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Mucositis; Radiation toxicities; Simultaneous care Mucositis; Toxicitats per radiació; Atenció simultània Mucositis; Toxicidades por radiación; Atención simultánea Treatment of locally advanced head and neck carcinoma not amenable for surgical resection or resected with high-risk features is usually based on (chemo-)radiation treatment. Oral mucositis represents one of the main side effects of (chemo-)radiation, with an important impact on quality of life and causing approximately 20% of early interruption of treatment, leading to a suboptimal dose administered. Treatment and prevention of oral mucositis have a central role in the therapeutic pathways of head and neck cancer patients but remains quite challenging. Although extensive research is conducted to identify interventions for the management of mucositis, very few interventions had sufficient evidence to generate an international expert consensus. This may be partially explained by confounding factors that could influence the development and assessment of oral mucositis. Little is known about the confounding factors of oral mucositis, which, if not well balanced in an experimental study, could lead to non-solid results. The current paper aims to review the main oral mucositis confounding factors related to head and neck cancer patients. Open access funding provided by Università degli Studi di Brescia within the CRUI-CARE Agreement. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Background: nasopharyngeal carcinoma (NPC) is a complex disease entity that mainly predominates in endemic regions. Real-world data with immunotherapy from nonendemic regions are limited. Methods: we collected data from patients with recurrent/metastatic (R/M) NPC treated at a center in Greece and 8 centers in Italy. Between 2016 and 2021, 46 patients who were treated with at least one cycle of immune checkpoint inhibitors (ICI) were identified. Herein, we present our results and a review of the literature. Results: assessment of response was available in 42 patients. Overall, 11 patients responded to immunotherapy (Overall Response Rate-ORR 26.2%). Three patients had complete response (CR), and 8 patients had partial response (PR). Disease control rate (DCR) was 61.9%. Median Progression Free Survival (PFS) was 5.6 months and median Overall Survival (OS) was 19.1 months. Responders to ICI improved PFS and OS as compared to that of nonresponders. A lower probability of responding to ICI was shown in patients with more than three metastatic sites (p = 0.073), metastatic disease at initial diagnosis, (p = 0.039) or EBV DNA positive before ICI initiation, (p = 0.074). Decline in EBV DNA levels was found to be statistically significant associated with best response to ICI (p = 0.049). Safety was manageable. Conclusions: among 46 patients with R/M NPC treated with immunotherapy in two nonendemic regions, ORR was 26.2% and durable responses were observed. Low disease burden could serve as a biomarker for response to ICI.

Purpose/Objective On September 2009: We started a randomized multicenter phase III study comparing chemoradiation (CRT) (Aldestein RTOG regimen) versus induction chemotherapy followed by Cetuximab radiation (IBRT). The main study’s aim was comparison of overall survival but no formal analyses have been made between the two arms because of low accrual and high amount of missing data. The goal of this paper is to identify the reasons of difference in accrual and quality of data among participating centers. Material/Methods Statistic: We correlated data collection quality with relevance of the centers, accrual and number of scientific papers (both specific on HNC and other topics) of each PI. We created an HNC publishing score dividing the number of HNC specific papers for the overall number of published papers. Results We observed a strong difference in the accrual of pts as well as in the quality of data among the participating centers. The accrual was independent from the quality of data since some centers with low accrual produced high quality data with an excellent follow up. We found a correlation among both number of published papers of each PI and HNC publishing score with the quality of data. Conclusion The study demonstrated that expertise in HNC is important not only to ensure a better outcomes but also to provide high quality data in phase III trials.

Background: Recommendations for managing nasopharyngeal carcinoma (NPC) patients in non-endemic areas are largely derived from studies conducted in endemic areas. We aimed to analyse the impact of treatment approaches on survival in this patients’ setting Methods: In an international, multicenter, retrospective study, we analysed clinical data of consecutive NPC patients diagnosed between 2004 and 2017 in 36 hospitals from 11 countries. Treatment was categorised as non-intensive (NIT), including radiotherapy (RT), three-dimensional conformal RT or intensity modulated RT, IMRT), alone or concomitant radio-chemotherapy (RT-CT), and intensive (IT) including RT-CT preceded by induction and/or followed by adjuvant chemotherapy (CT). We fitted Cox proportional hazard models for both overall and Epstein Barr-Encoded RNA (EBER) status-specific analyses. The impact of IT on overall survival (OS) and disease-free survival (DFS) was adjusted for all the available potential confounders. Findings: Overall, 1021 and 1113 patients were eligible for OS and DFS analyses, respectively (501 and 554 with EBER status available). In the whole group, 5-year OS and DFS were 84% and 65%, respectively. The use of NIT was associated with a risk of death or recurrence 1·37 times higher than patients receiving IT. Patients submitted to NIT and induction CT + concurrent 3DRT-CT had a risk of death or recurrence 1·5 and 1·7 times higher than patients treated with induction CT + concurrent IMRT-CT, respectively. The IT had no impact on OS in neither EBER+ nor EBER- patients; however, IT showed better DFS in EBER+ but not in EBER- patients. Interpretation: This study represents, the largest data analysis on NPC patients in low-incidence areas. Among IT approaches, induction CT followed by concurrent IMRT-CT achieved the highest DFS rate, confirming the potential role of this approach in advanced EBER+ disease. The benefit of IT on DFS was restricted to EBER+ patients, suggesting that additional therapy offers no advantages in EBER- cases. Funding: None to declare. Declaration of Interest: Dr Bossi reports personal fees from Merck, Sanofi Regeneron, BMS, MSD, GSK, Astrazeneca, Sunpharma, Angelini and grants from GSK and Sunpharma, outside the submitted work. Dr Buglione reports personal fees from Meck Serono, outside the submitted work. Dr Cirauqui Cirauqui reports congress support from MSD, Merck, BMS and Roche, and personal fees from BMS and Roche, outside the submitted work. Dr Ursino reports grants from Merck Serono, Nestle, Kyowakirin and Astrazeneca, outside the submitted work. Dr D’angelo reports personal fees from Astrazeneca, Nestle and Merck Spa, outside the submitted work. Dr. Licitra reports personal fees and grants from Astrazeneca, Bayer, BMS, Boehringer ingelheim, Debiopharm International SA, EISAI, Merck Serono MSD, Novartis, Roche; Personal fee from Bayer, SOBI, IPSEN, GSK, Doxa Pharma srl, Incyte Biosciences Italy srl, Amgen, Nanobiotics Sa; Grants from Celgene International, Exelixis inc, grants Hoffmann-La Roche ltd, IRX Therapeutics inc Medpace inc, grants Pfizer, outside the submitted work. Dr Mesia reports Consulting and advisory role for Merck, MSD, Roche, Astazeneca, BMS and speaker's Bureau for Merck, MSD, BMS, Roche. All the other authors have nothing to disclose. Ethical Approval: Ethics approval was obtained from all concerned Institutional Review Boards and the Ethics Committees.

Aim: Recommendations for managing patients with nasopharyngeal carcinoma (NPC) in non-endemic areas are largely derived from studies conducted in endemic areas. We analysed the impact of treatment approaches on survival in non-endemic areas. Methods: In an international, multicentre, retrospective study, we analyse consecutive patients with NPC diagnosed between 2004 and 2017 in 36 hospitals from 11 countries. Treatment was categorised as non-intensive (NIT), including radiotherapy alone or concomitant chemoradiotherapy (cCRT), and intensive (IT) including cCRT preceded by and/or followed by chemotherapy (CT). The impact of IT on overall survival (OS) and disease-free survival (DFS) was adjusted for all the available potential confounders. Results: Overall, 1021 and 1113 patients were eligible for overall survival (OS) and disease-free survival (DFS) analyses, respectively; 501 and 554 with Epstein Barr-encoded RNA (EBER) status available. In the whole group, 5-year OS was 84% and DFS 65%. The use of NIT was associated with a risk of death or recurrence 1.37 times higher than patients receiving IT. Patients submitted to NIT and induction CT thorn concurrent concomitant chemo and three-dimensional Conformal Radiation Therapy (3DCRT) had a risk of death or recurrence 1.5 and 1.7 times higher than patients treated with induction CT + cCRT with intensity-modulated radiotherapy (IMRT), respectively. The IT had no impact on OS in neither patients with EBER+ nor in patients with EBER-; IT showed better DFS in EBER+ but not in patients with EBER-. Conclusions: In low-incidence areas, patients with NPC treated with induction CT followed by concurrent IMRT cCRT achieved the highest DFS rate. The benefit of IT on DFS was restricted to patients with EBERthorn, suggesting that additional therapy offers no advantages in EBER- cases. (C) 2021 Elsevier Ltd. All rights reserved.

Simple Summary CD8+ T lymphocytes are among the immune cells reputed to kill tumor cells. Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of infiltrating CD8+ T cells in a cohort of 30 HNSCC patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, we identified an intratumoral CD8+CD28- T cell subpopulation, which expressed markers of both exhausted (i.e., with impaired effector functions) and regulatory (i.e., exerting suppressive activities) cells. This suggests that in HNSCC effector T cells progressively undergo exhaustion and acquisition of regulatory properties, hampering their anti-tumor functions. Abstract Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate in the majority of patients. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of HNSCC infiltrating CD8+ T cells in a cohort of 30 patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, high PD1 expression identified a CD8+CD28− T cell subpopulation, phenotypically/functionally corresponding to CD8+CD28−CD127−CD39+ Treg, which showed a high expression of markers of exhaustion. This observation suggests that development of exhaustion and acquisition of regulatory properties may configure the late differentiation stage for intratumoral effector T cells, a phenomenon we define as effector-to-regulatory T cell transition.

Objectives: To identify and validate baseline magnetic resonance imaging (b-MRI) radiomic features (RFs) as predictors of disease outcomes in effectively cured head and neck squamous cell carcinoma (HNSCC) patients. Materials and methods: Training set (TS) and validation set (VS) were retrieved from preexisting datasets (HETeCo and BD2Decide trials, respectively). Only patients with both pre- and post-contrast enhancement T1 and T2-weighted b-MRI and at least 2years of follow-up (FUP) were selected. The combination of the best extracted RFs was used to classify low risk (LR) vs. high risk (HR) of disease recurrence. Sensitivity, specificity, and area under the curve (AUC) of the radiomic model were computed on both TS and VS. Overall survival (OS) and 5-year disease-free survival (DFS) Kaplan–Meier (KM) curves were compared for LR vs. HR. The radiomic-based risk class was used in a multivariate Cox model, including well-established clinical prognostic factors (TNM, sub-site, human papillomavirus [HPV]). Results: In total, 57 patients of TS and 137 of VS were included. Three RFs were selected for the signature. Sensitivity of recurrence risk classifier was 0.82 and 0.77, specificity 0.78 and 0.81, AUC 0.83 and 0.78 for TS and VS, respectively. VS KM curves for LR vs. HR groups significantly differed both for 5-year DFS (p

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. Methods: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. Results: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, “significant nausea,” and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). Conclusions: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

Purpose We report a subgroup analysis primarily focused on human papillomavirus (HPV)-related oropharyngeal cancer (OPC) from the Cetuximab Plus Radiotherapy Versus Cisplatin Plus Radiotherapy in Locally Advanced Head and Neck Cancer (CTXMAB+RT; ClinicalTrials.gov identifier NCT01216020 ) trial comparing radiation therapy with concomitant cisplatin (CDDP) versus concomitant cetuximab (CTX) as first-line treatment of locally advanced head and neck cancer. Methods and Materials The data from all the patients in the CTXMAB+RT trial were reviewed and separately analyzed in 3 groups: p16-positive OPC, p16-negative OPC, and all other cancer sites. The endpoints of interest were locoregional control (LC), metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS). Severe and fatal infectious complications were also reanalyzed to more thoroughly investigate the association between CTX treatment and potentially life-threatening reactions. Results A total of 33 patients had OPC. The HPV status was available for 30 of the 33 patients. Thus, 3 patients treated with CDDP but with unknown HPV status were excluded from the survival analysis. The small number of patients in each group did not allow for significance to be reached for any of the outcomes analyzed. A trend favored the CDDP arm in the p16-positive group for the 2-year LC and OS/CSS rates (100% vs 72.9% and 100% vs 77.8% for CDDP vs CTX). In this group of patients, the hazard ratio for the treatment arm (CTX vs CDDP) was 4.7 (95% confidence interval [CI] 0.5-40.3) for LC, 3.4 (95% CI 0.4-30.5) for OS, and 2.4 for CSS (95% CI 0.2-23.2). A survival benefit favoring the CDDP arm was not evident in the p16-negative OPC group or for patients with cancer located in other sites. Serious or fatal infectious complications occurred only in the CTX arm. Conclusions In patients with p16-positive OPC in the CTXMAB+RT trial, CTX had lower efficacy than CDDP, with possible implications for treatment selection in this clinical setting.

The optimal treatment for T3 laryngeal carcinoma (LC) is still a matter of debate. Different therapeutic options are available: Transoral laser microsurgery (TLM), open partial horizontal laryngectomies (OPHLs), total laryngectomy (TL), and organ preservation protocols (radiation therapy (RT) or chemo-radiation (CRT)). This study aimed to retrospectively evaluate oncologic outcomes of 104 T3 LCs treated by surgery or non-surgical approaches from January 2011 to December 2016 at a single academic tertiary referral center. Each case was evaluated by a multidisciplinary team (MDT) devoted to the management of head and neck cancers. We divided the cohort into two subgroups: Group A, surgical treatment (TLM, OPHLs, TL) and Group B, non-surgical treatment (RT, CRT). For the entire cohort, two- and five-year overall survival (OS) rates were 83% and 56%, respectively. The two- and five-year disease-free survival (DFS) rates were 75% and 65%, and disease-specific survival rates were 93% and 70%, respectively. The N category was a significant independent prognosticator for OS (p = 0.02), whereas Group B was significantly and independently associated with DFS (HR 4.10, p = 0.006). Analyzing laryngo-esophageal dysfunction-free survival as an outcome, it was found that this was significantly lower in higher N categories (p = 0.04) and in cases that underwent non-surgical treatments (p = 0.002). Optimization of oncologic outcomes in T3 LCs may be obtained only by a comprehensive MDT approach, considering that different treatment options have heterogenous toxicity profiles and indications.

BackgroundWe conducted a multicenter retrospective analysis to describe the characteristics, frequency of skeletal-related events (SREs), and prognosis of head and neck cancer (HNC) in patients with bone metastases (BM).Patients and methodsThe data of 192 HNC patients with BMs were collected. Analyses were conducted separately in 64 nasopharyngeal cancer (NPC) patients and in 128 non-NPC patients.ResultsSREs occurred in 34 (27%) non-NPC and in 6 (9%) NPC patients, respectively. Median overall survival (OS) was 25 and 6 months in NPC and non-NPC patients, respectively. Locoregional recurrence (hazard ratio [HR] 2.33, 95% confidence interval (CI) 1.1-4.93), synchronous BM (HR 0.25, 95% CI 0.59-0.71) and bone-directed therapies (BDT) (HR 0.26, 95% CI 0.10-0.68) were independent prognostic factors for OS in NPC patients. Combined bone radiotherapy (RT) and BDT in NPC patients obtained longer survival (38 months) than either therapy alone (25 months) or neither of these therapies (8 months).ConclusionsPatients with BMs from non-NPC have a poor prognosis and are at high risk of SREs. NPC patients with BMs are at relatively low risk of SREs. BDT may potentially improve survival, particularly when combined with bone RT. This last finding deserves prospective confirmation.

The purpose of this study is to evaluate if, in elderly HNC patients, loco-regional control (LRC) is influenced by average weekly radiation dose (AWD). From 2009 to 2017, 150 consecutive HNC elderly patients were analyzed. AWD was calculated by dividing total dose in Gray by overall treatment time in weeks. Patients were divided in 2 groups: Group 1 (70–75 years) and Group 2 (> 75 years). Primary endpoint was LRC; secondary endpoints were overall survival (OS) and compliance to treatment. The median age was 76 years (range 70–92), the distribution of patients by age was 72 and 78 patients in Group 1 and in Group 2, respectively; overall median follow-up was 23 months. Optimal cut-off of AWD for LRC was 9.236 (p = 0.018). Median OS was 73 months. In univariate survival analysis low PS (p = 0.005), T3–T4 (p = 0.021), Stage III–IV (p = 0.046) and AWDLow ( 9.236 Gy was found to be beneficial for RT alone regimen. When radiotherapy alone is indicated in elderly patients an effort should be made to maintain an increased AWD in order to improve LRC.

The cardiovascular effects of estrogen deprivation induced by aromatase inhibitors are unknown. We carried out a cross-sectional study to evaluate the effect of estrogen deprivation induced by aromatase inhibitors on markers of cardiovascular risk. We enrolled 410 postmenopausal women: 200 consecutive breast cancer patients treated with aromatase inhibitors for a median of 53 months (range 23–122) and 210 volunteer controls. Carotid intima-media thickness, presence of carotid stenosis, and presence of abdominal aortic aneurism were evaluated through an ultrasound examination. Average carotid intima-media thickness was 0.97 ± 0.02 mm and 1.08 ± 0.02 mm for breast cancer group and control group, respectively (p

6553 Background: Emerging data suggest that radiomics can be used to predict outcomes in SCCHN. At present, only few data are available for pre-treatment MRI. Methods: Study population was retrieved from an ongoing multicenter, randomized, prospective trial (NCT02262221, HETeCo) evaluating health and economic outcomes of two different follow-up (FUP) strategies (intensive vs non-intensive) in effectively cured stage III-IV (VIII TNM ed.) SCCHN. We selected only patients with both pre- and post-contrast enhancement T1 and T2-weighted baseline MRI (b-MRI) and at least 2 years (2y) of FUP. A radiomic model was developed to identify high risk (HR) and low risk (LR) of disease recurrence. Radiomic features (RF) were extracted from the primary tumor in the b-MRI. The best RF combination was selected by Least Absolute Shrinkage and Selection Operator (LASSO). Ten-fold cross-validation was used to compute sensitivity, specificity and area under the curve (AUC) of the classifier. Kaplan-Meier (KM) curves were estimated for HR and LR, for both overall survival (OS) and disease-free survival (DFS) and log rank test was performed. Three years (3y)-DFS and OS were also estimated for the two groups. The radiomic risk class was used as a new variable in a multivariate Cox model including well established prognostic factors in SCCHN (TNM stage, subsite and HPV). Results: Out of 155 enrolled HETeCO patients, 98 baseline imaging were retrieved of which 57 b-MRI. Of these, 51 met the eligibility criteria (25 in intensive and 26 in non-intensive arm). Baseline patients’ characteristics were: median age 66 yr (38-86); sex (M 42; F 9); median smoking history: 30 packs/y (1-100); 25 oral cavity (49%), 18 oropharynx (35%, 14 HPV+), 6 larynx (12%), 2 hypopharynx (4%). At a median FUP of 42 months (25-64), 45 (88%) patients are still alive. The recurrence rate was 20% (10/51, of which 2 distant). In total, 1608 RF were extracted. The sensitivity, specificity and AUC of the classifier were 90%, 76%, and 80%, respectively. The radiomic risk class was found to be an independent prognostic factor for both DFS and OS (p=0.01 and p=0.046, respectively). KM curves for DFS and OS were significantly different between HR and LR groups (p=0.002 and p=0.04, respectively). In HR vs LR, 3-y DFS and OS were: 78% [61-100%] vs 97% [90-100%], and 88% [75-100%] vs 96% [88-100%], respectively. Conclusions: Radiomics of pre-treatment MRI can predict outcomes in SCCHN. External validation of this preliminary radiomics-based model is currently ongoing.

Highlights • Treatment of relapsed/metastatic head and neck cancer is unclear. • Cyclophosphamide, avelumab, and radiotherapy may be effective for R/M-HNC. • Combined treatment may improve avelumab activity without increasing its toxicity. • Ongoing trials will clarify the potential of immunotherapy in RM-HNC patients., Introduction and background Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited. This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors. Methods/design In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8. Discussion The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1–PD-L1 axis by avelumab. The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile. Finally, an ancillary translational study will be extended to all the patients’ population. Trial registration EudraCT n. 2017-000353-39.

Background B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Patients and methods Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. Results A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72–1.36,P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53–1.11,P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38–1.20,P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%,P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). Conclusion The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. Clinical trial number EudraCT# 2011-002564-24.

Background Nasopharyngeal carcinoma (NPC) is a rare cancer in many areas including Europe and Middle East/Mediterranean. Data regarding natural history, prognostic factors and treatment strategies in NPC patients (pts) are derived mostly from studies conducted in endemic regions. Methods We collected clinical data on consecutive NPC pts treated in non-endemic countries from 2005 to 2016. Main objective of the study was to collect clinical/biological parameters and to correlate them with the outcome, at uni- and multivariate analysis, using the Cox regression model. Results The database included 1220 pts from 34 Centers. They were mainly male (72%), with ECOG performance status (PS) 0 in 74% of the cases, with advanced stages (stage III 42%, IV 33%), and with a median age of 50 years. Tumoral EBER was assessed in 51% (42% positive); plasmatic EBV DNA was evaluated at baseline in 23% of the pts, with a mean value of 12,434 copies/mL (range 0-824,525). Induction, concurrent and adjuvant chemotherapy (CT), were administered to 45%, 83% and 11% of the pts, respectively. Main RT techniques employed were IMRT (81%) and 3DRT (19%). With a median follow up of 56.5 months, 3- and 5-year overall survival (OS) was 83% and 77%, respectively. Among the 411 pts who relapsed, distant metastases were the pattern of failure in 55%, with bone (49%), lung (31%) and liver (29%) as the most represented sites. At relapse, main treatment approach was CT (45%), surgery (24%), re-RT (9%), or supportive care only (10%). At univariate analysis, prognostic factors favorably correlated with OS were: PS (0-1 vs > 1, p 4000 copies/mL (p = 0.0073). At multivariate analysis, all the variables confirmed their prognostic value. Conclusions In non-endemic countries, NPC showed survival figures comparable to endemic areas. Stage, PS, gender and plasmatic EBV DNA turned out to be prognostic factors. These data represent the benchmark in non-endemic setting and the referral for building new prospective trials. Legal entity responsible for the study Fondazione IRCCS Istituto Nazionale Tumori Milano. Funding Has not received any funding. Disclosure P. Bossi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Angelini; Advisory / Consultancy: Merck; Advisory / Consultancy: Voluntis. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Nanobiotix. L.F. Licitra: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Research grant / Funding (institution): EISAI; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Research grant / Funding (institution): Boehringer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self), Travel / Accommodation / Expenses: Debiopharm; Honoraria (self), Travel / Accommodation / Expenses: Sobi; Honoraria (self): Doxa Pharma srl; Honoraria (self): Nanobiotics; Honoraria (self): GSK; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Exelixis Inc.; Research grant / Funding (institution): Hoffmann-La Roche Ltd.; Research grant / Funding (institution): IRX Therapeutics, Inc.; Research grant / Funding (institution): Medpace INC.; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Stilema, AccMed, Aiocc, Aiom; Honoraria (self): Amgen. All other authors have declared no conflicts of interest.

Background We present our experience in assessing the feasibility and efficacy outcomes of intensified intensity-modulated radiation therapy (IMRT) with simultaneous integrated boost (SIB) delivered to patients with nasopharyngeal carcinoma (NPC). Methods Between March 2009 and December 2014, 35 patients affected by advanced NPC with a median age of 53 years (range 11-77) were treated with definitive radiotherapy. Radiotherapy was delivered by helical tomotherapy with the SIB technique. The prescribed doses were 66 Gy to macroscopic disease, 60 Gy to high-risk subclinical disease, and 54 Gy to low-risk disease in 30 fractions. The daily SIB dose was 2.2 Gy to macroscopic disease. Results At the end of treatment 33 (94%) patients had obtained complete clearance of disease and 2 patients had died (1 of persistent disease after 3 months and 1 of cancer-unrelated causes after 4 months). At a median follow-up of 40 months (range 5-69), locoregional control rates at 2 and 4 years were 92.9% and 88.2%, respectively, and the overall survival after 4 years was 93.9%. The most significant acute toxicities were grade 2 and 3 mucositis (43%). No grade 3 and 4 late toxicities were observed; grade 2 xerostomia after 6 months from the end of treatment was reported in 11 patients; xerostomia toxicity decreased to grade 1 in 6/11 patients within 12 months. Conclusions These results show that intensified IMRT with SIB is an excellent strategy offering high local control rates for NPC patients with mild acute and late toxicity.

Purpose No randomized trials have been conducted to directly compare radiotherapy (RT) with concomitant cisplatin (CDDP) versus concomitant cetuximab (CTX) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck. In this randomized trial, we compared these two treatment regimens in terms of compliance, toxicity, and efficacy. Patients and Methods Eligible patients were randomly assigned in a 1:1 ratio to receive either CDDP 40 mg/m2 once per week or CTX 400 mg/m2 as loading dose followed by CTX 250 mg/m2 once per week concomitant to radical RT. For primary end points, compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction. The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria. Efficacy end points were local recurrence-free survival, metastasis-free survival, cancer-specific survival, and overall survival. Results The study was discontinued early because of slow accrual after the enrollment of 70 patients. RT discontinuation for more than 10 days occurred in 13% of patients given CTX and 0% given CDDP (P = .05). Drug dosage reduction occurred in 34% given CTX and 53% given CDDP (difference not significant). Toxicity profiles differed between the two arms, with hematologic, renal, and GI toxicities more frequent in the CDDP arm, and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm. Serious adverse events related to treatment, including four versus one toxic deaths, were higher in the CTX arm (19% v 3%, P = .044). Locoregional control, patterns of failure, and survivals were similar between the treatment arms. Conclusion CTX concomitant to RT lowered compliance and increased acute toxicity rates. Efficacy outcomes were similar in both arms. These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT.

The management of melanoma brain metastases (MBM) includes different therapeutic modalities, such as surgery, radiotherapy and chemotherapy. Despite the choice of treatments, survival remains poor, exceeding 1 year only in patients with solitary metastases and absence of extracranial disease. A total of 115 consecutive MBM patients observed between 1994 and 2010 were included in an historical cohort study. Demographic, clinical data and tumour characteristics were collected and survival status was ascertained across the follow-up window. The statistical associations between individual and tumour data and overall survival were investigated using Kaplan-Meier survival function and Cox's multiple regression analysis. The median survival was 4.3 months (95% confidence interval 2.6-6.1). Patients who underwent surgery or stereotactic radiosurgery showed a significantly (P

Objective: To identify through a substudy of a larger, multicenter study of adjuvant treatment in primary operable breast cancer patients any possible correlation between cellular proliferation rate, measured by thymidine labeling index (TLI), and perioperative chemotherapy (periCT). Methods: TLI was measured in slices of early breast carcinoma patients. The main trial was designed to randomize patients after primary surgery to receive one cycle of periCT consisting of cyclophosphamide, epidoxorubicin and 5-fluorouracil, or no periCT. Results: Of 600 patients randomized into the main study, 197 were eligible for inclusion in this substudy. Characteristics of patients were quite similar to those of the entire population entered into the main study. The TLI cutoff value in our series was 0.7% expressed as the median percentage ratio of thymidine-labeled cells undergoing DNA synthesis in the tumor cell population of specimens from the 197 patients. No differences were observed in terms of relapse-free survival (RFS) and overall survival (OS) after grouping the patients by TLI value (low and high) and by treatment. Among node-negative patients, a significant improvement in terms of OS (p = 0.02), but not RFS (p = 0.06), was seen in patients with a high-TLI value who underwent periCT versus controls. Conclusions: TLI may be a useful tool for the identification of node-negative patients with high-TLI values who may benefit from periCT.

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-α2a), for patients with metastatic melanoma. Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6–18 × 106 IU/m2/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-α2a was administered subcutaneously at 3 × 106 IU three times each week until progression. Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 × 109 (range, 1–43 × 109), and the median period of culture was 52 days (range, 45–60). rIL-2 was administered at doses ranging between 6 and 18 × 106 IU/m2/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2–35%). Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-α2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.

Although the presence of multiple cases of melanoma on the same side of a family is the best predictor of germline CDKN2A mutation, other features (i.e. early age at onset) may be useful to identify carriers. We analysed the records of 682 hospital-based Ligurian melanoma patients. Of these, 238 cases (34 familial, 14 non-familial multiple primary and 190 non-familial single primary melanomas) were consecutively enrolled for screening of the CDKN2A and CDK4 genes. Screening of the 34 familial patients revealed that nine were carriers of the CDKN2A G101W founder mutation. Of the 14 non-familial multiple primary melanoma patients, three carried the G101W founder mutation and one the P48T mutation. For the non-familial patients with a single melanoma, 17 of 190 carried germline CDKN2A mutations, with most (16/17) carrying the G101W Ligurian founder mutation and one a novel single base pair substitution, D74Y. The effect of mutation on age at diagnosis was significant (P=0.012) after correcting for melanoma type (familial or non-familial), number of primaries (single or multiple), gender and disease occurrence (incident or prevalent). Early age at onset may be a good predictor of CDKN2A mutation in Liguria, where the G101W founder mutation is prevalent among melanoma patients, independent of family history.

Background: In MBC patients the benefit of chemotherapy after the first line is poorly defined. We evaluated activity of subsequent line of chemotherapy in different BS of MBC. Methods: MBC patients treated in our center from 2007 to 2012 with ER, PgR and HER2 on primary tumor and at least one line of chemotherapy for MBC were evaluated. Patients were classified as luminal A (ER and/ or PgR +, HER2 -, Ki67 ≤ 14%), luminal B (ER and/or PgR +, HER2 -, Ki67 > 14%), HER2+ (HER2+, any ER/PgR) and triple-negative (ER-, PgRand HER2-). The objectives of our analysis were to estimate number of chemotherapy lines in different BS, to evaluate clinical benefit (CB) defined as RC+RP+SD and overall survival (OS) by chemotherapy line in every BS and to identify possible predictive factors for a greater number of chemotherapy line. Time on chemotherapy was calculated from the start of the first line to the end of the last line. Statistical analyses included Chi-square and Kruskal-Wallis tests, Kaplan-Meier curves and log-rank tests, and multivariate logistic regressions. Results: A total of 326 patients were identified, 50 were excluded because they did not receive any chemotherapy. Median follow-up was 32.3 months. Median number of chemotherapy lines was 2 (range 1-10). Median OS according to BS was 60.5 months in luminal A (58 patients), 50.0 months in luminal B (119 patients), 69.2 in HER2+ (57 patients) and 32.3 in TN (42 patients). The percentages of patients receiving second line, third line and four or more lines of chemotherapy were respectively: 58%, 41%, 22% for luminal A, 59%, 34%, 16% for luminal B, 71%, 52%, 39% for HER2+, and 69%, 43%, 16% for TN. CB was inferior in TN patients as compared with the other ones in first and in second lines (p=.027 and p=.093 respectively in first and second lines). From third line onward all patients showed the same CB independently from BS. Time on chemotherapy related to median OS for every BS was the same (18% in luminal A, 20% in luminal B, 27% in HER2+, 29% in TN). At multivariate analysis the characteristics independently associated with a greater probability of receiving more than four chemotherapy lines were HER2+ (p=.027) and less than three sites of metastasis (p=.05). Conclusions: Our analysis showed that, despite the same time spent on chemotherapy, TN patients received less benefit from first and second chemotherapy lines than other BS. On the other hand, HER2+ patients were more likely to receive multiple lines of chemotherapy with a significant impact on median OS (p=.044). PO55

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.