Advanced Head And Neck Cancer Research Articles

An approach to identify, from DCE MRI, significant subvolumes of tumors related to outcomes in advanced head‐and‐neck cancera)

To develop and investigate a method to identify, from dynamic contrast enhanced (DCE) MRI, significant subvolumes of tumors related to treatment outcomes. A method, called global-initiated regularized local fuzzy clustering, was proposed to identify subvolumes of head-and-neck cancers (HNC) from heterogeneous distributions of tumor blood volume (BV) and blood flow (BF) for assessment of therapy response. BV and BF images, derived from DCE MRI, of 14 patients with advanced HNC were obtained before treatment and 2 weeks after the start of 7-week chemoradiation therapy (chemo-RT). The delineated subvolumes of tumors with low BV or BF before and during treatment were evaluated for their associations with local failure (LF). Receiver operating characteristic (ROC) analysis was used to assess performance of the method for prediction of local failure of HNC. The sizes of the subvolumes of primary tumors with low BV, delineated by our method before and week 2 during treatment, were significantly greater in the patients with LF than with local control (LC) (p = 0.02 for pre-RT and 0.01 for week 2). While the total primary tumor volumes were reduced from baseline to week 2 during therapy to a similar extent for both the patients with LF and LC, the percentage decreases in the subvolumes of the primary tumors with low BV in the same time interval were significantly smaller for the patients with LF than those with LC (p < 0.05). ROC analysis shows that for any given sensitivity, the subvolume of the tumor with low BV week 2 during treatment has greater specificity for prediction of local failure than the pretreatment total tumor volume, the percentage change in the tumor volume week 2 during treatment, or the change in the averaged BV values of the entire tumor week 2 during therapy. We developed a method to identify the significant subvolumes of primary tumors related to local failure. Large poorly perfused subvolumes of primary or nodal HNC before treatment and persisting during the early course of chemo-RT have the potential for prediction of local or regional failure, and could be candidates for local dose intensification.

Evaluation of the trade-offs encountered in planning and treating locally advanced head and neck cancer: intensity-modulated radiation therapyvsdual-arc volumetric-modulated arc therapy

The primary purpose of this study was to assess the practical trade-offs between intensity-modulated radiation therapy (IMRT) and dual-arc volumetric-modulated arc therapy (DA-VMAT) for locally advanced head and neck cancer (HNC). For 15 locally advanced HNC data sets, nine-field step-and-shoot IMRT plans and two full-rotation DA-VMAT treatment plans were created in the Pinnacle(3) v. 9.0 (Philips Medical Systems, Fitchburg, WI) treatment planning environment and then delivered on a Clinac iX (Varian Medical Systems, Palo Alto, CA) to a cylindrical detector array. The treatment planning goals were organised into four groups based on their importance: (1) spinal cord, brainstem, optical structures; (2) planning target volumes; (3) parotids, mandible, larynx and brachial plexus; and (4) normal tissues. Compared with IMRT, DA-VMAT plans were of equal plan quality (p>0.05 for each group), able to be delivered in a shorter time (3.1 min vs 8.3 min, p<0.0001), delivered fewer monitor units (on average 28% fewer, p<0.0001) and produced similar delivery accuracy (p>0.05 at γ(2%/2mm) and γ(3%/3mm)). However, the VMAT plans took more planning time (28.9 min vs 7.7 min per cycle, p<0.0001) and required more data for a three-dimensional dose (20 times more, p<0.0001). Nine-field step-and-shoot IMRT and DA-VMAT are both capable of meeting the majority of planning goals for locally advanced HNC. The main trade-offs between the techniques are shorter treatment time for DA-VMAT but longer planning time and the additional resources required for implementation of a new technology. Based on this study, our clinic has incorporated DA-VMAT for locally advanced HNC. DA-VMAT is a suitable alternative to IMRT for locally advanced HNC.

Genomic profiling of a clinically annotated cohort of locoregionally advanced head and neck cancers (HNC) treated with definitive chemoradiotherapy.

5517 Background: Recent advances in genomic technology and sequencing have allowed the near comprehensive characterization of genetic abnormalities in HNC, but their correlation with clinical outcome remains to be determined. We analysed a clinically annotated cohort of locoregionally advanced HNC for copy number changes and mutations and correlated with outcome in an exploratory fashion. Methods: 120 head and neck cancers (frozen tissue) and matching normal tissues/blood from patients with locoregionally advanced HNC treated with definitive chemoradiation +/- induction at the University of Chicago were obtained from our tissue bank. DNA, RNA, protein were extracted. Barcoded, multiplexed sequencing libraries for 500 head and neck cancer associated genes (Agilent capture) were built and sequenced on Illumina HiSeq next generation sequencers. 150 commonly copy number altered and HNC relevant genes were analysed for copy number alterations (CNA) using the Nanostring nCounter platform. Respective genetic aberrations in curated pathways were allocated to tumor subgroups. Exploratory analysis correlated data with induction response and progression free survival. Confirmatory HPV testing was performed using an E6, nested, multiplex PCR. Results: ≥80% of targeted sequences were successfully captured and sequenced. Commonly mutated genes included: TP53, CDKN2A, PIK3CA, NOTCH1. Of note PIK3CA mutations were enriched in HPV(+) tumors. Commonly copy number altered genes included amplifications of VEGF1, CCND1, MYC, EGFR, MDM4, CTTN, as well as PIK3CA, and deletions of CDKN2A, SUCLG2, FHIT, TGFBR2, PTPRD, IKBKG, TRAF6, and RASSF1. CCND1, and MYC were commonly co-amplified and correlated with poor progression free survival, representing a distinct HNC phenotype. Analysis for additional genes and influence on induction response will be presented. Conclusions: Targeted, medium throughput genomic profiling is feasible, and provides the majority of HNC specific genetic aberrations at a comparably low cost. Impact on outcome (CCND1/MYC amplification) and potential treatment targets (PIK3CA mutations in HPV(+) tumors) were identified.

P16 and cyclin D1 (CYD1) as prognostic markers in hypopharyngeal (HSC) and oropharyngeal squamous cell carcinoma (OSC).

5580 Background: In head and neck cancer (HNC), dysregulation of cell cycle proteins p16 and CYD1 are common. Variable associations of p16 over- and under- expression and CYD1 overexpression with overall survival (OS) have been described in different HNC sites. We evaluated the relationship of p16 and CYD1 expression with clinical characteristics and OS in OSC and HSC. Methods: p16 and CYD1 expression was evaluated by immunohistochemistry in 77 HSC and 103 OSC patients (pts) and recorded as p16N (0% tumor cells stained), p16L (5-69%) and p16H (≥70%), CYD1-(&lt;10%) and CYD1+ (≥10%). OS between groups was evaluated by Kaplan-Meier method and compared by log rank test. Hazard ratio (HR) for death was estimated using multivariable Cox models. Results: Pts were predominantly Chinese (83.6% v 85.4%) with locally advanced HNC (91.4% v 92.2%). Compared to OSC, HSC pts were older (median age 67 v 61 yrs), more likely male (89.3% v 74.0%), current or ex-smokers (83.3% v 63.6%) with higher comorbidity-age combined risk score (ageCCI), less likely p16H (6.5% v 30.1%)(all p&lt;0.001) and had similar CYD+. p16H pts were younger (median age 58 (p16H) v 65 (p16L) v 66 (p16N) yrs, p=0.002), more likely non-smoker (51.4% v 23.4% v 13% p&lt;0.001) with lowest ageCCI (p&lt;0.001). Clinical characteristics did not differ by CYD1 status. At median f/u of 50mths, median OS was 33 mths. Median OS was poor in HSC compared to OSC (23.9 v 72.1, p&lt;0.001). Multivariate analysis showed associations of N2/N3 disease (HR 1.57, p=0.036), ageCCI (HR 1.22 per 1 pt increase, p&lt;0.001), p16 (p16H: ref; p16L: HR 2.34, p=0.045; p16N: HR 2.74, p=0.013) and CYD1+ (HR 1.94, p=0.015) with death, independent of gender, smoking and site. Association of p16 with OS was seen mainly in OSC (median OS p16H: not reached (NR), p16L: 62, p16N: 22 mths, p&lt;0.001) compared with median OS (HSC) (27 v 28 v 21, p=0.609). Similarly the association of CYD1 with OS was mainly in OSC (median OS CYD1-: NR v 23 mths, p&lt;0.001 v HSC: 25 v 25 mths, p=0.19). Conclusions: In OSC, p16 expression correlates with OS, with p16N associated with worst OS. CYD1 has an independent association with OS. Poorer OS in HSC may be due to adverse clinical characteristics. Assessment of p16 and CYD1 status in HSC did not predict for OS.

An exploratory study into the role of dynamic contrast-enhanced (DCE) MRI metrics as predictors of response in head and neck cancers

To assess the efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) in prediction of the response to treatment in patients with head and neck cancers (HNCs). Twenty-one patients with advanced HNC, suitable for concurrent chemoradiotherapy underwent DCE MRI, for the quantification of blood flow (BF) and volume (BV). All the patients received radical doses of conventionally fractionated radiotherapy up to a dose of 70Gy along with concurrent weekly cisplatin. The values of BV and BF were higher in complete responders as compared to partial responders at primary as well as nodes. Both BF and BV were found to be significantly higher in patients with high T-stage as compared to patients with lower T-stage. DCE metrics can be used as a predictor of response to treatment in locally advanced HNCs after validation of these observations in a larger number of patients.

Abstract 4051: A mouse model of head and neck cancer with infrared-based molecular imaging

Abstract Introduction Head and neck cancer (HNC) is notoriously difficult to treat and the five-year survival rate has improved very little over the past thirty years. Head and neck squamous cell carcinomas (HNSCC) mouse models are invaluable tools for furthering mechanistic HNC research. Molecular imaging (MI) is a promising new modality that may improve current HNC mouse models. Visible florescent proteins (VFPs) have been widely used with animal models for tumor detection using MI. However, the low emission wavelength of VFP results in its overlapping with the auto-fluorescence of many tissues and causes insufficient penetration into deeper tissues, preventing the application of VFP to track local and metastatic tumor progressions. The recent development of infrared-fluorescent protein (IFP) with Biliverdin as a chromophore has greatly advanced in vivo molecular imaging of deep tissues in animals. Hypothesis The ultimate goal of this study is to develop a novel orthotopic mouse model of HNC with regional spreading and distant metastasis tumors that closely mimics human HNC and can be accurately detected by a noninvasive IFP-based molecular imaging (MI) system. Methods A stable human HNC cell line expressing IFP was established. This stable cell line was used for generating a mouse model with HNC. The tumor formation and tumor progression with this model were accurately monitored by a MI system. Results The IFP signal was clearly detected in our mouse model of HNC. Scanned imaging demonstrated a progression pattern of tumor growth in this model. The tumor can be detected earlier with molecular imaging than by conventional external caliper measurement. Unlike surgical measurement, the tumor can be quantified without disturbing the tumor environment. More important, our data suggest that local-regional metastasis tumors can be detected with this model. Conclusion This novel animal model represents an orthotopic human HNC model. The IFP signals penetrate tissues well and can be detected in the deep tissues with this model. Thus, our model has the potential to be used for monitoring tumor spreading and metastasis of advanced stage HNC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4051. doi:1538-7445.AM2012-4051

Global quality of life during the acute toxicity phase of multimodality treatment for patients with head and neck cancer: Can we identify patients most at risk of profound quality of life decline?

Treatment intensification has improved outcomes for patients with head and neck cancer (HNC), but little has been reported on health-related quality of life (QoL) consequences. We investigated changes in QoL after (chemo)radiotherapy to identify patient characteristics that predict those whose QoL deteriorates most profoundly in the acute post-treatment period. Patients with locally advanced HNC treated with curative intent received intensity-modulated radiotherapy (60-70 Gy) in this prospective study. (Chemo)radiotherapy was either definitive or adjuvant. Induction chemotherapy consisted of three cycles of docetaxel, cisplatin, and 5-fluorouracil; responders received (chemo)radiotherapy; nonresponders underwent salvage surgery followed by (chemo)radiotherapy if appropriate. Patients completed the EORTC QLQ-C30 and HNC-specific HN35 module before and at the end of (chemo)radiotherapy and 6-8 weeks after therapy completion. Ninety-five patients participated. At baseline, patients reported significantly lower Global health status, functioning, and symptom scale scores than a reference German population (all p<0.001). At the end of (chemo)radiotherapy, patients had significantly lower QoL scores vs. baseline on all functioning scales (p<0.05). Most symptom and HN35 scores worsened during (chemo)radiotherapy but many recovered 6-8 weeks post-treatment. QoL deteriorated more in patients with high vs. low baseline QoL; no clinical or sociodemographic characteristics of patients most likely to experience a significant deterioration in QoL during treatment were identified. These standard QoL instruments did not predict patients at risk of profound global QoL impairments during acute treatment. Other than baseline QoL, no patient characteristics associated with significant QoL deterioration were identified.

Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC). Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT. Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%-100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median K(trans) values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median K(trans) values that decreased during therapy. Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure.

Phase I Trial Using the Proteasome Inhibitor Bortezomib and Concurrent Chemoradiotherapy for Head-and-Neck Malignancies

Advanced head-and-neck cancer (HNC) remains a difficult disease to cure. Proteasome inhibitors such as bortezomib have the potential to improve survival over chemoradiotherapy alone. This Phase I dose-escalation study examined the potential of bortezomib in combination with cisplatin chemotherapy and concurrent radiation in the treatment of locally advanced and recurrent HNC. Eligible patients received cisplatin once weekly at 30 mg/m(2) per week and bortezomib along with concurrent radiation. Bortezomib was given on Days 1, 4, 8, and 11 every 3 weeks, with an initial starting dose of 0.7 mg/m(2) and escalation levels of 1.0 and 1.3 mg/m(2). Dose escalation was performed only after assessment to rule out any dose-limiting toxicity. We enrolled 27 patients with HNC, including 17 patients with recurrent disease who had received prior irradiation. Patients received bortezomib dose levels of 0.7 mg/m(2) (7patients), 1.0 mg/m(2) (10 patients), and 1.3 mg/m(2) (10 patients). No Grade 5 toxicities, 3 Grade 4 toxicities (all hematologic and considered dose-limiting toxicities), and 39 Grade 3 toxicities (in 20 patients) were observed. With a median follow-up of 7.4 months, the overall median survival was 24.7 months (48.4 months for advanced HNC patients and 15.4 months for recurrent HNC patients). Bortezomib in combination with radiation therapy and cisplatin chemotherapy is safe in the treatment of HNC with a bortezomib maximum tolerated dose of 1.0 mg/m(2) in patients previously treated for HNC and 1.3 mg/m(2) in radiation-naive patients.

Non-English Speaking Language Rather than Non-white Race Predicts Treatment Outcomes in Patients Treated with Radiotherapy (RT) for Head and Neck Cancer (HNC)

Racial disparities in treatment outcome have been reported in HNC. The purpose of this study was to evaluate how language (in addition to race) affects treatment outcomes in patients (pts) treated with curative intent RT for HNC at a large tertiary care city hospital. From 2004 to 2010, 121 pts with non-metastatic, non-recurrent HNC underwent RT to a median dose of 70 Gy in 33 fractions; 81% received IMRT and 82% concurrent chemotherapy. At hospital registration, pts' self-reported race and primary spoken language were recorded. Race was categorized as White (W), Black (B), Hispanic (H) or Other (O); language as English (ES) or non-English (NES) speaking. Pts were evaluated for locoregional (LRC) and distant (DC) control, and cancer-specific (CSS) and overall (OS) survival. Cox regression and multivariate analyses (MV) were performed adjusting for pt and tumor factors. Non-white pts was reported in 45% of pts, with 24%, 12%, 9% and 55% for B, H, O and W pts, respectively. No statistically significant differences between races were noted for age, gender, T/N or AJCC stage, RT modality or RT duration. Differences between W, B, H and O were noted for smoking pack-years: 36.2, 38.8, 30.9 and 12.7 (p = 0.038) and concurrent chemotherapy: 85.1%, 86.2%, 64.3% and 72.7% (p = 0.025), respectively. Two-year actuarial LRC was 87.6%, 75.5%, 57.1% and 100% for W, B, H and O, respectively (p = 0.006). Corresponding CSS was 94.3%, 85.8%, 61.9% and 100% (p = 0.049). No significant differences were noted for DC and OS. On MV analysis, H as compared to W pts, had an increased risk of LR failure (HR 7.2, 95% CI 2.3 - 22.1) when adjusted for smoking pack-years, AJCC stage and concurrent chemotherapy. However, the significance was lost with further adjustment for language (HR 1.1, 95% CI 0.1 - 8.16). Non-English speaking was reported in 17%, with no significant differences in age, gender, T/N or AJCC stage, or RT duration. As compared to ES pts, NES pts had fewer smoking pack-years (22 vs. 37, p = 0.028), and received less concurrent chemotherapy (65.0% vs. 85.2%, p = 0.033). Two-year actuarial LRC was inferior in NES pts; 65.0% as compared to 85.7% in ES pts (p = 0.002). Two-year OS rates were 65.8% and 85.3% for NES and ES pts, respectively (p = 0.037). On MV analyses, NES pts had an increased risk of LR failure (HR 10.3, 95% CI 1.7 - 61.4) when adjusted for race, smoking pack-years, AJCC stage and concurrent chemotherapy. In this cohort of advanced HNC pts receiving definitive radiation-based treatment, non-English speaking language was a more significant predictor of treatment outcome than non-white race. Therefore, further interpreter/translation services are warranted in the care of such diverse patients.

Efficacy and safety of dose-modified docetaxel plus cisplatin-based induction chemotherapy in Asian patients with locally advanced head and neck cancer

The beneficial effects of docetaxel plus cisplatin-based induction chemotherapy for patients with unresectable, advanced head and neck cancer (HNC) have been documented in Western countries. However, the efficacy of such treatment has not been confirmed in Asian patients. We aimed to determine whether incorporation of dose-modified docetaxel into a cisplatin-based induction regimen would be both effective and tolerable in our Asian population of patients. Thirty-six patients with stage III or IV HNC who had undergone cisplatin-based induction chemotherapy were included in the current analysis. Fifty-three percentage of the patients had received induction chemotherapy with bolus cisplatin and continuous 5-fluorouracil (PF group), while the remaining 47% had additionally received dose-modified docetaxel (TPF group). We assessed the relative impact of the two treatments on clinical outcomes and treatment-related toxicities. The disease control rate was higher in the TPF group (92·9% vs. 76·5%), although the difference did not reach statistical significance (P = 0·217). Addition of docetaxel increased the median progression-free survival to 435 days, which was 2·3 times longer than that (188 days) of patients not receiving docetaxel (P = 0·019). Non-haematological toxicity profile was similar and acceptable in both treatment groups. Higher incidence of grade 3/4 neutropenia and more episodes of neutropenic fever-related hospitalization occurred in the docetaxel-treated patients, but most of them were managed uneventfully. Addition of dose-modified docetaxel to cisplatin-based induction chemotherapy was both efficacious and generally safe. Docetaxel addition significantly prolonged progression-free survival and had an acceptable safety profile in our Asian population of patients with locoregionally advanced HNC.

Antitumor activity of cetuximab associated with the taxotere–cisplatin–fluorouracil (TPF) combination on an orthotopic head and neck cancer model

Cetuximab (Cet), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is a standard of care in advanced head and neck (HN) cancer when combined with irradiation or cisplatin. The TPF association combining docetaxel (T), cisplatin (P) and fluorouracil (F) has become a chemotherapy of reference in the management of HN tumors. The aim of the study was to evaluate the anti-tumor activity of the association of Cet with TPF. In addition, the potential benefit from adding bevacizumab (Bev), an anti-VEGF monoclonal antibody, was examined. Investigations were performed on CAL33 human head and neck cancer cell line (high content of EGFR) injected as an orthotopic xenograft into the mouth floor of nude mice. The anti-tumor efficacy of Cet (2.5 mg/kg), Bev (20 mg/kg) and of TPF (at the MTD: T 20 mg/kg, P 6 mg/kg, F 17 mg/kg), administered alone or in combination on day 3 and day 10 after tumor cell injection, was assessed on day 12 (animal sacrifice for ethical reasons, 10 animals per treatment group). Tumor volume, tumor histology, tumor cell proliferation (Ki67, immunochemistry) and apoptosis (Bcl2, immunochemistry) were examined. As compared to controls, TPF-Cet and TPF-Cet-Bev had a significant impact on tumor volume and histological response. The highest efficacy was observed with the TPF-Cet combination. The effects of the TPF-Cet-Bev association were not significantly different from those observed with TPF-Cet. Data were corroborated by a diminution in Ki67 labeling and Bcl2 expression. The association of Cet with TPF can be considered a beneficial clinical option in advanced HN cancer patients.

Palifermin Reduces Severe Mucositis in Definitive Chemoradiotherapy of Locally Advanced Head and Neck Cancer: A Randomized, Placebo-Controlled Study

Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC. Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m(2) on days 1, 22, and 43) received palifermin (180 μg/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4). The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade ≥ 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug-related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms. Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated.

Functional outcome in patients with advanced head and neck cancer: surgery and reconstruction with free flaps versus primary radiochemotherapy

The objective was to compare functional outcome in patients with advanced head and neck cancer (HNC) treated with (a) surgical resection and reconstruction with microvascular free flaps (MVFF) followed by radiochemotherapy versus (b) primary radiochemotherapy (RCT) on the basis of the International Classification of Functioning, Disability and Health (ICF) from WHO. This was a cross-sectional, multi-institutional study. The outcome measures included ICF Core Sets for HNC, the EORTC-QLQ, modules c30 + hn35 and the University of Washington-Quality of life Questionnaire (UW-QOL). Analyses included descriptive statistics, ranking exercises, and regression analyses in a cumulative logit model; 27 patients were treated with MVFF and 22 with RCT. Global Quality of life scores suggested a slightly better functional outcome for the surgical approach. The majority of ICF categories (81/93, 87%) did not show a difference in functional outcome between the two treatment approaches. In the remaining 12 ICF categories, n = 3 body structures were more affected in the MVFF group, while n = 3 body functions, and n = 6 activities/participations were more problematic in the RCT group. This included oral swallowing and weight maintenance functions as well as social relationships, acquiring a job, and economic self-sufficiency. In addition, nine contextual environmental factors were more relevant to the RCT group. Both treatment approaches seemed appropriate to advanced HNC from the perspective of functional outcome. The influence of treatment modalities on the social and economic lives of cancer survivors needs to be explored further. In order to guide rehabilitation according to patients' needs, the ICF offers a multidimensional view comprising body structures, body functions, and activities and participation in life.

A randomized phase II trial of cetuximab-based induction chemotherapy followed by concurrent cetuximab, 5-FU, hydroxyurea, and hyperfractionated radiation (CetuxFHX), or cetuximab, cisplatin, and accelerated radiation with concomitant boost (CetuxPX) in patients with locoregionally advanced head and neck cancer (HNC).

5519 Background: Cetuximab is commonly used in combination with either chemotherapy or radiation in the treatment of HNC, although the optimal way to integrate cetuximab with concurrent chemoradiation (CRT) remains unclear. We explored the addition of cetuximab to induction chemotherapy and two established CRT platforms in a randomized phase II trial. Methods: Patients with locoregionally advanced HNC were treated with cetuximab, carboplatin, paclitaxel induction chemotherapy for 2 cycles. Patients were randomized to A: cetuximab, 5-FU, hydroxyurea, and hyperfractionated week-on week-off RT (72-74Gy) (CetuxFHX), or B: cetuximab, cisplatin, accelerated radiation with concomitant boost (CetuxPX)(72Gy). Primary endpoints were 1- and 2-year progression-free (PFS), and overall survival (OS). Results: 110 patients with locoregionally advanced HNC (108 with Stage IV) were enrolled. 57.3% of patients had oropharyngeal (OP) primaries (A: 49%, B: 66%, p16 staining is pending). Induction response rate was 91.8%. 99.1% of patients developed a rash (≥grade 3 in 16.4%); ≥grade 3 neutropenia developed in 36.3% of patients. Overall 1- and 2-year survival rates were 98.3% and 89.5% in CetuxFHX, and 94.2% and 91.4% in CetuxPX arm, with 21.1months median follow-up (not statistically significant, p=0.27, logrank test). Progression free survival at 1 and 2 years was 86.0% and 82.3% in CetuxFHX, and 95.9% and 89.7% in CetuxPX (p=0.18). Grade ≥3 mucositis was present in 91.1%(A) and 94.3%(B) of patients; grade ≥3 dermatitis in 82.1% and 50.9% of patients. 95% of patients completed therapy. Treatment failures occurred in both OP and non-OP tumors. Conclusions: Cetuximab-based induction chemotherapy is well tolerated and active. Cetuximab can safely be integrated with both FHX and cisplatin based CRT with acceptable toxicities. Survival is favorable on both study arms suggesting that either platform could be investigated further. Data on HPV versus non-HPV-related tumors will be available.

Abstract 3508: High antitumor activity of cetuximab combined with taxotere-cisplatin-flourouracil (TPF) association on an orthotopic head and neck cancer model

Abstract Background : Cetuximab (cetux), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard of care in advanced head and neck (HN) cancer when combined with irradiation or cisplatin. The TPF association including taxotere (T), cisplatin (P) and fluorouracil (F) has become a chemotherapy of reference in the management of HN tumors. The aim of the study was to evaluate the antitumor activity of the association of cetux with TPF. In addition the potential benefit to add bevacizumab (beva), an anti-VEGF monoclonal antibody, was also examined. Methods : investigations were performed on CAL33 human head and neck cancer cell line (high content of EGFR) injected as an orthotopic xenograft into the mouth floor of nude mice. The anti-tumor efficacy of cetux 2,5 mg/kg, beva 20 mg/kg and of TPF at the MTD (T : 20 mg/kg, P : 6 mg/kg, and F : 17mg/kg) administered alone or in combination at day 3 and 10 after tumor cell injection was assessed at day 12 (animal sacrifice for ethical reasons, 10 animals per treatment group). Tumor volume, tumor histology, tumor cell proliferation (Ki67 by immunohistochemistry) and apoptosis (Bcl2 by immunohistochemistry) were examined. Statistical analyses were performed according to non-parametric methods. Results : As compared to controls, TPF-cetux and TPF-cetux-beva had a significant impact on tumor volume and histological response. The highest efficacy was observed with the combination TPF-cetux. The effects of the association TPF-cetux-beva were not significantly different than those observed with TPF-cetux. Data were corroborated by a diminution in Ki67 labelling and Bcl2 expression. Conclusion : the association of cetux with TPF could be an interesting clinical option to evaluate in advanced HN cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3508. doi:10.1158/1538-7445.AM2011-3508

Intensity-modulated radiotherapy in patients with head and neck cancer: a European single-centre experience

The purpose of this study was to analyse retrospectively the intensity-modulated radiotherapy (IMRT) results in patients with head and neck cancer (HNC) treated between November 2003 and June 2007. Patients with early and locoregionally advanced HNC were treated with inverse-planned step-and-shoot IMRT. The prescribed dose varied from 66 Gy to 70 Gy in those receiving IMRT as definitive treatment and from 60 Gy to 70 Gy in the post-operative setting. IMRT was given alone, after induction chemotherapy (ICT), with concomitant chemotherapy (CRT) or with both. Acute and late toxicities are reported; locoregional control (LRC), locoregional relapse-free survival (LRRFS) and overall survival (OS) were calculated from the start of radiation. IMRT was used in 78 patients (48 as definitive treatment, 30 post-operatively), of whom 20 also received ICT and 35 CRT. Three patients stopped IMRT early, one for toxicity (mucosa). Acute toxicity scoring revealed 5 cases (6%) of severe skin toxicity and 65 cases (83%) of severe mucosal toxicity. After a median follow-up of 18.7 months, late toxicities included xerostomia (44%), loss of taste (14%) and fibrosis of the neck (9%). 16 patients had died, of whom 10 due to tumour recurrence/progression and 2 due to treatment (but not IMRT related). The LRC, LRRFS and OS at 3 years are 66.1%, 48.5% and 60.3% in the definitive IMRT group and 85.4%, 82.5% and 85.9% in the post-operative setting, respectively. We consider IMRT for locoregional HNC feasible not only as a single modality but also after surgery, after induction chemotherapy and concurrently with chemotherapy.

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer

Background: We investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC).Patients and methods: Treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m2; cisplatin at 70 mg·m2/day on day 1; and S-1 twice daily on days 1–14 at doses of 40, 60, and 80 mg·m2/day, repeated every 3 or 4 weeks.Results: Forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m2/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m2/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22a partial response, giving a response rate of 70%.Conclusions: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m2/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

IMRT Reirradiation with Concurrent Cetuximab Immunotherapy in Recurrent Head and Neck Cancer

In this retrospective investigation, the outcome and toxicity after reirradiation with concurrent cetuximab immunotherapy of recurrent head and neck cancer (HNC) in patients who had contraindications to platinum-based chemotherapy were analyzed. Ten patients with locally advanced recurrent HNC were retrospectively evaluated. In 9 cases, histology was squamous cell carcinoma, in one case adenoid cystic carcinoma. External beam radiotherapy was part of the initial treatment in all cases. Reirradiation was carried out using step-and-shoot intensity-modulated radiotherapy (IMRT) with a median dose of 50.4 Gy. Cetuximab was applied as loading dose (400 mg/m(2)) 1 week prior to reirradiation and then weekly concurrently with radiotherapy (250 mg/m(2)). The median overall survival time after initiation of reirradiation was 7 months; the 1-year overall survival (OS) rate was 40%. Local failure was found in 3 patients, resulting in a 1-year local control (LC) rate of 61%. The 1-year locoregional control (LRC) rate was 44%, while the 1-year distant metastasis-free survival (DMFS) was 75%. Acute hematological toxicity was not observed in the group. Severe acute toxicity included one fatal infield arterial bleeding and one flap necrosis. Severe late toxicities were noted in 2 patients: fibrosis of the temporomandibular joint in 1 patient and stenosis of the cervical esophagus in another. IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent HNC is feasible with acceptable acute toxicity. Further investigations are necessary to determine the clinical role of this therapy concept.

Induction docetaxel, cisplatin, and cetuximab followed by concurrent radiotherapy, cisplatin, and cetuximab and maintenance cetuximab in patients with locally advanced head and neck cancer.

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 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. 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. This cetuximab-containing regimen resulted in excellent long-term survival and safety, and warrants further evaluation in both HPV-positive and -negative HNC.