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Background: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. / Methods: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta‐Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta‐Analysis of Chemotherapy in Head and Neck Cancer [MACH‐NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH‐NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). / Results: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16‐negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85‐0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84‐0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90‐1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75‐0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78‐0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86‐1.08; P for interaction = .011). / Conclusions: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

6051 Background: In platinum-resistant recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts), survival improvements have been achieved with immune checkpoint inhibitors (ICI), however this benefit is limited to a relatively small subgroup of pts. Predictive biomarkers are still under investigation and their contribution to the clinic has been limited. An immune-related cluster (Cl6) has been defined by means of a metanalysis in locally advanced HNSCC. Methods: Gene expression profiling was performed on two cohorts of platinum resistant R/M HNSCC pts treated with ICI alone: i) 20 patients as training set, divided in long-term (OS >18 months; n=12) and short-term (OS < 6 months; n=8) survivors matched according to site of recurrence (distant metastases only, or locoregional recurrence with/out metastases); ii) 80 patients enrolled in a phase II trial (EudraCT number: 2017-000562-30; NIVACTOR study) as testing set. The molecular subtyping stratification (De Cecco, Oncotarget 2015) was applied. Subsequently, a score was determined between each sample and the centroids for the 6 clusters previously identified. The threshold point was imputed in the training set as the closest value to the observed prevalence. A Cox multivariable analysis including TMB, CPS and TPS PD-L1 status, age, tumoral subsite and performance status (PS) was performed. Results: Among all the clusters, Cl6 turned out to be significant and applied to training set it provided evidence to discriminate pts’ survivals (AUC=0.86, 95%CI=0.7-1.0; p=2E-05). The stratification based on Cl-6 along with the cut-off point defined in the training set were challenged in the testing set: samples were divided in 28 (35%) having high Cl-6 scores and 52 (65%) with low scores, reaching HR=0.46 (95% CI= 0.27-0.76; p=0.0024). Multivariate analysis showed that only Cl6 (high vs low, HR=0.44; p=0.00443) and PS (1,2 vs 0, HR 1.85; p=0.02686) resulted to be significant on pts’ OS. Conclusions: By analysing two series of pts receiving immunotherapy alone, we identified an immune-related gene expression signature, able to discriminate the prognosis of platinum-resistant R/M HNSCC pts. The multivariate analysis confirmed the immune-related Cl6 as factor linked to outcome in pts treated with immunotherapy, as well as it confirmed the importance of PS. An analysis of the signature on pts receiving first line treatment with immunotherapy is currently ongoing. [Table: see text]

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p&nbsp

Contains fulltext : 235407.pdf (Publisher’s version ) (Closed access) BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT(P)) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT(P) (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC(TaxPF)-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC(TaxPF) followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC(TaxPF)-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

The immune system is crucial in the evolution of head and neck cancer. Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic cells and immune cells in the tumor microenvironment. The main aim of this study was to apply univariate/multivariate analysis to investigate the prognostic significance of PD-L1, tumor-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLS) in laryngeal carcinoma (LSCC).PD-L1 (in terms of combined positive score [CPS]), TILs and TLS were assessed at pathology on 70 consecutive samples of LSCC.A CPS ≥ 1 coincided with a lower recurrence rate (RR) (p = 0.007) and longer disease-free survival (DFS) than a CPS 1 (p = 0.0027). Cases with higher TIL counts showed a lower RR (p = 0.036) and longer DFS than those with lower TIL counts (p = 0.0062). Cases revealing TLS had a lower RR (p = 0.004) and longer DFS (p = 0.0034) than those with no TLS. On multivariate analysis, the presence of TLS retained its positive prognostic value (p = 0.024), while CPS remained significant as regards disease recurrence (p = 0.050).PD-L1 seems to be an indirect marker of effective anti-tumor response in LSCC, possibly being expressed as a result of a greater immune pressure on cancer cells. The presence of TLS emerged as a positive prognostic factor. Further prospective studies are needed to characterize the role of PD-L1 as a marker of anti-tumor immune response and prognostic factor in LSCC, also with regard to the effectiveness of immunotherapeutic protocols.

Background: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease often presenting at an already advanced stage. Cisplatin chemoradiotherapy is the standard treatment for locally advanced disease, although its efficacy varies according to different studies. Thus, treatment selection is a challenge, especially in older patients, who frequently have several comorbidities. Moreover, the majority of patients with recurrent and/or metastatic disease are unsuitable for local treatment, either surgery or radiation therapy. The only treatment option for them is systemic therapy, but prognosis remains poor, with a median overall survival of less than 12 months. Methods: A group of Italian key opinion leaders in the field of HNSCC gathered several times in 2018 in order to retrieve a set of statements to help clinicians in their daily decision-making process for the treatment of patients with different scenarios of HNSCC. Results and Conclusion: The panel agreed on 22 statements that were identified as “good clinical points” based on the available literature or after discussion of the most relevant aspect of the underlying diseases when no international consensus was available. The panel identified a number of possible scenarios (namely 71) in which these statements may be helpful to guide decision-making for the best treatment selection.

Chemoradiotherapy as an alternative to surgery can be offered to patients affected by loco-regionally advanced head and neck cancer (HNC). Induction chemotherapy is a valid option, supported by few positive trials, but its real efficacy is still a matter of debate. The standard regimen for induction chemotherapy in Europe is a combination of docetaxel (75 mg/m2) and reduced dose doses of cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2 day, for five consecutive days) (TPF). It is less toxic and more effective than the historical therapy PF (cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/day for five consecutive days). However, in some studies treatment-related mortality has been reported to be as high as 6%. Therefore, some less toxic combinations, such as a modified TPF regimen and the combination of carboplatin plus paclitaxel have been studied. These regimens are showing promising results but deserve further validation in comparative trials. Furthermore, several trials are underway in order to enhance TPF with immune checkpoints inhibitors. Compared to chemoradiotherapy, induction chemotherapy followed by chemoradiation was shown to be non-inferior, and it could decrease the distant metastatic progression, especially in high-risk populations. For selected patients, induction chemotherapy could be a strong option. The chemoselective process that leads to immediate surgery for non-responders, the high response rate (complete responses are sometimes observed), and the survival data, are all arguments in favor of induction chemotherapy, if performed in experienced centers involving health professionals in the context of a skilled multidisciplinary team.

e18000 Background: Radiomics is the computerized extraction of quantitative features from medical images, beyond the level of detail accessible to an unaided human eye. Several studies on radiomic analysis have been carried out to identify predictive, prognostic and diagnostic biomarkers for diverse tumor types including HNSCC. Radiomic features proved to be effective in predicting outcomes in patients with locally advanced HNSCC. The aim of the present study was to dentify predictive and prognostic radiomic features in platinum-refractory HNSCC patients with recurrent and/or metastatic (R/M) disease treated with anti PD-1 monotherapy. Methods: We retrospectively reviewed the data of 38 patients treated with Nivolumab at our Institution between January 2018 and March 2020. Nasopharyngeal carcinomas were not eligible. CT radiomic textural features were extracted from regions of interests (ROIs) manually delineated around tumor volumes. Minimum Redundancy Maximum Relevance (mRMR) algorithm was the method of choice to rank radiomic features based on three outcomes: overall response rate (ORR); disease progression (PD) and overall survival (OS). Logistic regression was employed to build predictive/prognostic models. Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) was chosen as the metric to assess model performances. Results: Data from 29 out of 38 patients were ultimately analyzed. Nine patients were excluded due to nasopharynx as primary tumor site and/or inadequate CT scan imaging. A total of 57 ROIs were extracted and analyzed. We obtained 9 models: 3 radiomic models, 3 clinical models and 3 combined models (radiomic plus clinical) for each outcome of interest (ORR, PD, OS). In the radiomic models 2 features were identified as predictor for ORR (AUC 0.69), 1 radiomic feature was predictive for PD (AUC 0.83) and 1 predictive for OS (AUC 0.72). In the clinical models, 3 clinical characteristics were identified for both ORR (AUC 0.91) and PD (AUC 0.73) and 2 clinical features were found to be predictive for OS (AUC 0.91). The combined model identified 3 features (2 radiomics and 1 clinical) predictive for ORR (AUC 0.76). No clinical characteristics were found in the combined model for PD. No radiomics features have been shown to be related to OS. Conclusions: This is an explorative study to test the power of radiomics and the potential value of combining radiomics and clinical data as a prognostic and predictive instrument. In this small sample size, the quantitative analysis of CT images seems to be an interesting tool which has to be further explored as predictor of outcome in a larger series of patients.[Table: see text]

Objective To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Materials and Methods We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965–2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I 2 statistic. Results Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 [95%CI: 0.85–0.99] p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69–0.92). The benefit of chemotherapy was greater in women (HR women = 0.63, 95%CI: 0.50–0.80) compared to men (HR men = 0.96, 95%CI: 0.89–1.04; p for interaction = 0.001). Conclusions This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.

The treatment of HNSCC has rapidly evolved over the past 30 years and multidisciplinary management is required, especially for locally advanced disease (LAHNSCC). Concomitant chemoradiation (cCRT) is the standard of care and cetuximab/RT (CET/RT) is an alternative treatment option, especially for patients unfit for concurrent cisplatin. Several intensification strategies have been explored to improve the outcome of the concomitant treatment. The combination of cisplatin plus cetuximab concurrent to RT failed to improve overall survival (OS) in two phase III trials. Induction chemotherapy (IC) has a proven role in organ preservation; however, its ability in prolonging OS has not been clearly demonstrated. Immune checkpoint inhibitors (ICIs), specifically anti PD-1 inhibitors, have been recently approved for the treatment of patients with recurrent/metastatic platinum-refractory disease. Recent clinical trials are exploring the role of immunotherapy at earlier stages of the disease in combination with concomitant treatments. The purpose of this article is to review current evidence regarding treatment intensification strategies for LAHNSCC (except nasopharyngeal carcinomas) with particular emphasis on the role of induction chemotherapy.

Background: Predictors to identify which patients with locoregionally advanced head and neck cancer (LAHNC) benefit from intensive treatment are lacking. We sought to test the hypothesis that patients with a higher risk of cancer recurrence relative to competing mortality (ω score) selectively benefit from altered fractionation (AFX; MARCH data) and/or chemotherapy (MACH-NC data). Methods: We analyzed 22,339 LAHNC patients treated on 81 randomized trials testing AFX (MARCH data set) or chemotherapy (MACH-NC dataset). We applied generalized competing event regression to the control arms in MARCH, stratifying patients by tertile according to ω score. Model covariates were age, performance status (PS), sex, site, T and N category, p16 status, and smoking history. We externally validated the classifier on the MACH-NC dataset. We tested for interactions between ω score and treatment effects on overall survival (OS). Findings: Factors associated with a higher ω score were lower age, better PS, oral cavity site, higher T/N category, and p16 negative/unknown status. The effect of AFX on OS was greater in patients with high (hazard ratio [HR], 0.92; 95% CI, 0.85 to 0.99) and medium (HR, 0.91; 95% confidence interval [CI], 0.84 to 0.98) vs. low ω score (HR, 0.97; 95% CI, 0.90 to 1.05; p=0.086 for interaction). The effect of chemotherapy on OS was significantly greater in patients with high (HR, 0.81; 95% CI, 0.75 to 0.88) and medium (HR, 0.86; 95% CI, 0.78 to 0.88) vs. low ω score (HR, 0.96; 95% CI, 0.86 to 1.08; p=0.011 for interaction). Interpretation: LAHNC patients with a higher risk of cancer progression relative to competing mortality - as reflected by a higher ω score - selectively benefit from more intensive treatment. Funding Statement: Ligue National Contre le Cancer, Institut National du Cancer (PHRC-K 10-02-58; PHRC-K-15-189), Programme d'Actions Integrees de Recherche (2011-1-VADS-04), UC San Diego Head and Neck Cancer Center. Declaration of Interests: KZ, BL, LKV, QTL, VG, JO, AH, BZ, MKBP, BB, MGG, GS, BO, CF, JB, HS, JH, SM, JPP, LKM – none; FR is an employee of Innate Pharma, Marseille (France). Ethics Approval Statement: Analysis and reporting conformed to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, and followed a pre-specified protocol for the analysis.

Background: Nutritional support, including nutritional counseling and oral nutritional supplements (ONSs), has been recommended at the earliest opportunity in head and neck (H&N) cancer patients. The limited available evidence on the efficacy of immunonutrition during chemoradiotherapy (CT-RT) in H&N cancer patients is positive with regard to some secondary endpoints, but is still scanty, particularly with regard to toxicity and treatment tolerance. We hypothesize that early systematic provision of ONSs with a high-protein–high-calorie mixture containing immunonutrients (Impact) compared to standard high-calorie–high-protein nutritional blends, in addition to nutritional counseling, may be beneficial to patients with H&N cancer during CT-RT. Hence, we designed the present study to evaluate the efficacy, in terms of treatment tolerance, toxicity and response, body weight, body composition, protein-calorie intake, quality of life (QoL), fatigue, muscle strength and immunological profile of the early systematic provision of ONSs enriched in immunonutrients compared to isonitrogenous standard blends, in H&N cancer patients undergoing CT-RT. Methods: This is a pragmatic, bicentric, randomized (1:1), parallel-group, open label, controlled, pilot clinical trial. Discussion: Many efforts are still to be taken to improve the efficacy of nutritional support in oncology. Immunonutrition represents a promising approach also in H&N cancer patients, but the evidence on its efficacy in improving clinical outcomes during CT-RT is still inconclusive. The present pilot study, which guarantees the early provision of nutritional assessment and support to all the enrolled patients in accordance with the recent guidelines and recommendations, could represent one of the first proofs of the clinical effectiveness of early oral immunonutrition in cancer patients undergoing CT-RT and could stimulate further large randomized trials, potentially resulting in the improvement of supportive care quality. Trial registration: This study is registered on ClinicalTrials.gov Identifier: NCT04611113.

Background Nivolumab is an established treatment for recurrent/metastatic (RM) head and neck squamous cell carcinoma (HNSCC) patients (pts) failing platinum-based treatment. However, knowledge about safety and activity data are limited to pts enrolled into clinical trial leading to drug approval. Methods We conducted a single-arm, open-label, multicentre prospective phase IIIb clinical trial with nivolumab 240 mg in subjects with RM HNSCC. Primary objective was to assess the incidence of high-grade (CTCAE v 4.03 grade 3 or higher), treatment-related (TR), selected adverse events (AE); secondary objectives were to characterize the outcome of all AE in terms of duration, time to event onset, and event resolution. Moreover, we assessed Overall Response Rate (ORR), OS and PFS and we analysed in an exploratory way clinical and biomolecular factors associated with improved outcome. A subgroup analysis was also performed in 20 pts to define baseline immunologic profiles and their changes along the treatment. Results We enrolled 127 pts with the following characteristics: male (82%), age higher than 65 years (43%), with primary cancer in oral cavity (33%), oropharynx (31%), larynx (24%), hypopharynx (8%) or other sites (4%). Performance status was 0 in 34% and 1 in 63% pts; 27% of the pts had received 2 or more systemic lines of therapy before. Grade 3-4 TR AE happened in 11% of the pts (anemia 2%, pneumonitis and encephalitis 1%), while all-grade TR AE were 40% (fatigue 20%, hypothyroidism 8%, anemia and pruritus 6%). Median duration of grade 3-4 TR AE was 10 days (4-22) and of grade 1-2 TR AE 63 days (1-336). Median OS and PFS were 7 months (5-NR) and 2 months (1.5-2.5) and ORR 12%. Pts experiencing any TR AE had an improved OS; HR 0.459 (0.254-0.827, p = 0.0096). Analyses of stromal tumor-infiltrating lymphocytes (TILs) status and PD-L1 status (clone 28-8 Agilent) are ongoing. Conclusions In this phase IIIb trial, nivolumab confirmed the safety and efficacy profile of the registration trial. Experiencing any grade TR AE revealed to be a favorable prognostic factor, as possible expression of effective immune response. Legal entity responsible for the study GONO group. Funding Bristol Myers-Squibb. Disclosure P. Bossi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: Angelini; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Voluntis. M.C. Merlano: Honoraria (self), consultancy or A.B.: Bristol M.S.; Honoraria (self), consultancy or A.B.: Merck S.D.; Honoraria (self), consultancy or A.B.: Merck; Shareholder / Stockholder / Stock options, Stocks: Glaxo SK; Research grant / Funding (institution), Support for clinical trials: Merck. M.G. Ghi: Honoraria (self), Advisory role: BMS; Honoraria (self), Advisory role: MSD; Honoraria (self), Advisory role: Merck Serono. G. Rinaldi: Honoraria (self), Research grant / Funding (self), Speaker and PI in clinical Trial: Novartis; Honoraria (self), Research grant / Funding (institution), Speaker and PI in clinical Trial: BMS; Research grant / Funding (self), PI in clinical Trial: MSD. F. Morelli: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): BMS. A. Farnesi: Honoraria (self), speaker: Bayer; Honoraria (self), speaker: Novartis. D. Galizia: Honoraria (self), public speaker: BMS; Honoraria (self), congress travel costs coverage: Merck; Honoraria (self), congress travel costs coverage: Roche; Honoraria (self), congress travel costs coverage: Angelini. L.F. Licitra: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Speaker: BMS; Honoraria (self), Research grant / Funding (institution), Speaker: Eisai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Speaker: MSD; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Speaker: Merck-Serono; Honoraria (self), Research grant / Funding (institution), Speaker: Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution), Speaker: Novartis; Honoraria (self), Research grant / Funding (institution), Speaker: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Speaker: Roche; Honoraria (self), Travel / Accommodation / Expenses, Speaker: Bayer; Honoraria (self), Travel / Accommodation / Expenses, Speaker: Debiopharm; Honoraria (self), Travel / Accommodation / Expenses, Speaker: Sobi; Honoraria (self), For teaching in medical meetings: Incyte Biosciences Italy srl; Honoraria (self), Expert opinion in advisory board meetings: Doxa Pharma srl; Honoraria (self), For public speaking in medical meetings: Amgen; Honoraria (self), Expert opinion in advisory board meetings: Nanobiotics Sa; Honoraria (self), For public speaking in medical meetings and/or expert opinion in advisory boards: GSK; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2016-2017): Celgene International; Research grant / Funding (institution), Founds to my Institution for 2 clinical trials (2014-2018): Exelixis Inc.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2014-2015): Hoffmann-La Roche Ltd.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2017): IRX Therapeutics, Inc.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2016): Medpace Inc.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2014): Pfizer; Travel / Accommodation / Expenses, Travel coverage for medical meetings: Stilema, AccMed, Aiocc, Aiom. All other authors have declared no conflicts of interest.

The role of chemotherapy in multimodality treatment for locally advanced head and neck squamous cell carcinoma, although firmly established, presents several unresolved issues. Concomitant platinum-based chemoradiation (CRT) is a standard treatment for unresectable, resectable but nonsurgically treated, and postoperative high-risk patients with locally advanced head and neck squamous cell carcinoma. However, no clear conclusion can be drawn regarding the optimal platinum compound or combinations to use, the type of schedule, and number of cycles (ie, platinum total dose) to be delivered. Cetuximab administered concomitantly with radiotherapy has not been directly compared with CRT but offers a potential different approach using a noncytotoxic systemic agent. In the organ preservation setting, CRT, although yielding a superior 5-year larynx preservation rate, showed similar outcomes to induction chemotherapy (IC) followed by radiation in terms of 5-year laryngectomy-free survival and overall survival, with a higher incidence of grade 3-4 mucositis. The role of IC in nonorgan preservation programs has not yet been established. Phase III trials comparing concomitant CRT versus IC followed by CRT are ongoing with results anticipated in the near future.

What is the most effective treatment for head and neck squamous cell carcinoma? : An individual patient data network meta-analysis from the MACH-NC and MARCH collaborative groups

Predictor of effectiveness of treatment intensification on overall survival in head and neck cancer (HNC)

There is increasing interest in the use of induction chemotherapy before concurrent chemotherapy and radiotherapy in the treatment of locally advanced head and neck cancer. A modest but significant improvement in survival has been observed with cisplatin and 5-fluorouracil (PF) induction before radiotherapy over that seen with radiotherapy alone. The addition of docetaxel to the PF regimen (TPF) appears to provide further survival benefits. The phase II part of a phase II/III trial compared three cycles of TPF induction chemotherapy before concomitant PF chemoradiotherapy with PF chemoradiotherapy alone in 101 patients with locally advanced stage III–IV head and neck cancer. The incidences of hematologic and nonhematologic toxicities during concurrent chemoradiotherapy were not higher in the TPF plus chemoradiotherapy group, and the feasibility of chemoradiotherapy was not compromised. Radiologically evaluated complete response rates at 6–8 weeks from the end of chemoradiotherapy (the primary endpoint) were 21% (95% confidence interval [CI], 11%–36%) with chemoradiotherapy alone and 50% (95% CI, 35%–65%; p = .004) with TPF plus chemoradiotherapy. A median overall survival time of 33.3 months and a 1-year survival rate of 78% were observed with chemoradiotherapy alone, whereas the median survival time was 39.6 months in the TPF plus chemoradiotherapy group, with a 1-year survival rate of 86%. To conclude, increasing evidence suggests that TPF induction chemotherapy improves clinical response and does not compromise subsequent chemoradiotherapy. The results of the ongoing phase III part of the phase II/III study should provide further information about the efficacy and safety of this approach for patients with locally advanced head and neck cancer.

The reporting of infection/sepsis in chemo/radiation-treated head and neck cancer patients is sparse and the problem is underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met with the aim of reaching a consensus on a clinical definition and management of infections and sepsis. The Delphi appropriateness method was used for this consensus. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. The paper contains seven clusters of statements about the clinical definition and management of infections and sepsis in head and neck cancer patients, which had a consensus. Furthermore, it offers a review of recent literature in these topics. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Background: In advanced not selected NSCLC chemotherapy achieved an advantage of approximately 1–2 months on median survival versus best supportive care. Chemotherapy seems to improve symptoms control, even if randomised studies with quality of life as first endpoint are lacking and often chemotherapy toxicity compromises the frail cost/benefit ratio. The aim of the present study is to evaluate the impact on QoL, substituting cisplatin, a pivot drug in NSCLC therapy, with carboplatin, an analogue with an improved toxicity profile. The combination of cisplatin with Mitomycin and Vinblastine was one of the most frequently used in the palliative setting at the time of design of our study. Methods: Patients were randomized to receive MVP regimen (Mitomycin-C 8 mg/m 2 d1, Vinblastine 4 mg/m 2 d 1–8, Cisplatin 100 mg/m 2 d1) or MVC regimen (Mitomycin-C 8 mg/m 2 d1, Vinblastine 4 mg/m 2 d 1–8, Carboplatin 300 mg/m 2 d1) every 3 weeks. The QoL was evaluated by the Spitzer QL-Index and by the EORTC QLQ-C30+LC 13 questionnaires before chemotherapy, after one cycle, after three cycles, and then every 6 weeks in the first 6 months and every 3 months thenafter. Results: From September 1994 to July 1997, 153 consecutive patients were randomized to MVP (75 patients) or MVC arm (78 patients). Despite difficulties in carrying out and analysing QoL items in such patients, the global QoL evaluated by the Spitzer's questionnaire suggested an advantage for MVC regimen ( P =0.05) and a significant difference was observed in global health subdomain ( P =0.04). The disease-related symptoms improved with time, and the benefits lasted for the entire treatment period. When evaluated with the EORTC questionnaire there was significantly less nausea and vomiting ( P =0.0001), appetite loss ( P =0.01), insomnia ( P =0.03), constipation ( P =0.01) and peripheral neuropathy ( P =0.01) in favour of MVC, and a trend for less hair loss ( P =0.05). The advantage lasted for all the duration of chemotherapy. No differences were observed in global quality of life subdomain ( P =0.40) between the two regimen. QoL was the first endpoint and the statistical power was inadequate to assess other parameters. However, we reported a response rate of 43.1 and 38.6%, respectively, in MVP and MVC arm ( P =0.59) and a median survival of 10.2 and 7.2 months, respectively, for cisplatin and carboplatin arm ( P =0.39). Conclusions: The carboplatin containing regimen (MVC) has a significant better toxicity profile than the cisplatin containing (MVP) regimen as proven both by the EORTC questionnaires and by the WHO toxicity data reported by physicians. No significant differences in terms of response rate, time to progression and overall survival were observed between the two regimen. The two chemotherapy regimen showed a similar effectiveness in symptom palliation when evaluated with C30 addendum of EORTC QOL questionnaire. With the Spitzer's questionnaires a trend towards an improved quality of life index was observed during treatment with the carboplatin combination in comparison to the cisplatin combination. This difference, however, was not observed when the global quality of life was evaluated with the EORTC patients compiled questionnaires. A carboplatin containing regimen with better toxicity profile and a similar potentiality for symptoms control offers an option in comparison to similar cisplatin containing combinations in the palliative treatment of advanced NSCLC.

BACKGROUND: Concomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). We evaluated the efficacy of induction docetaxel (Taxotere), cisplatin, and 5-fluorouracil (TPF) before CT/RT versus CT/RT alone. PATIENTS AND METHODS: Patients with stage III-IVM0 SCCHN, Eastern Cooperative Oncology Group performance status of zero to one, were randomly assigned to receive CT/RT alone (arm A: two cycles of cisplatin 20 mg/m(2), days1-4, plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, during weeks 1 and 6 of radiotherapy) or three cycles of TPF (arm B: docetaxel 75 mg/m(2) and cisplatin 80 mg/m(2), day 1, and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT. The primary end point was the rate of radiologic complete response (CR) at 6-8 weeks after the end of CT/RT. RESULTS: A total of 101 patients were randomly allocated to the study (51 arm A; 50 arm B). CR rates were 21.2% (arm A) versus 50% (arm B). Median progression-free survival and overall survival were, respectively, 19.7 and 33.3 months (arm A) and 30.4 and 39.6 months (arm B). Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms. CONCLUSION: Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility.

In 1986, we initiated a multicenter, randomized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment (surgery and radiotherapy or radiotherapy alone) with locoregional treatment alone in patients with head and neck squamous cell carcinoma. Here we report the long-term results of the trial. A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were randomly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment (group A) or locoregional treatment alone (group B). Among all patients, overall survival at 5 and 10 years was 23% (95% confidence interval [CI] = 15.3% to 30.9%) and 19% (95% CI = 11.6% to 26.4%), respectively, for those in group A and 16% (95% CI = 9.6% to 23.4%) and 9% (95% CI = 3.5% to 14.7%), respectively, for those in group B (P = .13). Among operable patients, we observed no difference between group A and group B in overall survival at 5 and 10 years (group A, 31% [95% CI = 14.9% to 47.3%] and 22.7% [95% CI = 7.1% to 38.3%], respectively; group B, 43.3% [95% CI = 25.6% to 61.0%] and 14.2% [95% CI = 0.1% to 28.3%], respectively; P = .73). Among inoperable patients, overall survival at 5 and 10 years was 21% (95% CI = 12.3% to 30.1%) and 16% (95% CI = 7.7% to 23.9%), respectively, for group A and 8% (95% CI = 1.5% to 12.3%) and 6% (95% CI = 0.1% to 9.1%), respectively, for group B (log-rank P = .04). Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease.

Purpose To determine the feasibility of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CHT-RT) compared with the same CHT-RT regimen alone in locally advanced head-and-neck squamous cell carcinoma. Methods and materials We treated 24 patients (20 men and 4 women) who had Stage III-IVM0 squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, or hypopharynx. The median patient age was 59 years (range, 41–73 years). The stage distribution was as follows: Stage II, 1 patient; Stage III, 6 patients; and Stage IV, 17; 18 patients had a performance status of 0 and 6 had a performance status of 1. None had undergone previous CHT or RT. Group 1 underwent three cycles of CHT (carboplatin area under the curve 1.5 on Days 1–4 and 5-fluorouracil 600 mg/m 2 /d continuous infusion for 96 h) starting on Days 1, 22, and 43 during RT (one daily fraction, 66–70 Gy within 33–35 fractions). Group 2 underwent three cycles of neoadjuvant TPF (docetaxel 75 mg/m 2 , cisplatin 80 mg/m 2 , 5-fluorouracil 800 mg/m 2 /d continuous infusion for 96 h) followed by the same CHT-RT regimen. Results After the first 16 patients, 8 in Group 1 and 8 in Group 2, the concomitant CHT-RT schedule was modified. The limiting toxicity observed during concomitant CHT-RT was similar in Groups 1 and 2, independent of neoadjuvant TPF administration. An excess of G3-G4 mucositis and other relevant toxicity that did not allowing completion of CHT-RT without interruption occurred in 44% of the patients. A reduction of at least one cycle of concurrent CHT was required in 31% of patients. On the basis of these data, the next 8 patients (Group 3) received three cycles of neoadjuvant TPF followed by two cycles only of CHT (cisplatin 20 mg/m 2 on Days 1–4 and 5-fluorouracil 800 mg/m 2 /d continuous infusion for 96 h) (PF) during Weeks 1 and 6 of the planned 7 weeks of RT. In Group 3, 25% of the patients developed World Health Organization G3-G4 mucositis. No World Health Organization hematologic G3-G4 toxicity was seen. RT interruption was required for 2 patients (25%). In 1 patient (12%), one cycle of CHT was omitted. During neoadjuvant TPF (Groups 2 and 3), the principal toxicities were G3-G4 neutropenia (37.5%) and G2 mucositis (44%). At the end of therapy, the CR rate was 62.5% for CHT-RT alone (Group 1) and 80% for neoadjuvant TPF followed by CHT-RT (Groups 2 and 3). Conclusion Three cycles of neoadjuvant TPF followed by two cycles of PF during RT are feasible without limiting toxicity. Three cycles of TPF were well tolerated and did not compromise subsequent concomitant CHT-RT. A randomized multicenter Phase III study has been started with the aim of comparing two cycles of PF during RT as standard treatment vs. the experimental arm with three cycles of neoadjuvant TPF followed by two cycles of PF during RT.

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 p 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) 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.

Aim: Concurrent chemoradiation (CRT) is employed both in curative and postoperative settings in locally advanced head and neck cancer (HNC). The acute toxicity induced by this treatment is a major issue, affecting patients' quality of life and their compliance with timing and dose intensity. No guidelines exist for comprehensive best practices of supportive care (BPSC) to be adopted during this treatment. Methods: Due to the lack of evidence from randomized controlled trials on most aspects of BPSC during CRT, an alternative approach to provide guidance was adopted. A formal consensus methodology was employed according to the model proposed by ASCO (Loblaw DA, J Clin Oncol 2012), through a modified Delphi strategy. Briefly, a consensus group of 40 experts including medical oncologists, radiation oncologists, surgeons, nutritionists, speech language pathologists, infectious disease specialists, dentists and nurses was constituted. A panel of facilitators for each topic performed a systematic review of the literature and a series of statements were defined. These were differentiated according to the timing of intervention (pre-treatment, during and after the treatment) and included an indication of the person in charge of the management of each BPSC aspect (e.g., physician, nurse, patient, caregiver). All experts rated these statements through a two-round process. A 4-point scale was adopted (1 = high consensus, 2 = low consensus, 3 = no consensus and 4 = unable to express an opinion). Consensus was defined as agreement by > 75% of raters. The statements were then finalized according to the suggestions of external reviewers. The process lasted from March 2013 to April 2014. Results: The following topics were included: mucositis, dysphagia, hematological toxicity, infections, nutrition and hydration, pain, skin toxicity and stomatological problems. Recommendations were delivered for each topic. Conclusions: Practice guidelines for BPSC during CRT for HNC have been defined with a recognized methodology, in an area where high-quality evidence is lacking. The results of consensus as well as the areas identified for further consensus development will be presented. *Authors on behalf of the working group AIOM, AIRO, AIOCC. Disclosure: All authors have declared no conflicts of interest.

6004 Background: Platinum-based CRT is the standard treatment for LASCCHN. CET/RT is superior to RT alone and it is an alternative treatment to CRT. Induction TPF resulted to be superior to cisplat...

6003 Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1+ 130 Arm B1) and 160 received CET/RT (80 Arm A2+ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. [Table: see text]

5513 Background: The standard treatment options for LASCCHN are cCHT+RT or CET+RT. Strategies to improve the efficacy with the integration of induction chemotherapy are being investigated. Primary endpoints of this study were to compare: 1) the overall survival (OS) of induction vs. no induction arms; 2) the Grade(G)3-4 in-field toxicity of cCHT+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: cCHT+RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET+RTX; Arm B1: 3 cycles of TPF followed by the same cCHT+RT; Arm B2: 3 cycles of TPF followed by CET+RT. A total of 204 deaths over 420 pts ( including the 101 randomized in the phase II part of the study comparing cCHT+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: By February 2012, 387 pts over 413 pts were evaluable for toxicity. 82% of pts were male; median age was 60y; PS: 0=77.8% and 1=22.2%. Disease stage was III (31%) or IV (69%). Sites of disease were oral cavity (21.7%), oropharynx (54.8%), hypopharynx (23.5%). At a median follow-up of 21 months, 126 deaths occurred. Data on G3-4 in-field toxicity (primary endpoint) and compliance to cCHT+RT vs CET+RT are shown in the table. Conclusions: No advantage for CET+RT over cCHT+RT was observed regarding G3-4 in-field toxicities and feasibility. Pts are still being followed-up to assess OS. [Table: see text]

TPS196 Background: Concomitant chemoradiation (CRT) is the standard treatment for locally advanced squamous cell carcinoma (LASCC). RT plus cetuximab is superior to RT alone and it is an alternative treatment to CRT (Bonner, NEJM 2006). The efficacy of induction chemotherapy when added to standard treatment has never been demonstrated, however, induction cisplatin/fluorouracil [PF] plus docetaxel combination (TPF) is superior to PF when added to CRT or RT alone (Posner, NEJM 2005; Vermorken, NEJM 2005). Methods: This ongoing factorial phase III study is the implementation of a previous phase II randomized trial evaluating the efficacy of CRT with or without induction TPF. At the end of the phase II study a Monitoring Committee decided to continue the study as a phase III, as initially planned, based on the efficacy and safety data of the phase II study. This phase III four arm factorial study has now randomized 352 patients (target 420) with LASCC unresectable stage III-IVM0 of oral cavity, oropharynx, hy...

5534 Background: Concomitant platinum-based chemoradiation (CRT) is the standard treatment for locally advanced squamous cell carcinoma. As no consensus regarding the optimal concomitant platinum-based regimen exist, a literature based meta-analysis was performed. Methods: Randomized trials comparing radiation alone (RT) vs concomitant platinum-based CRT were identified by electronic search. The main endpoints were to compare the efficacy with regards to cisplatin total dose and platinum compounds (cisplatin vs carboplatin). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were used to measure the relative effect of treatments on overall survival (OS). Heterogeneity among trials wastested by Chi-Square test and I2index. The incidence of Grade (G) 3-4 mucositis was also analyzed by means of a Chi-Square test. Results: Fifteen trials were identified and 2502 patients were available for the analysis. No difference in OS was observed between cisplatin high dose (300mg/sqm) (HR 0.59, 95% CI 0.46-0....

7650 Background: We showed that PCG significantly increases both response rate (RR) (43.6% vs 20%) and median survival (10.8 mo vs 8.3 mo) over PC and that at Cox analysis, the only independent prognostic factors were PS and treatment (Paccagnella et al, J Clin Oncol 2006;24: 681–687). According to the Prentice criteria (Stat Med 1989;8: 431–440), to directly relate response and survival it is necessarily that responding patients (and non responding) of both arms have a similar survival and that the survival difference between the two arms disappear when the response factor is included in the multivariate analysis. Methods: Out of 324 pts included in the original analysis, 26 pts were not evaluable for response (early death, toxicity, refusal) before the planned response evaluation at two months and were excluded (15 pts from PC arm and 11 pts from PCG arm). The analysis however was also performed considering the non evaluable patients as non responders. Results: Overall, Responder patients had a median Survival that nearly doubled that of no responders: 14.73 mo vs 7.67 mo (HR: 0.49; CI: 0.31–0.54; P=0.000). No responder pts from PC and PCG arms had a similar survival (median 7.53 mo and 8.07 mo respectively; P= 0.96) as well as responder (CR + PR) patients (median 14.13 mo and 15.40 mo respectively; P=0.38). The principal difference between the two arms was that more than the double of patients in PCG arm responded (43.6% vs 20%) and consequently had a survival advantage of clinical relevance in comparison to patients in PC arm. When tumor response was introduced in the Cox model (as a four level variable), the difference in Overall Survival between PCG and PC changed from a significant level (HR=1.28; CI 1.00–1.63; P=0.049) to a not significant level (HR=0.99; CI: 0.76 - 1.28; P=0.97). Conclusions: To our knowledge this is the first report showing a significant direct correlation between response and survival in advanced NSCLC according to Prentice criteria. No significant financial relationships to disclose.

15039 Background: Patients with chemoresponsive tumors are more likely to have a survival advantage, consequently a great interest is being placed on the identification of predictive markers. Currently, the improving in the extraction techniques allow the detection of gene profile at the mRNA level from FFPE materials. The purpose of the study was to analyse the m-RNA level of specific genes from FFPE (Stanta et al, BioTechniques 1998), both primary tumor (T) and locoregional lymphnodes (N) in CRC patients treated with chemotherapy (CT), and to relate it with chemoresponsiveness. Material and Methods: RNA was extract from FFPE tumor specimen both in T and N. RNA was reversing transcribed to cDNA. From the cDNA sample, BRCA1, ERCC1, CES2 and TS gene transcripts were specifically amplified by PCR. ERCC1 and BRCA1 are involved in platinum-compound resistance; TS is involved in responses to 5Fluorouracil (5FU) and CES2 level expression was recently related to Irinotecan pro-drug activation. Eligible patients included metastatic CRC patients treated from March 2000 to December 2003 as first line CT with Oxaliplatin/5FU or Irinotecan/5FU or 5FU alone. Results: Forty-five consecutive patients were retrospectively analysed. 15 of them received Oxaliplatin/5FU, 15 Irinotecan/5FU and the other 15 5FU alone. Median age was 64 (range 46–75). 13 patients (28%) had received adjuvant CT. 32 patients (72%) had metastatic disease at the time of surgery. Global Response Rate was 44%. All 45 patients received 5FU and they were analysed for the level of TS expression. With Multiple Regression Analysis, no statistical significant relation between TS level expression and response to 5FU was observed (P=0.36). A strong relation was observed between ERCC1 and response to Oxaliplatin (P=0.006) and a possible correlation of BRCA1-exon11 level expression and response to Irinotecan (P=0.06). The analyses of CES2 and the relation between gene expression and survival are ongoing. Conclusions: The analyses of mRNA gene expression profile from FFPE could be use to predicting response to CT in CRC patients. To test this hypothesis, a randomized phase II-III prospective study of tailored therapy in metastatic CRC is planned. No significant financial relationships to disclose.

7351 Background: Preliminary results from a phase III trial in advanced NSCLC comparing CP vs CPG suggest an advantage in RR and TTP with a superior but acceptable toxicity for CPG. We used CPG as induction regimen in stage III pts. Eligibility Criteria: ECOG 0–1, unresectable stage III, measurable disease, no prior chemotherapy, informed consent. Treatment: induction CT: 2 cycles of Carboplatin AUC6, Paclitaxel 200mg/m2 day 1, and Gemcitabine 1000mg/m2days 1–8 q 21 days. Concurrent CT: Carboplatin AUC 2 and Paclitaxel 45 mg/m2 weekly with concomitant RT (60 Gy). After 40 Gy pts were revaluated for surgery, if inoperable they received definitive CT/RT. Results: From April 1998 to November 2002, 41 consecutive patients entered. Patient characteristics were: ECOG PS 0/1: 27/14(66/34%); stage IIIA/IIIB: 18/23(44/56%); median age 62 (41–77); male/female 34/7(83/17%); histology: 26(63.5%) squamous cell carcinoma, 8(19,5%) adeno, 3(7.3%) large cell and 4(9,7%) undifferentiated. The induction treatment was well ...