| Abstract|| |
The majority of patients with head and neck cancer present with locally advanced disease. Locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) poses one of the most complex management challenges. This stage of disease is still potentially curable, but requires combined-modality therapy. One of the novel approaches is the use of targeted agents, particularly the epidermal growth factor receptor (EGFR) inhibitors, in treatment strategies in LA-SCCHN. A Medline search covering topics related to targeted therapies in head and neck cancer over the last two decades was made and the facts were compiled. Cetuximab was the first novel agent to obtain regulatory approval in the United States for the treatment of patients with Head and Neck Squamous Cell Cancer HNSCC. Cetuximab has been evaluated in combination with radiotherapy, chemo-radiotherapy, and induction chemotherapies, and was found to increase the overall survival rates in all the arms without raising the toxicity level of the combined modality of treatment significantly. The tyrosine kinase inhibitors Gefinitib and Erlotinib also produced an average response rate of 11% and 4% in different studies and also prolonged the disease control rates when used with chemotherapy. This paper will review the role of targeted agents, particularly the EGFR inhibitors, in the present treatment strategies in advanced, recurrent/metastatic head and neck cancer.
Keywords: Cetuximab, epidermal growth factor receptor inhibitors, monoclonal antibodies, targeted therapy, tyrosine kinase inhibitors
|How to cite this article:|
Christy A W, Bojan A. Targeted therapy: A novel approach in head and neck cancer. Indian J Dent Res 2013;24:261-6
Head and neck cancer is the eighth most common cause of cancer death worldwide.  However, in India, head and neck cancer ranks first among both sexes. The majority of patients with head and neck cancer present with locally advanced disease. While head and neck cancer, particularly early stage disease, is potentially curable with standard treatments of surgery or radiation, long-term disease-free and overall survival rates for patients with advanced disease are poor. Approximately 50-60% of patients have local disease recurrence within 2 years and 20-30% of patients develop metastatic disease.  In addition, a substantial proportion of patients endure significant functional and esthetic consequences following definitive surgical management. In an effort to improve outcomes, chemotherapy has been integrated into a combined modality approach involving surgery and/or radiation therapy for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).
| LA-SCCHN-The Present Scenario|| |
LA-SCCHN implies advanced T-stage where tumor invasion into other structures has occurred or lymph node metastases without evidence of distant metastases. 
There are four general presentation categories of advanced stage SCCHN: Resectable disease, resectable disease for which organ preserving strategies are desirable, unresectable locally advanced disease and recurrent/metastatic disease. For many years, standard treatment approaches were: Surgery with or without postoperative radiotherapy for resectable disease, radiotherapy for un-resectable disease and palliative chemotherapy (with methotrexate or cisplatin in combination with 5-fluorouracil (5-FU) or, more recently, paclitaxel for recurrent/metastatic disease.  LA-SCCHN poses one of the most complex management challenges. This stage of disease is still potentially curable, but requires combined-modality therapy.
This paper will focus on the role of targeted agents, particularly the epidermal growth factor receptor (EGFR) inhibitors, in future treatment strategies in LA-SCCHN.
| What is Targeted Cancer Therapy?|| |
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progress. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy and radiotherapy, and less harmful to normal cells.
Targeted cancer therapies interfere with cancer cell division (proliferation) and spread in different ways. Many of these therapies focus on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, cell response to specific external stimuli and even cell death. By blocking signals that stimulate cancer cells to grow and divide uncontrollably, targeted cancer therapies can stop cancer progression. Targeted therapies also can cause cancer cell death directly by inducing apoptosis, or indirectly, by stimulating the immune system to recognize and destroy cancer cells and/or by delivering toxic substances to them. The development of targeted therapies requires the identification of targets that are known to play a key role in cancer cell growth and survival.
Most targeted therapies are either small-molecule drugs or monoclonal antibodies (mAbs). Small-molecule drugs are typically able to diffuse into cells and can act on targets that are found inside the cell. Most mAbs usually cannot penetrate the cell's plasma membrane and are directed against targets that are outside cells or on the cell surface.
Candidates for small-molecule drugs are compounds that best affect the specific target and are usually identified in studies known as drug screens. The best candidates are then chemically modified to produce numerous closely related versions, and these are tested to identify the most effective and specific drugs.
mAbs, by contrast, are prepared first by immunizing animals (typically mice) with purified target molecules. The immunized animals will make many different types of antibodies against the target. Next, spleen cells, each of which makes only one type of antibody, are collected from the immunized animals and fused with myeloma cells. Cloning of these fusion cells results in cultures of cells that produce large amounts of a single type of antibody, or a monoclonal antibody. These antibodies are then tested to find the ones that react best with the target. Before they can be used in humans, mAbs are "humanized" by replacing as much of the non-human portion of the molecule as possible with human portions. This is done through genetic engineering. Humanizing is necessary to prevent the human immune system from recognizing the monoclonal antibody as "foreign" and destroying it before it has a chance to interact with and inactivate its target molecule. 
| Targeted Therapies in Squamous Cell Carcinoma of Head and Neck|| |
EGFR is a transmembrane glycoprotein with tyrosine kinase (TK) activity that plays a critical role in the regulation of tumor cell growth and survival. EGFR ligand binding stimulates multiple cellular functions essential to tumor growth, including invasiveness, cell damage repair and angiogenesis. , EGFR is important in the pathogenesis of HNSCC, and its overexpression has been reported in more than 80% of cases.  EGFR is highly expressed by the majority of SCCHN cell lines and primary tumors, and this expression is correlated in clinical models with poor prognosis, including decreased survival and increased metastatic potential. , Moreover, EGFR up-regulation also has been documented in the normal-appearing epithelium adjacent to malignant tissue thus supporting the "field cancerization" concept, which refers to the multifocal development of premalignant and malignant lesions within the entire carcinogen-exposed epithelium.  Therefore, inhibition of EGFR signaling represents a rational new strategy in HNSCC therapeutics.
| EGFR Inhibition|| |
Various strategies have been developed to disrupt the EGFR signal transduction pathway. Among them, anti-EGFR mAbs and EGFR Tyrosine kinase inhibitors (TKIs) have undergone the most extensive investigation.
Putative mechanisms of EGFR mAb-based anticancer activity can be classified into two categories. First, they prevent ligands from binding to the EGFR extracellular domain, inhibit subsequent receptor dimerization/activation and finally induce receptor degradation.  The second potential mechanism of EGFR mAb therapy is indirect action mediated by the immune system, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and complement-dependent cell-mediated cytotoxicity. 
Receptor and non-receptor TKs are critical mediators in EGFR signaling pathways, and many are deregulated during aero-digestive carcinoma tumor igenesis. Small-molecule inhibitors that target these TKs are directly acting in tumor cells rather than mediating immune responses. TKIs have a variable selectivity for TKs, and some are dual-selective or multiselective. EGFR-TKIs are generally thought to be less specific than mAbs, which is potentially advantageous for antitumor activity but may be associated with increased toxicities due to the inhibition of several signaling pathways that potentially interfere with normal cell functions. 
| Why are Targeted Therapies Considered in Advanced Head and Neck Cancer?|| |
Compared with radiotherapy alone, chemo-radiotherapy provides more benefit in disease-free survival and overall survival in most of the studies. However, toxicities with cisplatin or 5-FU limit the use in this population where comorbidities and elderly age groups are very common. In contrast, targeted therapies affect specifically the tumor cells, and the toxicity profile is acceptable with almost similar benefit in disease control.
| EGFR-Directed mAbs|| |
Cetuximab was the first novel agent to obtain Food and Drug Administration FDA approval in the United States for the treatment of patients with HNSCC.
Cetuximab in LA-SCCHN
Cetuximab has been evaluated in combination with External Beam Radiotherapy XRT, Concurrent Chemoradiotherapy CRT and induction therapies.
Cetuximab with radiotherapy
A multinational, randomized study was performed to compare radiotherapy alone with radiotherapy plus cetuximab in the treatment of locoregionally advanced SCCHN.
Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy.
The median duration of loco-regional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. 
This trial provides an important proof of principle that modulating the biology of SCCHN in combination with a physically targeted agent can impact on therapeutic outcome. This increases the armamentarium of drugs that are active with radiotherapy. The favorable toxicity profile of cetuximab allows this drug to be combined with existing chemo-radiotherapy regimens in future trials. 
However, it is important to note that the trial described above did not compare cetuximab-radiotherapy with concurrent chemo-radiotherapy, which is the standard of care today for LA-SCCHN. Therefore, concurrent chemo-radiotherapy must not be equated with cetuximab-radiotherapy. Secondly, because the toxicities associated with standard chemo-radiotherapy may be poorly tolerated in elderly or frail patients, cetuximab-radiotherapy has often been considered in this setting. 
Cetuximab with concurrent chemoradiation
A pilot Phase II study was carried out by Pfister et al. to generate pilot data for a novel paradigm for combined-modality therapy through the integration of a biologically active, targeted agent with an established concurrent chemoradiotherapy program.
Here, 21 patients received concomitant boost radiotherapy (1.8 Gy/day weeks 1-6; boost: 1.6 Gy 4-6 h later weeks 5-6; 70 Gy total to gross disease), cisplatin (100 mg/m 2 intravenously weeks 1 and 4) and cetuximab (400 mg/m 2 intravenously week 1, followed by 250 mg/m 2 weeks 2-10).
The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths. However, these events have no clearly shared pathophysiology that convincingly implicates the addition of cetuximab as the cause. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56% and the 3-year locoregional control rate is 71%.
Despite the adverse events observed in this study, the preliminary survival data progression-free survival and locoregional control rates were encouraging in the predominantly stage IV population. These survival data also compare favorably with those reported in the major published randomized trials supporting concurrent chemoradiotherapy. The authors concluded that this regimen is not currently recommended outside of the clinical trial setting.  Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.
Cetuximab with induction chemotherapy
Chemotherapy is an integral component of the management of patients with locally advanced head and neck cancer, although the optimal use of chemotherapy remains to be defined. The combination of a platinum agent and 5-FU has been used as the standard neoadjuvant treatment, and has been shown to permit organ preservation in operable patients and improve long-term survival outcomes in operable and inoperable patients. Recently, three randomized trials have demonstrated superior response rates and survival outcomes with the addition of a taxane, docetaxel or paclitaxel to standard platinum plus 5-FU induction chemotherapy namely the DoceTAXel trials TAX323,TAX324 and GORTEC (Groupe Oncologie Radiotherapie Tκte et Cou) trial. 
In this scenario, can cetuximab improve our current induction therapy strategies?
Kies et al. reported a Phase II feasibility study of cetuximab with paclitaxel and carboplatin in a neoadjuvant setting and demonstrated a 98% overall response rate with a 26% complete remission rate. 
The prevalence of distant metastasis at presentation commonly involving the lung, bones, and liver varies from 2% to 17%. The most common sites of distant metastases are lungs, mediastinal lymph nodes, bone and liver. ,
Active chemotherapy in metastatic SCCHN
The platinum analogs have been one of the most active agents in metastatic SCCHN, with single-agent response rates of cisplatin being 15-40% and carboplatin being around 25%. ,
In platinum-refractory recurrent and metastatic disease, the activity of cetuximab plus cisplatin or carboplatin was confirmed in two Phase II studies. Response rates of 12% and 15%, respectively, and disease control rates of 28% and 54%, respectively, were reported. ,
Addition of cetuximab to cisplatin in a randomized trial resulted in higher response rates in the cisplatin/cetuximab arm (26%) compared with the cisplatin-alone arm (10%). Development of rash was highly correlated with response. However, despite the higher response rate and improved progression-free survival, both arms had similar median overall survivals (9 vs. 8 months). 
Another trial (EXTREME) evaluating cetuximab in combination with cisplatin/carboplatin and 5-FU as first-line treatment of recurrent and/or metastatic SCCHN shows a significant survival impact. This 442-patient randomized study found that the addition of cetuximab to chemotherapy improved median survival from 7.4 months to 10.1 months (P = 0.03), and the toxicity profile of the regimen was not increased. This is the first systemic therapy in the last three decades to show a survival benefit over platinum-based chemotherapy in recurrent and/or metastatic SCCHN. 
EGF variant III is the most common variant of the EGF receptor observed, and results from the in-frame deletion of exons 2-7 and the generation of a novel glycine residue at the junction of exons 1 and 8, which results in truncated versions leading to constitutive phosphorylation in a ligand-independent manner. In one study, it is present in 42% of head and neck tumors, which in turn leads to cetuximab resistance. Also, these tumors have large volume with decreased response to conventional chemotherapy. But, EGF receptor variant III is susceptible to TKIs that shows that both EGFR and EGFR Viii mutant have intact TK domains. ,
Other EGFR-directed MAbs
A number of other EGFR MAbs have been investigated, although these are at an earlier stage of development than cetuximab.
The humanized MAb, h-R3, showed preclinical activity in the head and neck setting. H-R3 induced apoptotic effects were thought to be mediated via anti-angiogenic activity, including an inhibition of the production of the vascular endothelial growth factor.  In a Phase I dose escalation study, the combination of h-R3 with radiotherapy was investigated in patients with unresectable advanced SCCHN. Seven complete responses were observed among eight evaluable patients.
In a Phase II study in 24 patients with advanced carcinomas of the head and neck, the combination of h-R3 and RT was well tolerated and appeared to have a positive effect on survival. An interesting observation of treatment with h-R3 is the notable lack of skin reactions reported with this EGFR-directed Mab.  These findings are in stark contrast with those reported for other MAbs and TKIs, with which rash is a common finding.
| EGFR TKIs Gefitinib|| |
Gefitinib has demonstrated single-agent activity in patients with recurrent/metastatic disease who had received no more than one prior therapy. In a study by Kane et al., patients who received gefitinib 500 mg/day had an overall response rate of 11% and a disease control rate of 53%, with a median duration of response of 1.6 months. With a median follow-up time of 11.4 months, the median survival was 8.1 months. The main toxicities reported were rash, diarrhea, nausea and hypercalcemia. In general, toxicities were mild-to-moderate (grades 1-2). In a subsequent Phase II study, the use of a lower daily dose of gefitinib (250 mg/day) was investigated in a similar patient population, and the results showed only three cases of grade 3/4 toxicity (two diarrhea and one nausea, all grade 3), but the tumor response rate appeared to be much lower. 
The use of gefitinib in unresectable, locally advanced disease is currently under investigation in a Phase II study.
In a Phase II study in 115 heavily pretreated recurrent/metastatic SCCHN patients, the use of single-agent erlotinib (at an initial dose of 150 mg daily) was associated with a response rate of 4% and a disease stabilization rate of 38%.  The median progression-free and overall survival times were 9.6 weeks and 6 months, respectively. In a similar group of patients, the combination of erlotinib and docetaxel was shown to be active and well tolerated.
Combinations of EGFR inhibitors with other EGFR inhibitors and with other growth factor inhibitors
Given the importance of the EGFR as an anti-cancer target, and the fact that EGFR MAbs and TKIs act at different sites along the signaling pathway, treatment with a combination of these types of EGFR inhibitors may be a viable strategy.
In vivo experiments showed that while single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses, sub-optimal doses of the combination of gefitinib and cetuximab led to the complete and permanent regression of large tumors. 
Similar findings were reported by Huang et al., with combinations of cetuximab and gefitinib or erlotinib augmenting the inhibition of EGFR phosphorylation in head and neck cancer cell lines over that obtained with single-agent therapy. 
| Conclusion|| |
In conclusion, cetuximab plus radiotherapy or chemotherapy or as a single agent drug represents a new therapeutic option for most patients with loco-regionally advanced head and neck cancer and provides a foundation for additional studies directed toward further improvement in the outcome of this disease. Well-designed trials using cetuximab and other TKIs are warranted. In the absence of these studies, targeted therapies are used as a last resort in treatment of locally advanced disease and the recurrent and metastatic disease.
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A Winnifred Christy
Department of Oral Medicine and Radiology, CSI College of Dental Sciences and Research, Madurai, Tamil Nadu
Source of Support: None, Conflict of Interest: None