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Background This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods Twelve patients with R/M HNSCC were enrolled. Patients were given oral buparlisib starting day 7 and daily thereafter. The dose of buparlisib was escalated in a 3 + 3 design followed by a dose expansion cohort of 6 patients. The MTD of buparlisib per protocol was 100 mg daily with cetuximab given intravenously every 14 days starting day 0. Results Ten patients had ≥2 previous treatment regimens (11 with prior cetuximab). There were no dose limiting toxicities observed during dose escalation. One patient achieved a partial response and 4 achieved stable disease. Conclusion Based on this pilot study, buparlisib at 100 mg daily plus cetuximab proved to be well-tolerated. Patients previously treated with cetuximab monotherapy showed benefit from this combination.

The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation.Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%.110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients.The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation.

Background Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. Patients and methods Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%–50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. Results Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P Conclusions Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. Clinical trial registration Clinical trials.gov identifier: NCT02258659.

Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improved outcome.This open-label, multi-institution, phase II study evaluated the activity of gefitinib at individually escalated doses up to 750 mg to achieve the skin toxicity grade ≥2.Forty four patients were enrolled. Only twenty-three (52%) experienced skin rash grade ≥2. Of 44 patients, partial responses were noted in 3 (7%), stable disease in 8 (18%) and progressive disease in 33 patients. Median progression-free survival was 1.9 months (95% CI 1.6-2.2) and median overall survival was 5.1 months (95% CI 2.4-7.8). Grade of skin rash was not associated with response rate (p=0.169) nor tumor control rate (p=0.284); however, higher gefitinib trough levels were associated with disease control. Of the 11 tissue samples analyzed for EGFR gene copy by FISH, 7 were EGFR FISH positive, but this was not associated with improved tumor control or survival.Gefitinib has clinical activity as monotherapy in SCCHN. Dose escalation of gefitinib is feasible and may increase skin toxicity, but our data do not support increased activity.

Background Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. Patients and methods Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. Results Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2–54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6–8.3) and 9.5 months (95% CI 7.2–15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. Conclusions The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.

Purpose Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations. Patients and Methods Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization. Results Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02). Conclusion Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

6038Background: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with tumor-induced inflammation and poor prognosis in a variety of treatment settings. Moreover, tumor-derived myeloid...

6014Background: Anti-programmed death receptor-1 (PD-1) therapies are approved for recurrent/metastatic head and neck (H&N) cancer progressing on or after platinum-based chemotherapy, and immune co...

6057Background: Immunotherapy efficacy is modulated by immune competence which lacks well established clinical measures. Nutritional status influences immune competence and has been associated with...

6020Background: The current most widely used standard for HPV status testing in head & neck cancer is p16 IHC. However, p16 IHC is a surrogate method which does not test directly for HPV genetic ma...

Objectives: This study was designed to determine an optimal dose range for the once-daily dosing (ODD) of tobramycin in the treatment of an acute pulmonary exacerbation in paediatric cystic fibrosis (CF) patients. In addition, we aimed to assess whether certain patient characteristics affect tobramycin pharmacokinetics and, therefore, dosing. Methods: Patient characteristics and pharmacokinetic parameters of patients receiving tobramycin three times daily from 1 January 1992 to 31 October 2005 were analysed using univariate analysis and multiple linear regression to determine statistically significant relationships and to derive dosing models. The binary partitioning method was used to derive critical values to determine stratification within the chosen dosing model. Results: Using multiple linear regression, age and sex were significantly associated with the volume of distribution divided by the body weight (V/kg). By the binary partitioning method, the critical value for age was 13.75 years. Conclusions: Age and sex were used to derive an ODD regimen for tobramycin in paediatric CF. Using a target peak concentration range of 25‐35 mg/L, the initial dose for female CF patients at least 14 years of age was calculated to be 7 mg/kg/day given intravenously as a single daily dose. All other CF patients would receive an initial dose of 9 mg/kg/day given intravenously as a single daily dose. These dosing guidelines will require prospective evaluation for safety and efficacy.

The purpose of this study was to determine the maximum tolerated dose (MTD) of docetaxel based induction and concomitant chemoradiotherapy (CRT) after using the FHX platform (5 = 5-FU, H = hydroxyurea, X = Radiation). Patients with Stage III/IV locally advanced HNSCC were enrolled. Induction chemotherapy (carboplatin/docetaxel) was followed by 5 cycles of concomitant docetaxel based CRT. No DLTs were observed in dose levels 1/2 for induction and CRT. Dose level 2 was expanded. The overall survival CR rate after CRT was 79 percent. Median overall (OS) has not been reached and 2-year OS is 80.7 percent. The recommended Phase II dose of docetaxel with FHX CRT is 25 mg/m(2) and 35 mg/m(2) in combination with carboplatin induction (AUC = 6).

Purpose: An objective response rate of 11% was reported in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with 500 mg daily gefitinib although the recommended dose in lung cancer is 250 mg. This study evaluated the efficacy and toxicity of 250 mg daily gefitinib in patients with recurrent and/or metastatic SCCHN.Experimental Design: Phase II trial with objective response rate as the primary end point. Measurements of quality of life and levels of serum vascular endothelial growth factor and transforming growth factor-α were assessed before and during therapy.Results: In 70 patients, 1 (1.4%) partial response was observed. Median progression-free survival and overall survival were 1.8 and 5.5 months, respectively. Quality of life scores improved transiently during the first weeks of therapy before returning to baseline. Median vascular endothelial growth factor and transforming growth factor-α levels were above the normal range but were not predictive of outcome. Four patients experienced grade 3 drug-related adverse events. Rash of any grade was observed in 64% of subjects. Correlation between disease control (partial response + stable disease), progression-free survival, and overall survival and grade of cutaneous toxicity was observed (P = 0.001, 0.001, and 0.008 respectively).Conclusions: Gefitinib monotherapy at 250 mg in recurrent and/or metastatic SCCHN seems to have less activity than was previously observed for 500 mg daily. A dose-response relationship may exist for this agent in SCCHN and grade of cutaneous toxicity attributable to gefitinib is a clinical predictor of better outcome.

6039 Background: R/M HNC carries a poor prognosis with a median survival of 10-12 months. PI3K pathway aberrations are present in 30% of HNC. This pilot dose-escalation study assesses the safety and tolerability of the PI3K inhibitor buparlisib when given concurrently with cetuximab in R/M HNC, as well as assess efficacy in an expansion cohort. Methods: Patients (pts) with R/M HNC who were not amenable to curative intent therapy were enrolled. Pts were given oral buparlisib starting day -7 and daily thereafter. The dose of buparlisib was escalated in a 3+3 design (Level 1: 80mg daily, Level 2: 100 mg daily) followed by a dose expansion cohort. The maximum dose of buparlisib was 100 mg daily. Cetuximab (500mg/m2) was given intravenously every 14 days starting day 0. Pts continued on treatment until progression of disease. Prior cetuximab failure was allowed. Results: Of the 12 pts enrolled, 10 had at least 2 previous treatment regimens (11 with prior cetuximab). 5 pts were HPV+, 4 were HPV-, and 3 had unknown HPV status. 3 pts were treated at the 80 mg dose level while 9 were treated at the 100 mg dose level (3 + 6 patient expansion). Treatment was well tolerated with 2 pts experiencing grade 3 adverse events (AEs) (no grade 4 AEs). The most common AEs were fatigue (83.3%), maculopapular rash (50.0%), and anorexia (50.0%). 3 pts experienced grade 1 anxiety. There were no SAEs. Of the 10 pts who were evaluable for response one patient achieved a PR (10%), and 4 achieved stable disease (40%) per RECIST 1.1. Median overall survival was 280 days (HPV+: 370 days, HPV-:191 days). The study was closed early due to poor enrollment on the expansion cohort as patients opted for concurrently open immunotherapy trials. Conclusions: Based on this pilot study, buparlisib plus cetuximab proved to be well-tolerated and showed limited evidence of activity in a heavily pre-treated patient population. Further research is warranted to determine activity of buparlisib in a larger cohort of R/M HNC. Clinical trial information: NCT01816984.

6066 Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or > 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p < .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.

detection of recurrence were abstracted. Patients either received definitive RT alone (nZ38, 15.4%) or concurrent systemic therapy and RT (nZ209, 84.6%). Outcomes, including local control (LC), regional control (RC), locoregional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) were calculated according to Kaplan-Meier method from the end of RT. Patients received a 3-month posttreatment positron emission tomographic/computed tomographic (PET/CT) scan and were seen every 3 months in the first year, every 4 months in Year 2, and every 6 months in Years 3 to 5. Results: Median follow-up of all patients was 36 months. LC was achieved in 239 of 245 patients, with a 3-year LC rate of 97.8%. Of the 6 local failures, all were detected by direct visualization (nZ2) or flexible laryngoscopy (nZ4). Three-year RC was 95.3%, where patients with 5 nodes or level 4 lymph nodes present were more likely to suffer regional failure (P

Background Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients. Methods Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. Results Twenty-two patients were accrued (Cohort A — 15 patients, Cohort B — 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A — 3patients, Cohort B — 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A — 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B — 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. Conclusions Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.

Summary Background Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Methods Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. Findings In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7·1 months (95% CI 5·7–9·0) and 4·1 months (2·8–4·4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0·704 vs 0·386, p=0·036 and 0·949 vs 0·332, p=0·036, respectively) and tumour shrinkage (p=0·007 and p=0·008, respectively) in a subset of 11 patients with available tissue. Interpretation The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue. Funding National Cancer Institute, National Institutes of Health, Bethesda, MD, USA (grant number N01-CM-17102) and the University of Chicago Cancer Research Center, Chicago, IL, USA (grant number P30 CA14599).

Purpose We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients. Patients and Methods Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m2 (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded. Results Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m2, HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/2, HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5). Conclusion Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.

This retrospective review evaluates the response to caspofungin when given to children with febrile neutropenia and describes adverse effects attributable to caspofungin, including risk of hepatotoxicity during concomitant therapy with cyclosporine. Sixty-seven courses of caspofungin administered to 56 patients (1-17 years) were surveyed; 53 (79%) courses resulted in an overall favorable response. Ten children (15% of courses) experienced an adverse drug-related event that was probably or possibly attributable to caspofungin. Rash and hypokalemia were the most commonly identified adverse effects. One of 19 children receiving caspofungin and cyclosporine concurrently developed hepatotoxicity possibly related to caspofungin.

Purpose The primary objective of our meta-analysis was to determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) after hematopoietic autologous and allogeneic stem-cell transplantation (SCT) reduced documented infections. Our secondary objectives were to determine whether prophylactic CSFs affected other outcomes including parenteral antibiotic therapy duration, infection-related mortality, graft-versus-host disease (GVHD), or treatment-related mortality. Methods We included studies if there was random assignment between CSFs and placebo/no therapy and CSFs were given after SCT and before recovery of neutrophils. From 3,778 reviewed study articles, 34 were included based on predefined inclusion criteria. All analyses were conducted using a random effects model. Results CSFs reduced the risk of documented infections (relative risk [RR] 0.87; 95% CI, 0.76 to 1.00; P = .05) and duration of parenteral antibiotics (weighted mean difference, −1.39 days, 95% CI, −2.56 to −0.22; P = .02) but did not reduce infection-related mortality (RR, 0.76; 95% CI, 0.41 to 1.44; P = .4). CSFs did not increase grade 2 to 4 acute GVHD (RR, 1.03; 95% CI, 0.81 to 1.31; P = .8) or treatment-related mortality (RR, 1.00; 95% CI, 0.78 to 1.29; P = .98). Conclusion CSFs were associated with a small reduction in the risk of documented infections but did not affect infection or treatment-related mortality.

We review our recent experience with intensity-modulated radiation therapy (IMRT) and conventional three-dimensional radiation therapy (C3DRT) in advanced head and neck cancer. Sixty-nine patients with Stage IV head and neck cancer (and stage III base of tongue and hypopharynx) enrolled in a Phase II study of definitive chemoradiation; 20 received all or part of their radiation with IMRT. Image-guided set-up, using video subtraction techniques, was used in all patients. Six weekly doses of induction carboplatin (AUC=2) and paclitaxel (135 mg/m 2 ) were followed by alternating weekly chemoradiation to 75 Gy with 1.5 Gy BID fractions, concurrent with paclitaxel (100 mg/m 2 /week), 5-fluorouracil (600 mg/m 2 /d) and hydroxyurea (500 mg PO BID). Two consecutive cohorts enrolled, differing in radiation scheme: 75 Gy to gross disease in both, 60 or 54 Gy to first echelon lymphatics and 45 or 39 Gy to second echelon lymphatics. With a median follow-up of 47 months, 3-year overall survival is 68.5% and 3-year locoregional control is 94.0%, with no significant differences between those treated with C3DRT versus IMRT, nor between the two radiation dosing schemes. Actuarial overall survival without tracheostomy or laryngectomy, or without a gastrostomy tube was also similar. Acute mucositis, dermatitis and pain were similar with C3DRT and IMRT. Preliminary data suggests IMRT is well tolerated, and does not compromise locoregional control, indicating that IMRT adequately covers the clinical volume at risk. Building on the present clinical experience, future directions include more directed efforts at reducing toxicity, with better planning software and planning techniques.

We review our recent experience with intensity-modulated radiation therapy (IMRT) and conventional three-dimensional radiation therapy (C3DRT) in advanced head and neck cancer. Sixty-nine patients with Stage IV head and neck cancer (and stage III base of tongue and hypopharynx) enrolled in a Phase II study of definitive chemoradiation; 20 received all or part of their radiation with IMRT. Image-guided set-up, using video subtraction techniques, was used in all patients. Six weekly doses of induction carboplatin (AUC=2) and paclitaxel (135 mg/m2) were followed by alternating weekly chemoradiation to 75 Gy with 1.5 Gy BID fractions, concurrent with paclitaxel (100 mg/m2/week), 5-fluorouracil (600 mg/m2/d) and hydroxyurea (500 mg PO BID). Two consecutive cohorts enrolled, differing in radiation scheme: 75 Gy to gross disease in both, 60 or 54 Gy to first echelon lymphatics and 45 or 39 Gy to second echelon lymphatics. With a median follow-up of 47 months, 3-year overall survival is 68.5% and 3-year locoregional control is 94.0%, with no significant differences between those treated with C3DRT versus IMRT, nor between the two radiation dosing schemes. Actuarial overall survival without tracheostomy or laryngectomy, or without a gastrostomy tube was also similar. Acute mucositis, dermatitis and pain were similar with C3DRT and IMRT. Preliminary data suggests IMRT is well tolerated, and does not compromise locoregional control, indicating that IMRT adequately covers the clinical volume at risk. Building on the present clinical experience, future directions include more directed efforts at reducing toxicity, with better planning software and planning techniques.

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 chemoradiat...

6064 Background: Sunitinib is an oral multitargeted tyrosine kinase inhibitor against RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of suniti...

6034 Background: Preclinical data supports inhibition of vascular endothelial growth factor (VEGF) to improve tumor radiosensitivity. Phase I data demonstates that BFHX was tolerable in HNC (Seiwert, pASCO2006). Here we present preliminary toxicity data from a randomized phase II trial in pts with PS 0–2, stage II-IV (T2–4 N0–1 M0) HNC. Methods: Pts were randomized (2:1) to receive either BFHX or FHX. Planned sample size is 72pts. Chemotherapy consists of 5- FU (600 mg/m2/day continuous infusion for 120 hrs), hydroxyurea (500 mg PO q12 hours for 11 doses) with or without bevacizumab (10 mg/kg IV on day 1), concurrently with twice daily RT on a week on-week off schedule. Results: 21pts (BFHX 14pt and FHX 7pt) have completed therapy and are evaluable for toxicity. Pt characteristics in the BFHX and FHX arms are: median age 61 vs. 55 yrs, males 78% vs. 85%, stage II-III 57% vs. 86% and IV 43% vs. 14%. All pts have PS 0–1. 20 pts are evaluable for toxicity. Two episodes of gr3 leukopenia and one episode of gr 3 neutropenia were observed in the BFHX arm; whereas no gr3 hematologic toxicities were seen in the FHX arm. Mucositis (Gr3 - BFHX 85% vs. FHX 86%) and dermatitis (Gr3 - 0% vs. 14%) were observed in every pt. Other common non- hematologic toxicities were pain (100% vs. 86%), fatigue (77% vs. 86%) and anorexia (62% vs. 51%). No hemorrhagic events were observed. In the BFHX arm, one episode of deep venous thrombosis and one non-neutropenic death from sepsis were observed. Pathologic complete response rates were 92% and 100% in the BFHX and FHX arms, respectively. Conclusions: Preliminary results support the tolerability of BFHX. Toxicity appears to be similar to FHX with an apparent increase in leukopenia consistent with prior reports. Bleeding complications were not increased with BFHX. No significant financial relationships to disclose.

6021 Background: EGFR activation up-regulates VEGF, which has been correlated with resistance to anti-EGFR agents. We previously reported early results (Vokes, JCO, 2005) of a phase I-II study of the EGFR inhibitor erlotinib (E) with the VEGF antibody bevacizumab (B) in recurrent or metastatic HNC. We now present results from the pharmacodynamic analysis as well as updated outcome data. Methods: Phase I/II trial of fixed dose erlotinib (E) 150 mg orally daily with escalation of bevacizumab (B) to a maximum of 15 mg/kg q 3 weeks and continued at 15 mg/kg in the phase II portion. Pts were randomized to receive the initial bevacizumab dose on either day 1 or 15. Paired biopsies were taken at baseline and after 2 weeks of treatment (after E alone or E+B) and analyzed by immunofluorescence and laser scanning analysis for target inhibition and apoptosis markers (VEGFR2/KDR, EGFR, CD31, and respective activated forms [pKDR, pEGFR]). Results: Paired biopsies were available from 20 patients. At baseline pKDR/KDR (ratio) correlated with clinical outcome and differed significantly between responses (CR>SD: pPD: pPD: p No significant financial relationships to disclose.

6028 Background: This study was undertaken to evaluate the tolerability and efficacy of substituting G for paclitaxel into a well- described CRT regimen (Clin Cancer Res 9: 5936; JCO 21: 320) and continuing G as adjuvant therapy. Endpoints included complete response (CR) rate to CRT, progression-free (PFS), disease-specific (DSS) and overall survival (OS), and local & distant control rates. Methods: Previously untreated subjects with stage III, IVa, or IVb squamous cell, poorly differentiated carcinomas, or lymphoepithelioma were enrolled. Organ sparing surgery was allowed. Subjects received 2 cycles of carboplatin/paclitaxel induction followed by CRT with G (250 mg PO qd), 5- fluorouracil, hydroxyurea, and twice daily radiation on day 1–5 of five 14d cycles. G was continued for 2 years from the start of CRT. Results: From 2/03 to 10/04, 67 eligible subjects accrued including 51 males; median age 56; ECOG PS 0 in 47, 1 in 19, and 2 in 1; stage IV in 61 (91%). With median follow-up of 858 days, 9 have had progressive disease (PD, 3 distant, 5 local, 1 with both) and 15 have died (12 related to HNC). Estimated OS=83% at 2y, 73% at 3y; PFS=77% at 2y, 64% at 3y; and DSS=86% at 2y, 80% at 3y. In 56 evaluable subjects we observed 51 CR (91 %), 4 partial responses and 1 PD after CRT. Non-evaluable subjects underwent surgery prior to CRT (10), or died prior to evaluation (1). Grade 3/4 toxicity included mucositis (75%/10%), dermatitis (29%/3%), rash (4%/0%) and diarrhea (1%/0%). Sixty-two patients received maintenance gefitinib, with 60 reliably reporting doses (median days on gefitinib=667). Reasons for holding G included LFT abnormalities, patient refusal, diarrhea, rash, recurrence, hospitalization for acute illness, and early death. Conclusions: Adding G to concurrent CRT after induction therapy, and as adjuvant therapy is tolerable and feasible. Favorable survival and CR data suggest that this is a promising regimen for patients with locally advanced HNC. [Table: see text]

5530 Background: Increased VEGF levels are found in HNC. Preclinical data suggest synergistic antitumor activity of B with radiation and chemotherapy. We conducted a Phase I dose escalation study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of B, when added to infusional 5-FU, Hydroxyurea (HU), and daily radiotherapy administered every other week in patients (pts) with poor prognosis HNC. Methods: Eligible pts had recurrent, or newly diagnosed HNC with high risk of recurrence, ± metastatic disease requiring local control, ECOG PS ≤2, and life expectancy >12 weeks. Two week cycles were repeated 6–7 times (see table ). Results: 43 pts were treated (34 completed). DLT was reached at level 3 with 2 pts having gr 3 transaminase elevations and one pt gr 4 neutropenia. Treatment of 7 (6 evaluable) pts on level 4 resulted in one DLT (SMV thrombosis) and this dose level was chosen for expanded evaluation. In all level 4 pts (N = 27) gr 3 mucositis occured in 73.1% and gr 3 hand-foot syndrome in 15.4%. Additional gr 3 or worse toxicities in the expanded level 4 included: esophageal bleed (tumor bed, grade 5), stroke (grade 4), carotid rupture (3 wks post RT, grade 5), and neck ulceration with need for carotid stent (3 months post RT, grade 4). One sudden death of unclear etiology occurred. Median overall survival is 389 days. One/two year survival is 52.1/26%. Median survival for patients treated with re-irradiation for recurrent, non-metastatic HNC is 314 days; one/two year survival is 45.9/17.2%. With a median follow-up of 317 days 13 patients are still alive (12 are cancer free). Conclusions: B can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks. While B related toxicities are seen, there appears to be no major synergistic toxicity. Long term activity is observed in this very high risk patient population. A randomized phase II trial of FHX with or without B in a lower risk population is ongoing. [Table: see text] No significant financial relationships to disclose.

5506 Background: This study was undertaken to evaluate the tolerability and efficacy of substituting G for paclitaxel into a well-described CRT regimen (Clin Cancer Res 9: 5936; JCO 21: 320) and th...

5546 Background: In a previous study by our group, induction chemotherapy (CT) with weekly carboplatin (C) [AUC=2] and paclitaxel (T) [135 mg/m2] x 6 weeks followed by chemoradiotherapy with the TF...