFS were analyzed., Results: 126 Patients met the inclusion criteria. Dysplasia was present at the final margin in 36% of the cases (severe: 9%, moderate: 15%, mild: 12%). Median follow-up was 52 months. 3 and 5-year actuarial LC for the entire cohort was 77% and 73%, respectively. Actuarial 5-year LC and DFS were significantly worse for patients with moderate or severe dysplasia at the margin vs. none or mild dysplasia at the margin (49% vs 82%, p=0.005 and 49% vs 80%, p=0.008, respectively); 3-year comparisons were not significant. When analyzed separately, the detrimental local effect of moderate dysplasia at the margin persisted (p=0.02) and the effect of severe dysplasia at the margin was approaching significance (p=0.1). Mild dysplasia at the margin did not significantly impair LC or DFS. Multivariate analysis demonstrated worse LC (HR: 2.99, p=0.006) and DFS (HR: 2.84, p=0.008) associated with severe or moderate dysplasia at the margin., Conclusions: Both severe and moderate dysplasia at the margin appear to be correlated with inferior LC and DFS. Additional therapy may be justified, despite added morbidity., (Copyright © 2013. Published by Elsevier Ltd.)

We report the case of a 77-year-old non-smoker and non-drinker with a solid-organ transplant who had malignant transformation of respiratory papillomatosis 3 years after the initial diagnosis of this benign lesion. This is the first case reported in the literature of malignant transformation of respiratory papillomatosis in a solid-organ transplant patient. Virus-associated cutaneous cancers occur more frequently and aggressively in solid-organ transplant patients. There may be a higher rate of malignant transformation of respiratory papillomatosis in immunosuppressed patients, as this is a virus-associated disease. Closer observation, airway evaluation with laryngoscopy and tracheobronchoscopy, and interval biopsies of immunosuppressed patients with respiratory papillomatosis is recommended.

Background: The purpose of this study was to determine whether the incidence of bilateral neck disease tonsillar cancer is rising., Methods: We reviewed tonsillar cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute., Results: The annual incidence of advanced neck disease (≥N2) with small primary tonsillar cancer is increasing (annual percent change [APC]; p < .05) during 2 evaluable time frames (1988-2003 and 2004-2008). The increase for small primary tonsillar cancer from 2004 to 2008 is associated with increased ipsilateral disease (ie, T1-2N2a-b, APC 10.6%; p < .05) rather than bilateral neck disease (T1-2N2c, APC 5.9%, APC = NS). The increase in bilateral neck disease is less than the overall rise in T1 to 2 tonsillar cancer (APC 7.2%; p < .05)., Conclusion: In the human papillomavirus (HPV) era, bilateral neck disease is increasingly common. This seems to be a consequence of the increasing incidence of tonsillar cancer rather than a new biologic behavior., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To determine differences in clinical outcomes using intensity-modulated radiotherapy (IMRT) or a standard low neck field (LNF) to treat low neck., Methods and Materials: This is a retrospective, single-institution study. Ninety-one patients with squamous cell carcinoma of the head and neck were treated with curative intent. According to physician preference, some patients were treated with LNF (Planning Target Volume 3) field using a single anterior photon field matched to the IMRT field. Field junctions were not feathered. The endpoints were time to failure and use of a percutaneous endoscopic gastrostomy (PEG) tube (as a surrogate of laryngeal edema causing aspiration), and analysis was done with χ(2) and log-rank tests., Results: Median follow-up was 21 months (range, 2-89 months). Median age was 60 years. Thirty-seven patients (41%) were treated with LNF, 84% were Stage III or IV. A PEG tube was required in 30%, as opposed to 33% without the use of LNF. Node 2 or 3 neck disease was treated more commonly without LNF (38% vs. 24%, p = 0.009). Failures occurred in 12 patients (13%). Only 1 patient treated with LNF failed regionally, 4.5 cm above the match line. The 3-year disease-free survival rate was 87% and 79% with LNF and without LNF, respectively (p = 0.2), and the 3-year LR failure rate was 4% and 21%, respectively (p = 0.04)., Conclusions: Using LNF to treat the low neck did not increase the risk of regional failure "in early T and early N diseases" or decrease PEG tube requirements., (Published by Elsevier Inc.)

Purpose: To determine the pattern of failures following intensity modulated radiation therapy for head and neck cancer., Material and Methods: A retrospective single institution study. Between May 2001 and June 2008, 176 patients with head and neck cancer were treated with intensity modulated radiation therapy at Fox Chase Cancer Center. Ninety-five (54%) were squamous cell carcinoma treated with curative intent. Tumor and nodal stage, tobacco history, definitive versus postoperative therapy (PORT), addition of chemotherapy and RT duration were analyzed for association with patterns of failure. In patients treated with definitive radiation, high-risk PTV (PTV1) was prescribed to 70 Gy and low-risk PTV (PTV2) to 56 Gy. In the PORT setting, PTV1 was prescribed to 60 to 66 Gy and PTV2 to 54 Gy. Patterns of failure were assessed. Local failure (LF) was defined as the persistence of disease or recurrence within PTV1, marginal failure as recurrence at the region of high-dose falloff, and regional failure as nodal recurrence within PTV2., Results: Median follow-up was 20 months (range: 1-117). Median age was 60 years (range: 28-88), with 80% smokers and 81% stage III or IV. PORT was given to 29% and 71% were treated definitively, with concurrent Cisplatin used in the majority. Three-year local and locoregional (LR) failure rates were 9% and 16%, respectively. Failures occurred in 14 patients: 8 local, 3 regional, 1 LR, and 2 distant. Five of the 8 LF and all 3 marginal failures were observed in PORT cohort. On univariate analysis, the only predictor of LF was the use of PORT (P = 0.06). LR control was 66% for PORT versus 87%, 97% for definitive RT and chemoRT., Conclusions: Local, regional failures were more common following PORT related to an increased risk of marginal failures.

Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC)., Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinib started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days., Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis., Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The impact of posttreatment neck dissection on prolonged feeding tube dependence in patients with head and neck squamous cell cancer (HNSCC) treated with primary radiation or chemoradiation remains unknown., Methods: We conducted a retrospective cohort study using propensity score adjustment to investigate the effect of neck dissection on prolonged feeding tube dependence., Results: A review of 67 patients with node-positive HNSCC (T1-4N1-3), treated with primary radiation or chemoradiation, with no evidence of tumor recurrence and follow-up of at least 24 months, was performed. Following adjustment for covariates, the relative risk (RR) of feeding tube dependence at 18 months was significantly increased in patients treated with posttreatment neck dissection (RR 4.74, 95% confidence interval [CI] 2.07-10.89). At 24 months, the relative risk of feeding tube dependence in the patients having undergone neck dissection increased further (RR 7.66, 95% CI 2.07-10.89). Of patients with feeding tubes 2 years after completing treatment, 75% remained feeding tube dependent., Conclusion: Neck dissection may contribute to chronic oropharyngeal dysphagia in HNSCC patients treated with primary radiation or chemoradiation.

Background: For patients with head and neck cancer who were treated using primary radiotherapeutic approaches, the pattern of pathologic residual carcinoma in the neck dissection specimen and its effect on clinical outcome remains unknown., Methods: Medical records of 65 patients who underwent 71 neck dissections a median 7 weeks after radiotherapy were reviewed. Median follow-up was 33 months., Results: Residual cancer, identified in 28 patients (43%), diminished locoregional control (p = .018), recurrence-free (p = .018), and overall survival (p = .02). Thirteen patients (20%) had 2 or more pathologically involved lymph nodes. Nine (13%) involved level V. Four (6%) had pathologic involvement of nodal levels not clinically involved by cancer before treatment. In N2-3 patients with positive pathologic specimens, the presence of these factors diminished recurrence-free survival (p = .01). The outcome of patients with pathologic carcinoma but without such ominous factors approached those with negative pathology., Conclusions: For patients with residual carcinoma in the neck following radiation, the pattern of residual disease is an effective predictor of recurrence.

Head and neck cancers are relatively less common tumors, but with complex anatomic and physiologic relationships to the structures from which they arise. Multimodal management is required for advanced stage disease, while single modality treatment is usually sufficient for early lesions. Treatment paradigms have shifted toward more functional preservation of speech and swallowing, when possible. Increased use of radiation, systemic/targeted therapies and function-preserving surgical approaches have allowed for organ preservation without compromising oncologic outcomes in properly selected patients.

The addition of chemotherapy to radiation in the treatment of advanced-staged head and neck cancer has improved local-regional control and increased complete clinical and pathologic response rates in the neck. However, for those patients with residual neck disease on a posttreatment computed tomography (CT) scan, there remains significant controversy as to how to further assess the neck for the presence of a viable tumor and when to perform a neck dissection. Recently, investigators from Australia have assembled level I evidence to support the use of positron-emission tomography (PET) scanning to assess treatment response and have shown a very high negative predictive value for patients with a negative PET at 12 weeks after the completion of therapy. These data support the practice of observing PET-negative necks and intervening with neck dissection in PET-positive necks. However, not all investigators, practitioners, and patients are comfortable with delaying intervention for such a long time interval after treatment. The authors favor assessment of the neck with a CT scan at 6 weeks after the completion of chemoradiotherapy and recommend neck dissection for patients with radiographic residual disease at this time point. One rationale is that 6 weeks is an optimal window for operative intervention after acute treatment effects have subsided and before extensive fibrosis and scarring, which translates to less morbidity for the patient who is treated surgically. Another rationale is that those who develop regional recurrence can be hard to salvage surgically, and waiting an additional 6 weeks could allow for the expansion of resistant clones. The significance of this is unclear, however, because patients with residual disease are at a higher risk for local and distant as well as regional failure. Thus, further prospective studies of the role of postchemoradiotherapy PET scanning and neck dissection are needed.

Purpose: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting., Experimental Design: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux., Results: EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells., Conclusions: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.

Purpose: The use of retinoids to prevent and/or treat cancers, including head and neck squamous cell carcinoma (HNSCC), has been limited by the development of resistance and unwanted side effects. Receptor-selective retinoids are potentially less toxic than nonselective compounds. The present investigation was undertaken to determine the mechanism of responsiveness to an retinoic acid receptor-selective retinoid (LGD1550) that has shown antitumor efficacy in a xenograft model of HNSCC., Experimental Design: A series of HNSCC cell lines were characterized with respect to proliferation and apoptosis after LGD1550 treatment. Relative responsiveness to LGD1550 was examined with respect to modulation of epidermal growth factor receptor (EGFR) signaling pathways., Results: Cells were either growth inhibited and underwent apoptosis or were resistant to treatment with this compound. Retinoids have been shown to decrease the gene transcription rates of transforming growth factor (TGF)-alpha and EGFR in HNSCC. LGD1550 responsiveness was accompanied by decreased expression of TGF-alpha, EGFR, and modulation of EGFR signaling pathways, including signal transducers and activators of transcriptions and mitogen-activated protein kinase. In contrast, EGFR autocrine signaling pathways were not altered in HNSCC cells that were resistant to the growth inhibitory effects of LGD1550., Conclusions: These results suggest that there is a correlation between the efficacy of receptor-selective retinoids and modulation of TGF-alpha/EGFR signaling in HNSCC. Therefore, alterations of these signaling pathways may serve as a biomarker of clinical response.

Background: Gastrin-releasing peptide receptor (GRPR)-mediated autocrine growth appears to be an early marker of susceptibility to tobacco-related lung cancers. Because expression of GRPR, however, has not been reported in squamous cell carcinoma of the head and neck (SCCHN), we investigated its expression and that of its ligand GRP in normal mucosa and SCCHN tissues and the involvement of these proteins in the proliferation of SCCHN cells., Methods: We assessed GRPR messenger RNA (mRNA) expression in specimens from 25 patients with SCCHN, six control noncancer patients, and 14 SCCHN cell lines by use of quantitative reverse transcriptase-polymerase chain reaction. We used neutralizing GRP monoclonal antibody 2A11 to block the GRP-GRPR interaction in SCCHN cell lines and xenografts and assessed the antibody's effect on proliferation by counting cultured cells or measuring xenograft tumor volume in vivo. All statistical tests were two-sided., Results: Tumor and mucosa tissues, respectively, from SCCHN patients expressed sixfold and fourfold higher levels of GRPR mRNA than normal mucosa tissue from noncancer patients (P<.001). The levels of GRPR expression in the tumor and adjacent normal epithelium of individual patients with SCCHN were correlated (r =.652; P =.001), suggesting that increased GRPR expression is an early event in SCCHN formation. SCCHN cells expressed fivefold higher levels of GRPR mRNA than did cultured normal mucosal epithelial cells (P =.005). GRP stimulated proliferation of SCCHN cells in a dose-dependent fashion (P =.006). Neutralizing GRP monoclonal antibody 2A11 inhibited SCCHN cell proliferation in vitro and in vivo. Median survival was 54 months in patients with higher levels of GRPR mRNA and was not reached in those with lower levels., Conclusions: GRP and GRPR appear to participate in an autocrine regulatory pathway in SCCHN. Thus, strategies that specifically target GRP and/or GRPR may be effective therapeutic approaches for this disease.