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Epidermal growth factor receptor (EGFR) pathway has been shown to play a crucial role in several inflammatory conditions and host immune-inflammation status is related to tumor prognosis. This study aims to evaluate the prognostic significance of a four-gene inflammatory signature in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with the EGFR inhibitor cetuximab plus chemotherapy. The inflammatory signature was assessed on 123 R/M HNSCC patients, enrolled in the multicenter trial B490 receiving first-line cetuximab plus platinum-based chemotherapy. The primary endpoint of the study was progression free survival (PFS), while secondary endpoints were overall survival (OS) and objective response rate (ORR). The patient population was subdivided into 3 groups according to the signature score groups. The four-genes-signature proved a significant prognostic value, resulting in a median PFS of 9.2 months in patients with high vs. 6.2 months for intermediate vs. 3.9 months for low values ( p = 0.0016). The same findings were confirmed for OS, with median time of 18.4, 13.4, and 7.5 months for high, intermediate, and low values of the score, respectively ( p = 0.0001). When ORR was considered, the signature was significantly higher in responders than in non-responders ( p = 0.0092), reaching an area under the curve (AUC) of 0.65 (95% CI: 0.55-0.75). Our findings highlight the role of inflammation in the response to cetuximab and chemotherapy in R/M-HNSCC and may have translational implications for improving treatment selection.

Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, cancer cells acquire and exhibit several characteristics including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, and expressing an immune phenotype, which allow them to evade recognition and destruction through cognate immune cells. In addition, cancer cells may acquire the ability to reprogram their metabolism in order to further promote growth, survival, and energy production. This phenomenon, termed metabolic reprogramming, is typical of all solid tumors, including squamous carcinomas of the head and neck (SCCHN). In this review, we analyze the genetic and biological mechanisms underlying metabolic reprogramming of SCCHN, focusing on potential therapeutic strategies that are able to counteract it.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent Coronavirus Disease 2019 (COVID-19) pandemic, which has spread all over the world over the past year. Comorbidities appear to affect the prognosis of patients with such diseases, but the impact of cancer on the course of SARS-CoV2 has remained largely elusive. The aim of the present study is to analyze the outcome of patients affected by squamous cell carcinoma of the head and neck (SCCHN) and a number of their comorbidities, if infected with SARS-CoV2. The clinical data of 100 patients affected by SCCHN, who were undergoing treatment or who had finished their oncologic treatment in the past 6 months, were retrospectively collected and analysed. For each patient, the Charlson Comorbidity Index (CCI) was calculated to provide a score assessing the real weight of comorbidities on the patient's outcome at the time of diagnosis. It was discovered that these patients, besides the SCCHN, frequently presented at diagnosis with several other comorbidities, including hypertension, type 2 diabetes, cardiac arrhytmia, chronic obstructive pulmonary disease and various forms of vasculopathy (and thus a poor CCI). This feature suggest that, given the high frequency of various comorbidities in patients with SCCHN, additional SARS-CoV2 infection could have particularly devastating consequences., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Perri et al.)

Baseline clinical prognostic factors for recurrent and/or metastatic (RM) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy are lacking. CT-based radiomics may provide additional prognostic information. A total of 85 patients with RM-HNSCC were enrolled for this study. For each tumor, radiomic features were extracted from the segmentation of the largest tumor mass. A pipeline including different feature selection steps was used to train a radiomic signature prognostic for 10-month overall survival (OS). Features were selected based on their stability to geometrical transformation of the segmentation (intraclass correlation coefficient, ICC > 0.75) and their predictive power (area under the curve, AUC > 0.7). The predictive model was developed using the least absolute shrinkage and selection operator (LASSO) in combination with the support vector machine. The model was developed based on the first 68 enrolled patients and tested on the last 17 patients. Classification performance of the radiomic risk was evaluated accuracy and the AUC. The same metrics were computed for some baseline predictors used in clinical practice (volume of largest lesion, total tumor volume, number of tumor lesions, number of affected organs, performance status). The AUC in the test set was 0.67, while accuracy was 0.82. The performance of the radiomic score was higher than the one obtainable with the clinical variables (largest lesion volume: accuracy 0.59, AUC = 0.55; number of tumoral lesions: accuracy 0.71, AUC 0.36; number of affected organs: accuracy 0.47; AUC 0.42; total tumor volume: accuracy 0.59, AUC 0.53; performance status: accuracy 0.41, AUC = 0.47). Radiomics may provide additional baseline prognostic value compared to the variables used in clinical practice.

Coronavirus disease 2019 (COVID-19) global pandemic has created unique challenges to healthcare systems throughout the world. Ensuring subjects' safety is mandatory especially in oncology, in consideration of cancer patients' particular frailty. We examined the proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and/or IgG positive subjects in three different groups from Istituto Nazionale Tumori - IRCCS "Fondazione G. Pascale" in Naples (Campania region, Italy): cancer patients treated with Innovative Immunotherapy (Immune Checkpoint Inhibitors, ICIs), cancer patients undergoing standard Chemotherapies (CHTs) and healthcare providers. 9 out of 287 (3.1%) ICIs patients resulted positive, with a significant lower percentage in respect to CHTs patients (39 positive subjects out of 598, 6.5%) (p = 0.04). There was no statistically significant difference between ICIs cohort and healthcare providers, 48 out of 1050 resulting positive (4.6%). Performing a Propensity Score Matching based on gender and tumor stage, the effect of treatment on seropositivity was analyzed through a regression logistic model and the ICIs treatment resulted to be the only protective factor significantly (p = 0.03) associated with positivity (odds ratio-OR: 0.41; 95% confidence interval-CI 0.18-0.91). According to these preliminary data, ICIs would appear to be a protective factor against the onset of COVID-19 infection.

Head and neck squamous cell carcinomas (SCCHN) are not rare malignancies and account for 7% of all solid tumors. Prognosis of SCCHN patients strongly depends on tumor extension, site of onset, and genetics. Advanced disease (recurrent/metastatic) is associated with poor prognosis, with a median overall survival of 13 months. In these patients, immunotherapy may represent an interesting option of treatment, given the good results reached by check-point inhibitors in clinical practice. Nevertheless, only a minor number of patients with advanced disease respond to immunotherapy, and, disease progressions/hyper-progressions are common. The latter could be a very difficult issue, especially in patients having a wide and highly symptomatic head/neck mass. Given the potentiality to boost the immune response of some local modalities, such as electrochemotherapy, a possible future approach may take into account the combination of electrochemotherapy and immunotherapy to treat patients affected by SCCHN, suffering from symptomatic lesions that need rapid debulking.

Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute., (Copyright © 2020 Iannelli, Zotti, Roca, Grumetti, Lombardi, Moccia, Vitagliano, Milone, Ciardiello, Bruzzese, Leone, Cavalcanti, De Cecio, Iachetta, Valiante, Ionna, Caponigro, Di Gennaro and Budillon.)

: Head and neck squamous cell carcinomas (HNSCCs) are a very heterogeneous group of malignancies arising from the upper aerodigestive tract. They show different clinical behaviors depending on their origin site and genetics. Several data support the existence of at least two genetically different types of HNSCC, one virus-related and the other alcohol and/or tobacco and oral trauma-related, which show both clinical and biological opposite features. In fact, human papillomavirus (HPV)-related HNSCCs, which are mainly located in the oropharynx, are characterized by better prognosis and response to therapies when compared to HPV-negative HNSCCs. Interestingly, virus-related HNSCC has shown a better response to conservative (nonsurgical) treatments and immunotherapy, opening questions about the possibility to perform a pretherapy assessment which could totally guide the treatment strategy. In this review, we summarize molecular differences and similarities between HPV-positive and HPV-negative HNSCC, highlighting their impact on clinical behavior and on therapeutic strategies., Competing Interests: The authors declare no conflict of interest.

Head and neck carcinoma (HNC) are diseases arising from several tracts of the aerodigestive ways. Most HNC are squamous cell carcinoma (SCCHN). Immunotherapy is a treatment strategy aimed to reinforce the immune system. Several types of immunotherapy are available in the clinical scenario. Checkpoint inhibitors were developed later in SCCHN; nivolumab and pembrolizumab have reached the clinical approval, having both drugs demonstrated to significantly improve the overall survival, if compared with the standard of treatment (according to the results of the CheckMate 141 and KEYNOTE-040 trials). Nevertheless, immunotherapy may fail because of the genetics of SCCHN. In fact, two genetically different types of SCCHN have been discovered, one virus-related (HPV) and the other mutagens-related. They seem to show in clinical trials very different responses to immunotherapy. Given the existence of a number of factors predictive of response to immunotherapy in SCCHN, a future clinical approach may be to characterize the genetic and immunologic feature of SCCHN and to perform a well-tailored immunotherapy. This review will summarize the main immunotherapy strategies available in SCCHN, discussing their real efficacy, highlighting also the ways to improve them., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe outcomes of Electrochemotherapy as palliative treatment in patients with advanced head and neck (H&N) tumours., Methods: Ninety-three patients (120 treatment sessions) with H&N recurrent and/or metastatic neoplasm were treated. Treatment response was assessed 4 weeks after ECT with clinical examination and two months after the first evaluation with a CT scan of the H&N for deep lesions evaluation. The grade of bleeding and pain before, at the end of treatment and one week after ECT were evaluated., Results: Five percent of complete responses, 40% of partial responses were registered. Disease progression was seen in 20% of patients after the first ECT procedure, the remaining 34% of patients experienced stable disease. A good control of pain and bleeding was obtained, especially in patients with moderate symptoms before the treatment. No toxicities related to ECT were seen., Conclusions: ECT is an interesting antitumoral therapy in advanced chemo and radio-refractory H&N neoplasms. ECT is able to reduce frequent symptoms, such as pain and bleeding, improving quality of life without damage to healthy tissue and with limited side effects. Moreover, ECT reduces hospitalization time and may contribute to an overall reduction in healthcare costs associated with advanced H&N cancers care., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Undifferentiated sinonasal carcinoma (SNUC) is defined as a small round blue cell tumor that is immunohistochemically distinct from other sinonasal malignancies, such as lymphoma, mucosal melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, and olfactory neuroblastoma. SNUCs are very aggressive malignancies, provoking quick destruction of the splanchnocranium structures. Being a very rare neoplasm, there are no prospective clinical trials assessing their treatment strategies, so lots of data are derived by small retrospective trials. Tri-modality treatments (namely those treatments which use together surgery, radiation therapy and chemotherapy) are now considered the best of care for this category of poor prognosis tumors, and whenever possible they should be employed. Despite the tri-modality treatments and the multidisciplinary management, SNUCs are characterized by poor prognosis with a median overall survival reaching 14 months. Ameliorating radiotherapy techniques and performing therapies adapted to the genetics of the disease could represent a promising strategy of therapy in the near future. In this report, we have presented our experience, describing the treatment and the prognosis of four patients seen at our Institution. Moreover, we have performed a review of the literature analyzing the now available therapy options and the possible future strategies.

Nasopharyngeal carcinoma is a rare disease in Western countries. Nevertheless, its incidence in China, Singapore, and other Eastern countries reaches 20 cases per 100,000 people. Being an extremely chemo- and radiosensitive disease, upfront treatment often consists in the association of intensity-modulated radiation therapy and concurrent cisplatin. Unfortunately, about 20% of the patients suffer from a radioresistant disease which recurs after upfront therapy. For these patients, mainly available therapeutic options consist in systemic therapy, in particular poly-chemotherapy. In those showing a single locoregional recurrence, chemotherapy is not considered to be the preferred approach and other different strategies may be employed. Re-irradiation and surgery are strategies that are always used more often, albeit related to high risk of morbidity. Immunotherapy and targeted therapy, such as heavy ions-based re-irradiations, are experimental but very intriguing options., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Squamous cell carcinoma of the head and neck (SCCHN) accounts for 5-7% of all malignancies. About 60% of newly diagnosed SCCHN are detected as locally advanced disease. Chemoradiation is a standard option and response rate to it is variable. Recently, a genetic classification of SCCHN has been proposed by Chung et al ., who categorized all SCCHN into four subtypes. The basal-like variant is characterized by high expression of EGFR. Literature data suggest higher efficacy of accelerated and/or hyperfractionated radiotherapy, if compared with conventional radiotherapy in the subgroup of patients with high EGFR expression. In this review, we will describe the genetic factors able to guide treatment choice, with a focus on EGFR expression., Competing Interests: Financial & competing interests disclosure Funds for this work have been provided by the Italian National Research Council of Naples. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Background: Squamous Cell Carcinoma of the Head and Neck (SCCHN) are neoplasms arising from the epithelium of the first aero-digestive tract. They are very heterogeneous both clinically and biologically. Classic and well acknowledged risk factors are alcohol and tobacco consumption and other forms of smokeless tobacco assumption, although lately the incidence of Human Papilloma Virus (HPV)-related SCCHN is rapidly increasing. HPV-related tumors are very different from their alcohol and tobacco-associated counterpart, as they show strong chemo and radio sensitivity and thus can often be treated with conservative treatment strategies. Moreover, peculiar biologic features characterize HPV-related tumors, such as wild type TP53, low expression of Epidermal Growth Factor Receptor (EGFR), wild type CCND1 and high expression of P16. In contrast, alcohol and tobacco related SCCHN show opposite features, together with higher number of chromosomal and genetic abnormalities, conferring them chemo and radio resistance., Methods: We have performed a narrative review of the PubMed database with the aim to study the mutational landscape of SCCHN., Results: Several lines of evidence support the existence of at least two genetically different types of SCCHN, one virus-related and the other alcohol and/or tobacco-related, characterized by both clinical and biological opposite features. Virus related SCCHN are very chemo and radiosensitive, so suitable for organ preserving strategy, which in the near future may be induction chemotherapy followed by association of chemotherapy and underpowered radiotherapy. Alcohol and tobacco related SCCHN are themselves strongly heterogeneous and can be divided in different entities on the basis of the "Driver" genetic aberration, responsible for carcinogenesis. The most frequently mutated genes in alcohol and tobacco-related SCCHN are TP53, NOTCH1, CCND1, CDKN2A, EGFR and PI3KCA., Conclusions: Virus-related SCCHN can be managed with chemo-radiotherapy. Alcohol and tobacco-related tumors should be further characterized on the basis of their "Driver Mutations" in order to select effective targeted therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Sinonasal carcinomas (SNcs) are rare neoplasms arising from the paranasal sinuses and nasal cavity. Although these tumours have a heterogeneous histology, they are commonly diagnosed as a locally advanced disease and are associated with a poor prognosis. The present retrospective study reviewed 30 patients with locally advanced SNc, who were treated with surgery followed by chemoradiotherapy or radiotherapy, or radiotherapy with or without concomitant chemotherapy between January 1999 and January 2013 at the Department of Radiation Therapy, University of Naples 'Federico II' (Naples, Italy). A total of 19 patients were treated with upfront surgery followed by adjuvant radio- or chemoradiotherapy (group A), while the remaining 11 patients received exclusive radiotherapy with or without concomitant chemotherapy (group B). Concurrent cisplatin-based chemotherapy (100 mg/m 2 , days 1, 22 and 43 for 3 cycles) was administered to 34% of patients in group A and 55% of patients in group B. At a median follow-up of 31 months, 33.3% of patients were alive. Cause-specific survival (CSS) and progression-free survival (PFS) times were 32 and 12 months, respectively. No difference in CSS rate was observed between the two treatment groups. Univariate analysis determined that disease stage was the only factor that significantly affected CSS (P=0.002) and PFS (P=0.0001) rates. Acute and chronic toxicities were mild, with only 23.3% of patients reporting G1-2 side effects and no treatment-related blindness. The present study reported moderate activity and efficacy of surgery followed by adjuvant radio- or chemoradiotherapy, and exclusive radiotherapy with or without chemotherapy in this poor prognosis category of patients.

Background: Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR., Method/design: V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day -14 with a titration strategy in each patient (target serum level of 50-100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response, overall survival, safety. Objectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. γH2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory activity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and proteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different time points during treatment., Discussion: Overall, this study could provide a less toxic and more effective first-line chemotherapy regimen in patients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and efficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder patients, and will add insights in the mechanism of the synergistic interaction between these agents., Eudract Number: 2014-001523-69 TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02624128.

Background: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years., Patients and Methods: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed., Results: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups., Conclusions: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients., Clinical Trial Registration: NCT01345682 (ClinicalTrials.gov)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Multiple dermal cylindromas and membranous basal cell adenoma of parotid gland in a 67-year-old woman with Brooke-Spiegler syndrome (BSS) were examined by fine-needle cytology. Histology, immunochemistry, and CYLD germline mutation testing were also performed. Cytomorphology and immunochemistry of the two lesions showed basaloid neoplasms, remarkably similar, composed by proliferating epithelial cells of basal type accompanied by a smaller proportion of myoepithelial cells. CYLD gene showed a novel germline splice acceptor site mutation (c.2042-1G>C) with skipping of the entire exon 15. The occurrence of analogous tumors, dermal cylindromas, and membranous basal cell adenoma of the parotid gland, in the same patient may result from the action of a single gene on ontogenetically similar stem cells. Therefore, patients with BSS should be offered a genetic counselling for an early and correct diagnosis., (© 2015 Wiley Periodicals, Inc.)

Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)-related tumors has shown a significant increase, and HPV-related tumors show distinctive features if compared with the HPV-negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance. Preclinical and clinical evidence highlighted that 3 main pathways, including the epidermal growth factor receptor (EGFR), the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and the p53 signaling cascades, play a crucial role in radioresistance development. A future approach may consist in the association of radiotherapy (RT) and selective inhibition of the key pathways involved in radioresistance. Phase I, II, and III clinical trials are currently testing these novel treatment strategies., (© 2015 Wiley Periodicals, Inc.)

Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy., Methods: In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682., Findings: Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients., Interpretation: Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC., Funding: Boehringer Ingelheim., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Thyroid carcinomas are rare and heterogeneous diseases representing less than 1% of all malignancies. The majority of thyroid carcinomas are differentiated entities (papillary and folliculary carcinomas) and are characterized by good prognosis and good response to surgery and radioiodine therapy. Nevertheless, about 10% of differentiated carcinomas recur and become resistant to all therapies. Anaplastic and medullary cancers are rare subtypes of thyroid cancer not suitable for radioiodine therapy. A small percentage of differentiated and all the anaplastic and medullary thyroid carcinomas often recur after primary treatments and are no longer suitable for other therapies. In the last years, several advances have been made in the field of molecular biology and tumorigenesis mechanisms of thyroid carcinomas. Starting from these issues, the targeted therapy may be employed as a new option. The MAP-Kinase pathway has been found often dysregulated in thyroid carcinomas and several upstream signals have been recognized as responsible for this feature. RET/PTC mutations are often discovered both in papillary and in medullary carcinomas, while B-RAF mutation is typical of papillary and anaplastic histologies. Also mTOR disruptions and VEGFR pathway disruption are common features in all advanced thyroid cancers. Some angiogenesis inhibitors and a number of RET/PTC pathway blocking agents are yet present in the clinical armamentarium. Vandetanib, cabozatinib and sorafenib have reached clinical use. A number of other biological compounds have been tested in phase II and III trials. Understanding the biology of thyroid cancers may help us to design a well shaped targeted therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Tobacco use and alcohol consumption are the main risk factors associated with head and neck squamous cell carcinoma (SCC) development due to their cytotoxic and mutagenic effects on the exposed epithelia of the upper aerodigestive tract. Epstein-Barr virus (EBV) and high-risk human papillomaviruses (HPVs), both encoding viral oncoproteins able to interfere with cell cycle control, have been recognized as the etiological agents of nasopharynx carcinoma and a fraction of oropharyngeal carcinoma, respectively. Head and neck SCC is a deadly disease and despite innovative treatments represents a major challenge for patients. Recently, a number of genomic studies have highlighted the molecular heterogeneity of head and neck SCC based on methylation profiles, microRNA expression, mutated genes and new druggable pathways which may represent new targets for cancer-tailored therapies. To date, cetuximab is the only FDA-approved anti-epidermal growth factor receptor therapy for the treatment of head and neck SCC. In addition, a number of monoclonal antibodies targeting AKT, mTOR and PI3K pathways are under evaluation. Several therapeutic vaccines against HPV16 and EBV proteins are also under study. The purpose of this article is to review the epidemiology, pathogenesis and molecular features of head and neck SCC, with an emphasis on new therapies., (© 2015 S. Karger AG, Basel.)

Head and neck cancers are a heterogeneous group of malignancies accounting for approximately 600,000 new cases every year worldwide. Human papillomavirus (HPV)-related oropharyngeal cancers represent a new nosological entity for pathogenesis, molecular mechanisms, prognostic trend and therapeutic response. Several clinical trials have shown that HPV-positive/p16-positive cancer patients have a favorable prognosis demanding for de-escalation of current therapies. Comprehensive genomic analyses allowed to identify specific genetic alterations in targetable genes envisaging novel approaches to treat different subset of HPV-related and HPV-unrelated oropharyngeal cancers. Furthermore virus associated head and neck cancers may benefit from new developed immunotherapies targeting HPV E6 and E7 oncoproteins. We reviewed recent studies on the role of HPV infection in these cancers and present our current understanding of carcinogenic mechanisms providing possible novel approaches to cancer treatment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Malignant tumors of salivary glands are rare lesions, often with poor prognosis. At present, surgery represents the only therapeutic choice, whereas chemotherapy is employed as palliative treatment in advanced disease. Over the years several molecular alterations associated with the pathogenesis and progression of the salivary glands tumors have been well-characterized. Particularly, the mutational status and/or aberrant expression of certain markers, such as EGFR, HER2, cKIT, BRAF and AR, also identified in some tumor histotypes of the salivary glands, currently represent molecular targets for new and efficacious drugs routinely employed in the treatment of other neoplasias, such as breast, lungs, GIST and melanoma. The expression analysis of these biomarkers associated with histomorphological data, could then provide the oncologist the opportunity to create a proper stratification of patients for customized therapies. This review represents an overview of the lesions of the salivary glands best characterized in terms of molecular aspects, focusing the attention on those markers and molecular alterations which can be important in the diagnosis as well as in the therapeutic stratification of these tumors.

A case of recurrent hyalinizing clear cell carcinoma (HCCC) of the parotid gland in a 46-year-old female is here introduced. The patient had undergone a left superficial parotidectomy 6 months ago in another institution for an alleged benign, circumscribed mass 2.4 cm in diameter of the left parotid gland. Histopathological examination revealed a poorly differentiated HCCC bearing a EWSR-1 translocation on FISH examination. Fine Needle Cytology (FNC) was performed on three separate soft tissue masses in the pre-masseterine area and a cytological diagnosis of recurrent, poorly differentiated, possibly aggressive variant of HCCC, was rendered. FISH performed on a destained Diff Quik stained smear demonstrated an ESWR-1 translocation, which supported the cytopathological diagnosis. The cytomorphologic features and the differential diagnosis of this aggressive variant of HCCC are briefly discussed., (Copyright © 2013 Wiley Periodicals, Inc.)

Integration of geriatric assessment into cancer clinical practice is strongly needed in squamous cell carcinoma of the head and neck (SCCHN) due to the frequent discrepancy between chronologic and biologic age. Comprehensive Geriatric Assessment (CGA) is a multidimensional assessment tool that examines age-related domains. These parameters can be well assessed by easier tests such as Activity Daily Living and Instrumental Activity Daily Living for functional status; Charlson Comorbidity Index for comorbidity; Mini Mental State examination for cognitive status; Mini Nutritional Assessment for nutritional status; Beers criteria for concomitant drug assumption. Early stage SCCHN is usually treated with either surgery or radiation therapy. Age is not an exclusion criteria for both modalities, but elderly patients have a higher complication rate. Patients with locally advanced SCCHN are preferably treated with concomitant cisplatin-radiotherapy, but the impact of chemotherapy on survival is lower with increasing patient age. The combination of cetuximab and radiation therapy can be a suitable option in elderly patients with locally advanced SCCHN. However, also in this group of patients, survival benefit is lower in elderly patients. Chemotherapy represents the mainstay of treatment in recurrent/metastatic SCCHN. However, elderly patients can receive more toxicity. Myelosuppression, diarrhea, mucositis, nephrotoxicity and neurotoxicity have to be early diagnosed and adequately treated. The initial approach for screening elderly SCCHN patients may benefit from relatively easy tests such as Vulnerable Elders Survey 13 (VES-13), which can screen patients who are to undergo full CGA.

Multidisciplinary team (MDT) is of paramount importance in the approach to patients with head and neck cancer. Its aim is to provide the best diagnostic work-up, tumor staging, and treatment. Furthermore, the prognosis of patients who are managed by MDT is usually better. MDT has a great value in all presentation settings. The role of the pathologist in the team is of utmost importance, in particular with regards to information provided on Human Papilloma Virus (HPV) status, which has a well acknowledged independent prognostic value mainly in oropharyngeal carcinoma. In early stage disease, namely in T1-2 N0 M0 patients, the meetings within the MDT mainly involve surgeons and radiation therapists. Surgery represents the mainstay of treatment, while radiation therapy is a suitable alternative, in particular in patients with advanced age, poor performance status and comorbidities. In locally advanced disease, surgeons, medical oncologists and radiotherapists are the key people, since different approaches have been carried out. In operable patients, adjuvant chemoradiation is indicated when resection margins are involved or close, or in presence of extracapsular nodal spread. Concurrent chemoradiotherapy, preceded or not by induction chemotherapy, is the favourite approach in this setting when surgery is strictly not indicated. In recurrent/metastatic disease chemotherapy and best supportive care are the main options, although local treatments, such as reirradiation and salvage surgery, are also worth considering. The standard chemotherapy treatment has finally evolved after about 30 years, and strong efforts are being pursued to further improve the outcome, mainly with the addition of new drugs.

The incidence of melanoma is rapidly increasing worldwide and the prognosis of patients with metastatic disease is still poor, with a median survival of 8-9 months and a 3-year overall survival (OS) rate less than 15% [1,2]. A complete surgical excision is the main treatment for primary cutaneous melanoma [3], but controversies about the extension of excision margins still remain [4]. Sentinel lymph node biopsy (SLNB) provides important prognostic and staging data by the identification of regional node-negative patients who would not benefit from a complete nodal dissection. However, there is no consensus in the definition of melanoma thickness to enforce the execution of the SLNB [5]. To date, Interferon-α (IFN-α)is the only approved adjuvant treatment after surgical excision of high-risk melanoma, but its indication remains still controversial [2,6].

Aim: To provide efficacy and safety data about the combined use of radiotherapy and chemo-radiotherapy in nasopharyngeal carcinoma (NPC)., Methods: We reviewed data of 40 patients with locally advanced NPC treated with induction chemotherapy followed by concomitant chemo-radiotherapy (CCRT) (22/40 patients) or CCRT alone (18/40) from March 2006 to March 2012. Patients underwent fiberoscopy with biopsy of the primitive tumor, and computed tomography scan of head, neck, chest and abdomen with and without contrast. Cisplatin was used both as induction and as concomitant chemotherapy, while 3D conformal radiation therapy was delivered to the nasopharynx and relevant anatomic regions (total dose, 70 Gy). The treatment was performed using 6 MV photons of the linear accelerator administered in 2 Gy daily fraction for five days weekly. This retrospective analysis was approved by the review boards of the participating institutions. Patients gave their consent to treatment and to anonymous analysis of clinical data., Results: Thirty-three patients were males and 7 were females. Median follow-up time was 58 mo (range, 1-92 mo). In the sub-group of twenty patients with a follow-up time longer than 36 mo, the 3-year survival and disease free survival rates were 85% and 75%, respectively. Overall response rate both in patients treated with induction chemotherapy followed by CCRT and in those treated with CCRT alone was 100%. Grade 3 neutropenia was the most frequent acute side-effect and it occurred in 20 patients. Grade 2 mucositis was seen in 29 patients, while grade 2 xerostomia was seen in 30 patients. Overall toxicity was manageable and it did not cause any significant treatment delay. In the whole sample population, long term toxicity included grade 2 xerostomia in 22 patients, grade 1 dysgeusia in 17 patients and grade 1 subcutaneous fibrosis in 30 patients., Conclusion: Both CCRT and induction chemotherapy followed by CCRT showed excellent activity in locally advanced NPC. The role of adjuvant chemotherapy remains to be defined.

Background: Cervical metastases from unknown primary tumors are rare and no clear therapeutic options are available. This retrospective analysis aimed to evaluate toxicity and activity of a sequential chemoradiation regimen consisting of induction chemotherapy followed by extended-field radiotherapy in patients with cervical metastases from unknown primary tumors., Patients and Methods: Patients with cytological or histological diagnosis of latero-cervical lymph-node metastasis from carcinoma with unknown origin treated with sequential chemotherapy (3 cycles of docetaxel and cisplatin, each administered as intravenous infusion at the dose of 75 mg/m(2) on day 1, every 21 days) and radiotherapy (cumulative dose of 70 Gy) were included in this study. The radiological response was assessed by central review according to the revised RECIST criteria., Results: Fifteen patients received three cycles of induction chemotherapy with the combination of docetaxel and cisplatin. Patients were subsequently treated with extended-field radiotherapy. Three complete responses were observed after induction chemotherapy and 13 after the chemoradiation treatment. The overall response rate after chemoradiation, was 93.3% (14 of 15 evaluable patients). One year disease-free-survival was 83.3% (10 of 12 evaluable patients). Treatment was well-tolerated; two cases of grade 4 neutropenia, two of grade 3 mucositis and eight of grade 2 nausea were the worst, most clinically-relevant side-effects., Conclusion: Induction chemotherapy followed by extended-field radiotherapy showed good activity and manageable toxicity in patients with cervical metastases from unknown primary tumors.

Objectives: To replace 5-fluorouracil with capecitabine within a trial of induction chemotherapy followed by cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). Also, to replace cisplatin with cetuximab after induction chemotherapy., Methods: Docetaxel and cisplatin were given at 75 mg/m(2), while capecitabine was initially given at 500 mg/m(2) twice a day and subsequently escalated. The maximum tolerated dose was used for the phase II study., Results: Seven patients were enrolled. At dose level 1, two dose-limiting toxicities were observed in the first 4 patients (grade 4 neutropenia and grade 3 diarrhea). In both patients, capecitabine was withdrawn and toxicities resolved. Dose escalation was halted and a lower capecitabine dose (750 mg/m(2) daily) was selected. Two complete responses and five partial responses were observed after induction chemotherapy. Four patients were evaluable for response after cetuximab-RT (3 complete response and 1 partial response)., Conclusion: Combined chemoradiotherapy is still the gold standard in LA SCCHN and no studies currently support the use of early induction chemotherapy. Our study did not contribute toward addressing this issue since it was discontinued early because of toxicity., (Copyright © 2013 S. Karger AG, Basel.)

Clinical management of patients with malignant tumors has dramatically changed over the last years with the introduction of novel therapeutics, such as receptor-targeted therapies, downstream effectors and antiangiogenic compounds. This has created a need to re-evaluate the existing criteria used to assess treatment response. Emerging diagnostic techniques, combining functional and structural data may play a relevant role in planning new treatment strategies in individual cancer patients. In the new scenario where biological treatment results in stable disease, standard Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST 1.1 criteria have limitations. Moreover, functional 18- fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging provides an additional tool to assess tumor activity, particularly consistent in some settings, such as Gastro Intestinal Solid Tumors (GIST), hepatocarcinoma, nonsmall lung cancer, and colorectal cancer. The integration of (18)FDG-PET and computed tomography (CT) enhances the evaluation of oncologic patients treated with molecularly targeted drugs, and accelerates drug development in many types of tumors.

Purpose: Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN)., Methods: Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m(2)) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m(2). The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination., Results: Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m(2)). Dose level 2 (brostallicin 7 mg/m(2) and cisplatin 75 mg/m(2)) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3-4 neutropenia was observed in 90.5% of patients, grade 3-4 thrombocytopenia in 38.1%, grade 3-4 anemia in 23.8%. The cycle 1 nadir (ANC < 500 x 10(9)/L) for neutrophils was Day 14 (median; range 11-17) with recovery to an ANC of >1,500 3.5 days after nadir (median; range 2-4) at dose level 3. The cycle 1 nadir (median of 51,000 x 10(9)/L) for platelets occurred on Day 13 (median; range 10-15) with recovery to a platelet count of >100,000 4 days after nadir (median; range 2-8). No objective responses were observed, but seven patients had a long lasting (>18 weeks) stable disease., Conclusions: Further studies of the combination of brostallicin and cisplatin are warranted.

Early-stage nasopharyngeal carcinoma (T1-2a;N0;M0) represents a small proportion of nasopharyngeal tumors. Radiotherapy alone is the current treatment approach for this tumor and the emerging role of new radiotherapy techniques will hopefully further improve the treatment outcome for these patients. The vast majority of patients with nasopharyngeal carcinoma is diagnosed with locally advanced disease. Concomitant chemoradiotherapy is now acknowledged as being a standard treatment option, even though it induces a considerable incidence of acute mucosal and hematologic toxicity. The issue of adding adjuvant chemotherapy is somewhat more controversial. Similarly, the role of neoadjuvant chemotherapy before concomitant chemoradiotherapy is a matter of interest. In patients with recurrent/metastatic nasopharyngeal carcinoma the prognosis is generally grim, as platinum-based chemotherapy results in a 50-70% response rate and in a median survival time of 11 months. Several trials have been performed on this subset of patients with both cytotoxic and biologic agents, but the results have not been particularly encouraging thus far. Epstein-Barr virus is associated with the vast majority of nasopharyngeal carcinoma. Concentrations of plasma Epstein-Barr virus DNA have been associated with treatment outcome in the clinic. Immunotherapy is generally well tolerated and can sometimes elicit significant immune response, which possibly induces clinical benefit in some patients.

Squamous cell carcinoma of the head and neck is a major health problem, and much effort is being made in the different settings of its presentation. Much of the recent progress has been made in locoregionally advanced inoperable disease, mainly with the optimal combination of concurrent chemoradiotherapy and with the introduction of new active drugs, such as docetaxel, in the induction phase of the treatment. The association of docetaxel, cisplatin, and 5-fluorouracil (TPF) regimen is now acknowledged as being the gold standard of induction treatment. The subset of patients with recurrent/metastatic disease still carries a grim prognosis. For the time being, new biological therapies have not dramatically changed this scenario, even in combination with conventional treatments. Little is known about the role of docetaxel and, in general, of chemotherapy in the adjuvant setting, even though it is increasingly acknowledged that, beyond a certain risk, concurrent adjuvant chemoradiotherapy is required. The main aim of the research on head and neck cancer probably lies in the identification of biomolecular markers that are able to predict clinical behaviour, thus allowing appropriate treatment tailoring. The identification of human papilloma virus infection as the agent of a particular form of oropharyngeal cancer is an example of this strategy in consideration of the peculiar characteristics.

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. The role of cetuximab is paramount in several subsets of head and neck cancer. In particular, the EXTREME study has indicated cetuximab as the only drug to improve survival when associated with cisplatin and 5-fluorouracil in patients with recurrent/metastatic disease. Furthermore, cetuximab, both alone and in combination with cisplatin, is active in patients with recurrent/metastatic disease who have failed prior platinum-based chemotherapy. Cetuximab, given in association with radiation therapy, is a treatment of choice in first-line therapy of patients with locally advanced inoperable disease. In the same setting, the role of induction chemotherapy has gained considerable interest over the last few years and a number of efforts are being pursued to optimally integrate induction chemotherapy with radiation therapy plus cetuximab. The combination of cetuximab and other targeted therapies is among the most promising new perspectives for patients with head and neck cancer.

The ubiquitin-proteasome system has become a promising molecular target in cancer therapy due to its critical role in cellular protein degradation, interaction with cell cycle and apoptosis regulation, and unique mechanism of action. Bortezomib (PS-341) is a potent and specific reversible proteasome inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies. In preclinical studies, bortezomib induced apoptosis of malignant cells through the inhibition of NF-|B and stabilization of pro-apoptotic proteins. Bortezomib also promotes chemo- and radiosensitization of malignant cells in vitro and inhibits tumor growth in murine xenograft models. The proteasome has been established as a relevant target in hematologic malignancies and bortezomib has been approved for the treatment of multiple myeloma. This review summarizes recent data from clinical trials in solid tumors.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.

Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. The standard '3+3' design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than one-third of patients of a given cohort had dose-limiting toxicity. Dose-limiting toxicity was observed in three of four patients treated at the dose of 500 mg, and included grade 3 stomatitis in three patients and grade 3 liver toxicities in one patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.

Purpose: Rubitecan is an oral camptothecin analogue that has shown activity against a broad spectrum of human tumor xenografts and has been tested in several diseases., Patients and Methods: In the present study, 19 patients with incurable, recurrent or metastatic head and neck cancer were treated with rubitecan at the initial dose of 1.5 mg/m(2) x 5 days per week. An appropriate dose modification program was set up according to the observed toxicities., Results: Thirteen out of the 19 treated patients were formally evaluable for tumor response. Ten patients had a disease progression and three patients had a stabilization of disease as their best response. The mean duration of stable disease was 141 days. Median survival was 16 weeks (range 2-22 weeks). Three patients died during the study or less than a month after their last dose of study medication. Hematologic toxicity was serious in this study since four patients discontinued their participation because of severe anemia. The drug was also associated with grade 1-4 neutropenia, and with 1-3 thrombocytopenia., Conclusion: We conclude that rubitecan is not effective as a single-agent in recurrent or metastatic head and neck cancer with the doses and schedule used in this study.

Salivary gland cancers include tumors of different histologic characteristics and biological behavior. Radical surgery, followed or not by radiation therapy, represents the main treatment approach for this disease. The role of systemic chemotherapy is less clearly defined since trials of single-agent chemotherapy have consistently shown low response rates. Polychemotherapy is likely to induce a higher response rate, but does not improve survival. The determination of the molecular abnormalities underlying the different subtypes of salivary gland cancers might lead to more active targeted therapies. C-kit is overexpressed in a wide percentage of salivary gland carcinomas, but clinical trials with single-agent imatinib have been negative. ErbB1 and ErbB2 are also frequently overexpressed in salivary gland cancers and this has provided the rationale for clinical trials with trastuzumab, cetuximab, gefitinib, lapatinib. Finally, new pathways, such as vascular endothelial growth factor, might be worth targeting and clinical trials with anti-angiogenic agents are ongoing.

The methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) regimen has been considered as standard treatment of metastatic bladder carcinoma till recent years. The superiority of M-VAC both to cisplatin alone and to another cisplatin combination regimen has been demonstrated in randomized studies. During the last years, the use of gemcitabine in metastatic bladder carcinoma has considerably increased, mainly in combination with cisplatin (CG). A phase III trial comparing M-VAC and CG demonstrated similar activity and less toxicity for CG, which has now become the new standard of care for patients with metastatic bladder carcinoma. The substitution of cisplatin with carboplatin, the combination of platinum and taxanes, and the addition of a third drug to basal CG combination represent possible ways to improve outcome. Among the novel cytotoxic compounds, pemetrexed has raised interest, since a phase II second-line study showed a 28% response rate with a manageable toxicity profile. Vinflunine is a novel antitubulin agent with a relevant clinical activity in pretreated metastatic bladder carcinoma (18% response rate, 6.6 months median survival). Novel biologic compounds (in particular drugs targeting epidermal growth factor receptor) are being tested in metastatic bladder carcinoma also and much effort is being pursued in understanding the determinants of tumor response. Crucial mutations to which the tumor becomes addicted have to be discovered so that more effective and specific drugs or combinations can be delivered.

In recent years, the knowledge about mutations in components of the intracellular signal transduction pathway has greatly improved. Pivotal target molecules, such as Ras, PI3K, mammalian target of rapamycin (mTOR) and PKC, form an important biochemical network, which, when mutated, drives cell growth in an unlimited manner. Cancer cells have been shown to be able to harness different growth factor signalling pathways. Protein kinase inhibitors, targeted to the above pathways, have demonstrated activity against several solid tumours and are generally better tolerated than standard cytotoxic agents. The future challenge will be to find the most clever way to use combinations of these novel compounds.

Proteasomes have a fundamental function since they degrade numerous different proteins, including those involved in the regulation of the cell cycle. Proteasome inhibition is a novel approach to the treatment of solid tumours. PS-341 (bortezomib) is a small, cell-permeable molecule that selectively inhibits the proteasome binding it in a reversible manner. The proteasome has been established as an important target in haematologic malignancies and has been approved for the treatment of multiple myeloma. Bortezomib induces apoptosis of malignant cells through the inhibition of NF-kappaB and stabilisation of proapoptotic proteins. In preclinical studies, bortezomib also promoted chemo and radiosensitisation of malignant cells in vitro and inhibited tumour growth in murine xenografts models. The single-agent and combination studies of bortezomib in solid tumours are detailed.

The heterogeneity of metastatic breast cancer mandates the need to select therapies taking into account tumor and patient characteristics. Chemotherapy is indicated in the palliative setting especially when the disease is unresponsive to hormonal therapy or is hormone-receptor negative. The main chemotherapeutic agents are anthracyclines, taxanes, and capecitabine. The knowledge of the effects of currently approved agents and of the biology of breast cancer have paved the way for the evaluation of new treatment options, among which are anti-angiogenic agents. Angiogenesis inhibition has resulted in clinically significant improvements in the outcome of a variety of malignancies, including breast cancer. Bevacizumab, a monoclonal antibody anti-vascular endothelial growth factor (VEGF), is the most extensively studied anti-angiogenic compound. According to the results of a phase III trial in patients with untreated metastatic breast cancer, bevacizumab increases both objective response rate and median progression-free survival when combined with standard chemotherapy vs chemotherapy alone. The combination of anti-angiogenic drugs and other biologic agents is also being explored in an attempt to improve efficacy.

Epidermal growth factor receptor (EGFR) is the best characterised member of the ErbB family of receptors. A lot of effort has been made to exploit the therapeutic potential of drugs acting on this receptor pathway. Monoclonal antibodies and oral tyrosine kinase inhibitors have undergone a thorough evaluation, both as single agents and in combination. However, over recent years, cancer cells have been shown to be able to harness different growth factor signalling pathways, so that single-agent therapy may not be the best way to use anti-EGFR drugs. Combinations with downstream effectors or other receptor-targeted therapies, or antiangiogenic compounds can be looked at more optimistically as effective weapons.

Platinum-based chemotherapy currently represents standard treatment for advanced non-small cell lung cancer (NSCLC). Gemcitabine is one of the most promising agents currently in use in advanced NSCLC. As a single-agent, epirubicin, showed tumour response rates ranging from 17% to 36% in NSCLC. The aim of the present study was to evaluate the combination of gemcitabine and epirubicin in a phase I-II study. Thirty chemotherapy-naive patients with stage III B-IV NSCLC received gemcitabine at a fixed dose of 1000 mg/m2 on days 1 and 8 every 3 weeks; epirubicin was administered every 21 days on day 1 at the initial dose of 80 mg/m2 which was subsequently escalated. Neutropenia was dose-limiting toxicity since it occurred in 3 out of five patients receiving epirubicin at the dose of 110 mg/m2. An objective response was observed in 14/30 patients, including 2 (7%) complete responses and 12 (40%) partial responses. Median duration of response was 12 months (range: 3 to 53 + months). Median overall survival was 16 months (range: 4 to 55 + months). The combination of gemcitabine and epirubicin is well tolerated. While the observed activity of this combinated treatment matches that of platinum-based regimens, the duration of response and survival have been sufficiently promising to initiate a phase II trial which is currently under way.