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F Perri,1 G Della Vittoria Scarpati,2 F Caponigro,1 F Ionna,3 F Longo,3 S Buonopane,4 P Muto,4 M Di Marzo,5 S Pisconti,6 R Solla7 1Head and Neck/Sarcoma Medical Oncology Unit, INT IRCCS G Pascale, Naples, Italy; 2Medical Oncology Unit, ASL NA3, Hospital of Pollena Trocchia, Naples, Italy; 3Department of Otolaryngology and Head and Neck Surgery, INT IRCCS G Pascale, Naples, Italy; 4Department of Radiation Therapy, INT IRCCS G Pascale, Naples, Italy; 5Department of Abdominal Surgery, INT IRCCS G Pascale, Naples, Italy; 6Medical Oncology Unit, POC SS Annunziata, Taranto, Italy; 7Italian National Research Council, Institute of Biostructure and Bioimaging, Naples, Italy Abstract: 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. Keywords: nasopharyngeal carcinoma, re-irradiation, poly-chemotherapy, radioresistant, immunotherapy &nbsp

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. Head Neck, 2015.

Background: Sabarubicin (MEN-10755) is a third generation anthracycline, with a remarkable antitumor activity in human tumor xenografts, including doxorubicin-resistant tumors. Phase I studies have shown that myelosuppression is the main toxicity of sabarubicin, while its cumulative cardiotoxicity is mild. Methods: The aim of the study was to evaluate the activity and safety profile of sabarubicin in patients with locally advanced or metastatic ovarian cancer failing 1st line platinum and/or taxane based chemotherapy, and relapsing earlier than 6 months after the last chemotherapy. Eligible patients received sabarubicin at the dose of 80 mg/m(2) (dose level 0) every 3 weeks over 30 minutes. Dose was to be escalated to 90 mg/m(2) (dose level + 1) after the 1st cycle in case of grade 0-1 toxicity, while it was to be reduced to 60 mg/m(2) (dose level-1) in case of toxicity. Response was assessed every 2 courses according to WHO criteria. Toxicity was graded according to Common Toxicity Criteria version 2.0. Gehan's design was used for sample size determination. Results: Nineteen patients were enrolled and received 65 courses. One patient had a confirmed partial response, 9 patients had stable disease, 5 patients had disease progression, 3 patients were not evaluable for response, while one patient had an early progressive disease. The duration of response was 88 days. Mean time to disease progression was 125 days (range 56-188). Median survival was 62 days (range 36-202). Hematologic toxicity was moderate, since grade 3-4 neutropenia was observed in 25 out of 52 courses at 80 mg/m(2), and grade 4 neutropenia occurred in one out of 12 courses at 90 mg/m(2). Other grade 3-4 toxicities were: fatigue (five cases), nausea (two cases), stomatitis, general health deterioration, anorexia, vomiting, abdominal pain, hyponatremia (one case each). Cardiac toxicity was observed in the study; in fact, left ventricular ejection fraction (LVEF) fell below 50% in 2 patients, and 3 patients had a >15% decrease of LVEF from baseline, but there were no signs/symptoms of congestive heart failure. Conclusions: Sabarubicin showed limited activity in patients with resistant ovarian cancer. However, the observed data on disease stabilization, together with the drug's overall manageable toxicity profile, may prompt to its further investigation in advanced ovarian cancer.

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.

Simple Summary Squamous cell carcinoma of the head and neck (SCCHN) represents a problem of utmost concern and, for many clinicians and surgeons, an enormous challenge. Currently, new generation immunotherapy which avails of check point inhibitors, namely molecules capable of restoring the host’s immune system strongly depressed by the presence of tumor cells, is gaining increasing importance. Nevertheless, immunotherapy alone is not always effective in some patients, in particular those having a bulky and highly symptomatic disease. These last require the addition of locoregional strategies able to reduce the tumor mass and to assist immunotherapy in producing its effect. Electrochemotherapy (ECT) is a strategy able to associate the electroporation of tumor cells and the simultaneous administration of antineoplastic drugs, so as to concentrate the latter directly in the tumor site. The combination of ECT and immunotherapy could be very effective particularly in patients having a bulky/highly symptomatic SCCHN. Abstract 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.

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., Lay abstract Management of head and neck squamous cell carcinomas is very challenging, with malignancies often strongly dampening the quality of life of the patients. Surgery has gradually lost its importance and it is often replaced by combined chemoradiotherapy. Response to chemoradiotherapy is very variable and, at present, it is not possible to know which patients will benefit from it. Genetic assessment of head and neck squamous cell carcinomas may help clinicians to perform a well-shaped therapy, adapted on the basis of the patient's genetic features. This strategy is presently experimental, but it may become the ‘standard’ in the future.

The incidence of melanoma is increasing worldwide and prognosis of melanoma patients is still poor. The median survival for melanoma patients with metastatic disease is 89 months, and the 3-year overall survival (OS) rate is less than 15% (1, 2). Surgical excision is the main treatment for primary cutaneous melanoma (3). However controversies about the necessary margins of excision still remain (4). Sentinel lymph node biopsy (SLNB) provides an 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 about SNLB and the depth of the primary melanoma (5). To date, IFN-α is the only approved adjuvant treatment after surgical excision of melanoma. However its indication remains controversial because of the limited benefit upon disease-free survival and the smaller potential improvement of overall survival (2, 6). Dacarbazine has been the standard first-line therapy for patients with metastatic disease for a long time. However treatment with this agent was associated with a response rate less than 15% and no clinical trials have been reported to improve the overall survival (OS) (7). Recently, two drugs have been approved for the treating patients with metastatic melanoma. The first one, ipilimumab, is a monoclonal antibody which targets the Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). Two phase III clinical trials, comparing ipilimumab with dacarbazine, demonstrated an improved survival for patients treated with ipilimumab. Nevertheless, this agent resulted to be effective only in a subset of patients and the toxicity caused by the treatment was considerable. Vemurafenib is the second drug that has been approved for the treatment of metastatic melanoma. It is an agent that selectively targets BRAF, a component of the MAPK pathway. Approximately 60% of all melanomas harbor activating mutations in BRAF oncogene such as the substitution of glutamic acid for valina at amino acid 600 (V600E). Treatment with vemurafenib has shown to improve OS and to induce tumor regression in approximately 50% of treated patients with metastatic melanoma carrying a BRAF V600E. However the response are rarely complete and the median time to disease progression is less than 7 months due to develop of intrinsic or secondary resistance. Several mechanisms of resistance have been described and clinical trials are testing new combinatorial strategies with the aim to overcome the intrinsic or the acquired BRAF-inhibitor resistance. In addition, several other biological agents are in phase of experimentations in melanoma but really promising drugs are not yet available.

Docetaxel (Taxotere, DTX) is a promoter of apoptosis in cancer cells. Since cytotoxic mechanisms of DTX are not yet fully understood, we have investigated the effects of DTX on apoptosis and ras-->Erk-mediated signal transduction in human epidermoid KB, colon HT-29 and breast HCC1937 cancer cells. We have found that the exposure to 0.78 or 1.56 or 2.5 ng/ml DTX for 48 h induced apoptosis and growth inhibition in about 50 % of KB, HCC1937 and HT-29 cell population, respectively. In these experimental conditions, PARP and caspase 3 cleavage was also showed in all cell lines. KB and HCC1937 cells express a wild type p53 while HT-29 display a mutated form. Interestingly, we have found that DTX reduces the expression of mutated p53 in HT-29 and increases the expression of wild type in KB and HCC1937 cells. Moreover, DTX reduces ubiquitination of the wild type p53 in KB and HCC1937 cells and increases the ubiquitin-conjugated form of mutated p53 in HT-29 cells. Furthermore, exposure of cancer cells to DTX for 48 h increases the expression and activity of Ras and up-regulates Raf-1 and the phosphorylated isoforms of Erk-1/2. On the bases of these data, we have hypothesized that the increased activity of the ras-->erk-dependent pathway induced by DTX could be a protective signalling from the apoptosis caused by the drug. Therefore, we have used R115777, a farnesyl transferase inhibitor that inactivates ras, in combination with DTX. The combined treatment with DTX and R115777 resulted in a strong synergism in growth inhibition in the three cell lines. These data suggest the use of the combination in these therapeutic settings even if further experiments are required for the clinical translation.

44 patients with advanced breast cancer were treated with high-dose epirubicin (130 mg/sqm), because of its steep dose-response curve. Lonidamine and alpha interferon were administered as well with the aim of increasing epirubicin uptake and overcoming drug resistance. Granulocyte-colony stimulating factor support was provided. 14 complete responses and 22 partial responses were observed in 40 evaluable patients for a 90% overall response rate. Median duration of response was 12 months for complete responders, 7 months for partial responders. In two cases the complete response has lasted for more than two years. Myelosuppression, infection, and cardiac toxicity were the main treatment-related toxic effects. These results are encouraging enough to justify a randomized comparison of our chemotherapy program with standard regimens used in advanced breast cancer.

Eighteen patients with advanced ovarian cancer not or no longer responding to cisplatinum and epidoxorubicin including combination chemotherapy were retreated with the above two drugs in combination with lonidamine and interferon, administered with the aim of restoring chemosensitivity. Overall response rate was 32%, with one durable complete response and four partial responses. Toxicity was quite manageable, myalgia being the main additional toxic effect with respect to those reported with conventional chemotherapy. Our study emphasizes the need for additional trials with agents able to overcome drug resistance, which is the chief determinant of treatment failure in advanced ovarian cancer.