Immunotherapy may protect cancer patients from SARS-CoV-2 infection: a single-center retrospective analysis.

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.

Clinical management of localized undifferentiated sinonasal carcinoma: our experience and review of the literature.

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.

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.

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.

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.

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.

Update on Head and Neck Cancer: Current Knowledge on Epidemiology, Risk Factors, Molecular Features and Novel Therapies.

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.

Induction chemotherapy with docetaxel, cisplatin and capecitabine, followed by combined cetuximab and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck: a phase I-II study.

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.

Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review.

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.

An Inflammatory Signature to Predict the Clinical Benefit of First-Line Cetuximab Plus Platinum-Based Chemotherapy in Recurrent/Metastatic Head and Neck Cancer.

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.

Patients affected by squamous cell carcinoma of the head and neck: A population particularly prone to developing severe forms of COVID-19.

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.

A CT-Based Radiomic Signature Can Be Prognostic for 10-Months Overall Survival in Metastatic Tumors Treated with Nivolumab: An Exploratory Study.

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.

Treatment approaches to nasopharyngeal carcinoma: a review.

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.

Management of HPV-Related Squamous Cell Carcinoma of the Head and Neck: Pitfalls and Caveat.

: 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.

Immune Response Against Head and Neck Cancer: Biological Mechanisms and Implication on Therapy.

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.

Boosting the Immune Response with the Combination of Electrochemotherapy and Immunotherapy: A New Weapon for Squamous Cell Carcinoma of the Head and Neck?

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.

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance.

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.

Docetaxel in the management of head and neck cancer.

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.

Electrochemotherapy as palliative treatment in patients with advanced head and neck tumours: Outcome analysis in 93 patients treated in a single institution.

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.

Genetics and management of locally advanced carcinomas of the head and neck: role of altered fractionation radiotherapy.

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.

Phase II study of rubitecan in recurrent or metastatic head and neck cancer.

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.

The proteasome: a worthwhile target for the treatment of solid tumours?

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.