1016O
PHASE 2, RANDOMIZED TRIAL (CONCERT-2) OF PANITUMUMAB (PMAB) PLUS RADIOTHERAPY (PRT) COMPARED WITH CHEMORADIOTHERAPY (CRT) IN PATIENTS (PTS) WITH UNRESECTED, LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (LASCCHN)

Abstract

Background

We evaluated the safety and efficacy of pmab, a fully human monoclonal antibody against the epidermal growth factor receptor, by comparing PRT with CRT in pts with LASCCHN.

Methods

Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PRT. CRT included 2 cycles of cisplatin 100 mg/m2 during accelerated fractionation radiotherapy (XRT; 70-72 Gy over 6-6.5 weeks). Pmab included 3 cycles at a dose of 9.0 mg/kg with each cycle administered with XRT. This was an estimation study with no formal hypothesis testing. The primary endpoint was locoregional control (LRC) rate at 2 years; key secondary endpoints were progression free survival (PFS), overall survival (OS), and safety. Preplanned HPV subset analysis (determined by p16 immunohistochemistry) was performed on available samples.

Results

Of 151 treated pts (90 PRT, 61 CRT), 84% were men; median age was 58 years; ECOG PS 0: 64%. Overall, the 2-year LRC rate (95% CI) was 51% (40%-62%) for PRT and 61% (47%-72%) for CRT. For both PFS (hazard ratio [HR] = 1.73 [95% CI: 1.07-2.81]; p = 0.03) and OS (HR = 1.59 [95% Cl: 0.91-2.79]; p = 0.10), outcomes favored the CRT arm. Of 99 pts with tumors evaluable for HPV, 24% were HPV+. In 75 HPV- tumors, a difference was observed in PFS (HR = 2.04 [95% Cl: 1.05-3.96]; p = 0.04), with trends also favoring CRT in LRC and OS. Overall, dose intensity was high for all components of therapy in both arms (median relative dose intensity: 100% for pmab and 99% for cisplatin, median XRT dose: 100% in both arms). Grade 3+ adverse events (AEs) occurred in 85% PRT vs 81% CRT pts. Key differences in grade 3+ toxicity between arms (PRT, CRT) included skin disorders (which is a composite of skin-related AEs) (35%, 3%), neutropenia (0%, 13%), and febrile neutropenia (0%, 8%).

Conclusions

Trends favored the CRT arm for the primary endpoint (LRC at 2 years), as well as other measures of efficacy, in this predominantly HPV- LASCCHN population. Small numbers limit conclusions in the HPV+ group. Both PRT and CRT appeared well tolerated.

Disclosure

G. Hatoum: Advisory Board Member for Amgen

K. Oliner: Amgen stock

A. Vanderwalde: Corporate-sponsored research (Amgen), full-time employee of Amgen

All other authors have declared no conflicts of interest.

1017O
PRECLINICAL RATIONAL, SAFETY, AND PRELIMINARY EFFICACY RESULTS OF WEEKLY EVEROLIMUS, CARBOPLATIN AND PACLITAXEL AS AN INDUCTION THERAPY FOR PATIENTS WITH UNRESECTABLE LOCALLY ADVANCED HEAD & NECK SQUAMOUS CELL CARCINOMA (CAPRA): A GERCOR-IRC PHASE I/II STUDY

Abstract

Background

PI3K/mTOR is a survival pathway that was shown activated in 57-81% of patients (pts) with head & neck squamous cell carcinoma (HNSCC) and might drive resistance to cytotoxics.

Methods

We have previously shown synergistic cell-cycle dependent effects between rapamycin/everolimus and carboplatin, or paclitaxel in HNSCC cells (Aissat 2008). Based on this preclinical translational rationale, a two-step phase I/II trial was designed using 9 consecutive weekly (w) cycles of oral everolimus combined with carboplatin (AUC2) and paclitaxel (60mg/m2) followed by chemoradiotherapy in pts with untreated locally advanced HNSCC.

Results

A total of 27 pts with stage IV HNSCC (median age 58, range 46-84; ECOG 0-2) have been enrolled in this phase I/II study (42 pts scheduled for the phase II). Among the 7 pts enrolled in the everolimus dose escalation phase I step, 6 pts were evaluable for safety (3pts at 30 mg/w and 3pts at 50 mg/w). No dose-limiting toxicity (defined during the first 4 weeks of treatment) was reported. Transient asymptomatic grade 3 neutropenia (3 pts), anemia (3 pts), and thrombocytopenia (1 pt) were observed. The most frequently reported adverse events were mild to moderate asthenia, skin toxicity, and alopecia. The recommended dose of everolimus for the phase II step was 50 mg/w. So far, among pts treated in the phase I/II, 11/13 objective responses (1CR, 10 PR, 2SD) were observed in evaluable pts. Interestingly, several major responses (ranging -60 to -80% by RECIST) were observed in large necrotic primary tumors and lymph nodes of >6cm diameters. Preliminary genetic analysis of tumors showed neither KRAS, BRAF, PI3KCA, nor EGFR mutations in tumors responding to this combination.

Conclusions

Weekly 50 mg everolimus combined with carboplatin and paclitaxel was well tolerated with no DLT, allowing repeated cycles. Major clinical responses in pts with bulky, locally advanced and necrotic diseases deserve further evaluation of this combination in pts with HNSCC. Updated results will be presented at meeting.

Disclosure

S. Faivre: Novartis, honorarium, compensated

E. Raymond: Novartis, honorarium, compensated

K. Slimane: Novartis, employment, compensated

All other authors have declared no conflicts of interest.

1018O
SAFETY AND EFFICACY OF CISPLATIN PLUS 5-FU AND CETUXIMAB IN HPV-POSITIVE AND HPV-NEGATIVE RECURRENT AND/OR METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (R/M SCCHN): ANALYSIS OF THE PHASE III EXTREME TRIAL

Abstract

Background

Tumor human papillomavirus (HPV) status is a strong predictor of survival and response to treatment in patients (pts) with early and locally advanced oropharyngeal cancer, but its effects in R/M SCCHN remain to be clarified. This retrospective analysis of data from the EXTREME trial assessed the role of tumor HPV status in pts with R/M SCCHN receiving cisplatin + 5-FU chemotherapy (CT) alone or in combination with cetuximab. Material and methods: Immunohistochemical detection of p16INK4A was used to determine HPV status: p16-positive and p16-negative disease is referred to as HPV-positive (HPV+) and HPV-negative (HPV-) disease, respectively.

Results

196/222 (88%) pts in the CT + cetuximab and 185/220 (84%) pts in the CT arm had tissue evaluable for p16. Of these, 91% and 88%, respectively, had HPV- tumors. Among HPV- pts, CT + cetuximab (n = 178) improved overall survival (OS), progression-free survival (PFS) and overall response rate (ORR), compared with CT (n = 162) (Table). A similar pattern was observed among HPV+ pts, between CT + cetuximab (n = 18) and CT (n = 23) for OS, PFS and ORR. Interaction tests between treatment and HPV status for OS and PFS confirmed that the treatment effect of CT + cetuximab vs CT was independent of tumor HPV status (p = 0.482 and p = 0.430, respectively: no significant interaction was noted). Within the CT + cetuximab and CT arms, HPV (p16) expression is associated with a more favorable outcome than HPV- (Table). In the CT + cetuximab arm, the overall incidence of grade 3/4 adverse events was slightly higher among HPV+ than HPV- pts.

Conclusions

Although the number of HPV+ pts in this analysis was low, the results suggest that in R/M SCCHN pts in the EXTREME trial, the survival benefits of CT + cetuximab vs CT are independent of tumor HPV status and HPV (p16) expression is associated with a more favorable outcome than HPV-.

Table: 1018O: Tumor HPV status: effects on prognosis and efficacy of CT + cetuximab and CT in R/M SCCHN.

Population Comparison OS PFS ORR 
CT + cetuximab vs CT 
HPV- (n = 340) Median (months)/rate (%) 9.7 7.3 5.7 3.1 37 17 
HR/odds ratio 95% CI p 0.822
(0.647–1.043)
0.1064 
0.486
(0.376–0.628) <0.0001 
2.753 (1.655–4.579) <0.0001 
HPV+ (n = 41) Median (months)/rate (%) 12.6 9.6 5.6 3.6 50 22 
HR/odds ratio 95% CI p 0.628
(0.295–1.338)
0.2241 
0.730
(0.363–1.469) 0.3761 
3.600
(0.929–13.953) 0.0614 
HPV+ vs HPV- 
CT + cetuximab
(n = 196) 
Median (months)/rate (%) 12.6 9.7 5.6 5.7 50 37 
HR/odds ratio 95% CI p 0.592
(0.319–1.098) 0.0925 
1.172 (0.685–2.005) 0.5624 1.738 (0.657–4.600) 0.2620 
CT (n = 185) Median (months)/rate (%) 9.6 7.3 3.6 3.1 22 17 
HR/odds ratio 95% CI p 0.827
(0.504–1.355) 0.4492 
0.871 (0.529–1.434) 0.5870 1.329 (0.455–3.880) 0.6025 
Population Comparison OS PFS ORR 
CT + cetuximab vs CT 
HPV- (n = 340) Median (months)/rate (%) 9.7 7.3 5.7 3.1 37 17 
HR/odds ratio 95% CI p 0.822
(0.647–1.043)
0.1064 
0.486
(0.376–0.628) <0.0001 
2.753 (1.655–4.579) <0.0001 
HPV+ (n = 41) Median (months)/rate (%) 12.6 9.6 5.6 3.6 50 22 
HR/odds ratio 95% CI p 0.628
(0.295–1.338)
0.2241 
0.730
(0.363–1.469) 0.3761 
3.600
(0.929–13.953) 0.0614 
HPV+ vs HPV- 
CT + cetuximab
(n = 196) 
Median (months)/rate (%) 12.6 9.7 5.6 5.7 50 37 
HR/odds ratio 95% CI p 0.592
(0.319–1.098) 0.0925 
1.172 (0.685–2.005) 0.5624 1.738 (0.657–4.600) 0.2620 
CT (n = 185) Median (months)/rate (%) 9.6 7.3 3.6 3.1 22 17 
HR/odds ratio 95% CI p 0.827
(0.504–1.355) 0.4492 
0.871 (0.529–1.434) 0.5870 1.329 (0.455–3.880) 0.6025 

Data are medians and hazard ratios (HR) for PFS and OS and rates and odds ratios for ORR. p: log-rank test for OS/PFS; Cochran-Mantel-Haenszel test for ORR.

Disclosure

B. De Blas: The author is an employee of Merck KGaA.

I. Celik: The author is an employee of Merck KGaA

J.B. Vermorken: I have participated in advisory boards of Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech and Sanofi-aventis and have lectured (compensated) for Merck-Serono, Amgen, Bristol-Myers Squibb and Sanofi-aventis

All other authors have declared no conflicts of interest.

1019O
HEALTHCARE ASSOCIATED INFECTIONS IN HEAD AND NECK CARCINOMA PATIENTS TREATED WITH CHEMOTHERAPY AND/OR RADIOTHERAPY

Abstract

Background

Healthcare associated infections (HAIs) cause prolonged hospitalization, treatment delay and/or interruption, mortality in cancer patients (pts). Head and neck carcinoma (HNC) pts are predisposed to infections due to risk factors such as malnutrition, comorbidity, immunocompromission, life-style, site of tumour and often the presence of CVC, trach- and gastrostomy. We aimed at HAIs, typing and reporting antibiotics susceptibility.

Table: 1019O
Infectious Site Gram + N 49 (35%) Gram - N 69 (49%) Fungi N 22 (16%) Total 140 (100%) 
Respiratory tract S. aureus 9 (15%) P. aeruginosa 18 (30%) Aspergillus species 2 (3%) 60 (43%) 
Corinebacterium species 3 (5%) Enterobacteriaceae 16 (27%)  
S. pneumoniae 3 ( 5%) H. influentiae 6 (10%)  
Others 3 (5%)   
Surgical S. aureus 5 (13%) P. aeruginosa 6 (15%) C. albicans 9 (22%) 40 (29%) 
Others 6 (15%) Enterobacteriaceae 5 (12%) C. species 5 (13%) 
  C. glabrata 4 (10%) 
Blood S. epidermidis 9 (26%) Enterobacteriacae 12 (34%) C. tropicalis 2 (6%) 35 (25%) 
S. aureus 4 (12%) P. aeruginosa 4 (11%)  
Others 4 (11%)   
Other S. aureus 4 (80%) G. vaginalis 1 (20%)  5 (3%) 
Infectious Site Gram + N 49 (35%) Gram - N 69 (49%) Fungi N 22 (16%) Total 140 (100%) 
Respiratory tract S. aureus 9 (15%) P. aeruginosa 18 (30%) Aspergillus species 2 (3%) 60 (43%) 
Corinebacterium species 3 (5%) Enterobacteriaceae 16 (27%)  
S. pneumoniae 3 ( 5%) H. influentiae 6 (10%)  
Others 3 (5%)   
Surgical S. aureus 5 (13%) P. aeruginosa 6 (15%) C. albicans 9 (22%) 40 (29%) 
Others 6 (15%) Enterobacteriaceae 5 (12%) C. species 5 (13%) 
  C. glabrata 4 (10%) 
Blood S. epidermidis 9 (26%) Enterobacteriacae 12 (34%) C. tropicalis 2 (6%) 35 (25%) 
S. aureus 4 (12%) P. aeruginosa 4 (11%)  
Others 4 (11%)   
Other S. aureus 4 (80%) G. vaginalis 1 (20%)  5 (3%) 

Materials and methods

We analyzed retrospectively 2288 HNC hospital admissions at our dept between 2005 and 2009. Pts admitted with a suspected infection were studied microbiologically. Contaminants were excluded.

Results

One hundred forty HAIs were confirmed in 84 admissions out of 71 pts. Thirty-three pts had more than 1 HAI (range 2-7) and 25 pts had concomitant HAIs (range 2-4). HAIs occurred in pts with advanced disease (56% stage III/IV) or recurrence (33%), during chemoradiotherapy (60%) or CT alone (28%). Moreover 74% of pts had CVC, 47% gastrostomy and 16% tracheostomy. We isolated 140 colonizers pathogens: 49% Gram -, 35% Gram + and 16% fungi. Table1 reports the frequency and site of infection by microrganisms. Eighty-eight percent of P. aeruginosa and 100% of Enterobacteriaceae were sensible to meropenem and piperacillin/tazobactam. Methicillin-resistant S. aurei (MRSA) were 42%, all responsive to daptomycin, linezolid, rifampicin, tetracycline, teicoplanin, vancomycin.

Conclusions

We observed more Gram- related HAIs, especially into the respiratory tract. The high frequency of MRSA may require to tailor antibiotics first approach of HNC pts treated with CT and/or RT.

Disclosure

All authors have declared no conflicts of interest.

1020PD
CONCOMITANT CHEMORADIOTHERAPY (CT/RT) OR CETUXIMAB/RT (CET/RT) WITH OR WITHOUT INDUCTION DOCETAXEL/CISPLATIN/5-FLUOROURACIL (TPF) IN LOCALLY ADVANCED HEAD AND NECK CANCER (LASCCHN). PRELIMINARY TOXICITY RESULTS OF A RANDOMIZED, 2X2 FACTORIAL, PHASE II-III STUDY. (NCT01086826)

Abstract

Background

CT/RT or CET/RT are standard treatment options for LASCCHN. Strategies to improve the efficacy with the integration of induction chemotherapy are being investigated. Primary endpoints of this study were to compare: 1) the 3 y overall survival (OS) of induction vs. no induction arms; 2) the Grade(G)3-4 in-field toxicity of CT/RT vs. CET/RT.

Methods

Patients (pts) with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CT/RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET/RT; Arm B1: 3 cycles of induction TPF followed by the same CT/RT; Arm B2: 3 cycles of induction TPF followed by CET/RT. A total of 204 deaths (420 ptsincluding the 101 randomized in the phase II part of the study comparing CT/RT with or w/o induction TPF) were required to detect a HR of death of 0.675 (A1 + A2 vs. B1 + B2; 2-sided a = 0.05; b = 0.20) and a 10% difference in G3-4 in-field mucosal toxicity (A1 + B1 vs. A2 + B2).

Results

Accrual was completed (421 pts) in April 2012. By May 2012, 348 patients were evaluable for toxicity during the planned concomitant treatments. 82% of pts were male; median age was 60y; PS of 0 (77.8%) or 1 (22.2%). Stage was III (31%) or IV (69%). Sites of disease were: oral cavity: 21.7%, oropharynx: 54.8%, hypopharynx: 23.5%. Data on G3-4 in-field toxicity (primary endpoint) and compliance to CT/RT vs CET/RT are shown in table 1.

 CT/RT N 215 CET/RT N 133 
In-field mucositis Grade 3 Grade 4 37% 4% 35% 2% 0.79 0.45 
In-field skin reaction Grade 3 Grade 4 13% 1% 20% 1% 0.07 0.58 
RT median dose, Gy (range) 70 (8-70) 70 (14-70) 0.32 
RT median duration, weeks (range) 7 (1-13) 8 (1-14) <0.01 
Pts with RT interruption >3days 32% 38% 0.22 
RT modification due to acute toxicity 37% 40% 0.58 
 CT/RT N 215 CET/RT N 133 
In-field mucositis Grade 3 Grade 4 37% 4% 35% 2% 0.79 0.45 
In-field skin reaction Grade 3 Grade 4 13% 1% 20% 1% 0.07 0.58 
RT median dose, Gy (range) 70 (8-70) 70 (14-70) 0.32 
RT median duration, weeks (range) 7 (1-13) 8 (1-14) <0.01 
Pts with RT interruption >3days 32% 38% 0.22 
RT modification due to acute toxicity 37% 40% 0.58 

Conclusions

No advantage for CET/RT over CT/RT were observed regarding G3-4 in-field toxicities and feasibility. Pts are still being followed-up to assess OS. Table 1:

Disclosure

All authors have declared no conflicts of interest.

1021PD
MODULATION OF THE PERITUMORAL MICROENVIRONMENT BY CETUXIMAB: A WINDOW PRE-OPERATIVE STUDY IN PATIENTS WITH SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN)

Abstract

Background

Only a subset of SCCHN pts benefits from anti-EGFR mAbs. Trials with pre- and post-therapy tumor biopsies (windows studies) in treatment-naïve patients are crucial to better characterize the molecular pathways involved in treatment response or resistance.

Methods

Cetuximab (C) (400mg/m2 first wk followed by 250mg/m2/wk) was given pre-operatively during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 0) to 20 treatment-naïve SCCHN pts selected for primary curative surgery. As controls, 5 additional pts were included without C treatment but with the same requirements regarding biopsies and imaging. Tumour biopsies, FDG/PET, and CT were performed at diagnosis and surgery. The aims of the study were (i) safety, (ii) C activity by FDG-PET (Po = 0.10, P1 = 0.35, a = 0.05 and b= 0.10) and (iii) translational research. We compared pathologic changes in surgical specimens of the C group with control specimens and correlated these results with microarray analysis performed on paired biopsies in the C group.

Results

C infusion given 24 hrs before surgery was safe. 90 % had a FDG-PET partial response (PR) (EORTC guideline) in the C group vs 0% in the controls. 52% had a ΔSUVmax decrease of >50%. In surgical specimens we detected modifications of the peritumoral environment. By immunochemistry, we found more fibrosis arranged in a compact manner in the C group than in the non-treated samples (histological score) (p = 0.04). Genome-wide expression analysis (Affymetrix HG U133 Plus 2.0) of the paired biopsies taken in the tumor center before and after C supports this histological observation. Results show a significant increase in expression (Student's T test p = 0.02; n = 20) of a previously published stroma signature (Finak et al., Breast Cancer Res 2006) after C. A trend was also observed between this stroma signature score and the fibrosis histological score.

Conclusions

Pre-operative study with C is safe. Our findings suggest that C induces quantitative modifications in the microenvironment of the tumor. We are currently investigating other components of the peri-tumoral environment (inflammation and vascularization).

Disclosure

J.P. Machiels: consultant/advisory role: Boehringer Ingelheim

All other authors have declared no conflicts of interest.

1022PD
PHASE II STUDY OF PEMETREXED PLUS CISPLATIN AND CETUXIMAB IN ADVANCED SQUAMOUS CELL CARCONIMA OF THE HEAD AND NECK

Abstract

Background

Patients (pts) with recurrent or metastatic SCCHN have a very poor prognosis. Platinum-based chemotherapy has long been standard treatment. Adding cetuximab to cisplatin-based combinations has improved overall survival (OS) and is currently standard treatment in SCCHN. In a phase III study, pemetrexed has shown benefit in SCCHN, particularly in performance status (PS) 0-1 pts.

Patients and methods

Pts who had no more than 1 prior systemic therapy for locally-advanced disease received cetuximab 250 mg/m2 (loading dose:400 mg/m2), pemetrexed 500 mg/m2, with vitamin supplementation, and cisplatin 75 mg/m2 day 1, up to 6 cycles. Pts completing at least 4 cycles had the option to receive maintenance with pemetrexed and cetuximab, or monotherapy, if toxicity occurred. Primary objective was progression-free survival (PFS); secondary objectives were OS, overall response rate (ORR) and safety. Sixty-five patients were needed to meet an objective median PFS of 5.5 months (mos.), with 90% power; 2-sided α of 0.05.

Results

Sixty-six Caucasians (53 male), median age of 62 years (42-87) received at least 1 dose of therapy. Nineteen pts had a PS of 0; 47 pts had a PS of 1. Median cycles received = 5.0 (1-27). Median PFS was 4.4 mos. (95% CI: 3.6, 5.4); median OS was 9.7 mos. (95% CI: 6.5, 13.1). Fifty-eight pts were evaluable for ORR analysis. ORR was 29.3% (95% CI: 18.1, 42.7); 1 complete response (1.7%); 16 partial responses (27.6%); 20 pts had stable disease (34.5%). An exploratory subgroup analysis showed larynx tumor pts had greater improvement in survival than non-larynx pts; median OS = 20.8 mos.(HR = 0.44; 95% CI= 0.20, 0.95); p = 0.032. Drug-related grade 3/4 toxicities included leukopenia (34.8%), neutropenia (33.4%), fatigue (24.2%), anorexia (12.1%) and hypomagnesemia (10.6%). There were 5 drug-related deaths (7.6%) on treatment (respiratory failure = 2; implant site hemorrhage = 1, sepsis = 1; death, not otherwise specified = 1).

Conclusions

Efficacy results were consistent with current standard treatment for SCCHN, but the pre-specified goal of median PFS of 5.5 mos. was not met. Although toxicities were consistent with the safety profiles of this combination, there were 5 deaths on treatment.

Disclosure

J.B. Vermorken: Dr. Jan B. Vermorken is a member of an advisory board for Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech and Sanofi-Aventis and has lectured (compensated) for Merck-Serono, Amgen, Bristol-Byers Squibb and Sanofi-Aventis.

T.C. Gauler: Dr. Gauler is an Advisory board member and received honoraria from Eli Lilly and Company.

J. Stoehlmacher-Williams: Dr. J. Stoehlmacher-Williams received honoraria for an advisory board and presentations, travel support and various translational research grants from Eli Lilly and Company.

J.M. Lopez-Picazo: Dr. Lopez-Picazo is an advisory board member for Eli Lilly and Company.

O. Hamid: Dr. Hamid is an employee of Eli Lilly and Company and has stock ownership.

A.M. Hossain: Anwar Hossain is an employee of Eli Lilly and Company and has stock ownership.

T. Burkholder: Tiana Burkholder is an employee of Eli Lilly and Company and has stock ownership.

S. Chang: Dr. Chang is an employee of Eli Lilly and Company and has stock ownership.

L. Licitra: Dr. Licitra served as an advisory board member and received research sponsorship from Eli Lilly and Company.

All other authors have declared no conflicts of interest.

1023PD
TEMSIROLIMUS IS ACTIVE IN REFRACTORY SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN) FAILING PLATINUM-BASED CHEMOTHERAPY AND CETUXIMAB: EFFICACY AND TOXICITY DATA FROM THE PHASE II TEMHEAD STUDY

Abstract

Background

Prognosis of patients with failure of cisplatin-based 1st line chemotherapy for recurrent or metastatic SCCHN remains poor. We therefore evaluated temsirolimus after failure of cisplatin and cetuximab in SCCHN.

Methods

Patients with progressive SCCHN and failure of platinum-based chemotherapy and cetuximab were eligible. Patients with loco-regional recurrence as the sole lesion had to have a progression free survival (PFS) of at least 6 months from last therapy. 18 years of age, ECOG 0-2, life expectancy of at least 3 months, and adequate organ function are key inclusion criteria. Brain metastases were allowed, provided local therapy has been completed successfully. Tumor assessment was performed every 6 weeks and assessed according to RECIST 1.0. Primary endpoint was the progression free survival rate (PFR) at 12 weeks >20%. Secondary endpoints were time to progression (TTP), objective response rate (ORR), overall survival and toxicity (according CTCAE 3.0). 25 mg temsirolimus was given i.v. weekly until progression or toxicity prevail. PFS, PFR, and OS estimates were calculated by Kaplan-Meier-Curves.

Results

A total of 42 patients entered the trial, of whom 40 were eligible. ECOG performance status of 0/1/2 was found in 7/29/5 pts and missing in 1 patient. Mean age was 61.6y (range: 42-79y) with male predominance (31 pts; 74%). Progression free survival rate at 12 weeks was 40% (CI95% 25-55%), TTP was 56 d (CI95% 36-113d), and OS 152d (CI95% 76-256d). Stable disease (SD) was obtained in 19 pts. (56%), progressive disease (PD) in 10 pts. (29%), 1 pts. was not evaluable for response, and 10 pts. had missing scans. Treatment with temsirolimus was well tolerated. Safety data will be presented at the meeting.

Conclusions

Temsirolimus reaches its prespecified endpoint with a PFR at 12weeks of 40%. Efficacy data is encouraging and compare to single agent cetuximab activity in platinum-refractory SCCHN. Further studies with this drug in SCCHN are warranted.

Disclosure

V. Grünwald: research funding: Pfizer Advisory Board: Merck KG

U. Keilholz: Research support and honorarium Whyeth / Pfizer.

T.C. Gauler: ADVISORY BOARD: MERCK KG, Pfizer HONORARIA: Pfizer

All other authors have declared no conflicts of interest.

1025P
PLASMATIC EPSTEIN-BARR VIRUS MICRO-RNA -BART-17 IN NASOPHARYNGEAL CARCINOMAS PATIENTS: HIGH POTENTIAL AS A TUMOR BIOMARKER ASSOCIATED TO EBV DNA CONCENTRATION

Abstract

Background

Because latent Epstein Barr (EBV)-infection is a specific characteristic of malignant Nasopharyngeal carcinoma (NPC) cells, various molecules of viral origin are obvious candidate biomarkers. EBV microRNAs are of particular interest because at least some of these (such as miR-BARTs) deregulate the expression of key cellular and viral genes.

Patients and methods

We performed RT- real-time quantitative PCR targeted on two cellular miRNAs (has miR16 and 146) and two viral miRNA (ebv-miR BART7 and 17-5p) after RNA extraction on plasma samples from 27 advanced NPC patients,10 patients with advanced head and neck Squamous cell carcinoma and 3 EBV healthy carriers.

Results

We showed presence of cellular miRNAs in all the samples, whereas viral miRNAs were mostly found in NPC patients plasma samples, with significant differences for ebv-miR-BART-17 (p = 9,69910−6 Wilcoxon test) but not for miR-BART7 and cellular miRNAs. A detection threshold of 0,3 ebv-miR-BART17 copy/plasma µL was specific for NPC diagnosis (ROC curve analysis (AUC= 0,919) with a sensitivity of 0.9259 and specificity of 0,973) There was no significant relationship between plasma concentrations of either ebv-DNA copy number or viral and cellular miRNAs and studied clinicopahtological factors.

Conclusion

miR-BART-17 concentrations seem specific of nasopharyngeal carcinomas and could bring additional information to viral DNA concentrations especially when DNA is undetectable. Further investigations are needed especially in the context of new generation immunoadpative treatment.

Disclosure

All authors have declared no conflicts of interest.

1026P
EXPRESSION PROFILING OF 21 BIOMOLECULES IN LOCALLY ADVANCED NASOPHARYNGEAL CARCINOMAS (LA-NPC) OF CAUCASIAN PATIENTS TREATED WITH CHEMOTHERAPY OR CHEMO-RADIOTHERAPY (CRT) IN THE CONTEXT OF A HELLENIC COOPERATIVE ONCOLOGY GROUP RANDOMIZED TRIAL

Abstract

Introduction

Since scarce data exist on the pathogenesis of NPC in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population.

Patients and methods

Formalin-Fixed Paraffin-Embedded tumor tissue samples from 107 patients, diagnosed with LA-NPC and treated with chemotherapy or CRT, were analyzed by immunohistochemistry (IHC) for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGFA, VEGFC, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-Akt, phospho-mTOR, and phospho-GSK3b. EBER status was assessed by in situ hybridization. The majority of cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 – 99.2) months.

Results

Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK3b, and Fascin-1. WHO II + III tumors were more frequently EBER & PTEN positive and VEGFA negative. Advanced age was significantly associated with positive phospho-GSK3b and ERCC1 expression, male gender with positive phospho-Akt and phospho-p44/42MAPK, and worse performance status (PS), 1 or 2, with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier TNM stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for Disease-Free Survival (DFS) (p = 0.034) and EBER as a positive one for Overall Survival (OS) (p = 0.048). In multivariate analysis, advanced age and stage, poor PS, and positive ERCC1 emerged as predictors of worse DFS and OS, as opposed to positive phospho-mTOR. Clustering analysis defined two protein-expression groups being predictive of better OS (p = 0.043).

Conclusion

Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets.

Disclosure

All authors have declared no conflicts of interest.

1027P
PRECLINICAL ANTI-TUMOR ACTIVITY OF XL880 IN NASOPHARYNGEAL CARCINOMA

Abstract

Background

Outcomes for locoregionally advanced nasopharyngeal carcinoma (NPC) patients have certainly improved with chemoradiation but eventually local and distant failure remains a very important clinical problem. An earlier study showed increased c-Met and VEGFR2 expression in NPC sample compared to normal nasopharyngeal tissue. XL880 (Foretinib, GSK1363089) is an oral, ATP-competitive small molecular inhibitor against multiple kinases, in particular c-Met and VEGFR2 that are involved in tumor cell growth, migration, and angiogenesis. The objective of this study was to investigate the therapeutic potential of XL880 in NPC.

Methods

Expressions of total and phosphorylated c-Met, VEGFR2, PDGFR, AXL and Tie-2 were evaluated by western blot in a panel of six NPC cell lines. The effect of XL880 on NPC cell proliferation was evaluated by Tilter-Glo luminescent Cell Viability Assay. We further studied the effect of XL880 on NPC cell cycle and apoptosis. In vivo activities of XL880 as single agent and in combination with Cetuximab were investigated in NPC xenografts.

Results

In vitro study showed that XL880 inhibited phosphorylation of both c-Met and VEGFR2. XL880 repressed the growth of both c-Met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. For the most XL880-sensitive NPC cell line (HK1-LMP1), which harbored the highest levels of both c-Met and VEGFR2, inhibition of cell growth was associated G0/G1 cell cycle arrest as well as significant downregulation of FAK, Mcl-1 and cyclin D1. XL880 eliminated ∼70% of tumor vasculature in xenograft models, inhibited tumor growth, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 decreased invasiveness of primary tumors and reduced metastasis. XL880 in combination with Cetuximab achieved greater antitumor responses than treatment with either agent alone in NPC xenograft models. Additionally, mRNA levels of EGFR ligands TGF alpha and Epiregulin were significantly downregulated by XL880 in vivo.

Conclusions

This is the first report of preclinical activity of c-Met/VEGFR2 inhibitor XL880 in NPC. LMP1 (latent membrane protein 1)-positive NPC shows a higher sensitivity to XL880. Further clinical investigation of XL880 is warranted in NPC patients.

Disclosure

All authors have declared no conflicts of interest.

1028P
PLASMA EBV DNA CONCENTRATION CORRELATES WITH FDG PET IN NASOPHARYNGEAL CARCINOMA TREATED WITH INDUCTION CHEMOTHERAPY

Abstract

Background

While local control rate in locally advanced NPC (LA-NPC) has improved with concurrent Cisplatin and IMRT, development of distant metastases remains common in these patients and limits survival. The role of induction chemotherapy in the treatment of LA- NPC is still a matter of debate. The aim of this retrospective review is to evaluate the effect of induction chemotherapy and to correlate between EBV-DNA concentration and tumor response by PET-CT.

Methods

Patients with stage III-IVB, WHO II/III received induction chemotherapy with 2 cycles of TPF : Docetaxel: 75 mg/m2, Cisplatin: 75 mg /m2, 5Fluorouracil: 750 mg / m2 CI for 96 hours followed 3-4 weeks later by concurrent weekly Cisplatin ( 40 mg /m2) and IMRT (GTV:70 Gy over 35 fractions). EBV-DNA quantification was performed at baseline and repeated before each cycle of TPF. PET scans were performed at baseline and repeated before IMRT. The max standard uptake values (SUV) were recorded in the primary tumors. Metabolic response was defined as a decrease in maximum SUV of 35% or more.

Results

20 patients with LA-NPC (75%Stage IVA/IVB) were reviewed. All but one completed therapy. Objective response, according to RECIST criteria: CR: 4; PR: 14 NE: 2. Median concentration of EBV-DNA was 11,300 copies /ml (range: 1,184 - 43,000). Post TPF, reduction of EBV-DNA copies by >50% was observed in 83% pts and 66% achieved complete biochemical response. In the FDG-avid tumor pts, the median SUV at baseline was 12 (range 10.5 - 17.4); post TPF metabolic response was observed in 100% and was complete in 33%.All patients with complete biochemical response had also a complete metabolic response by PET. At 2-year loco-regional progression free rate is 95% and 2 year overall survival rate is 85%. No recurrence was seen in complete (biochemical / metabolic) responders.

Conclusion

A negative post induction FDG-PET and complete biochemical response after TPF are of significant value in LA-NPC and are useful determinant to predict outcome.

Disclosure

All authors have declared no conflicts of interest.

1029P
CIRCULATING TUMOR CELLS (CTCS) IN PATIENTS WITH RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC): FREQUENCY, CLINICAL SIGNIFICANCE AND EGFR EXPRESSION

Abstract

Introduction

Recurrent/metastatic (R/M) HNSCC have a poor prognosis. Palliative chemotherapy is often used without adequate prognostic and predictive stratification due to the lack of validated predictors in this setting. Furthermore, anti-EGFR therapy is used under the assumption that more than 80% of the primary tumors overexpresses EGFR. CTCs have been identified as prognostic and predictive indicators in several metastatic cancers. We prospectively studied the frequency, clinical significance and EGFR expression of CTCs in pts with R/M HNSCC.

Patients and methods

Pts with local and/or distant relapse of HNSCC at first or second relapse were included between January 2009 and December 2011. CTCs were measured at baseline and at end of treatment or progression. CTCs analysis was performed with the CellSearch® system. The diagnostic performance of the system with squamous cancer cells was tested with cell lines spiking experiments. The CellSearch® fourth channel was used to analyze EGFR expression on CTCs.

Results

Fifty-three pts were evaluable for CTCs analysis and clinical response. CTCs were detected in 14 (26%) pts at baseline and in 22 (41%) pts at any time point. Median CTCs number was 1 CTC/7.5 mL. CTCs were not associated to any of the clinico-pathological variables considered. EGFR was expressed in 45% of CTC-positive pts. After treatment, CTC numbers decreased, remained stable and increased in 8%, 54% and 38% of pts, respectively. Baseline CTCs or their increase were predictive of stable or progressive disease (p .007). In 42 evaluable pts, baseline CTCs were prognostic indicators of worse progression-free (PFS) (3 vs 8 months, p .003) and overall (OS) (5 vs 10 months, p .013) survivals, respectively.

Conclusion

This study demonstrates that: a) low numbers of CTCs are detectable by CellSearch® in more than 40% of R/M HNSCC pts; b) CTCs at baseline or at any time point are independent predictors of poor PFS and OS; c) presence of CTCs during treatment is predictive of chemo-resistant disease; d) EGFR is expressed on CTCs with a high intra-sample and inter-patient variability. These results encourage further development of CTCs in this setting.

Disclosure

All authors have declared no conflicts of interest.

1030P
INSULIN GROWTH FACTOR RECEPTOR AS A PROGNOSTIC MARKER IN OPERABLE SQUAMOUS-CELL LARYNGEAL CANCER

Abstract

Introduction

Prognosis of patients with operable squamous-cell laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The Insulin-Growth Factor Receptor (IGFR)-mediated signaling pathway plays a critical role in laryngeal carcinogenesis.

Patients and methods

We identified all patients with localised TNM stage I-III laryngeal cancer managed with potentially curative laryngectomy between May 1985 and June 2008. Immunohistochemical (ICH) expression of IGFR1-alpha, IGFR1-beta and IGFR2 was evaluated using the Histo-score (H-score) climax and mRNA levels of important effectors of the IGFR-mediated pathway were assessed, including IGFR1, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MA2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PI3KCA, PI3KR1) families. Cox-regression models were applied to assess the predictive value of the components of the IGFR-mediated pathway on disease-free survival (DFS) and overall survival (OS).

Results

Among 289 eligible patients, 95.8% were male, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive diease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median H-score as the pre-defined cut-off value, IGFR1-alpha overexpression was associated with decreased DFS (p = 0.0538) and OS (p = 0.0157). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0209) and OS (p = 0.0108), as were increased mRNA levels of PI3KCA, albeit not significantly (p = 0.0723 and 0.0726 for DFS and OS respectively). In multivariate analysis, IGFR1-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, 95%CI: 1.610-4.100, p < 0.0001), subglotic or transglotic location (HR = 1.756, 95%CI: 1.016-3.036, p = 0.0438) and IGFR1-alpha IHC overexpression (HR = 1.475, 95%CI: 1.000-2.178, p = 0.05).

Conclusion

IGFR1-alpha IHC overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of IGFR1-alpha prognostic utility is warranted.

Disclosure

All authors have declared no conflicts of interest.

1031P
CYCLIN D1, EGFR AND AKT/MTOR SIGNALLING IN LOCALIZED LARYNGEAL SQUAMOUS CELL CARCINOMA

Abstract

Introduction

EGFR pathway, Akt/mTOR and Cyclin D1 are activated and interact in squamous cell head and neck cancer.

Patients and methods

We assessed relative mRNA expression of EGFR, Akt1, 2, 3, mTOR and cyclin D1, copy number variants of EGFR and CCND1 genes and immunohistochemical (IHC) expression of EGFR, pAKT308, pAKT473, pmTOR, PTEN, p53 and cyclin D1 in paraffin-embedded tissue of localized laryngeal carcinomas.

Results

In 289 patients with T3-4 (77.8%), node-negative (84.1%) tumours of the larynx, high EGFR and CCND1 mRNA correlated with never or ex smoking, (p = 0.003) and (p = 0.029) respectively, while low AKT3 correlated with alcohol abuse. At a median follow-up of 74.5 months, high mTOR RNA was marginally associated with shorter DFS, HR = 1.54, p = 0.093 and high Akt3 mRNA with shorter OS, HR = 1.49, p = 0.0786 whereas high EGFR IHC expression was associated with shorter DFS HR = 1.60, p = 0.0311 and OS HR = 1.57, p = 0.056, pAKT308 with shorter OS, HR = 1.003, p = 0.0586 and pAKT473 with shorter DFS HR = 1.004, p = 0.021 and OS HR = 1.004, p = 0.033, all in univariate analysis. An interaction between mRNA levels of mTOR and cyclin D1 was found to be associated with shorter DFS, namely at high mTOR mRNA expression, one unit increase of CCND1 mRNA expression had a HR = 2.16 and this remained statistically significant in multivariate analysis (p-value for interaction = 0.0010). In multivariate analysis, node-positive status, subglottic-transglottic localization, surgery other than total laryngectomy and mTOR/cyclin D1 mRNA interaction, were independent predictors of relapse, while node-positive status, and subglottic-transglottic localization were associated with higher risk of death.

Conclusions

In laryngeal cancer, an interaction of high mTOR and cyclin D1 mRNA expression is associated with poor patient outcome.

Disclosure

All authors have declared no conflicts of interest.

1032P
GENOME-WIDE ASSOCIATION STUDY OF BASE OF TONGUE SQUAMOUS CELL CARCINOMA RISK

Abstract

Background

Inherited genetic alterations, such as single nucleotide polymorphisms (SNPs), were described in association with oropharyngeal cancer risk. However, existing studies have analyzed a limited number of genetic variants. Base of tongue (BT) squamous cell carcinoma (SCC) is a common tumor of oropharynx; however, the association of SNPs and BTSCC risk is still not clarified and, therefore, this was the aim of the present study.

Methods

Genomic DNA of 49 BTSCC patients and 49 controls was extracted from peripheral blood samples using the QIamp kit (Qiagen®). Each sample was genotyped individually using DNA high-resolution microarrays containing 500.568 SNPs (SNP array 5.0, Affymetrix®). Further sample processing, including digestion, adaptor ligation, amplification, fragmentation, labeling, hybridization, washing and scanning was assayed according to the standard protocol. Genotype data were acquired by genotyping calling of samples using the crlmm algorithm provided by Bioconductor software. The differences between groups were analyzed by the logistic regression model. The SNPs localized in genes of interest were selected by data base analysis in DAVID and NCBI websites. The validation of selected SNPs was performed by RT-PCR, using TaqMan® SNP Genotyping Assays (Applied Biosystems®) in all samples studied.

Results

We observed 6.609 SNPs with distinct frequencies between BTSCC patients and controls. Fifty-two SNPs (0.8%) were located in coding sequence (CDS), 51 (0.8%) in 3' and 5'-untranslated regions (UTR), 3.461 (52.4%) in up or downstream regions (DWS) and 3.045 (46.0%) in introns. Ten SNPs were selected for validation and eight of them were validated, evidencing those localized in genes related to cell cycle (3'-UTR: ERP29, rs7114; MCC, rs7033; DWS: LEF1, rs2107028 and rs4245926; PTCH1, rs16909856 and rs16909859) and transcription process (CDS: IKBKAP, rs3204145; 3'-UTR: ZNF415, rs3814).

Conclusions

Our preliminary results suggest that SNPs in genes involved in tumor origin and development may predispose individuals to BTSCC in southeastern Brazil. However, the roles of these SNPs in BTSCC susceptibility should be confirmed by functional protein studies and validated in larger epidemiological studies from distinct parts of the world. Financial support: FAPESP and FINEP.

Disclosure

All authors have declared no conflicts of interest.

1033P
HYPOXIA AND METABOLISM GENE EXPRESSION PROFILE PREDICTS POOR SURVIVAL IN HEAD AND NECK CARCINOMA

Abstract

Background

Despite multimodal treatments combining surgery, radiotherapy, chemotherapy and now targeted therapies, head and neck squamous cell carcinomas (HNSCC) remain of poor prognosis. Hypoxia being an important biological characteristics of many HNSCC, we aimed to assess the prognostic value of the expression of 42 genes related to hypoxia and metabolism in non metastatic HNSCC.

Patients and methods

Expression of 42 genes was retrospectively analyzed by high throughput real-time PCR in 80 patients treated for a non metastatic HNSCC. Fresh tissue samples were collected at diagnosis. After extraction, RNA quality was evaluated by an Agilent 2100® Bioanalyzer. After reverse transcription of total RNA, cDNA were analysed using a 1536 LightCycler®. An unsupervised hierarchical clustering analysis was performed. Usual prognostic factors and clustering analysis results were related to overall survival (OS).

Results

Only 61 patients presented suitable quality RNA for gene expression analysis. With a median follow-up of 39.4 months, 41 patients were alive and 20 were dead of cancer evolution. Among usual prognostic factors, capsular rupture of involved nodes and lymphovascular invasion were related to poor OS (p = 0.008, p = 0.03, respectively). Gene expression profile distinguished 2 groups. The group 1 composed of 34 patients (7 dead, 27 alive) had a better OS than the group 2 composed of 27 patients (13 dead, 14 alive) (2 years OS = 85.3% and 2 years OS = 63.0%, respectively, p = 0.02). The group 1 had frequent overexpression of genes related to inflammation (SDF1, CXCR4, EP4). The group 2 had frequent overexpression of genes related to lactate metabolism (LDHA, GLUT1, HK2), hypoxia (HIF1, BNIP3) or pH regulation (CA9, MCT1). Multivariate analysis based on the usual prognostic factors and the clustering analysis confirmed that capsular rupture, lymphovascular invasion and gene expression profile were related to poor OS (p = 0.005, p = 0.02, p = 0.003, respectively).

Conclusion

In this cohort, clustering analysis underlined the prognostic value of hypoxia and lactate metabolism gene expression. If confirmed by further studies, tumor metabolism in HNSCC may become a promising target for anticancer drugs.

Disclosure

All authors have declared no conflicts of interest.

1034P
STUDY ON ASSOCIATION OF POLYMORPHISM OF CYP P 450 2D6 WITH HEAD AND NECK CANCER AND TREATMENT RESPONSE IN PATIENTS RECEIVING NEOADJUVANT CHEMOTHERAPY (TPF) FOLLOWED BY CHEMORADIATION

Abstract

Aim of study

1.To study the association of genetic polymorphism in Cyp 2D6 in patients of locally advanced head and neck cancer. 2. Try to assess a correlation between this polymorphism & response to treatment. Need of the study- To find out a possible genetic level explanation for the different response achieved in patients with similar histopathology, stage, exposure to carcinogen & ethinicity undergoing similar treatment.

Material & method

A study comprising of 150 patients & 150 controls was done to analyse the association between polymorphs of Cyp 450 2d6 with Head & neck cancer and treatment response (TPF- > CTRT). Two cycles of TPF(paclitaxel-175 mg/m2 D1,cisplatin 35 mg/m2 D2-D3 and 5Fu 1gm/m2 D1-D3 ) were given followed by radiotherapy with concurrent cisplatin (40 mg/m2).The response to the treatment was assessed clinically, radiologically & by laryngoscopy- post treatment .Genotyping of the blood samples was done. Analysis of the association between genetic polymorphisms and risk of HNSCC was estimated by calculating crude odds ratio (OR). A p-value of <0.05 was considered statistically significant. The statistical analysis was performed with the SPSS software package (version 11.0 for Windows; SPSS Chicago, IL).

Results

1. Patients with Cyp 2D6*1 showed good response to the therapy given, while Cyp 2D6*4 and *10 were poor responders.

Conclusion

1. There is a strong association of polymorphs of Cyp 2D6 (*4 &*10) with occurrence of head and neck cancer. 2. Response to treatment (TPF- > CT + RT) is polymorph graded. Our study, thus provides an insight in to the concept of “Right therapy to the right patient” & may also explain to the fact that why, only some people are more prone to develop head and neck cancer despite the usage of tobacco,alcohol by so many people.

Disclosure

All authors have declared no conflicts of interest.

1035P
THE RANDOMIZED STUDY COMPARING THE EFFICACY AND SAFETY OF RADIO-CHEMOTHERAPY PLUS ADJUVANT CHEMOTHERAPY (CCRT) VS. NEO-ADJUVANT CHEMOTHERAPY PLUS RADIO-CHEMOTHERAPY (NAC-RT) FOR LOCALLY ADVANCED NASOPHARYNGEAL CANCER

Abstract

Purpose

Nasopharyngeal carcinoma is radio-chemosensitive. Local control and survival of patients with advanced disease treated by radiotherapy alone remains unsatisfactory. Chemotherapy has been combined with radiotherapy to increase local-regional control, decrease distant metastasis, and improve survival of the patients. We have developed a randomized trial comparing the efficacy and toxicities of CCRT versus NAC-RT for locally advanced nasopharyngeal cancer.

Patients and methods

A total of 175 patients were included in the study. The 87 patients received concurrent radio-chemotherapy daily 70 Gy/7 weeks with cisplatin 100 mg/m2 q 3 weeks then followed by adjuvant chemotherapy for 3 cycles (q 3 weeks), consisting of cisplatin 80 mg/m2 on day 1 and 5-FU 1,000 mg/m2 on day 1-4. The 88 patients received neoadjuvant chemotherapy for 3 cycles (q 3 weeks) consisting of docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and 5-FU 750 mg/m2 on days 1- 4 followed by concurrent radiotherapy daily 70 Gy/7 weeks with carboplatin AUC 1.5 weekly for 6 weeks.

Results

The number of patients who completed treatment for the CCRT group was 34 (39.1%) and for the NAC-RT group was 54 (61.4%). The most common reasons for study discontinuation were adverse events and patient's willingness. The grade 3 and 4 treatment-related adverse events were two times higher in the CCRT group (p < 0.06), mostly mucositis / stomatitis and nausea / vomiting. There was no difference in hematologic adverse events between groups. The 1-year progression-free survival rate was 91.8% and 89.3% in the CCRT and NAC-RT group, respectively. No evidence of disease at the time of this interim analysis was found in 76.5% in the CCRT group and 85.2% in the NAC-RT group.

Conclusion

Induction chemotherapy with docetaxel / cisplatin and 5-fluoro-uracil followed by concurrent radio-chemotherapy was tolerable and provided well control of disease. These interim early results revealed no difference in PFS but less side effects and increase number of the patients with no evidence of disease in the NAC-RT arm.

Disclosure

All authors have declared no conflicts of interest.

1036P
INDUCTION THERAPY WITH CETUXIMAB, DOCETAXEL, CISPLATIN, AND FLUOROURACIL IN PATIENTS WITH RESECTABLE NON METASTATIC STAGE III OR IV SQUAMOUS CELL CARCINOMA OF THE OROPHARYNX. A GERCOR PHASE II STUDY

Abstract

Background

Docetaxel/cisplatin/5-FU (TPF) has been reported to be more active than cisplatin/5-FU in Squamous Cell Carcinoma (SCC) of the head and neck (HN). A clinical Complete Response (CR) rate of 8.5% was achieved after TPF induction therapy (IT) in patients (pts) with unresectable pharyngolaryngeal SCC (Vermorken et al, NEJM 2007). EGFR is overexpressed in up to 90% of HN cancers. Cetuximab (Cet) was active in combination with radiotherapy and with cisplatin. The aim of this multicenter single-arm phase II study was to evaluate Cet with TPF as IT in oropharyngeal SCC.

Methods

Main inclusion criteria were: previously untreated histologically proven oropharyngeal SCC, non-metastatic stage III or IV disease (UICC 2002), surgically resectable, age 18-75 years, ECOG Performance Status (PS) 0-1. Pts received Cet iv /1-2h (400 mg/m2 loading dose, then weekly 250 mg/m2) followed by docetaxel iv 75mg/m2 /1h and cisplatin iv 75mg/m2 /1h (day 1); and 5-FU iv 750mg/m2/day continuously (days 1-5), every 3 weeks for 3 courses. After completion of IT, the treatment of the primitive tumor was at the investigator's discretion. The primary endpoint was the clinical and radiological CR of primitive tumor at 3 months. Correlative studies investigated several EGFR-related biomarkers and HPV analyses in tumor and blood samples.

Results

Among 42 pts enrolled from 07/2008 to 11/2011 in 9 centers, 41 pts were treated. The main pts characteristics were: male 81%, mean age 56y, PS0 79%, tonsil area 88%, stage III/IV 76%/24%. The planned 9 infusions were given in 31 (76%) pts. A clinical and radiological CR of the primitive tumor at 3 months was achieved in 9 (22%) pts, and a clinical CR in 17 (41%) pts. The most frequent G3-4 toxicities were: neutropenia (39%), febrile neutropenia (20%), diarrhea (10%), and mucositis (12%). Any grade acnea-like syndrome was observed in 18 (44%) pts. One toxic death occurred secondary to chemo-induced colitis with colonic perforation.

Conclusions

The combination of cetuximab with TPF is highly active. A systematic therapy with granulocyte colony-stimulating factor is necessary to prevent febrile neutropenia.

Disclosure

All authors have declared no conflicts of interest.

1037P
DOCETAXEL, CARBOPLATIN AND FLUORO-URACIL (TCF) INDUCTION THERAPY IN LOCALLY ADVANCED HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) PATIENTS WITH CONTRAINDICATION FOR CISPLATIN BASED COMBINATION (TPF)

Abstract

Background

TPF regimen is a standard induction combination for fit locally advanced HNSCC patients (pts). TCF with carboplatin may be an option in frail pts with contraindication for cisplatin, but data are missing about safety and efficacy of such an approach.

Method

Retrospective study of monocentric cohort of HNSCC patients treated from 2007 to 2011 with TCF induction regimen at Gustave Roussy Institute. TCF regimen combined Docetaxel 75mg/m2, Carboplatin AUC4, and 5FU: 750 mg/m2/day for 5 days.

Results

Population included 34 pts, median age 59 years (44-78), all with Charlson Comorbidity Index score ≥ 2, with oropharynx, hypopharynx, oral cavity, larynx and paranasal sinuses HNSCC localization (32.3, 23.5, 17.6, 14.7 and 11.8% respectively). TNM stage were: T1-2 : 4 pts (11.7%), T3-4: 27 pts (79.4%), rTx: 3 pts (8.8%); N0: 8 pts (23.5%), N1: 4 pts (11.8%), N2a-N2b: 6 pts (17.6%), N2c-N3: 13 pts (38.2%); M1: 1 pt (2.9%). TPF contraindications were respiratory disease (di.) (11 pts: 32.3%), heart di. (6 pts: 17.6%), liver di. (3 pts: 8.8%), alcohol related neuropathy (3 pts: 8.8%), hearing di. (5 pts: 14.7%), renal di. (5 pts: 14.7%), other co-morbidities (3 pts: 8.8%).Patients received 2 to 4 cycles of TCF. GCSF was delivered in 31 pts (91.2%). Cumulated incidence of Grade 3-4 toxicity was 37.2%, and one toxic death occurred at C2. Five pts (14.7%) stopped treatment because of toxicity. RECIST evaluation found complete response in 1 patient (2.9%), partial response in 23 pts (67.6%), stable disease in 6 pts (17.7%), and progression disease in 1 pt (2.9%). Subsequent treatment was surgery followed by radiotherapy (9 pts, 26.5%), radiotherapy or chemoradiotherapy (22 pts, 64.7%), chemotherapy (3 pts, 8.8%). Response after RT was: CR: 16 pts (64%), PR: 4 pts (16 %), SD: 3 pts (12 %), PD: 2 pts (8 %). Median recurrence-free survival was 8.7 months, median overall survival (OS): 22.9 months. Personal history of cancer (HR = 4.6, p = 0.02), tobacco (HR = 37.5, p = 0.04), alcohol intake (HR = 0.12, p = 0.01), hypertension ( HR = 4.4, p = 0.01), T4 stage ( HR = 0.1, p = 0.02), N2c-N3 stage (HR = 18.5, p = 0.003), BMI < 20 (HR = 9.6, p = 0.02) and lymphopenia (HR = 4.3, p = 0.01) were associated with OS in multivariate analysis.

Conclusion

TCF induction regimen was manageable and provided objective responses in 70% of frail HNSCC patients.

Disclosure

All authors have declared no conflicts of interest.

1038P
INDUCTION CHEMOTHERAPY WITH DOCETAXEL, CISPLATIN AND 5-FLUOROURACIL FOLLOWED BY RADIOTHERAPY WITH CETUXIMAB FOR LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Abstract

Purpose

To determine the efficacy and feasibility of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab in patients with locally advanced head and neck cancer.

Patients and methods

Forty-nine previously untreated patients (median age: 53 years) with local advanced stage III and IV squamous cell carcinoma of the head and neck received three courses of induction chemotherapy consisting of docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and infusional 5-Fluorouracil 750 mg/m2/day on days 1-5 followed by radiotherapy plus cetuximab at 250mg/m2/week (after an initial loading dose of 400mg/m2). Patients with an ECOG performance score of 0 or 1 without severe co-morbidities adequate hematopoietic, hepatic, and renal functions were eligible.

Results

After completion of induction chemotherapy 44 of 49 patients received radiotherapy plus cetuximab. In 45 patients ICT was delivered without delay or dose reduction and 38 patients received RT at the full dose. Three months after therapy completion tumor response was observed in 33 patients and after 2 years, 25 patients were in complete remission. Although treatment was accompanied with a rate of grate 3 and 4 toxicity of 30% during induction chemotherapy and up to 68% during radiotherapy with cetuximab, our treatment seems feasible. Toxicities resolved within 3 months after end of treatment and only two patients became dependent on gastric feeding tubes after two years, compared to 21 patients during treatment. We lost one patient because of treatment related toxicity and 73% of the 49 included patients finished treatment without dose reduction or delay of treatment. 2-year progression-free survival rate was 59% and 2-year overall survival rate was 63%, respectively.

Conclusion

Concurrent radiotherapy plus cetuximab after three courses of induction chemotherapy was feasible and associated with promising complete remission, progression-free and overall survival rates. Further optimization of dose and sequence is warranted.

Disclosure

All authors have declared no conflicts of interest.

1039P
INDUCTION CHEMOTHERAPY USING DOCETAXEL, CISPLATIN AND FLUOROURACIL (TPF) FOLLOWED BY CONCOMITANT CHEMORADIOTHERAPY VS THE SAME CONCOMITANT CHEMORADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (LASCCHN)

Abstract

Background

Concomitant chemoradiotherapy (CCRT) with cisplatin is considered a standard treatment of LASCCHN. The role of induction chemotherapy (IC) followed by CCRT remains controversial. Our aim was to compare neoadjuvant chemotherapy with 3 cycles of TPF followed by CCRT to CCRT alone. The 1ry objective of the study was ORR and the 2ry objectives were toxicity, PFS and OS.

Patients and methods

Between 2006 & 2008, 100 patients with histologically proven SCC of the Head & Neck (stage IIB-IVA) were enrolled. WHO PS 0-1, with adequate bone marrow, liver and kidney functions. Fifty patients received 3 cycles of IC including docetaxel 75 mg/m2 IV over 1h D1, cisplatin 75mg/m2 IV over 3h D1 and 5-FU 750 mg/m2 IV continuous infusion over 24h D1-5 (repeated every 3 wks). Premedications before and after docetaxel and cisplatin with prophylactic antibiotic on D5 and G-CSF on D6. This was followed by CCRT in the form of radiotherapy using conventional fractionation (2Gy/day, 5 fr/week, total dose of 70Gy) with concurrent weekly cisplatin 20 mg/m2 IV (Gp A). In gp B, patients received CCRT alone. Response was assessed by physical examination, CT scan and endoscopy after 2 cycles, after completion of IC, and 6-8 wks after completion of CCRT.

Results

All patients in both gps had completed the treatment schedule and were evaluable for response, toxicity and survival. The median age was 44.5 years in both gps (range 27-62). Seventy percent of patients had PS 0, 65 patients had cervical LN involvement (N2-3). The ORR after the completion of CCRT were 88% & 68% in the two groups respectively. Toxicity was manageable in both groups. The main severe toxicities during IC were G3 alopecia and neutropenia. During CCRT, the most severe side effects in both groups were mucositis and weight loss. The 2-year PFS and OS rates were 70%, 86% and 75%, 80% respectively.

Conclusion

Induction chemotherapy using TPF followed by CCRT is safe, tolerable and effective treatment and can significantly improve survival in patients with LASSCHN.

Disclosure

All authors have declared no conflicts of interest.

1040P
THE IMPACT OF INDUCTION CHEMOTHERAPY ON CISPLATION DOSE INTENSITY DURING CHEMO-RADIOTHERAPY (CTRT) IN OROPHARYNGEAL SQUAMOUS CELL CANCER (OPC)

Abstract

Background

Induction (IC) with TPF (Taxotere, Cisplatin, 5-FU) has been associated with improved outcome in advanced head and neck squamous cell cancer patients (pts). Full dose of cisplatin (300 mg/m2) during CTRT has been demonstrated to impact on patients' outcome. The aim of the current study is to investigate whether the IC could impact on cisplatin dose intensity during CTRT in a homogeneous population of OPC.

Materials and methods

The study population consisted of 101 pts with stage III-IV OPC treated from 07/2004 to 12/2011 with IC (n = 53) plus CTRT or CTRT alone (n= 48). IC consisted of TPF, while weekly 50 mg/m2 or 3-weekly 100 mg/m2 cisplatin was administered concurrently with RT (planned chemotherapy dose = 300 mg/m2; planned RT dose = 66-70 Gy, 3DRT or IMRT with a conventional or accelerated fractionation). Carboplatin substituted cisplatin in case of creatinine clearance less than 60 mL/min. HPV status, concurrent cisplatin dose intensity and RT overall treatment time (OTT) were analyzed.

Results

Stage IV pts were 100% in the IC group and 83% in CTRT, while HPV positive OPCs were detected in 58% and 63% of the cases respectively. TPF median number of cycles was 3, with induction cisplatin median dose administered of 200 mg/ m2. RT median total dose administered was 70 Gy in both group. Accelerated fractionated RT was adopted in 65% of CTRT alone group and in 21% of IC group. Two pts (1 in each group) did not complete CTRT because of cardiovascular events. Mean and median dose intensity of cisplatin concurrent to RT in the IC group was 77.7% and 75% (35%-100%) while in CTRT group was 86% and 91.7% (33%-100%), with a p value = 0.014. In 11 pts (21%) treated with IC and only in 1 pts (2%) treated with CTRT alone cisplatin was substituted with carboplatin. No different cisplatin dose intensity was identified in HPV positive versus HPV negative cases. Prolonged OTT (longer than 5 days) was observed in two patients in IC group due to sepsis and severe mucositis as well as in one patient in CTRT group due to machine failure.

Conclusions

Concurrent cisplatin dose intensity was significantly reduced in pts receiving IC compared to CTRT alone, irrespective of HPV status. Whether this has an impact on the results of IC followed by full dose CT/RT has to be clarified.

Disclosure

All authors have declared no conflicts of interest.

1041P
THE TOLERANCE OF TPF CHEMOTHERAPY REGIME STANDARD OR MODIFIED IN HEAD NECK CANCER PATIENTS OVER 65 YEARS OLD

Abstract

Background

Docetaxel, Cisplatin, 5FU regimen (TPF) has became a standard for induction chemotherapy in locally advanced squamous cell cancer of head and neck (SCCHN). However, little is known about tolerance and efficacy of TPF in older patients Objective of the study was to evaluate the tolerance of induction chemotherapy with TPF regimen in SCCHN patients over 65 years, looking for side effects especially degree 3 and 4.

Materials and methods

retrospective study of the database of Head and Neck Cancer Department of Gustave Roussy Institute between 2006 and 2009: all patients over 65 years who received a TPF induction chemotherapy were included.

Results

Among 300 patients treated with TPF induction chemotherapy, we found 57 pts over 65 years : 41 (70%)between 65 - 70, 9 (15%)between 70 - 75 and 7 (12%)over 75. Most of patients received an organ preservation treatment for T3N0-1M0 hypopharynx and larynx cancer (52%) . 30 pts had an impaired nutritional status and 37(64%) an ACE 27 index superior of 2. 40 pts (70%) accomplished their planed cycles but only 37( 65%) received the planed doses. 23 pts (41%) presented a grade 3 or 4 hematological or gastrointestinal adverse events and 5 toxic deaths were observed.

Conclusion

This retrospective study confirms the high risk of toxicity of induction chemotherapy with TPF combination in elderly SCCHN patients that may compromise the postsurgical outcome in patients over 65 years presenting at least one comorbidity and denutrition. Geriatric assessment is probably useful in this population to better select candidates to induction chemotherapy.

Disclosure

All authors have declared no conflicts of interest.

1042P
SERIAL COMPREHENSIVE GERIATRIC EVALUATION IN ELDERLY HEAD AND NECK CANCER PATIENTS UNDERGOING RADIOTHERAPY

Abstract

Background

Elderly head and neck (H&N) cancer patients can present with significant co-morbidities whilst treatment induces additional morbidity. Comprehensive geriatric assessment (CGA) has been proposed as a key treatment approach in elderly cancer patients. We studied the feasibility of serial CGA during radiotherapy in this population.

Material and methods

Patients aged ≥ 65 years with primary H&N cancer undergoing curative radiotherapy (with or without systemic treatment), were evaluated by the screening instruments Vulnerable Elders Survey-13 (VES-13) and G8, and CGA, at baseline and in the 4th week of their treatment at General Hospital Groeninge or Ghent University Hospital.

Results

Ninety eligible patients with a median age of 72 (range 65-87) consented. Patients mostly presented with an advanced stage tumour (67.8%, stage III-IV) of the larynx (46.7%) and pharynx (32.2%). Thirteen patients declined assessment in the 4th week of therapy. Of those patients, one withdrew from further study participation, one died and in two patients, a change of therapeutic intent was indicated. Nine patients declined because they felt too ill. At baseline, 40.3%, 64.9% and 71.4% of patients were defined vulnerable, based on respectively VES-13 (cut-off ≥3), G8 (cut-off ≤14) and CGA (defined as impairments in two or more domains). Significantly more patients were considered vulnerable at week 4 by VES-13 (55.8%, P < 0.0001), G8 (90.9%, P < 0.0001) and CGA (81.8%, P < 0.05). Patients presented with deficits in the following domains: co-morbidity (CIRS-G), nutrition (MNA), community functioning (IADL), physical status (Tinetti), self-care (ADL), emotional wellbeing (GDS) and cognition (MMSE) at both points in time. In addition, the incidence of vulnerability in all health domains increased during treatment, with especially deterioration of nutritional (P < 0.0001), functional (P < 0.0001), mental (P < 0.01) and emotional (P < 0.01) status.

Conclusion

Serial CGA identifies multidimensional health problems and their evolution during radiotherapy. It indicates the need for re-evaluation of a patient's health status and could guide intensive supportive care in elderly patients treated for H&N cancer. Acknowledgement: Our work is supported by a grant from the Belgian Government, National Cancer Plan (NKP_024_018).

Disclosure

All authors have declared no conflicts of interest.

1043P
PHASE II STUDY OF BIWEEKLY DOSE-INTENSE PACLITAXEL PLUS GEMCITABINE (GEM/TAX) IN PATIENTS WITH RECURRENT LOCOREGIONAL OR METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA

Abstract

Background

Patients with metastatic head and neck squamous cell carcinoma (HNSCC) have a poor prognosis, limited treatment options, and median survival of 6 to 9 months. Paclitaxel (TAX) and gemcitabine (GEM) have both shown activity in HNSCC. The optimal combination, dosing, and scheduling of both drugs is, however, unknown. Thus, we investigated the efficacy and safety of biweekly dose-intense GEM/TAX in patients with recurrent locoregional or metastatic HNSCC.

Methods

An open-label, single-institution, single-arm, phase II study was conducted for patients (pts) who were previously treated with no more than two cytotoxic regimens. The pts received paclitaxel (150 mg/m2IV) and gemcitabine (3000 mg/m2 IV) on day 1 and 15. The treatments were repeated every 28 days (one cycle), until disease progression or unacceptable toxicity. The primary end point was response rate. RECIST-defined response was evaluated every 2 cycles (8 wks) and toxicities were evaluated after each cycle (4 wks).

Results

Fifty-five pts were enrolled into the trial (M: F 42:13, median age (range): 56 years (23-84), performance status 0-2, 48 pts had previous radiation therapy and 39 had previous surgery), 41 of whom were response evaluable. Of these 41 patients, two pts (4.8%) achieved complete response (CR) and 17 (41.4%) demonstrated a partial response (PR). Thus, the overall response rate was 46%. Thirteen pts (31.7%) had stable disease (SD), resulting in tumor control in 32 of 41 pts (78% with CR, PR or SD), whereas 9 pts (21.1%) had disease progression (PD). Among those pts who achieved objective response or stable disease, the median response duration was 5 months and median time to progression was 4 months. Median overall survival (OS) was 15 months. Myelosuppression was the most common adverse event. Grade 3-4 neutropenia and anemia were observed in 5 (12%) and 11 (26%) pts, respectively. Eight (19%) pts developed grade 3 infection. None of these pts, however, had febrile neutropenia and there were no treatment-related deaths.

Conclusions

The combination of biweekly dose intense GEM/TAX was tolerable and active regimen in patients with recurrent locoregional or metastatic HNSCC. Our findings warrant further investigation in a larger patient population.

Disclosure

All authors have declared no conflicts of interest.

1044P
PHASE IB TRIAL OF IMO-2055 IN COMBINATION WITH 5-FU, CISPLATIN AND CETUXIMAB IN 1ST-LINE PTS WITH RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (R/M SCCHN)

Abstract

Purpose

IMO-2055 is a toll-like receptor 9 agonist with potential to enhance the efficacy of antitumor agents through immune stimulation.

Methods

IMO-2055 was administered to 1st-line pts with R/M SCCHN on days 1, 8 and 15 of each 3-wk cycle in combination with 5-FU, cisplatin and cetuximab. IMO-2055 doses were to be escalated (3 + 3 design) from dose level (DL) 1 (0.16 mg/kg) to DL2 (0.32 mg/kg) and DL3 (0.48 mg/kg) if <1/3 pts or <2/6 pts in the previous DL had dose-limiting toxicities (DLTs). DLTs were defined as any Gr3/4 treatment-related toxicity in cycle 1 confirmed by the safety monitoring committee (SMC). Expansion cohorts were planned at DL1 and at the maximum tolerated dose (MTD) level. A maximum of 6 cycles of combined treatment was planned; pts were to continue cetuximab and IMO-2055 until disease progression. Primary objective was to determine the MTD; other objectives included evaluation of safety profile, PK and antitumor effects.

Results

13 pts (1 F, 12 M) with a median age of 59 (range 42-67) yr received IMO-2055. No DLTs occurred at DL1 (n = 3); at DL2 (n = 4), 2/4 pts experienced DLTs. Although during the DL1 expansion cohort (n = 6), only 1 pt experienced DLTs, the overall safety profile of the combined treatment led to early trial termination. Formally, DL1 (0.16 mg/kg IMO-2055) can be considered as the MTD although it was not confirmed by the SMC, as the trial was prematurely stopped. 12 (92%) pts experienced Gr ≥ 3 treatment-emergent adverse events (TEAEs) with 4 pts having Gr ≥ 3 TEAEs related to IMO-2055. 1 patient died during the trial with serious AEs related to IMO-2055. Most frequently reported Gr ≥ 3 TEAEs were neutropenia (DL1 = 78%; DL2 = 50%), hypokalemia (DL1 = 22%; DL2 = 75%) and hypomagnesemia (DL1 = 11%; DL2 = 75%). PK assessment was very limited; partial responses were observed in 3/13 pts.

Conclusion

High rates of Gr ≥ 3 neutropenia and electrolyte disturbances were observed. Based on the overall safety data, regimens combining IMO-2055, cetuximab, 5-FU and platinum-containing chemotherapy cannot be recommended for phase ll trials.

Disclosure

J.P. Machiels: Consultant relationship with Boerhinger Ingelheim Research funding of Sanofie

U. Keller: advisory board and speaker

T.H. Brümmendorf: I am member of advisory boards for Merck and I received honoraria from Merck for educational talks at symposia.

T. Goddemeier: Employee of Merck KGaA

U. Forssman: Employee of Merck Serono S.A.

All other authors have declared no conflicts of interest.

1045P
OUTCOME OF OROPHARYNGEAL CANCER ACCORDING TO TREATMENT IN DIFFERENT RISK-PROFILE GROUPS: ANALYSIS OF A RETROSPECTIVE SERIES OF PATIENTS TREATED IN A TERTIARY CANCER CENTRE

Abstract

Background

Epidemiology and outcome of oropharyngeal cancer (OPC) are changing in the last decades, due to the role of HPV infection. No different treatment modality has been identified as more effective in treating OPC according to HPV or smoking status.

Material and methods

Two series of locally advanced (stage III-IV) squamous cell OPC patients (pts) treated at our Institution were considered:

1) treated with surgery followed by radiotherapy (dose 50-66 Gy), from 1/1991 to 7/2000 (“surgical series”)

2) receiving concurrent chemoradiation (CTRT) (RT dose = 66-70 Gy), with/without induction docetaxel, cisplatin, 5-fluorouracil (TPF) chemotherapy (CT), from 7/2004 to 3/2011 (“CTRT series”)

Smoking habits and tumoral p16 expression were analyzed in order to stratify each series according to Ang risk profile (low, intermediate, high risk). Overall survival (OS) and disease free survival (DFS) were calculated with Kaplan-Meier method.

Results

Globally, 171 pts were considered, 56 in surgical and 115 in CTRT series. In CTRT series, 40% of the pts received induction TPF chemotherapy; in surgical series 57% of the pts had extracapsular extension and/or microscopically involved surgical margins.

 Surgical series CTRT series 
p16 expression 39% 59% 
Stage III 13% 7% 
Stage IV 87% 93% 
Low risk 20% 20% 
Intermediate risk 23% 41% 
High risk 57% 39% 
 Surgical series CTRT series 
p16 expression 39% 59% 
Stage III 13% 7% 
Stage IV 87% 93% 
Low risk 20% 20% 
Intermediate risk 23% 41% 
High risk 57% 39% 

Five-year (yr) OS for p16 positive pts was 50% in surgical and 88% in CTRT series, while for p16 negative was 38% and 49% respectively (p < 0.0001).

When stratifying for risk profile, 5-yr OS of low risk CTRT pts was 100% vs 54% of surgical pts (p = 0.0042) and 5-yr DFS was 93% vs 53% (p = 0.0079); 5-yr OS of intermediate risk CTRT pts was 76% vs 46% of surgical pts (p = 0.0141) and 5-yr DFS was 79% vs 38% (p = 0.0359). High risk CTRT pts had a 5-yr OS of 51% vs 36% of surgical pts (p = 0.1902) and a 5-yr DFS of 24% vs 36% (p = 0.6411).

Discussion

In this retrospective analysis, low and intermediate risk OPC pts had a greater survival benefit when treated with CTRT compared with surgery followed by RT. Although with the limits of different RT techniques and lack of CT in adjunct to postoperative RT, these data should be considered as hypothesis generating for new trials design.

Disclosure

All authors have declared no conflicts of interest.

1046P
ELECTROCHEMOTHERAPY (ECT) WITH BLEOMYCIN AS A PALLIATIVE TREATMENT OF REGIONAL RELAPSE IN HEAD AND NECK CANCER (H&NC) PATIENTS (PTS). A PILOT STUDY

Abstract

Background

ECT is the administration of electrical pulses in the tumour during perfusion of chemotherapy allowing the introduction of the drug in neoplastic cell. H&N regional relapse no suitable for local or systemic treatment has a median survival of 3 months causing local pain and anxiety to the pts. We prospecively analysed antitumoral activity of ECT in regional relapse of H&NC not suitable for other therapies.

Methods

Pts with local-regional relapse of H&NC from mucosa (squamous carcinoma), thyroid gland, salivary gland, cutaneous squamous or cutaneous melanoma were included. Other inclusion criteria were good general condition, no history of reaction to Bleomycin, life spectancy of 3 or more months and no possibility of salvage local surgery. All pts were previously treated with local radiation and systemic chemotherapy.

Results

Between 2009-2011, 26 ECT courses were performed in 18 consecutive pts with local relapse of squamous H&NC n = 7(39%); malignant melanoma n = 6(33%);thyroid carcinoma n = 4(22%); or parotid carcinoma n = 1(6%). Objective responses were: complete n = 3(17%); partial n = 11(61%); complete plus partial n = 14(78%); or no response n = 4(22%). The median follow-up was 12 moths, time to progression was 6 months and overall survival was 9 months for all the pts. All responding pts had a reduction of local pain and anxiety. Mild local pain for few days and skin necrosis were the only side effects.

Conclusions

ECT has a high antitumoral activity in regional relapse of H&NC of different histologies. This local therapy may have a place in the future as palliative treatment of H&NC.

Disclosure

All authors have declared no conflicts of interest.

1047P
PSYCHOLOGICAL DISTRESS AND QUALITY OF LIFE EVALUATION IN HEAD AND NECK CANCER: THE ROLE OF FAMILY CAREGIVER

Abstract

Background

Recently the figure of family caregiver (FCG) has become a hot topic and is still largely un-investigated among head and neck cancer patients; aim of our study was to describe in a more detailed way the role of FCG, to evaluate quality of life (QoL) and psychological distress of FCGs and patients, and to investigate relationships between FCG's wellbeing and patient's QoL and emotional pattern.

Methods

Sixty couples of patients and their caregivers were enrolled in this observational cross-sectional study between April 2007 and May 2011 at 1st ENT Division, 2th Medical Oncology Division and 2th Radiotherapy Division of San Giovanni Battista Hospital of Turin. Inclusion criteria were: histological diagnosis of SCC, advanced stage (III-IV), completion of curative treatment and no evidence of disease at the enrolment. Psycho-oncological assessment was performed using Distress Thermometer (DT), Stay-Trait Anxiety Inventory Manual in Y1 and Y2 form (STAI Y1-Y2), Beck Depression Inventory (BDI), Montgomery-Asberg Depression Rating Scale (MDRS), EORTC-QLQ-C30 and Head and Neck-35 module and Caregiver Quality of Life Index-Cancer (CQOLC).

Results

Patients state and trait anxiety are 46,7% (STAI Y1 mean value 40,2 ± 10,2; cut-off 40) and 36,7% (STAI Y2 mean value 36,7 ± 8,2; cut off 40) respectively; self reported and clinician rated depression are 31,6% (BDI mean value 8,2 ± 5,3; cut-off 9) and 48,3% (MDRS mean value 7,9 ± 5,9; cut-off 6) respectively. FCGs: state and trait anxiety are 50% (STAI Y1 mean value 42,5 ± 9,9; cut-off 40) and 41,7% (STAI Y2 mean value 39,1 ± 8,7; cut off 40) respectively; self reported and clinician rated depression are 28.3% (BDI mean value 7,3 ± 4,7; cut-off 9) and 41.7% (MDRS mean value 7,6 ± 5,8; cut-off 6) respectively. Data analysis underlined a positive association among emotional scales of patients and caregivers. Patients' psychological aspects are negatively associated with caregivers' QoL and viceversa.

Conclusions

Anxiety and depression are often present in FCGs and cured HNC patients. Long term patient's QoL is the result of a frail balance between FCG and patient emotional and psychological distress. A psychological support for FCG could improve patient wellbeing.

Disclosure

All authors have declared no conflicts of interest.

1048P
RADIATION-INDUCED MALIGNANCY FOLLOWING DEFINITIVE RADIOTHERAPY FOR NASOPHARYNGEAL CARCINOMA

Abstract

Purpose

To analyze the clinicopathological characteristics, treatment modalities, and potential prognostic factors of radiation-induced malignancy (RIM) in patients with nasopharyngeal carcinoma (NPC).

Methods

We reviewed institutional electronic medical records of 39,118 patients with NPC treated by definitive radiotherapy between February 1964 and 2003. A total of 228 patients with confirmed RIM were included in this study.

Results

The median latency between radiotherapy for NPC and the diagnosis of RIM was 9.5 years (range, 3.1 to 30.2 years). Squamous cell carcinoma was the most common histologic type, followed by fibrosarcoma, osteosarcoma, and adenocarcinoma. Median progression-free survival and overall survival (OS) of the 216 patients who underwent treatment were 18.7 months (95% CI, 12.8 to 24.5) and 32.0 months (95% CI, 23.8 to 40.1), respectively. Five-year OS rates were 36.9% and 20.2% for carcinoma and sarcoma, respectively (P = 0.004). The 5-year OS rates were 45.4%, 21.8%, and 0% for the surgery (140 patients), radiotherapy (44 patients), and chemotherapy (32 patients) groups, respectively (P = 0.000). The independent prognostic factors associated with improved OS were histologic diagnosis of carcinoma and complete surgical resection.

Conclusion

Histologic type and treatment modality were the significant prognostic factors for patients with RIM. Complete resection apparently offers the best chance for long-term survival. In select patients with locally advanced and unresectable RIM, reirradiation should be strongly considered as a curative option.

Disclosure

All authors have declared no conflicts of interest.

1049P
THE CHANGING ORAL MICROBIAL ECOSYSTEM IN OSCC FROM DIAGNOSIS TO RADIOTHERAPY

Abstract

Purpose

Multiple factors influence the oral microflora (OMF) in oral squamous cell carcinoma (OSCC). These could range from tobacco habits to radiotherapy administered. A preliminary study performed in our hospital revealed the differential support offered by each of these factors on various microbial groups - aerobes, anaerobes, gram negative anaerobes (GNAB) and Candida.

Method

The study attempts to analyse the microbial alteration so as to improve understanding of the possible impact that OMF could create on mucositis and other morbidities that radiation would leave behind. Microbial analysis of saliva samples was done from healthy volunteers (n = 35), tobacco chewers (n = 37) (Age & Sex matched), OSCC (n = 32) and during radiotherapy (n = 31) of these patients (∼ 50% study samples form a series). Frequency of isolation and mean colony forming units obtained were subjected to Kruscal - Wallis, Mann - Whitney (unpaired values) and Wilcoxson - signed rank test (paired values) for comparison.

Results

No isolation of Citrobacter, Enterobacter, Proteus in normal samples and Corynebacteria, Staphylococcus epidermidis in study samples. Tobacco – induced change: Among aerobes, E. coli, Citrobacter, Proteus, Klebsiella pneumonia and Enterobacter increased (p < 0.05), whereas, Streptococcus pneumoniae, Corynebacteria, Staphylococcus epidermidis, aerobic Streptococci decrease (p < 0.05) significantly. Amongst the anaerobes, anaerobic Streptococci, Prevotella decreased while Fusobacteria, P. gingivalis increased, but, all non - significantly (p > 0.05). Tumor - induced change: E. coli, Enterobacter and anaerobic Streptococci, Fusobacteria, Prevotella (anaerobes & GNAB) significantly increased (p < 0.05). Radiation – induced change: Among aerobes, Streptococcus pneumoniae, Staphylococcus epidermidis decreased. Proteus, Klebsiella pneumoniae, Enterobacter, and amongst anaerobes, Streptococci increased (p < 0.05) significantly. A non-significant increase was noted in Fusobacteria and P. gingivalis.

Conclusions

The study impresses on the rapidly modifying nature of OMF that accommodates non – residents and increasing proportions of more pathogenic microorganisms that may contribute to the enhanced morbidity.

Disclosure

All authors have declared no conflicts of interest.

1050P
WHOLE-BODY DIFFUSION MRI AND SKELETAL LESIONS IN THYROID CANCER: DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS

Abstract

Background

Forty-fifty percent of the patients with metastatic TC suffer from bone metastases. 99mTc scintigraphy is employed to assess bone lesions although it lacks of accuracy, mostly in lytic lesions of differentiated thyroid cancer (DTC). CT scan has a sensitivity of 71-100% while data on the accuracy of 18F-FDG-PET/CT are scanty. MRI captures both bone and bone marrow involvement, more common in medullary thyroid cancer (MTC). Whole body MRI (WB) and whole-body diffusion (WB-DWI) are emerging as accurate tools for detection and therapy monitoring of bone metastases. We investigated the role of WB and WB-DWI in bone lesions from TC i) sensitivity and specificity; ii) evaluation of response during TKIs.

Material and methods

Radiological records of patients with metastatic TC submitted to WB-DWI at the baseline staging were reviewed. For our first purpose, patients with at least one another bone imaging were included. A false-positive was a positive bone imaging not confirmed by histopathology or/and another imaging technique or by two imaging exams. A false-negative was a negative finding on bone imaging and a positive one on another imaging method plus histopathology or by two imaging methods. For each imaging modality, sensitivity, specificity and accuracy were calculated. For the secondary aim were considered only patients scanned by WB-DWI at baseline and during TKIs treatment.

Results

Since 2010, nine MTC (5M/4F) and five DTC (3M/2F) patients were selected. Results of the first aim are listed in the table.

 WB-DWI Bone scan Bone CT 
Number of exams 14 12 12 
True-positive 10 
True-negative 
False-positive 1 (MTC) 
False-negative 1 (DTC) 1 (MTC) 
Sensitivity % 100 88 88 
Specificity % 100 80 100 
Accuracy % 100 86 92 
 WB-DWI Bone scan Bone CT 
Number of exams 14 12 12 
True-positive 10 
True-negative 
False-positive 1 (MTC) 
False-negative 1 (DTC) 1 (MTC) 
Sensitivity % 100 88 88 
Specificity % 100 80 100 
Accuracy % 100 86 92 

In five (4 MTC/1 DTC) out eight (62%) true-positive bone scan, WB-DWI demonstrated a higher number of bone lesions. In three patients (2 MTC/1 DTC), WB-DWI showed a cystic evolution in the responding lesions during TKI (apart from the histotype).

Conclusions

In our hands WB-DWI is the best imaging method to identify bone lesions from TC. It could potentially address unmet clinical and therapeutic needs for a reliable measure of bone lesion response in this rare tumors.

Disclosure

All authors have declared no conflicts of interest.

1706P
ANTI-ANDROGEN THERAPY FOR THE PATIENTS WITH RECURRENT AND/OR METASTATIC SALIVARY DUCT CARCINOMA EXPRESSING ANDROGEN RECEPTORS: A RETROSPECTIVE STUDY

Abstract

Background

Salivary duct carcinoma (SDC) is one of the WHO classified histological types of salivary gland tumors (SGT) and consists of less than 10% among all the SGT. SDC is known as highly malignant with its aggressive clinical course, high rate of recurrence and metastasis and 2-3 years of median survival time. Up-front therapy is surgery, but treatment option is quite limited when it recurs and/or metastasis not being suitable for surgical resection. Androgen receptor (AR) is expressed in about 90% of SDC. Several reports suggest that AR would be a good candidate for treatment target for this entity.

Patients and methods

We conducted a retrospective analysis in patients with AR positive, recurrent and/or metastatic SDC treated anti-androgen therapy in our institution from January 1997 and April 2012. AR positivity was defined by immunohistochemistry (AR441, DAKO). Anti-androgen therapy was given as a single agent LH-RH analogue every four weeks until disease progression or intolerable adverse events. Responses to anti-androgen therapy were assessed according to RECIST.

Results

Eight patients were included. All were male. Median age was 57 years (range 40-76). Primary site was parotid gland in 7 and submandibular gland in 1. Initial clinical stage was II in 2, IVA in 5 and IVC in 1. All patients had received surgery for SDC prior to anti-androgen therapy. The patterns of relapse were locoregional recurrence in 4 and distant metastasis in all. Median number of cycles of anti-androgen therapy was 4 (range 2-10). No serious adverse event was seen. The best responses were PR in 2 and SD in 3, and median time of response duration was 4.6 months. After progression of anti-androgen therapy, all but one received chemotherapy included platinum compounds, taxanes and fluorouracil. Median overall survival time from receiving anti-androgen therapy was 22 months.

Discussion and conclusion

Anti-androgen therapy was well tolerated and demonstrated promising clinical activity for patients with recurrent and/or metastatic SDC. This might delay the start of chemotherapy and provide survival benefits, and this approach warrants further investigation.

Disclosure

All authors have declared no conflicts of interest.

1051
INDUCTION CHEMOTHERAPY (CT) WITH DOCETAXEL, CISPLATIN, AND FLUOROURACIL (TPF) FOLLOWED BY CONCOMITANT CISPLATIN PLUS RADIOTHERAPY IN LOCALLY ADVANCED NASOPHARYNGEAL CANCER (NPC) RESULTS AFTER 03 YEARS

Abstract

Backround

in squamous cell carcinoma of head and neck cancer,TPF induction CT improved survival over cisplatin and fluorouracil (MR POSNER NEJM, vol 357 oct 2007 ). The main objectif of this study is to evaluate the activity and safety of TPF in patients (pts) with locally advanced NPC followed by concomitant cisplatin plus radiotherapy (cCTRT).

Methods

pts with undifferenciated NPC were enrolled from December 2006 to December 2010, and received 3 cycles of TPF (docetaxel 75mg/m2 day, and cisplatin 75mg/m2 day 1, plus fluorouracil 750 mg/M2 days 1-5, every 4 wks) with G-CSF days 1-5 post CT. Induction CT was follwed by cCTRT with cisplatin 40 mg/m2/wk and radiotherapy (65-70 gy) starting 4-6 wks after the third cycle of induction CT. The primary endpoint was overall response rate (ORR) after induction CT and after cCTRT. Secondary end points were toxicity, disease free survival (DFS), and overall survival (OS).

Results

Fourty-two (42) pts with locally advanced NPC have been enrolled (26M/16F). UICC 1997 classification: n = 9 stage II, n = 10 stage III, n= 23 stage IV (n = 10 IVA; n = 11 IVB). Median age is 37 yrs (range 18-64). Evocative clinical signs are cervical nodes n = 20, rhinologic n = 13, otologic n = 5, and neurologic n = 4. All pts were evaluated for safety and 38 for response. TPF was well tolerated with main toxicities grade 3-4 (WHO) consisting of neutropenia 36%, thrombocytopenia 23%, anemia 18%, diarrhea 6%,and mucositis 18%. Four pts died from sepsis that was probably treatment-related. ORR was 90% with 71,4% (n = 27) complete response (CR) rate, 23,6% (n = 9) partial response (PR), and 5,2% (n = 2) stable disease. No pts progressed after induction CT. Main toxicity during cCTRT was neutropenia grade 3-4 in 9%, mucositis grade 3 in 45% and grade 4 in 4%. Late toxicities were xerostomia grade 3 in 50%. At treatment completion, CR and PR rates were 79% and 20%; 2 pts had stable disease. At a median follow up of 36 months (7-48), 5% of pts have shown recurrence or progressive disease. DFS and OS rates at 36 months were 70% and 75%, respectively.

Conclusion

TPF followed by cCTRT appears to be an active and feasible regimen with an acceptable tolerability profile and may be a promising therapeutic option for pts with high stage NPC.

Disclosure

All authors have declared no conflicts of interest.

1052
DNA-REPAIR GENE POLYMORPHISMS ASSOCIATED WITH FAVORABLE CLINICAL OUTCOME FOLLOWING CETUXIMAB-BASED THERAPY FOR ELDERLY AND MULTI-MORBID PATIENTS WITH PRIMARY AND RECURRENT SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Abstract

Background

Recent evidences suggest adding cetuximab to standard treatment is an effective option for recurrent and metastatic head and neck cancers. While platinum-based chemotherapy is challenging for elderly and multi-morbid patients, DNA-repair gene polymorphisms may help identifying patients who are more likely to benefit from the regimen.

Methods

Fifty-two patients were retrospectively identified from patients with treatment-naïve, primary, recurrent, or metastatic squamous cell carcinoma of the head and neck, who had received cetuximab-based therapy during 2006 and 2011. Treatment response, survival, and the presence of the single nucleotide polymorphisms, XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and XRCC1-Arg399Gln, were currently obtained for twelve patients.

Results

Complete or partial remission was observed in all six patients (100%) who had one or more polymorphic variants, compared to that in three of the six patients (50%) who had only common alleles (one tailed Fisher's exact test P = 0.091). Annual overall survival (OS) was 75.0% (median not reached), one-year progression-free survival (PFS) was 60.0% (median not reached) in the patients with any polymorphic variant, while one-year OS and PFS was 33.3% (median 11.5 months) and 16.7% (median 3.7 months) in the patients with only common alleles (Log-rank P = 0.321 for OS and 0.078 for PFS).

Conclusion

Our preliminary results suggest cetuximab might be an effective and safe option for elderly and patients with multiple comorbidities, especially for patients with DNA-repair gene polymorphic variant. Further investigation is needed to validate our findings and adjust for other prognostic factors.

Disclosure

All authors have declared no conflicts of interest.

1053
THE USEFULNESS OF G8 EVALUATION IN THERAPEUTIC DECISION AND PREDICTION OF TOLERANCE IN LOCALLY ADVANCED OR METASTATIC SQUAMOUS CELL HEAD AND NECK CANCER (SCCHN) PATIENTS OLDER THAN 65 YEARS

Abstract

Background

2/3 of H&N cancer patients are locally advanced or metastatic and 20% are older than 65. Those not amenable to radiation or surgery, must be treated evaluating their biological age. The current standard is Erbitux based chemotherapy and there are not enough dates about the tolerance for aged pts. G8 was validated like tool in geriatric oncology but the presence of swallowing difficulties and weight loss in most of HNC patients may alter its usefulness in this population.

Objective

evaluate prospectively the G8 score and to report to the incidence and degree of chemotherapy toxicities.

Methods

Prospective study of SCCHN patients over 65 years old, addressed from January to April 2012 to the Department of Head & Neck Cancer of Gustave Roussy Institute. Parameters studied: G8 score; age, TNM, histology, nutritional status, ACE -27 index, toxicity of treatment.

Results

We studied 21 patients: 9 pts (42%) less than 70, 4 pts (19%) between 70 -75 and 7 pts (33%) over 75, mostly locally advanced, squamous histological type; denutrition in 9 pts (42%) 2 over 75 years; 33% had swallowing problems and 25% loss weight superior of 10% in the last 3 months before treatment. ACE 27 index was over 2 for 18 (85%) patients.We found a G8 score < 14 for 9 (42%), of whom 8 aged over 70 years, 7 with denutrition, 5 with ACE 27 at 3. 16 patients (47%) were treated with Cetuximab based chemotherapy. The mostly observed toxicities were cutaneous with 3 grade 3 and 1 grade 4, 41%hematological and g-I from whome only 4 pts (19%) degree 3 or 4. One toxic death was observed. 12 pts were evaluated and 4 (33%) were in PR, 5 (41%) were SD and only 3 (25%) were in progression.

Conclusions

this preliminary prospective study demonstrates that G8 score identify frailty in 42% of elderly SCCHN patients older than 65 years. An adapted tool for geriatric asessement in SCCHN patients seems necessary.

Disclosure

All authors have declared no conflicts of interest.

1055
EFFICACY OF MYOFIBROBLASTS AS AN INDICATOR FOR INVASION AND NODAL METASTASIS IN OSCC

Abstract

Purpose

Tumour cells work in close coordination with stromal elements from its stage of initiation to metastasis. Oral squamous cell carcinoma (OSCC) is one of the top ten cancers in the world with only survival rate of 56%. Myofibroblasts (MF), a cell that is identified transiently in the wounds have also been shown in tumor stromogenesis in a variety of malignancies. MFs been highlighted for their proinvasive role in tumors. These cells remain less explored in OSCC in terms of invasion and nodal metastasis – Prognosticators.

Method

The study was aimed towards understanding the possibility of MF being an indicator of invasion and nodal metastasis. This was achieved through assessing the presence and distribution pattern of MF in OSCC using α-SMA. To improve further our understanding a semiquantative analysis (0= No staining, 1= Focal Positivity, 2 = Multifocal Positivity) was performed and compared with that from normal mucosa (NM, number of cases (n) =10), chronic inflammatory lesions (CIL, n= 22), surgical margins of OSCC patients (SM, n = 24) and pN0, pN+ OSCC samples (n = 56, 28 each). Mann-Whitney test was applied.

Results

No MFs were present in NM and SM. 84% and 32% of OSCC and CIL showed MFs respectively. Heterogenous pattern (Presence/absence in a location, Loose/Syncitial arrangements, and Focal/Multifocal distribution) of MFs was seen in OSCC while they were seen closer to the center of the lesion away from the epithelium in CIL. Lesions reported for longer duration showed MF in CIL. The MFs were not seen in all the invasive fronts. Significant difference in the number of MFs was observed between NM and OSCC (p = 0.00), CIL and SM (p = 0.003), CIL and SCC (p = 0.00), SM and OSCC (p = 0.00).

Conclusion

MF formation and its retention seems to be influenced by duration (reactive lesions), and basement membrane invasion with stressed extracellular matrix (OSCC). Stress-dictated distribution patterns may prove valuable in distinguishing pN0 and pN+ groups. Smaller incisional biopsies may not be useful in predicting both invasion and nodal metastasis either by quantitation or by distribution pattern analysis owing to the heterogeneity that is displayed.

Disclosure

All authors have declared no conflicts of interest.

1056
TREATMENT FAILURE IN HIGH-RISK HEAD AND NECK CANCER TREATED WITH ADJUVANT CHEMORADIATION

Abstract

Background

Adjuvant chemoradiation (adCRT) is the standard of care in resectable high-risk head and neck squamous cell carcinoma (HNSCC). We select patients (pts) for adCRT if they are physically fit and have at least 1 major (extra-capsular nodal spread or positive resection margins) and/or 2 minor (pT4, pN2, perineural or vascular invasion) high risk pathological factors. Loco-regional control and disease-free survival (DFS) are good and the toxicities manageable. The aim of our study was to evaluate the patterns of treatment (tt) failure with this therapy.

Methods

We reviewed the charts of all pts with resected high-risk HNSCC treated with adCRT, from 2007 to 2011. Pts and disease characteristics, compliance to tt, date and first site of tt failure and disease status at last follow-up (FU) were reviewed. Overall survival (OS) and DFS were estimated using Kaplan-Meier method.

Results

221 consecutive pts were included, 93.6% male, median age 52 years. The incidence of stage IVA−B disease (72.8%) and major high risk pathological features such as involved surgical margins (50.6%) and extranodal spread of the disease (52.0%) was high. Compliance to tt was good with 94.5% of pts completing at least 2 cycles of chemotherapy. There were no toxic deaths. With a median FU of 18.8 months, 57 pts (25.8%) experienced disease recurrence. Local or regional recurrence as the first site of tt failure occurred in 25 pts (11.3%) and distant metastasis (mets) occurred in 32 pts (14.5%). The most common site of metastatic disease was the lung (26 pts; 11.7%). Lung recurrence occurred at a median FU of 8 months. Nine pts (4%) recurred with lung mets less than 6 months after the end of adCRT. Five pts were diagnosed of primary lung cancer during FU. At last FU 175 pts (79.2%) were alive; 154 (69.9%) in complete remission. The Kaplan-Meier estimates of 3-year OS and DFS were 68% and 59%, respectively.

Conclusions

Through adequate selection of pts and supportive measures, high tt compliance and manageable toxicity of adCRT are achieved. The observed early recurrence in a small number of pts, mainly in the lung, might suggest that more detailed pretreatment staging and FU evaluation for early lung disease detection are warranted.

Disclosure

All authors have declared no conflicts of interest.

1057
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF 5-FLUOROURACIL IN CHINESE HEAD AND NECK CANCER (HNC) PATIENTS

Abstract

Background

Pharmacokinetic (PK) variability of 5-fluorouracil (5-FU) has been demonstrated for +30 years and a significant link between exposure and therapeutic response has been identified. A maximum tolerated exposure (MTE) from the area under curve (AUC) has been characterized for various regimens and therapeutic dose management (TDM) has been used to optimize dosing.

Objective

The objective of this study was to characterize the PK variability of 5-FU in the Chinese HNC population and examine the relationship between AUC, toxicity and efficacy. The 5-FU MTE in this population was compared with MTE identified for European HNC patients.

Methods

89 treatment naïve patients with HNC were administered cisplatin (80mg/m2, d1) and 5-FU (4g/m2, 120h IV). Blood samples were collected at steady state after the first 18h of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay and AUC was calculated. Relationship between 5-FU AUC and 5-FU related toxicities was examined. Preliminary efficacy results were evaluated for 5-FU related toxicity.

Results

The patient 5-FU AUC values varied widely: from 15 to 103 mg · h/L. 33% of patients were within the target range of 25-35 mg· h/L; 18% were below and 49% were above . Toxicity was recorded for 89 patients. Among the 44 patients with AUC above the target range, severe mucositis or mylesupression was experienced by 32 patients. By comparison, among the 45 patients within or below target range, only 3 experienced severe toxicities. ROC analysis for 5-FU AUC and severe mucositis identified a cut-point of 36 mg· h/L (p < 0.0001). These results are listed in the table below.

Incidence of severe mucositis and myelosuppression with 5-FU AUC
 
AUC ≤35 mghr/L >35 mghr/L 
Grade 3 3% 36% 
Grade 0 - 2 47% 13% 
Incidence of severe mucositis and myelosuppression with 5-FU AUC
 
AUC ≤35 mghr/L >35 mghr/L 
Grade 3 3% 36% 
Grade 0 - 2 47% 13% 

Conclusion

Results of this study demonstrate wide PK-variability of 5-FU exposure and a significant relationship between severe toxicity and AUC in HNC cancer patients. The study confirms that the MTE in this population is similar to a European HNC population treated with cisplatin/5-FU. TDM using the target range of 25-35 mg· h/L may have benefit in lowering toxicity in HNC patients.

Disclosure

All authors have declared no conflicts of interest.

1058
CISPLATIN + VINORELBINE (DDP + VNB) ADMINISTERED IN 60 CASES OF RECURRENT/METASTATIC SALIVARY GLAND MALIGNANCIES (RMSGM): FINAL REPORT

Abstract

Background

RMSGM are not amenable to the usual treatment with surgery and post-operative radiotherapy. The role of chemotherapy (CT) for RMSGM is palliative only. VNB showed moderate activity in our experience (Bull Cancer 85:892; 1998) and in a randomized phase II trial we had demonstrated that the DDP + VNB combination had a better outcome than VNB alone (Cancer 91:541; 2001). In this abstract we report the final results of this combination in 60 cases.

Methods

From April 2001 to February 2009, 60 cases with RMSGM were enrolled. All patients received the following regimen: DDP 80 mg/sm d.1 + VNB 25 mg/sm d. 1,8 every 3 weeks. The study foresees a maximum of 6 cycles.

Results

Patients characteristics were as follows: 35 males (58%) and 25 females (42%); median age: 56 yrs (range 20-68); median ECOG PS: 1 (0-2); histology: adenocarcinoma 15 (25%), adenoid cystic ca. 34 (57%), others 11 (18%); site of disease: local 30 (50%), mts +/- local 30 (50%). Forty-two pts received DDP + VNB as first line CT (70%) while 18 pts (30%) had the combination as second-line CT (30%). After a median of 5 cycles of first line DDP + VNB responses were: 3 CR (7%), 10 PR (24%), 14 NC (33%) and 15 PD (36%). After a median of 4 cycles of second line CT responses were: 0 CR; 1 PR (5%), 6 NC (33%) 11 PD (62%). Median survival: 10 months (3-29) for first line CT; 4 months (1-12) for second line CT. G3-4 toxicity: neutropenia (20%), anemia (12%), nausea/vomiting (12%), peripheral toxicity (3%).

Conclusions

DDP + VNB is an effective first line CT in RMSGM; second line CT has a low palliative activity. Toxicity seems acceptable. This regimen could be suitable for an integration with new biologic target agents.

Disclosure

All authors have declared no conflicts of interest.

1059
ANTI OXIDANT CAPACITY OF CALENDULA OFFICINALIS FLOWERS EXTRACT AND PREVENTION OF RADIATION INDUCED OROPHARYNGEAL MUCOSITIS IN PATIENTS WITH HEAD AND NECK CANCERS: A RANDOMIZED CONTROLLED CLINICAL STUDY

Abstract

To determine the effect of Calendula officinalis flower extract mouthwash as gel formulation on radiation-induced oropharyngeal mucositis (OM) in patients with head-and-neck cancer. Forty patients with neck and head cancers who were treated with radiotherapy or chemoradiotherapy were randomly assigned to receive either 2% calendula extract mouthwash or placebo (20 patients in each group). The subjects were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, five fractions weekly, 20–35 fractions within 4–7 weeks). Oropharyngeal mucositis was evaluated by two doctors (a radiation oncologist and a dentist), using the oral mucositis assessment scale (OMAS). The patients also received concurrent chemotherapy. Calendula mouthwash significantly decreased the intensity of OM compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs. 10.95, p < 0.0001) and week 6 (score: 11.4 vs. 13.35, p = 0.031). Total antioxidant, polyphenol and flavonoid contents and quercetin concentration of the 1% extract were 2353.4 ± 56.5 µM, 76.66 ± 23.24, 313.40 ± 6.52 mg/g and 19.41 ± 4.34 mg/l, respectively. Calendula extract gel could be effective on decreasing the intensity of radiotherapy- induced OM during the treatment and antioxidant capacitiy may be partly responsibe for the effect.

Disclosure

All authors have declared no conflicts of interest.

1060
HORIZONTAL LATERAL THYROIDECTOMY-“THOMAS TECHNIQUE”A NOVEL SURGICAL APPROACH TO THYROID NEOPLASMS

Abstract

Background

Kochers' anterior approach is the universal standard for thyroidectomy but with several complications. Feasibility of horizontal lateral thyroidectomy (Thomas' Technique,) based on 3 D volumetric anatomy is a novel concept to minimize complications to the superior, Recurrent Laryngeal nerves, Para thyroids and vessels which are posterior and lateral. Unique anatomy of platysma, safeguarding of sub platysmal venous plexus and investing layer of deep fascia in relation to Cosmetic outcome is highlighted.

Objectives

This feasibility study was designed to avoid all the known complications of thyroidectomy and an unaesthetic anterior scar.

Methods

Superior results from the pilot study, prompted to extend the study for the next 2 years.

Of 283 subjects thus enrolled, 231 were females and 52 males. 118 had benign disease out of which 75 were MNGs, 31 adenomas and 9 cysts. Out of 165 Cancers, 160 were differentiated (96papillary, 44 follicular, 20 mixed and 5 medullary).18 had intra thoracic extensions. Using single ipsilateral incision 40 hemi thyroidectomies, 70 total thyroidectomies of benign and 55 total thyroidectomies of early cancers were done. Bilateral approach used in 110 cases of carcinomas requiring bilateral node dissection and for 8 benign cases of bilateral intrathorasic extensions. Para thyroids were dissected pulverized and injected into Sternocleidomastoid muscle before dissection if required.

Results

Blood loss was 10-15 ml and hospital stay 24 hrs. There were no nerve injuries. Parathyroid deficiency was reported in 10/283. 165 thyroidectomies (115 totals) were performed with single lateral incision. Within 6 months scar disappeared, touch sensations returned to normal. Cosmesis and quality of life were excellent.

Conclusions

“Horizontal lateral thyroidectomy”–”Thomas technique”, is a novel method applicable for all thyroid neoplasms. Avoidance of “handling” of the gland upfront, direct vision of nerves, and ligation of vascular pedicles upfront leading to an avascular gland makes this approach unique and “bloodless”. It facilitates better lymph adenectomy and is safest for hemi as well as Total thyroidectomy and for intrathorasic extensions. Complications described in the literature are minimised. Superior cosmetic results compared to Kocher's technique.

Disclosure

All authors have declared no conflicts of interest.

1061TiP
FIRST-IN-MAN PHASE I STUDY OF TPCS2A-BASED PHOTOCHEMICAL INTERNALISATION (PCI) OF BLEOMYCIN IN LOCALLY RECURRENT OR ADVANCED/METASTATIC, CUTANEOUS OR SUBCUTANEOUS MALIGNANCIES

Abstract

Objective

PCI is a novel technique in which chemotherapeutic cytotoxicity is enhanced with a photosensitiser and light exposure. This dose-escalation study assessed the safety and tolerance of TPCS2a (tetraphenyl chlorin disulphonic acid, Amphinex®) in bleomycin PCI, pharmacokinetic profiles, and determined the maximum tolerated dose (MTD).

Method

Cohorts of 3 to 6 patients were enrolled and the TPCS2a dose escalated by a pre-specified amount until dose-limiting toxicity (DLT) occurred in at least two patients (≥33%). Patients received TPCS2a at a starting dose of 0.25mg/kg. Four days later they received bleomycin (15,000IU/m2 IV) and after 3 hours red light laser (652nm) was applied to target lesions for 600 seconds to initiate a therapeutic response. Patients were followed for 3 months.

Results

Nineteen patients were enrolled: 4 with cutaneous breast cancer, 13 squamous cell carcinoma (SCC) of head and neck and other regions, 2 other cancers. 17/19 patients experienced 94 AEs, most commonly pain, photosensitivity and nausea. Most (83%) were mild or moderate. Fourteen episodes of pain (3 severe) were treatment-related. Mean patient-reported pain using a VAS scale declined from 4.9 to 1.3 24 hours after treatment. Four patients experienced skin photosensitivity reactions; 3 were in the highest dose cohort. 10/19 patients experienced 15 serious adverse events: 3 (swelling, and blistering of hands, tongue oedema) were probably related to treatment. The MTD of TPCS2a was found to be 1.5mg/kg. At day 28, 11/16 patients had a complete response (CR) in target lesions, 2 had a partial response (PR), 2 had stable disease (SD) and 1 had progressive disease (PD). At last visit there were 8 CRs, 2 PRs, 2 SDs and 2 PDs. During the course of the study four patients died (no relation to treatment) and six were withdrawn prematurely.

Conclusion

With appropriate analgesia and anaesthesia TPCS2a-based PCI of bleomycin was well tolerated in these patients with locally advanced cancer. Treatment-related AEs were as expected and can be managed. Preliminary efficacy data are very encouraging and a phase II study in HNSCC has just begun.

Disclosure

All authors have declared no conflicts of interest.