Menu Close

The study was structured in two phases: a concomitant phase (gefitinib or placebo with chemoradiation) and a maintenance phase (gefitinib or placebo alone)

The study was structured in two phases: a concomitant phase (gefitinib or placebo with chemoradiation) and a maintenance phase (gefitinib or placebo alone). deserves to be further explored. with and without radiation in human SCCHN cell lines. They found that combining cetuximab and radiation therapy with adjunct treatment that targets the JAK1 enhances the anti-proliferative, apoptotic, and radio-sensitizing effects of radiation, causing an increase of unrepaired radiation-induced DNA double-strand breaks when cells are exposed to both drugs [15]. In addition, clinical evidence also shows that the EGFR CD246 blockade activates the MET pathway (as a compensatory mechanism, thus causing resistance to EGFR inhibitors. This further supports the strategy that aimed at pathways [16]. Another mechanism that supports the innovative strategy of integrating with a combined therapeutic approach is the cross-talk between survival pathways. Several clinical studies have yielded positive results when using a combination of bevacizumab, cetuximab, and chemotherapy in addition to radiation or when adding bevacizumab to the combination of erlotinib, chemotherapy, and radiation [17C19]. Further exploration of these combined strategies and their safety profiles thus seems like a promising direction to pursue. Moreover, there is also evidence of the Hedgehog pathway being relevant to a novel cetuximab resistance mechanism involving (EMT). Specifically, a recent phase I trial has shown that cetuximab in combination with IPI-926, a hedgehog pathway inhibitor, yields anti-tumour activity with well-tolerated toxicities [20]. Inhibition of EGFR: monoclonal antibodies and tyrosine kinase inhibitors There are two main ways to inhibit EGFR signalling pathways: monoclonal antibodies targeting EGFR, which directly interfere with the ligand receptor, and tyrosine kinase inhibitors, which block the intracellular domain with tyrosine kinase activity [1]. Monoclonal antibodies When speaking of SCCHN, the most investigated monoclonal antibodies that specifically bind to EGFR LTβR-IN-1 are cetuximab, panitumumab, nimotuzumab, and zalutumumab. Table?1 summarizes the main trials in locoregionally advanced SCCHN. Table 1 Main trials with monoclonal antibodies associated with radiotherapy in locally advanced SCCHN cetuximab, panitumumab, nimotuzumab, zalutumumab, nimorazole, cisplatin, chemotherapy, radiotherapy, locoregional control, Overall Survival, response rate, Progression-Free Survival, response rate, grade Cetuximab was the first monoclonal antibody to be investigated and until now has been deployed in various treatment strategies based on radiation therapy (which we discuss in detail below). The pivotal study by Bonner et al., already mentioned above and discussed in several journals, showed that in cases of locoregionally advanced SCCHN, patients treated with a combination LTβR-IN-1 of cetuximab plus radiotherapy had an advantage in 5-year overall survival (OS), compared to those threated by radiation alone (5-year OS 45.6% vs. 36.4%). In addition, overall survival improved significantly if the patient developed rashes of grade-2 severity [6, 21]. Cetuximab plus LTβR-IN-1 radiation has also been investigated after induction chemotherapy (docetaxel, cisplatin and 5-fluorouracil, TPF). For instance, the Tremplin study, which explored a new combination strategy for organ preservation in cases of laryngeal and hypopharyngeal cancer, involved TPF followed by radiation in combination with either cisplatin or cetuximab. The study proved that there was no difference in disease control and in overall survival between the two combinations. The only differences found were that cisplatin yielded higher local control and that only the cetuximab treated group required salvage surgery [22]. A Spanish trial investigated the same strategy in cases of locally advanced SCCHN, most of which HPV negative. The results showed a trend of better PFS (HR 1.20) and OS (HR 1.17) when using cisplatin in addition to radiation after induction TPF [23]. As expected, the two drugs yielded a very different toxicity profile: cetuximab was associated with more mucosal and skin toxicity and cisplatin with greater nephrotoxicity. Another important trial study, known as GORTEC 2007C02, compared the use of chemoradiation (with carboplatin and 5FU) in concurrence with induction TPF followed by radiation with cetuximab, in locally advanced clinical stage N2b-N3 SCCHN and found no difference between the two test groups. This suggests that concurrent chemoradiation (even if not performed with cisplatin) remains the best treatment also with a high burden of nodal disease [24]. Another randomized phase II trial, instead, explored an adjuvant treatment strategy that consisted of administering cetuximab for twelve weeks after use in combination with radiotherapy. Despite favourable results for locoregional control after 1?year, no difference was observed at the 2-year stage [25]. There is also a number of.